CADTH Reimbursement Review

Encorafenib (Braftovi)

Sponsor: Pfizer Canada ULC

Therapeutic area: Metastatic colorectal cancer

This multi-part report includes:

Clinical Review

Pharmacoeconomic Review

Clinical Review

Executive Summary

An overview of the submission details for the drug under review is provided in Table 1.

Introduction

Colorectal cancer is the third most commonly diagnosed cancer in Canada with an expected 26,900 new cases in 2020.¹ One-fifth of colorectal cancers are expected to be considered metastatic at initial diagnosis.² Patients with metastatic colorectal cancer (mCRC) are expected to have a low 5-year survival rate (between 10% and 13%).^3,4 The presence or inheritance of mutations may not only affect a patient’s likelihood of developing colorectal cancer, but may serve as predictors of patient outcomes. BRAF mutations account for 10% to 15% of colorectal cancer cases, and the presence of this mutation is associated with poorer survival outcomes.^4,5 The V600E mutation is the most common variant of the BRAF mutations. Mutation drivers may help clinicians guide patient care; therefore, standard of care for colorectal cancer patients involves genetic testing, which typically occurs at initial diagnosis. The clinical experts consulted by CADTH for this review indicated that regional centres for testing of the BRAF mutation are available in all Canadian provinces. A common method for identifying BRAF mutations is next-generation sequencing (NGS).

Currently, there are no funded treatment options in Canada that target BRAF mutations. Patients with BRAF-mutated mCRC are often treated with therapies approved for patients with wild-type mCRC. Surgery is typically considered as the initial treatment for patients and, in some patients, may be used to treat oligometastatic disease. However, for most patients, surgery may not be possible.⁴ The choice of treatment can be dependent on a patient’s clinical and disease characteristics. First- and second-line therapies are often combination therapies that can include regimens based on oxaliplatin, irinotecan, and/or bevacizumab.⁶ Depending on patient and disease characteristics, molecularly driven therapies may also be considered. However, most patients will eventually develop resistance to treatment and their disease will progress.

Encorafenib is a kinase inhibitor that targets the BRAF V600E mutation. Mutations in the BRAF gene can result in activated BRAF kinases that stimulate the growth of tumour cells.⁷ Encorafenib is indicated, in combination with cetuximab, for the treatment of patients with mCRC with a BRAF V600E mutation, as detected by a validated test, after prior therapy. The recommended dose of encorafenib is 300 mg daily. Encorafenib is to be administered along with cetuximab, which is recommended to be administered to patients at a dose of 400 mg/m² followed by 250 mg/m² every week as an IV infusion. Treatment with encorafenib plus cetuximab should continue until disease progression or unacceptable toxicity.⁷ Previous CADTH reviews for mCRC have included trifluridine plus tipiracil,⁸ cetuximab,⁹ and panitumumab,^10,11 none of which received a positive recommendation, except for the review of panitumumab in combination with chemotherapy for the treatment of patients with wild-type RAS mCRC who are contraindicated for or intolerant of bevacizumab in the first-line treatment setting; none of the previous reviews were specific to patients with the BRAF V600E mutation.

The objective of this CADTH drug Reimbursement Review is to perform a systematic review of the beneficial and harmful effects of encorafenib in combination with cetuximab for the treatment of patients with mCRC with a BRAF V600E mutation, as detected by a validated test, after prior therapy.

Stakeholder Perspectives

The information in this section is a summary of input provided by the patient groups that responded to CADTH’s call for patient input and from the clinical experts consulted by CADTH for the purpose of this review.

Patient Input

Two patient groups, Colorectal Cancer Canada (CCC) and the Colorectal Cancer Resource and Action Network (CCRAN), submitted input for this review. Information from CCC was collected via online surveys from 2 patients and 4 caregivers from Canada, the US, the UK, and Turkey. Information from CCRAN was collected through online surveys. Respondents included 63 patients, 17 caregivers, and 5 patients who were also caregivers. There was also a focus group discussion and phone interviews with 3 patients from Canada and the Netherlands to provide direct experiences for encorafenib plus cetuximab.

The patient input indicated that fatigue, bloody stool, diarrhea, and abdominal cramping were the most commonly occurring colorectal cancer symptoms. Fatigue and pain were the symptoms of colorectal cancer that patients considered most important to control. The patients identified difficulty with being able to work and being unable to fulfill family obligations due to their disease. Side effects of therapies considered the most difficult to tolerate included vomiting, nausea, pain, rash, neuropathy, hair loss, and low platelets. Patients indicated that prolonged life, delayed progression, and improved quality of life were the most important considerations for new therapies.

In general, among patients who had experience with encorafenib plus cetuximab, the side effects were reported to be more tolerable compared with their previous therapies. However, gastrointestinal side effects, fatigue, emotional drain, and medication management were reported to be the most difficult aspects of treatment with encorafenib plus cetuximab. Overall, patients reported that, aside from not being a cure, encorafenib plus cetuximab was able to meet most patient expectations for new treatments.

Clinician Input

Input From Clinical Experts Consulted by CADTH

The clinicians consulted by CADTH identified unmet treatment needs for patients with BRAF-mutated mCRC, as patients face poor clinical prognoses and there are currently no funded treatments that target the BRAF mutation. Encorafenib in combination with cetuximab (doublet regimen) would be used as per the BEACON trial, and most likely after first-line therapy. While there is a lack of clarity as to the most optimal first-line treatment for these patients, the doublet regimen is considered to be a promising new therapy and an important new consideration for patients with BRAF-mutated mCRC. As encorafenib is provided alongside cetuximab, cancer clinics will be necessary to deliver the doublet regimen, with treatment guidance from a medical oncologist with experience in managing patients with colorectal cancer.

Clinician Group Input

Input was received from 3 joint clinician submissions on behalf of the Canadian Gastrointestinal Oncology Evidence Network (CGOEN), the Ontario Health (Cancer Care Ontario) (OH-CCO) Gastrointestinal Cancer Drug Advisory Committee (DAC), and 9 clinicians who treat mCRC. The opinions in these 3 submissions align with the opinions of the clinical experts for this CADTH review. The clinicians highlighted the poor clinical outcomes faced by patients with BRAF mutations and the lack of currently funded treatments that can target this mutation. Improved survival, delayed disease progression, and improved quality of life were considered important treatment goals for patients. The clinicians agreed that earlier treatment with a BRAF-directed therapy may help to improve patient outcomes; therefore, encorafenib plus cetuximab would most likely be used as a second-line therapy.

Drug Program Input

Input from the Provincial Advisory Group identified factors pertaining to relevant comparators, generalizability, prescribing of therapy, companion diagnostics, and discontinuation criteria. The clinical experts consulted by CADTH weighed evidence from the BEACON trial and other clinical considerations to provide responses, which can be found in the Drug Program Input section.

Clinical Evidence

Pivotal Studies and Protocol Selected Studies

Description of Studies

One multi-centre, multinational, randomized, open-label, phase III study met the criteria for the CADTH systematic review. The BEACON trial evaluated the efficacy and safety of 3 treatment groups: encorafenib plus cetuximab (doublet group), encorafenib plus cetuximab plus binimetinib (triplet group), and the control group, which was the investigator’s choice of either irinotecan in combination with cetuximab or folinic acid plus 5-fluorouracil and irinotecan (FOLFIRI) in combination with cetuximab. Eligible patients included adults with mCRC whose tumours expressed the BRAF V600E mutation and whose disease had progressed after 1 or 2 prior regimens in the metastatic setting. A safety lead-in phase assessing the safety and tolerability of encorafenib plus cetuximab plus binimetinib initiated the BEACON trial, the results of which are not discussed in this CADTH report. Local assay testing was only accepted via polymerase chain reaction (PCR) or NGS; patients enrolled based on local assays were required to have a confirmation of their BRAF mutation status by central laboratories no later than 30 days after the first dose of study treatment.¹²

A total of 220 patients were randomized to the doublet group and 221 patients to the control group. Within the control group, 92 patients (41.6%) received cetuximab plus irinotecan and 129 patients (58.4%) received cetuximab plus FOLFIRI.¹³ Randomization was stratified according to baseline Eastern Cooperative Oncology Group Performance Status (ECOG PS) (0 versus 1), prior use of irinotecan (yes versus no), and cetuximab source (US-licensed versus EU-approved).¹⁴ Patients randomized to the doublet group received encorafenib at 300 mg daily in combination with cetuximab. Patients randomized to the control group received either irinotecan (180 mg/m² every 2 weeks) plus cetuximab, or FOLFIRI plus cetuximab; dosage for FOLFIRI is presented subsequently, and cetuximab was administered at 400 mg/m² followed by 250 mg/m² every week via IV infusion in all treatment combinations¹²:

• irinotecan at 180 mg/m² IV infusion every 2 weeks

• folinic acid at 400 mg/m² IV infusion or maximal dose tolerated in a prior regimen every 2 weeks

• 5-fluorouracil at 400 mg/m² initial dose bolus, then 1,200 mg/m² per day for 2 days continuous infusion or maximal dose tolerated in a prior regimen every 2 weeks.

The primary end points for this trial were based on comparisons between the triplet and control groups. Key secondary end points included analyses of overall survival (OS), objective response rate (ORR) and progression-free survival (PFS) between the doublet group and the control group. A statistical hierarchy ensured that key secondary end points were formally tested only if OS between the triplet group and the control group was found to be statistically significant. Health-related quality of life (HRQoL) was an exploratory end point that was analyzed using the following questionnaires: the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30), the Functional Assessment of Cancer Therapy–Colorectal (FACT-C), the EuroQol 5-Dimensions 5-Levels questionnaire (EQ-5D-5L), and the Patient Global Impression of Change (PGIC).

Baseline characteristics were generally balanced across the doublet group and the control group. Patients had a mean age of 59 years, were mostly from Europe (61%), and were mostly White (81%). A similar proportion of patients had an ECOG PS of 0 (50%) or 1 (49%); all patients were diagnosed with stage IV disease at study entry, 42% of patients had a primary tumour location in the right colon, 34% of patients had a primary tumour location in the left colon, and 56% of patients had their tumour completely resected. Two-thirds of patients had received 1 prior regimen, with the remaining patients having received 2 prior regimens; only 1 patient had received more than 2 prior regimens and this patient was randomized to the control group. Most patients (92%) had liver metastases and had a microsatellite instability (MSI) status of normal as assessed via PCR (69%). A greater proportion of patients in the control group had missing data regarding their MSI status than in the doublet group (23% versus 12%, respectively).¹⁴

Efficacy Results

The key efficacy results for the BEACON trial are summarized in Table 2. An interim analysis was pre-specified in the protocol of the BEACON trial to occur after a minimum of 188 OS events in the triplet and control groups combined and a minimum of 169 OS events in the doublet and control groups combined. The median OS was 8.41 months (95% confidence interval [CI], 7.46 to 11.04) in the doublet group compared with 5.42 months (95% CI, 4.76 to 6.57) in the control group (P = 0.0002, log-rank test). A 40% lower risk of death was observed in the doublet group (hazard ratio [HR] = 0.60; 95% CI, 0.45 to 0.79). The median PFS was 4.21 months (95% CI, 3.71 to 5.36) in the doublet group compared with 1.51 months (95% CI, 1.45 to 1.71) in the control group (P < 0.0001, log-rank test). A 60% reduction in progression or death (HR = 0.40; 95% CI, 0.31 to 0.52) was observed in the doublet group compared with the control group.¹⁴ An additional updated analysis that was not pre-specified in the protocol of the BEACON trial was conducted that added approximately 6 months of data. The results of these post-hoc analyses were generally consistent, with the primary results in supporting efficacy favouring treatment with encorafenib plus cetuximab over therapies in the control group observed at the interim analysis.¹⁵ However, results from the post-hoc analysis are considered descriptive and should be interpreted with caution.

Quality-of-life data were assessed using a time to deterioration (TTD) analysis; TTD analysis of all HRQoL questionnaires indicated longer TTD (improvement) for patients in the doublet group over the control group. However, the analyses of HRQoL are exploratory and should be interpreted with caution.

Harms Results

A similar proportion of any-grade adverse events (AEs), treatment-emergent AEs (TEAEs), serious AEs (SAEs), and grade 3 or greater SAEs were observed in similar proportions across the doublet and control groups. Grade 3 or greater AEs and grade 3 or greater TEAEs occurred more frequently in the control group than in the doublet group. In general, most AEs observed were grade 1 or 2. AEs of any grade with a difference of 10% between the doublet and control groups, and which occurred more frequently in the doublet group, included arthralgia (19.0% versus 0.5%, respectively), headache (19.4% versus 2.6%), melanocytic nevus (14.4% versus 0%), myalgia (13.4% versus 2.1%), and musculoskeletal pain (12.5% versus 1.6%).¹⁴ The most commonly occurring any-grade AEs were diarrhea (33.3% in the doublet group versus 48.2% in the control group), dermatitis acneiform (29.2% versus 39.4%), nausea (34.3% versus 41.5%), fatigue (30.1% versus 27.5%), vomiting (21.3% versus 29.0%), decreased appetite (26.9% versus 26.9%), abdominal pain (22.7% versus 24.9%), and asthenia (21.3% versus 35.4%).¹⁴ The most frequently reported TEAEs of any grade included dermatitis acneiform (27.8%), fatigue (22.7%), and nausea (20.4%) in the doublet group, and diarrhea (44.0%), dermatitis acneiform (38.9%), nausea (36.3%), asthenia (22.3%), and stomatitis (21.2%) in the control group.¹⁴ Deaths occurring during treatment or within 30 days of the last administered dose occurred in 7 patients (3.2%) in the doublet group and 8 patients (4.1%) in the control group.¹⁴

Critical Appraisal

The BEACON trial was an open-label phase III trial; therefore, patients and investigators were aware of treatment assignment. Appropriate measures were put in place to mitigate biases of an open-label trial, such as implementation of a blinded independent central review (BICR) for analyses of efficacy outcomes and limiting the number of study team members who were unblinded to trial results. However, the biases of an open-label trial may have affected the results for HRQoL and safety, as reporting of side effects and impacts on quality of life may have been influenced by knowledge of treatment assignment.

Post-hoc analyses for efficacy were conducted by the sponsor after the interim analysis. The updated analyses were not pre-specified; therefore, all analyses conducted at this time point are considered descriptive and should be interpreted with caution.

The use of subsequent therapies differed across treatment groups and may have influenced observed survival in the BEACON trial. As analyses for OS did not control for subsequent therapies, results for OS could have been over- or underestimated.

Patients were stratified according to baseline ECOG PS (0 versus 1), prior use of irinotecan (yes versus no), and cetuximab source (US-licensed versus EU-approved). The efficacy of cetuximab was considered to be broadly similar regardless of source of manufacturing. A previous phase III trial supported noninferiority of the 2 formulations of cetuximab. The clinical experts consulted for this review suggested the source of cetuximab should not affect the efficacy of treatment.

Cetuximab was administered as a 400mg/m² dose followed by a 250 mg/m² IV infusion every week. Clinicians consulted for this CADTH review noted that cetuximab is often provided to patients at an alternative dosing of 500 mg/m² every 2 weeks. No direct evidence has been published that supports the equivalence of the alternative dosing and administration schedules for cetuximab; however, pooled analyses did support noninferiority.¹⁷ The clinical experts who consulted with CADTH for this review agreed that cetuximab may be given at either dose and the administration schedule should be equally efficacious, and that administration of cetuximab in clinical practice is typically a dosage of 500 mg/m² every 2 weeks.

Indirect Comparisons

Description of Studies

Two studies, the BEACON trial and NCT00339183 trial, were included in the sponsor’s indirect treatment comparison (ITC). The sponsor’s ITC compared the efficacy of encorafenib plus cetuximab with FOLFIRI among patients with BRAF-mutated mCRC after prior therapy. While the BEACON trial specifically enrolled patients with the BRAF V600E mutation, the NCT00339183 trial enrolled only a small subsample of patients with the BRAF mutation.

Efficacy Results

The results of the sponsor’s ITC suggested that encorafenib plus cetuximab was |||||||||||||||||||||||||||||||| to FOLFIRI based on OS |||| OS |||||||||||||||||||||||||||||||| and PFS ||||||||||||||||||||||||||||||||||||.¹⁸

Harms Results

No comparisons for harms or safety were incorporated in the sponsor’s ITC.

Critical Appraisal

Little published, peer-reviewed literature was available for the assessment of the feasibility of the sponsor’s ITC. Only 1 trial, NCT00339183, was included in the sponsor’s ITC to provide a comparison with encorafenib plus cetuximab based on evidence from the BEACON trial. The trial was limited in the number of patients with the BRAF mutation; therefore, generalizations about baseline characteristics and clinical outcomes for all patients in NCT00339183 were made to the small BRAF-mutated subsample included in the trial. Patients in the NCT00339183 trial had received only 1 previous systemic therapy, whereas patients in the BEACON trial could have received 2. As patients with BRAF mutations face poorer prognoses, these generalizations of baseline characteristics and trial results between patients with BRAF-mutated versus wild-type colorectal cancer may not be appropriate and may have resulted in the underestimation of the benefit of encorafenib plus cetuximab. In addition, a number of assumptions regarding clinical equivalence between different treatments were made; assumptions were considered reasonable by the clinicians consulting on this CADTH review. However, without direct evidence, it is not possible to know the comparative efficacy of different treatments with certainty. While the results of the sponsor’s ITC, which favour encorafenib plus cetuximab over FOLFIRI, may be true, the magnitude of this benefit is uncertain.

Conclusions

Patients with mCRC face poor survival rates, and patients with BRAF mutations face poorer prognoses and rapid disease progression with few available treatment options. There are currently no funded treatment options that target BRAF mutations for patients with mCRC. Based on the results of 1 phase III study (the BEACON trial), encorafenib in combination with cetuximab (doublet group), compared with FOLFIRI plus cetuximab or irinotecan plus cetuximab demonstrated statistically significant improvements in OS and PFS in adult patients with mCRC with a BRAF V600E mutation, after prior therapy. ORR was also superior in the doublet group, with only a few patients achieving response in the control group. HRQoL outcomes were noted as important to patients; however, the doublet group’s effect on HRQoL was uncertain due to the study's open-label design, lack of control for multiplicity, and lack of analyses based on the estimated minimal important differences (MIDs). The CADTH reviewers did not identify direct comparative evidence for encorafenib plus cetuximab with FOLFIRI. One sponsor-submitted ITC comparing encorafenib plus cetuximab with FOLFIRI suggested that encorafenib in combination with cetuximab may be more efficacious for patients in the second line of treatment compared with FOLFIRI. However, there is uncertainty around the ITC results due to the numerous assumptions. The safety results also suggested a lower frequency of AEs and a manageable toxicity profile.

Introduction

Disease Background

Colorectal cancer is a potentially fatal disease that begins in the colon or rectum and is characterized by a group of cancerous cells (a tumour) that grow into and destroy nearby tissue. In metastatic disease, the tumour spreads to and damages other parts of the body.¹⁹ About 70% to 90% of colorectal cancers are diagnosed after symptom onset, although population-based screening is increasing the number of asymptomatic cases identified.²⁰ Risk factors for colorectal cancer include lifestyle choices (i.e., diet, obesity, smoking, alcohol) as well as non-modifiable risk factors, such as race, ethnicity, age, and the presence of mutations.⁴ Colorectal cancer is 1 of the most commonly diagnosed cancers in Canada; estimates from 2020 suggested that colorectal cancer was projected to be the third most commonly diagnosed cancer among Canadians, with an expected 26,900 new cases.¹ Colorectal cancer impacts both men and women; it is the second most commonly diagnosed cancer in men and the third most commonly diagnosed cancer in women. Estimates from 2020 suggested that colorectal cancer was expected to result in 11.6% of all cancer-related deaths, second only to lung cancer.¹ At diagnosis, approximately 1-fifth of colorectal cancers will be classified as metastatic disease.² The 5-year survival rate for mCRC is low, with most estimates indicating a 5-year survival rate of 10% and 13% for patients with mCRC.^3,4,21

BRAF mutations may account for 10% to 15% of colorectal cancer cases.^4,5 The BRAF V600E mutation is the most common variant of the BRAF mutations. The presence of the BRAF mutation is associated with poorer survival compared with BRAF wild-type colorectal cancer.² The clinical experts consulted by CADTH for this review stated the presence of the BRAF mutation can be associated with right-sided colon cancers and MSI; such patients often respond poorly to systemic therapies and progress rapidly, despite optimum cancer care.²² Testing for the mutation is considered the standard of care and typically occurs at initial diagnosis to help guide treatment options and care for patients. The clinical experts consulted by CADTH for this review indicated that every Canadian province has a designated regional centre for the testing of BRAF V600E mutations. NGS was acknowledged as a common method for identifying tumour mutations. A summary of BRAF mutation testing in colorectal cancer is provided in Appendix 5.

Standards of Therapy

Colorectal cancers are a heterogenous group of diseases driven by different mutations and mutation-causing agents, such as radiation of chemical substances. Due to the varying nature of driving mutations, molecular therapies may not be effective for all types of colorectal cancers. Primary treatment typically involves surgery when diagnosis occurs early. However, in some cases of metastatic disease, surgery may not be effective.⁴ When surgical resection is not possible, the clinical experts consulted by CADTH for this review indicated that, in select patients, aggressive intervention with surgical salvage for low-burden metastatic disease may be attempted. Stereotactic body radiotherapy may also be used for patients with oligometastases or oligoprogression. For most patients with mCRC, the disease is not curable, and patients are often treated with chemotherapy. Molecularly driven therapies may also be considered for some patients, depending on their disease characteristics and prior courses of therapy.

The clinical experts consulted by CADTH for this review indicated that currently available therapies for the treatment of mCRC patients in Canada include 5-fluorouracil or capecitabine, oxaliplatin, irinotecan, bevacizumab, and panitumumab or cetuximab; up-front treatments may include a chemotherapy regimen with or without a biologic drug, such as bevacizumab. Trifluridine plus tipiracil and regorafenib were also stated to be available treatments for patients; however, these treatments are not funded and are often used only when patients progress on all other treatment options and are able to either self-fund treatment or access coverage through private insurance. Choice of treatment can be dependent on a patient’s performance status, organ function, and comorbidities, in addition to tumour characteristics, including location (right versus left), presence of primary tumour, and RAS status. Current principles for first- and second-line therapy are often combination therapies, which can include regimens based on oxaliplatin, irinotecan, and/or bevacizumab.⁶ Ultimately, most patients will develop resistance and eventually die from their disease. Currently, there are no approved treatments that target the BRAF mutation. Patients with the BRAF mutation are often treated with standard treatment regimens for mCRC, which can include chemotherapy combinations. However, patients with mCRC with a BRAF mutation may benefit less from these regimens than patients with BRAF wild-type mCRC.²³ A growing body of evidence is suggestive of improved patient outcomes for patients with BRAF-mutated colorectal cancer when treated with BRAF and MEK inhibitors combined with anti–epidermal growth factor receptor (EGFR) therapies.² Current goals for treatment include prolonging life, delaying disease progression, ensuring well-tolerated treatments with easy administration, and improving patient’s quality of life.

Drug

Encorafenib is indicated by Health Canada to be used in combination with cetuximab for the treatment of patients with mCRC with a BRAF V600E mutation, as detected by a validated test, after prior therapy.⁷

Encorafenib is a kinase inhibitor that targets the BRAF V600E mutation. Mutations in the BRAF gene can result in activated BRAF kinases that stimulate the growth of tumour cells. Encorafenib is able to suppress oncogenic pathways and lead to inhibition of tumour cell growth. Induction of EGFR-mediated and mitogen-activated protein kinase (MAPK) pathways for patients with BRAF V600E–mutated mCRC has been observed to lead to resistance to BRAF inhibitors. Treatments with a combination of a BRAF inhibitor and anti-EGFR therapies have been shown to overcome the resistance and result in greater anti-tumour activity compared with single-drug treatments.⁷

The Health Canada–recommended dose for encorafenib is 300 mg daily (four 75 mg capsules) taken orally once daily in combination with cetuximab until disease progression or unacceptable toxicity.⁷ Cetuximab is to be administered to patients as per the recommended dosing in the cetuximab product monograph, which is a dose of 400 mg/m² followed by 250 mg/m² every week as an IV infusion.²⁴ If cetuximab is discontinued, encorafenib should also be discontinued.⁷

The sponsor has requested reimbursement of encorafenib as per the indication under review, which is in combination with cetuximab, for the treatment of patients with mCRC with a BRAF V600E mutation, after prior therapy.²⁵ Encorafenib has not been reviewed previously by CADTH.

The key characteristics of commonly used treatments for mCRC with a BRAF V600E mutation are presented in Table 3.

Stakeholder Perspectives

Patient Group Input

This section was prepared by CADTH staff based on the input provided by patient groups.

About the Patient Groups and Information Gathered

CADTH received submissions from 2 patient groups for this review. CCC and the CCRAN are national, not-for-profit, patient advocacy groups.

CCC obtained information through an online survey posted on its social media platforms as well as those of other international colorectal cancer organizations between October 30 and December 23, 2020. Respondents included 2 patients and 4 caregivers from Canada (n = 1), the US (n = 3), the UK (n = 1), and Turkey (n = 1). Four of the 6 respondents were female. At diagnosis, 4 out of 6 patients were between 30 and 39 years old, 1 was between 40 and 49 years, and another was between 70 and 79 years; 4 respondents presented with stage IV disease, while 2 presented with stage I disease. At the time of the survey, 4 respondents had stage IV cancer, while the 2 remaining patients had died. All patients alive at the time of the survey were undergoing treatment.

CCRAN collected information through 3 separate processes for its submission and advertised with the help of its support group members and members of their medical advisory board:

• A national online survey, available from December 6 to December 30, 2020, provided input from 63 patients, 17 caregivers, and 5 patients who were also caregivers, all of whom were living in Canada. Almost 59% of respondents were female and their ages varied from 31 to 90 years, although most were between 41 and 70 years old. Most patients had stage II (11%), III (29%), or IV (44%) disease.

• A focus group discussion conducted over Zoom (a teleconference platform) took place on November 15, 2020 to gain insight on the experiences and symptoms of 7 patients who had mCRC.

• Phone interviews were conducted between December 16, 2020 and January 18, 2021 to provide information about patients’ first-hand experience with encorafenib plus cetuximab. Input was obtained from 3 patients who received encorafenib plus cetuximab as first-line (n = 1) and second-line (n = 2) therapy. The patients included 1 male and 2 females who were between 30 and 50 years of age and living in Ontario (n = 2) and the Netherlands (n = 1).

Disease Experience

Patients responding to the CCC and CCRAN surveys reported fatigue, bloody stool, diarrhea, and abdominal cramping as the most commonly occurring colorectal cancer symptoms; fatigue and pain were identified as being the most important symptoms to control. Furthermore, both patients and their caregivers experienced the hardships of living with a cancer that affected their social lives, daily routines, mental health, quality of life, and their ability to work, resulting in lost income. More specifically, 51% of respondents to the CCRAN survey noted being unable to work, while 42% were unable to fulfill family obligations. The CCRAN focus group identified pain in various locations, breathing issues, debilitating fatigue, and diminished appetite as key burdens resulting from the spread of the disease to other organs. Moreover, respondents also noted that, from their experience, there were often no warning signs before the cancer had advanced and was more difficult to treat. Hardships related to the disease were illustrated in the following quotes from patients and caregivers responding to the CCC survey. “Between the constant nausea, and decreased energy I find it very difficult most days to do even a fraction of what I used to do in a day” (patient). “I lost 15 lbs, had to be on anti-anxiety drugs” (caregiver). “Everything revolves around what he needs and this varies each day depending on pain levels and energy” (caregiver).

Experiences With Currently Available Treatments

Five of 6 patients from the CCC group had accessed therapies before receiving encorafenib; all of them felt that the previous therapies (chemotherapy and/or surgery) either only partially controlled or did not control their symptoms. Based on what therapies are currently available for treating colorectal cancer, 3 of the 6 respondents felt that patient needs are still unmet and that there are limited options available, particularly for those with the BRAF V600E mutation. The side effects most difficult to tolerate varied slightly among patients and included vomiting, nausea, pain, rash, neuropathy, hair loss, and low platelets. On a scale from 1 to 10 (10 being very important), when asked how important it was to have a choice of which drug to receive based on known side effects, most responded with a score of at least 7.

Regarding treatment access, 3 of the 6 respondents expressed difficulties doing so, with 1 stating that it took more than 4 weeks for the drug to be available and another facing a lack of insurance coverage. Respondents also reported that treatment recommendations were based solely on what was funded in their region. Patients and caregivers highlighted the financial burden of having to pay co-pays out of pocket for medical visits, medications, and tests, as well as the additional costs for travel and medical supplies. Fortunately, 3 respondents had received financial assistance that covered from 20% to 100% of their treatment expenses. All 6 respondents felt it was very important to be able to access new, effective cancer treatments and nearly all were willing to pay out of pocket to access new medications. One patient stated, “I am determined to live as long as possible” and a caregiver expressed, “This disease is very severe and unfair.”

Patients from the CCRAN survey listed the variety of therapies they had received, including folinic acid plus 5-fluorouracil and oxaliplatin (FOLFOX) (72%), capecitabine (40%), folinic acid plus 5-fluorouracil and irinotecan (FOLFIRI) (34%); bevacizumab-awwb (Mvasi), (21%), panitumumab (15%), cetuximab (6%), pembrolizumab (6%), trifluridine plus tipiracil (4%), regorafenib (2%), and encorafenib (2%), among others. Most noted that diarrhea, hand and foot syndrome, and neuropathy were common with their current medication, but fatigue and nausea were the 2 side effects most difficult to tolerate. In addition to the previous list of drugs, respondents also had surgery, radiation therapy, and other forms of chemotherapy.

Improved Outcomes

Respondents from both the CCC and CCRAN surveys felt it was very important for new therapies to improve both patients’ physical condition and quality of life. Furthermore, nearly all patients and caregivers expressed interest in a treatment that was proven to provide a better quality of life, even if it did not extend OS, as this would allow them to engage in social activities and return to daily life without worrying about side effects. When asked about what severity of side effects (on a scale from 1 to 10) patients would be willing to tolerate for extended survival, the survey results indicated that all respondents were willing to tolerate some level of side effects; the lowest scores reported tolerance of medium severity of side effects (score = 4), and the highest scores reported maximum severity (score = 10). Respondents from the CCRAN survey indicated the following 3 outcomes as the most important expectations for new cancer treatments: provides a cure, if possible (94%); prolongs life by a substantial amount of time (86%); and promotes good quality of life (82%). Other key outcomes included limited side effects, treatment funding, improvement in symptoms, and simpler administration.

Regarding access to treatment, 4 of 6 respondents from CCC reported they had appropriate or fair access to therapies versus 2 respondents who reported that access was limited or restrictive. All respondents also felt it was very important to be given a choice, along with their physicians, when deciding which treatment they would receive, and to understand the expected length of benefit from a new therapy.

Experience With Drug Under Review

From the CCC survey, 1 patient had received encorafenib as a first-line therapy, 4 as a second line, and 1 as a fourth line. Patients had switched to encorafenib for the following reasons: specific biomarker testing (n = 2), failure of first-line treatment (n = 1), and disease recurrence (n = 2). All patients had tested positive for the BRAF V600E mutation before receiving encorafenib, which was administered in combination with chemotherapy, targeted therapy, or immunotherapy. At the time of the survey, individuals had reported being on the new treatment for 3 weeks to 3 months. Access was gained through pharmaceutical company assistance and insurance plans, though most respondents faced access issues, whether it was financial or was related to encorafenib not being available through their cancer centre or related to them having no provincial coverage. One caregiver emphasized the importance of having knowledgeable clinicians and being presented with all possible options: “Patients that are BRAFv600e should be informed about BRAFTOVI by their oncologist and not have to seek 2nd opinions to learn about it. They should be treated by a colorectal cancer specialist, not an oncologist that treats all cancers.” All respondents felt encorafenib should be funded in their region and 1 caregiver stated, “[Treatments] should not be restricted based on what is covered/funded…. When someone has such an aggressive form of cancer, every moment counts and time spent waiting to get coverage allow the cancer to spread.”

Respondents reported the following as common, but somewhat tolerable, side effects: fatigue, joint pain, muscle weakness, headache, rash, dry skin, itching, nausea, hair loss, and fever. They also noted that fatigue, shortness of breath, diarrhea, constipation, platelet levels, and liver function were better managed with encorafenib compared with previous therapies. Conversely, they felt that emotional drain, fatigue, and medication management were the most difficult hardships of their treatment. With encorafenib, 2 patients believed their cancer was gone, shrunk, or controlled, while 2 others reported their tumours had partially shrunk. Nearly all felt the oral therapy was easy to administer and all found it simple to integrate into their routines. Caregivers and patients alike noticed the benefits the drug had offered: “On day 2 of the new targeted treatment his liver values began to improve. His quality of life improved significantly! Ultimately these drugs bought him 8 more weeks with us before he passed away. His quality of life was greatly improved, which was such a blessing for him, myself and our 6 year old son.” And, “I don't know that I would have made it this far without the current drug combination. I was in the hospital in liver failure before my treatment was changed. After the first 2 weeks my liver functions started falling back into the normal range and at my 2 month scan my mets had shrunk considerably.”

CCRAN interviewed 3 patients who had received encorafenib plus cetuximab either as a first-line (n = 1) or second-line (n = 2) treatment. The patient treated with encorafenib as a first-line therapy gained access through a compassionate-use program, while the others were through special access programs. Prior to starting encorafenib, first-line therapies included chemotherapy (FOLFOX, FOLFIRI, or capecitabine plus oxaliplatin [CAPOX]) and/or surgery and radiation; the 2 respondents who received these first-line therapies agreed that these methods did not control the cancer and their quality of life was very poor during this time. In general, respondents believed that it was fewer than 5 months before the disease had progressed while receiving or once completing chemotherapy. One patient shared their experience with FOLFOX, “Oh, gosh, it was horrible. I had terrible neuropathy, and nausea was horrible…. I was not able to keep up with my young kids. For the first 5 days, I was in bed and unable to do anything and constantly debilitated. I found it painful to touch anything. And the smells, oh the smells they made me so ill. They made me nauseous. And I couldn’t eat or drink.”

Patients noted a variety of side effects they have experienced while receiving encorafenib and cetuximab: gastrointestinal problems, fatigue, constipation, itching and burning skin, skin spots or rash, and hair growth or loss in different locations. Two of the 3 respondents felt these side effects were more tolerable compared with those with previous chemotherapy, and rated their quality of life as at least a 9 out of 10 (10 being very good). One gave a rating of 5 due to the extreme fatigue after cetuximab infusions but was hopeful it would improve. Two patients had to pause their treatment due to gastrointestinal problems and heart issues, but were able to restart within 1 week. When asked if the current treatment was easier than their previous ones, the responses were unanimously in favour of encorafenib: the side effects were much more manageable and less severe, it was convenient and took less time than chemotherapy infusions, and their overall quality of life was much better. Additionally, all respondents felt it was worth accessing encorafenib and cetuximab, noting the improvement in length and quality of life, being able to return to daily routines, caring for their families, and 1 considering returning to work. One patient stated, “…it’s a great therapy. It’s easy to use, gives me great quality of life. One of the drugs is oral so I get to take it at home. The other one is infused at the hospital but it’s a quick infusion and the side effects are nowhere near as toxic as the other therapies I have had. I feel really lucky.”

At the time of the interviews, 2 patients had CT scans and carcinoembryonic antigen (CEA) testing showing disease regression, while the third had not had any imaging performed but still felt the medications were effective. When asked what outcomes they would like to see with new treatments, the 3 patients listed improved OS and quality of life, a better side effects profile, no toxicities, easy administration and, ideally, a cure. They mostly felt that encorafenib with cetuximab fulfilled the previous list of desired outcomes, aside from the treatment not being a cure. Finally, the group was adamant that encorafenib plus cetuximab should be an option for all who qualify without having to fail first-line treatments and for the improved outcomes it provides to both patients and caregivers. One patient stated:

You shouldn’t have to go through a useless first-line therapy to prove that it will not work to access a second-line treatment designed to target your particular cancer and your genetic mutation. I was essentially told be prepared for first line to not work and then you’ll be able to access something that will work and be easier on your body! That’s just wrong and unconscionable. I just couldn’t understand that and on top of that, to wait for the treatment to 6 weeks, to fight for it to get here in 4 weeks and was yes grateful to know people who helped get it here sooner is again unconscionable and should be that way for people who are fighting for their life, who have my mutation, an aggressive form of cancer!

Companion Diagnostic Test

Most patients from the CCC survey were unaware that biomarker testing could help specify a treatment. Furthermore, all respondents reported being tested after diagnosis and were confirmed to be positive for the BRAF V600E mutation. After receiving their results, 5 patients were treated with chemotherapy (1 with additional surgery) and the sixth received immunotherapy.

Two of 3 patients from the CCRAN interviews who had received encorafenib were not aware what type of biomarker testing was being performed. All 3 tested positive for the BRAF V600E mutation, which qualified them for the drug, though none were aware of what form of test was used. They also noted not having to travel to complete the test, nor did any of them pay out of pocket.

Clinician Input

Input From the Clinical Experts Consulted by CADTH

All CADTH review teams include at least 1 clinical specialist with expertise in the diagnosis and management of the condition for which the drug is indicated. Clinical experts are a critical part of the review team and are involved in all phases of the review process (e.g., providing guidance on the development of the review protocol, assisting in the critical appraisal of clinical evidence, interpreting the clinical relevance of the results, and providing guidance on the potential place in therapy). The following input was provided by 2 clinical specialists with expertise in the diagnosis and management of colorectal cancer.

Unmet Needs

Patients with BRAF mutations generally have a much worse prognosis compared with patients without the mutation. Patients with the BRAF mutation were stated to have an inferior response to currently available systemic treatments due to the deregulation of cell division introduced by the BRAF cellular pathway. There was consensus among the clinicians that there are currently no treatments that specifically target the BRAF mutation. Patients and their treating physicians are in need of new treatments that address the challenges posed by the disease’s limited response to currently available treatment options. Without directed treatments, patients are subjected to toxicities from treatments that offer limited benefit on disease control and that result in quicker disease trajectory and early mortality. The clinicians agreed that treatment goals include improved survival, disease control, and delayed disease progression, tolerability and ease of administration of treatment, and improved quality of life.

Place in Therapy

Encorafenib plus cetuximab was stated to be used for patients with BRAF-mutated mCRC after they have received prior therapy. Both clinicians suggested that encorafenib plus cetuximab would be used after first-line therapy for mCRC, which typically involves chemotherapy. One of the clinicians acknowledged there is a lack of clarity on what is considered standard first-line therapy. In addition, a proportion of patients enrolled within the BEACON trial were previously treated with an irinotecan regimen and then re-challenged with irinotecan when randomized to the control group; this practice was acknowledged as being generally unacceptable. Current evidence does not support the upstream migration of the encorafenib-based regimen to first-line therapy.

This encorafenib regimen was acknowledged to be the first treatment targeting the BRAF mutation. While patients with BRAF mutations may continue to face poorer outcomes, the encorafenib regimen offers a novel therapy for such patients and introduces hope for more effective treatments in the future.

Patient Population

The clinical experts believe that encorafenib in combination with cetuximab would be suitable for adult patients with mCRC with a BRAF V600E mutation who are not suitable for surgical salvage therapy, have progressed after first-line therapy, have reasonable performance status (ECOG PS 0 or 1), and have reasonable lab parameters and organ function. Suitability for treatment should be based on clinical standards, including a patient’s clinical status, and based radiographically through CT scans. Identification of patients with the BRAF V600E mutation would be requested by the medical oncologist through genomic analysis, which is the standard of care for patients with advanced colorectal cancer. The majority of patients with advanced colorectal cancer were stated to have known BRAF mutation status. Patients without the BRAF V600E mutation, or with other BRAF mutations, were stated to be the least suitable patients for treatment with encorafenib plus cetuximab after prior therapy.

The clinical experts also stated it is not possible to identify patients who would be most likely to exhibit a response to treatment with encorafenib in combination with cetuximab. Further information may be needed to assess the magnitude of a patient’s outcomes and how to better utilize initial and subsequent therapies.

Assessing Response to Treatment

Regular clinical and radiological assessments to assess for signs and symptoms and laboratory parameters attributable to disease (i.e., ECOG PS, pain, feeling of well-being, and weight loss) would be conducted to assess patients’ response to treatment. In addition, radiological assessments per Response Evaluation Criteria in Solid Tumors (RECIST), including CT scans, would be performed every 2 to 3 months. Clinically meaningful responses to treatment were stated to include improvements in OS, PFS, and quality of life. Functional improvement and better pain control were also stated to be important when assessing improvement in patients.

Treatment should be continued for as long as patients respond and tumour shrinkage or stability is confirmed, side effects remain manageable, treatment remains medically reasonable, and patients wish to continue receiving treatment. Assessment of treatment response was suggested to be tailored to the patient. Typically, patients may be assessed clinically every 2 to 4 weeks, with radiological assessments every 2 to 3 months. More prompt investigations of treatment response may be warranted if patients exhibit clinical changes.

Discontinuing Treatment

Treatment should be discontinued when patients are no longer responding to treatment and show signs of clinical and/or radiological disease progression, or when there are intolerable side effects, such as severe skin toxicities. Alternatively, the decision to continue or discontinue therapy may depend on opportunities to enrol in new clinical trials that offer potentially novel or superior treatments.

Prescribing Conditions

As encorafenib is provided in combination with cetuximab, cancer clinics with the facilities and personnel to deliver IV chemotherapy are necessary for treatment. There was agreement among the clinicians that treatments should be guided by a medical oncologist experienced in managing patients with colorectal cancer.

Additional Considerations

One of the clinicians highlighted that patients with BRAF-mutated mCRC are a distinct group with poor prognoses and limited effective treatment options. There is a lack of data to help patients and clinicians choose the optimal first-line treatment. The clinical expert indicated that first-line treatment with the triplet regimen of folinic acid plus 5-fluorouracil, oxaliplatin, and irinotecan (FOLFOXIRI) plus bevacizumab and subsequent therapy with a combination of BRAF, MEK, and EGFR inhibitors, appears to provide patients with effective treatments and improved clinical outcomes.

Clinician Group Input

This section was prepared by CADTH staff based on the input provided by clinician groups.

Three clinicians provided input on the review of the use of encorafenib (Braftovi) in combination with cetuximab or panitumumab, after prior therapy, for the treatment of patients with mCRC with a BRAF V600E mutation.

One clinician input submission came from a group of Canadian clinicians who were investigators in the BEACON CRC trial, along with a submission from the CGOEN and select members of the CCC Medical Advisory Board. The input noted that the CCC Medical Advisory Board works alongside the patient group to ensure that activities and health information are useful and relevant to patients and caregivers. They provide oversight of health-related information, identify treatment and access issues, and provide a link to the Canadian medical community. Additionally, the CGOEN was noted as a recently formed virtual network of Canadian gastrointestinal oncology clinicians who contribute knowledge on gastrointestinal cancer and treatments, participate in clinical trials, conduct observational research, and are involved in local, provincial, and national clinical guideline developments and health technology assessments. Information for the input from this group of clinicians was gathered through personal experience in treating patients with mCRC with a BRAF V600E mutation. The group also conducted a literature review and held a virtual discussion among experts.

A joint clinician input was received on behalf of 9 gastrointestinal clinicians who treat mCRC. The clinicians who provided input were located across Canada. CCRAN assisted with the coordination of the joint clinician input. CCRAN prepared a clinician survey based on input on a template received from the lead clinician on the review. The survey opened on December 14, 2020 and closed on January 10, 2021. The joint input was circulated on January 15, 2021 to clinicians for feedback and additional input.

Additionally, a third input was received on behalf of the OH-CCO DAC. That input noted the DAC’s role in supporting OH-CCO’s mandate, including provincial drug reimbursement programs and the Systemic Treatment Program. The input was collected and jointly discussed at a DAC meeting.

Unmet Needs

The CGOEN clinician input noted that BRAF V600E–mutated mCRC is an aggressive form of colon cancer and the options for standard of care have limited efficacy. The input indicated that BRAF V600E mutations are present in up to 15% of patients with mCRC and these patients have a poor prognosis. The current standard of care in first-line treatment of BRAF-mutated colorectal cancer, as noted by CGOEN, is chemotherapy plus bevacizumab. The clinician input also noted that OS for this population is approximately 11 months in clinical trials and is about 1-third of what would be expected for patients without the BRAF mutation.²³ The clinicians also noted that many of these patients are too unwell to undergo cytotoxic chemotherapy, and population-based survival is expected to be around 6 months, with only 60% of patients undergoing first-line chemotherapy.²⁹

The joint clinician input from the 9 clinicians provided through CCRAN noted that before the results of the BEACON study, the standard of care for Canadian patients with mCRC and the BRAF V600E mutation was standard chemotherapy such as FOLFOX or FOLFIRI, with or without a biologic drug. The clinicians noted that the benefit of these chemotherapies in this population is substantially inferior, with worse OS and tumour response rates. The 9 clinicians noted that encorafenib and cetuximab specifically target the BRAF V600E mutation and the feedback loop that affects tumour growth.

Input submitted on behalf of the OH-CCO’s DAC added that patients are currently treated with 5-fluorouracil backbone regimens (FOLFIRI, FOLFOX, FOLFOXIRI, folinic acid plus 5-fluorouracil, irinotecan, and oxaliplatin [FOLFIRINOX]) with or without biologics (i.e., bevacizumab) or anti-EGFR therapy, and that only panitumumab is funded in the first-line setting in Ontario for patients who are contraindicated for bevacizumab.

All 3 clinician inputs noted the V600E mutation accounts for more than 90% of BRAF mutations in colorectal cancer and, despite major improvements in survival for advanced colorectal cancer, patients with BRAF mutations continue to have a very poor prognosis. The clinicians also noted the prognosis in this group of patients with metastatic disease is significantly worse than among those who do not have this mutation, with a median survival of fewer than 12 months compared with greater than 30 months in patients without metastatic disease. The group added that patients with the BRAF V600E mutation have a particularly grim prognosis. All 3 clinician inputs noted that the most important treatment goals are to prolong life, delay disease progression, and improve quality of life or performance status (which could help promote independence while reducing the burden on caregivers). Additionally, the clinician inputs also noted that patients with this mutation have a higher incidence of peritoneal disease and fewer liver-only metastases, making long-term treatment strategies less likely to benefit. The CGOEN input noted that peritoneal metastases could lead to challenges in maintaining patients’ quality of life due to intermittent bowel obstructions and abdominal pain.

For the current needs that are not being met by available therapies, all 3 inputs noted that patients with BRAF-mutant mCRC exhibit decreased sensitivity to chemotherapy and derive little benefit from existing standard therapies. The inputs noted this is most pronounced in the second- and third-line settings. The CGOEN clinician input group also added that not only do these patients have a poor response to chemotherapy, anti–EGFR antibody drugs (a standard drug for RAS wild-type colorectal cancer) do not work in this population without the addition of a BRAF-directed drug. The input from CGOEN noted that a considerable proportion of patients might not be able to receive second-line chemotherapy due to rapid progression and declining performance status. Due to the rapid attrition of patients with this type of colorectal cancer, the input from CGOEN noted a need for more effective therapies. The group added that only 60% of all patients with the mutation receive a first-line therapy, and approximately 20% receive a third line.²⁹ Additionally, the input from 9 clinicians note response rates to second-line chemotherapies and third-line anti-EGFR therapies were significantly inferior compared with tumours that do not have the V600E mutation.

All 3 clinician inputs noted that the greatest unmet need is for patients who have the V600E BRAF mutation, as they have a particularly grim prognosis and represent a population with 1 of the greatest unmet needs within colorectal cancer. The drug under review, encorafenib plus cetuximab, is noted by CGOEN as the first FDA-approved targeted regimen that is specifically for adults with previously treated mCRC with a BRAF V600E mutation. The clinicians indicated that the majority of goals are not met by the currently available standard-of-care therapies in Canada for patients whose tumours have the BRAF V600E mutation. The clinicians also noted that no treatments have been available that have demonstrated an improvement in survival, until now, and that the therapy under review provides these patients with the highest chance of PFS and maintaining HRQoL.

Place in Therapy

The clinicians from CGOEN noted that encorafenib plus cetuximab is the first targeted regimen specifically for adults with previously treated mCRC with a BRAF V600E mutation. The clinicians added that this treatment combination would be used following disease progression after 1 or more previous chemotherapy regimens. The clinicians from CGOEN added that following disease progression or intolerance after classical fluoropyrimidine plus irinotecan- or oxaliplatin-containing chemotherapy regimens, there are no other appropriate treatments in this setting to recommend to patients because of the rapid progression of these cancers while receiving chemotherapy. The clinicians noted that clinical trials may still be considered for certain patients. Input collected through CCRAN from 9 clinicians added that encorafenib would be used in combination with cetuximab in the second-line setting for patients with mCRC whose tumours have the BRAF V600E mutation.

For the sequencing of therapies, the clinician input from CGOEN noted that, currently, fluoropyrimidine with or without an additional drug (irinotecan or oxaliplatin) appears to be the most appropriate initial management approach for patients with BRAF-mutant mCRC. The CGOEN clinicians noted that more intensive chemotherapy regimens such as FOLFOXIRI may also be used in the first line to overcome the resistance to chemotherapy in BRAF-mutant mCRC; however, it is not often an option, as this combination of 4 medications can be very toxic to some patients. Clinician input from CGOEN also highlighted that single-drug BRAF inhibitors do not have significant activity in BRAF V600E mCRC, and that treatment following progression on prior chemotherapy with doublet treatment of encorafenib (a BRAF inhibitor) and cetuximab (an EGFR inhibitor) would represent a long-awaited improvement in the treatment algorithm for BRAF V600E mCRC. The clinician group noted that the combination would become a new standard of care that both improves patient outcomes and HRQoL. Similarly, the 9 clinicians who provided input through CCRAN noted that encorafenib in combination with cetuximab has demonstrated clinical efficacy in patients who have previously received first-line standard-of-care therapy and subsequently received the therapy in the second-line setting. The 9 clinicians added there may be a shift of existing second-line chemotherapy such as FOLFOX or FOLFIRI to the third-line setting. The clinicians also added that if encorafenib plus cetuximab fails, patients would not receive any further anti-EGFR therapy in a subsequent line of therapy. The clinician input from OH-CCO’s DAC added that, currently, patients with a contraindication to bevacizumab can receive panitumumab in the first-line setting. The OH-CCO’s DAC clinicians noted there is uncertainty whether these patients can be treated with panitumumab (or another EGFR inhibitor) again in a later line, and that the BEACON study was not able to inform on this.

Patient Population

All clinician inputs agreed that patients with BRAF V600E–mutated mCRC who have had progression after 1 or more previous lines of therapy are best suited for treatment with encorafenib and cetuximab. The input collected from 9 clinicians by CCRAN specified that patients best suited for treatment with encorafenib plus cetuximab would be patients with BRAF V600E–mutated mCRC who have previously received first-line chemotherapy, have preserved ECOG PS (0 to 2), and who have adequate organ function. The input from OH-CCO’s DAC added that patients should have good performance status and the criteria for treatment should be as per the pivotal trial’s inclusion criteria.

With respect to identifying patients best suited for treatment with the drug under review, the CGOEN clinician input noted that BRAF mutation is an important prognostic factor and detection of the BRAF V600E mutation in mCRC identifies a subgroup of patients who derive little benefit from standard therapies and who have an extremely poor prognosis. The CGOEN clinician input noted the detection of this mutation has predictive value for identifying patients suitable for BRAF V600E–targeted treatment with encorafenib and cetuximab.³⁰ The clinician input from CCRAN collected from 9 clinicians notes that tumours would have to be tested for the presence of the BRAF V600E mutation, and that patients should have their tumours tested at the time of diagnosis of metastatic disease. The CGOEN clinician input also added that molecular profiling is essential for the treatment of mCRC when surgery cannot be considered and systemic therapy is recommended; the CGOEN input also added that the clinical application of biomarkers in colorectal cancer are needed for prognostic stratification, surveillance, and therapy selection. Available testing methods at many centres were identified to be immunohistochemistry (IHC) and NGS testing.

The patients who would be least suited for treatment with encorafenib and cetuximab were those who are unable to take oral medications or who have an ECOG PS greater than 2, as per the CGOEN clinician input. The clinician inputs from CGOEN and the OH-CCO’s DAC also noted that the drug under review is associated with a companion diagnostic that already selects the population that is most likely to benefit. The 9 clinicians who provided input through CCRAN noted that patients with a poor ECOG status (> 2) and tumours with non-V600E mutations would be least suited for treatment.

Assessing Response to Treatment

The CGOEN clinician input noted that treatment would be continued if the disease is stable or if it shows a response, has good tolerance, and no limiting side effects. The outcomes used in clinical practice were noted in the CCRAN and CGOEN clinician inputs as being in line with what was used in the clinical trials; according to the 9 clinicians, these include tumour response by imaging (CT and/or MRI), clinical symptom (including toxicity) assessment, CEA measurement, and HRQoL assessment. Input from the OH-CCO’s DAC added that CEA, biochemistry, standard imaging, and clinical improvement are outcomes used to determine whether a patient is responding to treatment in clinical practice. The 9 clinicians from CCRAN added that a clinically meaningful response to the treatment includes a reduction in tumour volume (by imaging), improvement or stabilization of disease-related symptoms (pain, dyspnea, fatigue, weight loss), improvement in performance status, improvement in survival and PFS, ability to perform activities in daily living, improvement or maintenance of HRQoL, and perhaps a reduction in CEA correlating with any of the other responses listed in this section, most notably with a reduction in tumour volume through imaging. The OH-CCO’s DAC clinicians agreed that reduction in the frequency or severity of symptoms, ability to perform activities of daily living, improvement in symptoms, and stabilization (no deterioration of symptoms) would be considered a clinically meaningful response to treatment. The CGOEN clinician input added that the patient’s wishes and decisions are also part of the decision to continue or stop treatment.

The CGOEN clinician input noted that patients will typically have a CT scan performed every 2 to 3 months to assess response to treatment. The 9 clinicians noted that clinical response assessments can be performed every 2 to 4 weeks. Tumour response assessment through radiographic imaging should be performed every 8 to 12 weeks and a CEA measurement should be considered every 4 weeks. The OH-CCO’s DAC clinicians noted that treatment response should be assessed as per the clinical review of a patient, per current standard-of-care practices.

The CGOEN clinician input noted that OS is the most important measure for a clinically meaningful outcome, though PFS and ORR are commonly used end points in clinical trials for mCRC. Delaying worsening in quality of life related to progressive cancer was also noted as an important factor and treatment goal by the CGOEN clinician input. Clinically meaningful response to treatment was noted in the CGOEN input as a reduction in the frequency or severity of symptoms specific to colorectal cancer, and a reduction in abdominal pain, rectal bleeding, anemia, and constipation.

Discontinuing Treatment

The clinician input from CGOEN noted that treatment should be discontinued when there is intolerance to treatment. All clinician inputs agreed that treatment discontinuation should be based on evidence of disease progression based on patients’ clinical status and through objective radiographic imaging, intolerable toxicities, and patient preferences.

Prescribing Conditions

The clinician input from CGOEN noted that the appropriate setting for administration should be an approved oncology infusion clinic in an outpatient setting, because of the cetuximab component, which is administered intravenously. However, the input added that encorafenib can be taken at home, as prescribed by a medical oncologist. The 9 clinicians whose input was collected by CCRAN noted that most practices, including community hospitals and large cancer centres, have physician, pharmacy, and nursing expertise in treating patients with colorectal cancer and thus should be able to care for patients receiving encorafenib plus cetuximab, given appropriate knowledge translation. Input from the OH-CCO’s DAC added that outpatient chemotherapy suites for cetuximab plus panitumumab, and the community setting for encorafenib as an oral take-home cancer drug, are the most appropriate settings.

Additional Considerations

The clinician input from CGOEN indicated there is considerable urgency to have this therapy available to Canadian patients. The CGOEN input also noted that encorafenib plus cetuximab is the first targeted regimen specifically for adults who have been previously treated for mCRC and who have the BRAF V600E mutation. The CGOEN input added there is significant unmet need for patients with the BRAF V600E mutation.

The 9 clinicians who provided input through CCRAN noted that, given the association between BRAF mutations and MSI status and the emerging data on the use of immune checkpoint inhibitors in patients with high MSI tumours, the role of drugs such as pembrolizumab in those with BRAF V600E and high MSI tumours is not yet defined.

The OH-CCO’s DAC added that anti-EGFR therapy should be funded in the second- or third-line setting, as per the BEACON trial.

Drug Program Input

The drug programs provide input on each drug being reviewed through CADTH’s Reimbursement Review processes by identifying issues that may impact their ability to implement a recommendation. The implementation questions and corresponding responses from the clinical experts consulted by CADTH are summarized in Table 4.

Clinical Evidence

The clinical evidence included in the review of encorafenib plus cetuximab is presented in 3 sections. The first section, the systematic review, includes pivotal studies provided in the sponsor’s submission to CADTH and Health Canada, as well as those studies that were selected according to an a priori protocol. The second section includes indirect evidence from the sponsor that met the selection criteria specified in the review. The third section includes sponsor-submitted long-term extension studies and additional relevant studies that were considered to address important gaps in the evidence included in the systematic review.

Systematic Review (Pivotal and Protocol Selected Studies)

Objectives

To perform a systematic review of the beneficial and harmful effects of encorafenib in combination with cetuximab and route of administration for the treatment of mCRC in adult patients with a BRAF V600E mutation, after prior therapy.

Methods

Studies selected for inclusion in the systematic review included pivotal studies provided in the sponsor’s submission to CADTH and Health Canada, as well as those meeting the selection criteria presented in Table 5. Outcomes included in the CADTH review protocol reflect outcomes considered to be important to patients, clinicians, and drug plans.

Of note, the systematic review protocol presented in the following table was established before the granting of a Notice of Compliance from Health Canada.

The literature search for clinical studies was performed by an information specialist using a peer-reviewed search strategy according to the PRESS Peer Review of Electronic Search Strategies checklist (https://www.cadth.ca/resources/finding-evidence/press).³²

Published literature was identified by searching the following bibliographic databases: MEDLINE All (1946‒) through Ovid and Embase (1974‒) through Ovid. The search strategy comprised both controlled vocabulary, such as the National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. The main search concept was Braftovi (encorafenib). Clinical trials registries were searched: the US National Institutes of Health’s clinicaltrials.gov, Health Canada’s Clinical Trials Database, and the European Union Clinical Trials Register.

No filters were applied to limit the retrieval by study type. Retrieval was not limited by publication date or by language. Conference abstracts were excluded from the search results. See Appendix 1 for the detailed search strategies.

The initial search was completed on January 20, 2021. Regular alerts updated the search until the meeting of the CADTH pan-Canadian Oncology Drug Review Expert Review Committee (pERC) on May 15, 2021.

Grey literature (literature that is not commercially published) was identified by searching relevant websites from the Grey Matters: A Practical Tool For Searching Health-Related Grey Literature checklist (https://www.cadth.ca/grey-matters).¹⁴ Included in this search were the websites of regulatory agencies (US FDA and European Medicines Agency). Google was used to search for additional internet-based materials. See Appendix 1 for more information on the grey literature search strategy.

Two CADTH clinical reviewers independently selected studies for inclusion in the review based on titles and abstracts, according to the predetermined protocol. Full-text articles of all citations considered potentially relevant by at least 1 reviewer were acquired. Reviewers independently made the final selection of studies to be included in the review, and differences were resolved through discussion.

A focused literature search for network meta-analyses (NMAs) dealing with colorectal cancer was run in MEDLINE All (1946–) on January 20, 2021. No limits were applied.

Findings From the Literature

One study was identified from the literature for inclusion in the systematic review (Figure 1). The included study is summarized in Table 6. A list of excluded studies is presented in Appendix 2.

Figure 1: Flow Diagram for Inclusion and Exclusion of Studies

Description of Studies

One multi-centre, multinational, randomized, open-label, phase III study met the criteria for the CADTH systematic review protocol. The BEACON trial (N = 665) was a 3-group study evaluating the efficacy and safety of encorafenib plus cetuximab, and encorafenib plus cetuximab and binimetinib, compared with the investigator’s choice of either irinotecan or cetuximab, or FOLFIRI or cetuximab (control group). Eligible patients included adults with mCRC whose tumours expressed the BRAF V600E mutation and whose disease had progressed after 1 or 2 prior regimens in the metastatic setting. Patients were randomized to each treatment group in a 1:1:1 ratio using an interactive web response system (IWRS). Randomization was stratified according to baseline ECOG PS (0 versus 1), prior use of irinotecan (yes versus no), and cetuximab source (US-licensed versus EU-approved).¹⁴ The randomization schedule was created and managed by an independent statistician, and treatments were assigned according to a computerized central randomization list using an IWRS. As per the protocol of the trial, the number of patients who would be receiving third-line treatment was limited, to account for no more than 35% of all randomized patients (n = 215). Once the maximum number of patients who had already received 2 prior regimens was reached, only patients who had received 1 prior regimen were to be randomized; patients who had received 2 prior regimens who had entered the trial during the screening period after the limit was reached were permitted to continue into the trial if they were determined to be eligible.¹⁴

This international trial was conducted in 28 countries across 221 sites¹⁴; a total of 7 Canadian patients were enrolled in the BEACON trial.²⁵ The BEACON trial was initiated with a safety lead-in phase that assessed the safety and tolerability of encorafenib plus cetuximab and binimetinib; the results of the safety lead-in phase are not discussed in this CADTH report, as only the triplet regimen containing encorafenib was administered to patients. An overview of the BEACON trial is illustrated in Figure 2. The BEACON trial is currently ongoing, although enrolment was completed on February 11, 2019.¹⁴ Efficacy analyses for the BEACON trial were based on 2 data cut-off dates: February 11, 2019 and August 15, 2019. The end-of-study period was defined as the point when all patients had the opportunity to be followed for a minimum of 1 year after the randomization date of the last enrolled patient, and once a minimum of 80% of patients had an OS event or were lost to follow-up. Patients still receiving the study treatment at the end of the study period were permitted to continue treatment at the discretion of the investigator and as long as the treatment discontinuation criteria were met. Access to study treatments was provided in accordance with local regulations and requirements.¹⁴ The original version of the trial protocol did not permit crossover within the trial; an amendment was made on July 11, 2019 that allowed patients in the control group to cross over to treatment with the triplet regimen.³³

Figure 2: BEACON Trial Study Design

BICR = blinded independent central review; DOR = duration of response; ECOG = Eastern Cooperative Oncology Group; FOLFIRI = folinic acid plus 5-fluorouracil and irinotecan; JSLI = Japanese safety lead-in; ORR = objective response rate; OS = overall survival; PFS = progression-free survival; PS = performance status; SLI = safety lead-in; TTR = time to response; vs. = versus .

Note: The study was initiated with the SLI cohort (US and EU), in which the safety and tolerability of the triplet combination of encorafenib + binimetinib + cetuximab were assessed before initiation of the randomized phase III portion of the study. The JSLI cohort (Japan) was conducted later and before initiation of randomization in Japan.

Source: BEACON Clinical Study Report.¹⁴

BRAF Mutation Testing: Testing for the BRAF V600E mutation occurred in a central laboratory as part of the molecular pre-screening for the trial or through a local assay result obtained any time before screening. Only PCR or NGS local assay testing was accepted; patients enrolled based on local assays were required to have their BRAF mutation status confirmed by central laboratories no later than 30 days from the first dose of study treatment. Patients whose local assays were not confirmed within 30 days of initiation of study treatment via central laboratory testing, or whose tumour testing could not be conducted centrally due to an inadequate sample or poor sample condition, were permitted to continue receiving treatment if there was no indication of deterioration or disease progression and if the treating investigator determined the patient was deriving a benefit.¹²

Centrally tested tumour samples confirming local assays for BRAF status were not permitted to be retested if a discordant result was observed. A maximum of 37 patients (6% of the total planned enrolment) lacking BRAF V600E mutation status were permitted to be enrolled, and a maximum of 1 patient (3% of the total planned enrolment) with a discordant local and centrally assessed assay was permitted to be enrolled within the trial; subsequently enrolled patients were required to have their mutation status tested via a central laboratory.¹²

Molecular Pre-Screening: Patients were able to undergo BRAF mutation screening via a central laboratory before the screening such that molecular pre-screening criteria were met (Table 7).

Tumour Assessments: Tumour assessments were to be performed every 6 weeks (± 7 days) from the date of randomization for the first 24 weeks of treatment, then every 12 weeks thereafter until disease progression, withdrawal of consent, initiation of subsequent anti-cancer therapy, or the patient was lost to follow-up or died, regardless of whether treatment had been discontinued.¹²

Populations

Inclusion and Exclusion Criteria

Eligibility criteria for the BEACON trial are reported in Table 6. Briefly, eligible patients included adults with histologically or cytologically confirmed mCRC whose tumours expressed the BRAF V600E mutation and whose disease had progressed after 1 or 2 prior regimens in the metastatic setting. Enrolled patients had to have an ECOG PS of 0 or 1 and adequate vital functions, and had to be able to take oral medications. Exclusion criteria included previous treatment with a RAF or MEK inhibitor, or cetuximab, panitumumab, or other EGFR inhibitors. Patients unable to tolerate irinotecan and with concurrent malignancies were also not eligible for enrolment.³³

Baseline Characteristics

In general, demographic characteristics were balanced across both the doublet and control groups. Patients had a mean age of 59 years, were mostly from Europe (61%) or the rest of the world (26%), and were mostly White (81%). However, slightly more patients in the doublet group were male compared with the control group (52% versus 43%, respectively). In addition, more patients in the doublet group than in the control group were from Europe (66% versus 57%, respectively), whereas more patients in the control group were from the rest of the world (30% versus 21%); approximately 13% of patients were from North America in both treatment groups. The clinical experts consulted by CADTH for this review indicated that differences in demographic characteristics were not expected to impact patient outcomes in the BEACON trial.¹⁴

Clinical characteristics were similar across both treatment groups. Similar proportions of patients had an ECOG PS of 0 (50%) or 1 (49%), and all patients were diagnosed with stage IV disease at study entry. Forty-two percent of patients had a primary tumour location in the right colon, 34% of patients had a primary tumour location in the left colon, and 56% of patients had their tumour completely resected. Two-thirds of patients had received 1 prior regimen, with the remaining patients having received 2 prior regimens; only 1 patient had received more than 2 prior regimens and this patient was randomized to the control group. Most patients (92%) had liver metastases and had an MSI status of normal, as assessed via PCR (69%); more patients in the control group had missing data regarding their MSI status (23% versus 12%).¹⁴

Within the control group, 92 patients (41.6%) received cetuximab plus irinotecan and 129 patients (58.4%) received cetuximab plus FOLFIRI. Among 92 patients in the control group who received cetuximab plus irinotecan, 50 (54.3%) received 1 prior systemic therapy, while 41 patients (44.6%) received 2 prior therapies and 1 patient received greater than 2 therapies. Among the 129 patients in the control group who received cetuximab plus FOLFIRI, 95 patients (73.6%) received 1 prior systemic therapy and 34 patients (26.4%) received 2 prior therapies (Table 9).¹³

Interventions

Patients randomized in the BEACON trial were allocated to either the doublet (encorafenib plus cetuximab), triplet (encorafenib plus cetuximab and binimetinib), or control group. Treatments and doses are included in Table 10. Treatments were administered in 28-day cycles until disease progression, unacceptable toxicity, withdrawal of consent, initiation of subsequent anti-cancer therapy, or death.^12,34

Premedication was permitted for routine cetuximab infusions and was allowed within the label per national and/or institutional standards; however, a combination of H₁ antagonists (e.g., diphenhydramine) and dexamethasone (10 mg IV) was preferred. For patients enrolled in the control group, the choice of either irinotecan or FOLFIRI was declared before randomization; patients randomized to the control group with known contraindications to either 5-fluorouracil or folinic acid were treated with irinotecan and cetuximab.¹²

If AEs occurred due to cetuximab, folinic acid, 5-fluorouracil, or irinotecan, doses of any of these could be omitted. Doses that were omitted were not to be made up.¹²

Duration of Treatment: Treatment was administered in 28-day cycles until disease progression, unacceptable toxicity, withdrawal of consent, initiation of subsequent anti-cancer therapy, or death. Once a patient discontinued treatment they were followed for OS every 3 months, or more frequently if it was required, or until death, consent for survival follow-up was withdrawn, the patient was lost to follow-up, or the defined end of the study.¹² Treatment beyond disease progression was permitted in special situations where it was believed that a patient could clinically benefit from continued treatment and if it was in the patient’s best interests, per investigator assessment. Special circumstances were defined by the sponsor by mixed responses and the appearance of new brain metastases (only), which were treatable with stereotactic radiotherapy or surgery but which did not require whole-brain radiotherapy. Treatment beyond progression was not allowed if the patient had¹²:

• clear evidence of disease progression at multiple sites or clear evidence of new lesions outside of the central nervous system

• rapid progression of disease at critical anatomic sites (e.g., cord compression) that required urgent alternative medical intervention

• a clinically relevant worsening of laboratory values

• a clinically significant decline in performance status at the time of disease progression.

Dose Modifications: Patients were monitored for AEs on an ongoing basis based on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.03. Toxicities that resulted in the discontinuation of encorafenib or cetuximab required the discontinuation of treatment combinations containing these drugs due to their lack of efficacy as a monotherapy for patients with BRAF V600–mutated mCRCs.¹²

Outcomes

Efficacy End Points

The primary end points of the trial were OS and ORR between the triplet and control groups of the BEACON trial. A list of efficacy end points identified in the CADTH review protocol that were assessed in the BEACON trial is provided in Table 11. These end points are further summarized subsequently. Only end points pertaining to the doublet and control groups of the BEACON trial are discussed in this report. A detailed discussion and critical appraisal of the outcome measures is provided in Appendix 4.

OS: This was defined as the time from randomization to death due to any cause. Patients were censored at their last contact date if they had not died by the data cut-off.³⁵

ORR: This was defined as the number of patients achieving a best overall response of complete response or partial response divided by the total number of patients in that treatment group. The best overall response (i.e., complete response or partial response) was assessed by BICR and the investigator according to RECIST v1.1 criteria. Tumour assessments performed before the start of any subsequent anti-cancer therapies and no later than 30 days after the last dose were considered in the assessment of best overall response. Confirmed and unconfirmed responses of best overall response were captured for each treatment group.³⁵

PFS: This was defined as the time from randomization to the earliest documented date of progression per RECIST v1.1 criteria by BICR and investigator assessment, or until death due to any cause.³⁵ For patients not experiencing death or progression, censoring occurred in the following manner:

• For patients without any baseline assessment, censoring occurred on the date of randomization.

• Patients who were alive and event-free were censored for PFS at the date of their last adequate tumour assessment (i.e., assessment of complete response, partial response, or stable disease) before either the cut-off date or the date on which a subsequent therapy was started (e.g., systemic therapy, surgery, radiotherapy).

• If a PFS event or death was observed after 2 or more missing or inadequate tumour assessments, PFS was censored at the last adequate tumour assessment. If PFS was observed after a single missing or inadequate tumour assessment, the actual date of the event was used.

Analysis of PFS was also conducted at the end of the study.

Duration of response (DOR): DOR was defined as the time from first radiographic evidence of response to the earliest documented progressive disease or death and was calculated for responders only. DOR was assessed by BICR and investigator.³⁵ Censoring for DOR was done in the following manner:

• Responders who did not have a progressive disease or death date by the cut-off date were censored for DOR at their last adequate radiological assessment (i.e., at the date of last tumour assessment of complete response, partial response, or stable disease) before the cut-off date or date of subsequent anti-cancer therapy.

Time to response (TTR): TTR was defined as the time between randomization until the first documented complete response or partial response.³⁵ Patients who did not achieve a partial response or complete response were censored in the following manner:

• For patients who did not have a PFS event, censoring occurred on the date of the last adequate tumour assessment. These patients were thought to theoretically have a chance of responding, as they had not yet progressed.

• For patients who had a PFS event, censoring occurred at the maximum follow-up date.

HRQoL: HRQoL was assessed in patients using the following tools: EORTC QLQ-C30, FACT-C, EQ-5D-5L, and PGIC. Changes in HRQoL were based on changes from baseline for all 4 tools using the full analysis set (FAS). Each of the HRQoL tools was scored according to its respective scoring manual. The compliance of each tool was assessed for each scheduled assessment time point. Descriptive statistics were used to summarize scored scales during each assessment time point. Change from baseline domain scores at the time of each assessment were also summarized.¹² HRQoL assessments were not conducted using MIDs.

The EORTC QLQ-C30 global health status scale was considered the primary patient-reported outcome variable of interest. The physical, emotional, and social functioning subscales were considered secondary.¹²

The functional well-being score of the FACT-C was considered the primary variable of interest. The physical well-being, social/family well-being, emotional well-being, and additional concern scores were considered secondary.¹²

The EQ-5D-5L captures 5 dimensions of HRQoL: mobility, self-care, usual activities, pain or discomfort, and anxiety or depression. Patients could indicate their response to each item as having no problems, moderate problems, or extreme problems.¹²

TTD in the domains of the HRQoL tools was assessed for each treatment group using the FAS. TTD was defined as the time from the date of randomization to the date of the event, which was defined as at least a 10% worsening relative to baseline of the corresponding scale score, with no later improvement above this threshold observed during the course of the study or upon death due to any cause. Censoring occurred at the date of the last adequate quality-of-life evaluation for patients who did not have an event before the analysis cut-off or the start of another anti-cancer therapy.¹²

Safety

Assessment of safety involved the determination of the incidence and severity of AEs according to NCI CTCAE v4.03, changes in clinical laboratory parameters, vital signs, echocardiogram, or multigated acquisition scans, and ophthalmic examinations.¹²

Dose-limiting toxicities were defined as any AE or abnormal laboratory value assessed as unrelated to disease, disease progression, intercurrent illness, or concomitant medications or therapies occurring within the first 28 days of treatment that satisfy at least 1 of the pre-specified criteria as per the BEACON trial protocol; pre-specified dose–limiting toxicity criteria specific to cardiac, vascular, respiratory, skin, and subcutaneous tissue; gastrointestinal or eye disorders; hematologic and nonhematologic toxicities; investigations and general disorders; and administration-site conditions.¹²

After the end of the treatment period, patients were followed up with a safety visit 30 days after their last dose of the study drug or before the initiation of a subsequent anti-cancer therapy, whichever occurred first.¹²

Statistical Analysis

The trial was planned to have a sample size of approximately 646 to 651 patients, which included 31 patients in the safety lead-in phase and 36 patients in the Japanese safety lead-in phase. Approximately 615 patients (approximately 205 patients per treatment group) were expected to be randomized in the phase III portion of the trial.³⁵

Primary and Interim Analyses

The primary analysis for the ORR of the triplet group versus the control group of the BEACON trial was to be performed when all of the following 3 criteria were met:

• It had been approximately 9 months since the randomization of the 330th patient (after approximately 110 patients were enrolled in each treatment group). This was pre-specified to allow the majority of the 330 patients enrolled to have had the opportunity to have approximately 6 months of follow-up or longer after their first response.

• There had been a minimum of 188 OS events in the triplet and control groups combined.

• There had been a minimum of 169 OS events in the doublet and control groups combined.

An interim analysis was for OS to test for superiority or (non-binding) futility of the triplet group versus the control group.³⁵ The interim analysis of OS was to occur during the primary analysis of ORR between the triplet and control groups. Analysis of ORR and OS at these time points was conducted by an independent statistician and reviewed and interpreted by an independent data-monitoring committee. If the analysis of OS at the interim analysis exceeded the boundaries for superiority, then patients in both the triplet and doublet groups of the trial were to be continued to be followed for a more mature comparison. If the analysis of OS at the interim analysis did not cross the boundary for superiority, the final analysis of OS was pre-specified to occur when a minimum of 268 events were observed in the triplet and control groups combined and a minimum of 338 OS events in the doublet and control groups combined. Futility and superiority boundaries for the OS at the interim and final analyses were determined using a Lan-DeMets spending function approximating O’Brien-Fleming stopping boundaries.³⁵

A fallback procedure described by Wiens and Dmitrienko was used to control for type I error for the primary end points. A 1-sided alpha of 0.005 was assigned to the triplet versus control end point assessing ORR; the remaining alpha of 0.020 was assigned to the assessment of OS between the triplet and control groups. If the P value of the comparison for ORR between the triplet and control groups was less than 0.005 at the primary analysis, then a 1-sided alpha of 0.025 was assigned for the comparison of OS between the triplet and control groups; otherwise, the alpha remained at 0.020.³⁵ Efficacy and futility was determined using Lan-DeMets approximation of O’Brien-Fleming alpha- and (non-binding) beta-spending boundaries, respectively.

Testing of Key Secondary End Points

Unless otherwise stated, the FAS was used for efficacy analyses. The per-protocol set was used for efficacy analyses of the primary end points as supportive analyses. End points, including PFS, ORR, DOR, and TTR, which require tumour evaluations, were based on BICR assessment for the primary analysis; investigator assessment for these end points was part of a secondary supportive analysis. During the primary analysis, the ORR between the triplet and control groups, as assessed by BICR, was pre-specified to occur. ORR was included as a primary end point to provide a more rapid assessment of potential clinical benefit.³⁵

Overall Survival

Primary End Point (Triplet Group Versus Control Group)

Analysis of OS was performed via comparison of Kaplan–Meier curves in the FAS, reporting estimated medians in months with corresponding 95% CIs, 25th and 75th percentiles, and Kaplan–Meier estimated probabilities and corresponding 95% CIs at several time points (i.e., 2, 4, 6, 8, 10, 12, and 14 months). Overall estimates of OS were provided in addition to estimates by stratum. The null hypothesis in the comparison between the triplet regimen and the control group is that the survival distribution function for the triplet group is less than or equal to that of the control group; this was tested using a stratified log-rank test against a 1-sided alpha of 0.025. The analysis of OS was stratified by randomization factors (ECOG PS, prior use of irinotecan, and source of cetuximab). HR estimates of treatment with corresponding 95% CIs were determined using a stratified Cox proportional hazard model. The primary analysis of OS was based on the intention-to-treat principle. Violation of the proportional hazard assumption was conducted graphically by plotting Schoenfeld residuals, including a local regression (LOESS) curve.³⁵

Key Secondary End Point (Doublet Group Versus Control Group)

This end point was tested hierarchically using a gatekeeping procedure that was dependent on the primary end point of OS between the triplet and control groups showing statistical significance.³⁵ The analysis of OS for this comparison was conducted in a manner similar to the analysis of OS for the primary end point (see previous paragraph).

Objective Response Rate

Primary End Point (Triplet Group Versus Control Group)

ORR was assessed using a Cochran-Mantel-Haenszel test with a 1-sided alpha of 0.005. ORR was assessed by BICR using the phase III response efficacy set. Formal testing of ORR was based on confirmed responses of ORR. Analysis was stratified based on randomization factors (baseline ECOG PS [0 versus 1], prior use of irinotecan [yes versus no], cetuximab source [US-licensed versus EU-approved]). The primary analysis of ORR was presented by treatment group along with stratum, and presented with corresponding 95% and 99% CIs. Analysis of ORR will be performed using the FAS at the final analysis.³⁵

Other Secondary End Points

Analysis of ORR performed for other secondary end points was conducted in a manner similar to the primary analysis using the phase III response efficacy set and FAS.³⁵

Progression-Free Survival

PFS was compared via Kaplan–Meier curves and summarized by treatment group. The FAS was used for formal testing of PFS for the phase III portion of the BEACON trial. Formal testing of PFS end points part of the statistical hierarchy (described subsequently) were performed using a Lan-DeMets spending function approximating O’Brien-Fleming stopping boundaries.³⁵ The information fraction for formally tested analyses of PFS was calculated using the spending function which assumed that an interim analysis had occurred based on the number of events observed at the data cut-off date for the interim analysis:

• For the comparison of the triplet versus control groups, a total of 315 events were estimated to occur at the final analysis; this estimation was based on actual enrolment rates of the BEACON trial and assuming a median PFS of 8 months for the triplet group and 2 months for the control groups, with censorship of 15% and 25%, respectively, at the final analysis occurring approximately 30 months after randomization.

• For the comparison of the doublet versus control groups, a total of 330 events were estimated to occur at the final analysis; this estimate was based on the actual enrolment rates of the BEACON trial and assumed a median PFS of 5 months for the doublet group and 2 months for the control group, with censorship of 20% and 25%, respectively, at the final analysis occurring approximately 30 months after randomization.

Duration of Response

DOR was compared using Kaplan–Meier curves and summarized for each treatment group using the phase III response efficacy set and the FAS. The proportion of patients with a DOR of 6 or more months was summarized for each treatment group.³⁵

Time to Response

Analysis of TTR was compared using Kaplan–Meier curves that were used to estimate the median in months with corresponding 95% CIs and 25th and 75th percentiles with corresponding 95% CIs at several time points (i.e., 2, 4, 6, 8, 10, and 12 months). Analysis of TTR was performed using the phase III response efficacy set and the FAS.³⁵ An analysis of TTR was also conducted for responders only (i.e., patients achieving at least 1 complete response or partial response). TTR at the primary analysis was based on assessment by BICR. No formal statistical testing was performed.³⁵ The distribution was presented descriptively using Kaplan–Meier curves. Median time to definitive deterioration along with 2-sided 95% CI will be provided. A Cox model was fit with treatment arm and stratification factors as the covariates to obtain an HR estimate of the treatment effect along with the 95% CI. The stratification factors used in the test were those used for randomization and were based on the actual randomization (IWRS) information.¹²

A gatekeeping procedure using hierarchical testing was performed to control for the overall type I error for the key secondary end points at a 1-sided alpha level of 0.025. Hierarchically tested end points comparing the triplet group or doublet group with the control group were assessed for statistical significance based on a pre-specified criterion for comparing with 1-sided P values, as summarized in Table 13 (end points for the doublet group only). Since the tests for OS and PFS for the doublet group represent an interim analysis, the criterion for significance for these end points were adjusted based on O’Brien-Fleming stopping boundaries approximated using Lan-DeMets spending function to preserve alpha for comparing these end points at the predetermined final analysis had the trial continued.

The following tests were conducted sequentially, conditional on statistical significance being observed at the interim for OS of the triplet versus control groups³⁵:

• OS (doublet versus control groups)

• ORR per BICR (doublet versus control groups)

• PFS per BICR (triplet versus control groups)

• PFS per BICR (doublet versus control groups)

The testing of the key secondary end points outlined in Table 13 was conducted at the same alpha level assigned to the assessment of OS between the triplet versus control groups and the critical P value was calculated using a Lan-DeMets spending function that approximates O’Brien-Fleming stopping boundaries. If any of the end points outlined in Table 13 were not statistically significant, subsequent comparisons were summarized descriptively with nominal P values.³⁵ A depiction of the formal testing of end points is provided in Figure 3.

Figure 3: Statistical Testing Strategy for the BEACON Trial

BICR = blinded independent central review; ORR = objective response rate; OS = overall survival; PFS = progression-free survival.

^a A Lan-DeMets spending function that approximates O’Brien-Fleming boundaries was used to account for the multiple (i.e., interim and final) analyses of OS.

^b Subsequent end points were tested in the following order: Doublet versus control OS, doublet versus control ORR per BICR, triplet versus control PFS per BICR, and then doublet versus control PFS per BICR.

Source: BEACON Statistical Analysis Plan.³⁵

Analysis Populations

Efficacy analyses were performed using the FAS, which followed the principles of intent-to-treat analyses. HRQoL analyses were also conducted using the FAS. Analyses of safety were performed using the safety set (Table 14).¹²

Results

Patient Disposition

Randomization of the phase III portion of the BEACON trial was conducted between May 4, 2017 and January 31, 2019. Including the safety lead-in cohorts, a total of 1,677 patients were screened for enrolment into the BEACON trial, 975 of whom (58.1%) were not enrolled or randomized mainly due to lack of BRAF V600E mutation (56.9%), not meeting other inclusion or exclusion criteria (30.7%), and not providing informed consent (12.3%). In the overall phase III component of the BEACON trial, 665 patients were randomized, including 224 patients in the triplet group, 220 in the doublet group, and 221 in the control group.¹⁴ A summary of the disposition of patients randomized to the doublet and control groups of the trial as of the most recent data cut-off (August 2019) is included in Table 15.

It should be noted that encorafenib and binimetinib were approved in June 2018 in the US for the treatment of patients with BRAF-mutated melanoma; due to this, BRAF and MEK inhibitors, including encorafenib and binimetinib, were used off-label for patients with mCRC, which led to the constant withdrawal of patients randomized to the control group of the BEACON trial, and screening sites in the US were closed on July 15, 2018. Correspondingly, of patients randomized to treatment, a greater proportion of patients randomized to the control group were not treated compared with the doublet group (12.7% versus 1.8%, respectively).¹⁴

Of patients continuing in the trial, a greater proportion of patients in the doublet group discontinued treatment due to progressive disease (65.9%) compared with patients in the control group (55.7%). A large proportion of patients in both the doublet and control groups discontinued tumour assessment follow-ups, although a higher proportion of patients in the doublet group continued with tumour assessment follow-ups compared with the control group (13.2% versus 4.5%, respectively). More patients in the doublet group discontinued tumour assessment follow-ups due to progressive disease than in the control group (70.5% versus 61.5%, respectively), but fewer patients in the doublet group discontinued due to withdrawal of consent compared with the control group (2.7% versus 16.7%, respectively). Fewer patients in the doublet group discontinued from the trial (61.4%) compared with the control group (77.8%). Reasons for discontinuation were mainly due to death (58.2% in the doublet group and 68.3% in the control group), followed by withdrawal of consent (2.3% versus 9.0%), and lost to follow-up (0.9% versus 0.5%).¹⁵

Exposure to Study Treatments

The median duration of exposure was longer in the doublet treatment group at 19.3 weeks (range = 1.0 week to 103 weeks) versus 7.0 weeks (range = 1 week to 70.6 weeks) in the control group; this is to be expected, as more patients in the control group discontinued study treatment than patients in the doublet group earlier in the trial. Duration of exposure to each treatment within the doublet group was similar, with a median duration of exposure of 19 weeks for both encorafenib and cetuximab. Dose intensity and relative dose intensity of treatments is reported in Table 16. Relative dose intensity in the doublet group was 88% for encorafenib and 87% for cetuximab. In the control group, relative dose intensity was between 67% and 77%. More patients in the control group had less than 50% of the assigned dose compared with patients in the doublet group.¹⁵

As per protocol, patients were permitted to be treated with the study treatment beyond locally determined disease progression. A total of 104 of 141 patients (73.8%) in the doublet group whose disease had progressed received treatment beyond progression compared with 37 of 116 patients (31.9%) in the control group whose disease had progressed.³¹

Prior Systemic Anti-Cancer Therapies (FAS): All patients in the BEACON trial received prior systemic anti-cancer therapies, as per protocol; a summary is provided in Table 17. Most patients (66%) in both treatment groups received 1 prior systemic anti-cancer treatment for mCRC. Only 1 patient in the control group received greater than 2 lines of prior systemic anti-cancer therapy. A similar proportion of patients in both treatment groups received prior irinotecan (52% in the doublet group versus 53% in the control group) or oxaliplatin (96% versus 91%). Neither irinotecan nor oxaliplatin were administered to 0.9% of patients in the doublet group compared with 3.2% in the control group.¹⁴

A similar frequency of patients had received prior surgery: 183 patients (83.2%) in the doublet group and 180 patients (81.4%) in the control group. Prior anti-cancer radiation therapy was administered to 35 patients (15.9%) in the doublet group and 21 patients (9.5%) in the control group.¹⁴

Concomitant Medications: Concomitant medications for rash, pain, or pre-existing conditions and gastrointestinal toxicities or pre-existing gastrointestinal conditions were generally similarly administered across treatment groups. Tetracyclines were used for 32.9% of patient in the doublet group and 49.7% of patients in the control group. Medications for pain or pre-existing conditions included anilide analgesics (53.2% in the doublet group versus 42.0% in the control group) and opium alkaloids (38.4% versus 31.6%). Medication for gastrointestinal toxicities or pre-existing gastrointestinal conditions included proton-pump inhibitors (43.5% in the doublet group versus 42.5% in the control group) and propulsive medications (29.6% versus 42.0% in the control group).¹⁴

Pre-treatment for cetuximab and chemotherapy infusions were permitted, as per protocol. Pre-treatments included the following and were provided in similar frequency across both the doublet and control groups: glucocorticoids, such as steroids (74.1% in the doublet group versus 82.4% in the control group), and substituted alkylamines, such as antihistamines (37.5% versus 39.9%), serotonin antagonist antiemetics (19.4% versus 74.6%), and belladonna alkaloids and semisynthetic and quaternary ammonium compounds, specifically atropine medication (0.0% versus 31.1%).¹⁴

Subsequent Treatments: As of the August 15, 2019 data cut-off date, subsequent anti-cancer therapies were reported in 99 patients (45.0%) in the doublet group and 10 patients (47.1%) in the control group (Table 18). The most common subsequent systemic treatments (> 10%) in the doublet group were irinotecan (26.8%), fluorouracil (25.9), folinic acid (16.4%), and bevacizumab (12.7%). The most common subsequent systemic treatments (> 10%) in the control group were fluorouracil (19.9%), irinotecan (16.3%), cetuximab (14.5%), oxaliplatin (13.1%), folinic acid (10.9), and bevacizumab (10.9).¹⁵

More patients in the doublet group than in the control group received subsequent therapy with an irinotecan combination (7.3% versus 1.8%, respectively), or irinotecan combination plus a vascular endothelial growth factor inhibitor (11.8% versus 5.4%). Fewer patients in the doublet group received a protein kinase inhibitor as a subsequent systemic therapy compared with the control group (6.8% versus 18.6%, respectively); vemurafenib was the most commonly reported subsequent treatment for patients in the control group, having been received by 21 patients (9.5%) versus 3 patients (1.4%) in the doublet group.¹⁵ A subsequent BRAF inhibitor plus a MEK inhibitor plus an EGFR inhibitor was administered to 0.5% of patients in the doublet group versus 8.1% of patients in the control group. Similar proportions of a subsequent programmed cell death protein 1 (PD-1) or programmed death ligand 1 (PD-L1) inhibitor were reported between the doublet and control groups (3.2% versus 3.6%, respectively). Subsequent therapy with encorafenib plus binimetinib was administered to 3 patients in the control group and none of the patients in the doublet group.

Based on the February 11, 2019 data cut-off date, more patients in the doublet group had a subsequent anti-cancer radiation therapy than in the control group (18.3% versus 4.3%). Subsequent anti-cancer surgery was provided to 5.6% and 3.8% of patients in the doublet and control groups, respectively.

Efficacy

The primary end points of the BEACON trial were based on the comparisons between the triplet and control groups. Comparisons of ORR, OS, and PFS between the doublet and control groups were considered key secondary end points and were part of a statistical hierarchy, whereby they were tested only upon observing statistical significance in ORR and OS between the triplet and control groups. At the time of the interim analysis, the P value for ORR and OS between the triplet and control groups both met their respective thresholds for statistical significance, each with P values of less than 0.0001; based on this, a total alpha of 0.025 was assigned to the subsequent analysis of key secondary end points for conducting 1-sided tests at the interim data cut-off of February 11, 2019. Therefore, analyses of OS, PFS, and ORR between the doublet and control groups were formally tested.¹⁴ It should be noted that PFS comparing the triplet group and control group was also a part of the sequential testing procedure and also met the pre-specified threshold for significance, with a P value of less than 0.0001. Results for comparisons involving the triplet regimen in the BEACON trial are not discussed in this CADTH report.

A post-hoc analysis was performed by the sponsor (data cut-off: August 2019), which was not pre-specified in the protocol of the BEACON trial. The results are considered descriptive and are also reported here. A summary of results for the doublet and control groups is provided in Table 19.

Overall Survival

Interim Analysis (Data Cut-Off: February 11, 2019)

At the pre-specified interim analysis, the median duration of follow-up for OS was 7.56 months (95% CI, 6.44 to 9.20) in the doublet group and 7.23 months (95% CI, 6.14 to 8.11) in the control group. The median OS was longer in the doublet group at 8.41 months (95% CI, 7.46 to 11.04) compared with 5.42 months (95% CI, 4.76 to 6.57) in the control group (P = 0.0002, stratified log-rank test), resulting in a 40% lower risk of death in the doublet group (HR = 0.60; 95% CI, 0.45 to 0.79) (Figure 4).¹⁴ Based on the specified critical threshold of 0.0041 (Table 13), encorafenib plus cetuximab showed statistically significantly improved OS compared with the control group.

Figure 4: Kaplan–Meier Plot of OS, Doublet Group Versus Control Group (Data Cut-Off: February 11, 2019)

CETUX = cetuximab; CI confidence interval; ENCO = encorafenib; HR = hazard ratio; OS = overall survival; Ref = reference.

Note: The statistical model for the HR and P value was a stratified Cox proportional hazard model and stratified log-rank test.

Source: BEACON Clinical Study Report.¹⁴

Results for the subgroup analyses of OS are illustrated in Figure 13 (Appendix 3). Most subgroup analyses were consistent with the primary results of the study. Some subgroup analyses estimated HRs that numerically favoured the control group; those HRs were for patients who received US-licensed cetuximab from North America and who had unknown or abnormally high MSI status. However, it should be noted that for each of these subgroups, the reported 95% CI included the null, and each subgroup included few patients (≤ 44).

Post-Hoc Analysis (Data Cut-Off: August 15, 2019)

At the post-hoc analysis, the median follow-up for OS was 7.90 months (range, 0.03 to 25.76) in the doublet group and 5.55 months (range, 0.03 to 22.01) in the control group. The median OS was 9.30 months (95% CI, 8.05 to 11.30) in the doublet group compared with 5.88 months (95% CI, 5.09 to 7.10) in the control group (nominal P = 0.0001, log-rank test), resulting in a 39% lower risk of death in the doublet group (HR = 0.61; 95% CI, 0.48 to 0.77) (Figure 5).¹⁵ Subgroup analyses of OS are illustrated in Figure 14 and display results similar to the subgroup analyses conducted at the interim analysis.¹⁵

Figure 5: Kaplan–Meier Plot of OS, Doublet Group Versus Control Group (Data Cut-Off: August 15, 2019)

CETUX = cetuximab; CI confidence interval; ENCO = encorafenib; HR = hazard ratio; OS = overall survival; Ref = reference.

Note: The statistical model for the HR and P value was a stratified Cox proportional hazard model and stratified log-rank test.

Post-hoc analyses were not controlled for multiplicity. Reported P value is nominal.

Source: BEACON Clinical Study Report Addendum.¹⁵

Objective Response Rate

Interim Analysis (Data Cut-Off: February 11, 2019)

The analysis of ORR was conducted as per the pre-specified statistical hierarchy and was conducted among the first 331 randomized patients to ensure the patients included in the analysis had sufficient follow-up for assessment of response to treatment. Based on assessment by BICR, a greater proportion of patients in the doublet group had a confirmed response (20.4%; 95% CI, 13.4 to 29.0) versus the control group (1.9%; 95% CI, 0.2 to 6.6).¹⁴ Based on the specified critical threshold of 0.025 (Table 13), patients treated with encorafenib plus cetuximab showed statistically significantly improved ORR compared with the control group (P < 0.0001, Cochrane-Mantel-Haenszel test).

Subgroup analyses are summarized in Table 32 (Appendix 3). In general, subgroup analyses of ORR showed a greater proportion of patients with a response in the doublet group versus the control group (results not shown); however, as few patients in the control group had a confirmed response, the subgroup analyses should be interpreted with caution.¹⁴

Post-Hoc Analysis (Data Cut-Off: August 15, 2019)

Based on assessment by BICR, a greater proportion of patients in the doublet group had a confirmed response (19.5%; 95% CI, 14.5 to 25.4) versus the control group (1.8%; 95% CI, 0.5 to 4.6). Analysis of ORR showed improvement in ORR among patients treated in the doublet group compared with the control group; these analyses were not controlled for multiplicity (nominal P < 0.0001, Cochrane-Mantel-Haenszel test).¹⁵

Subgroup analyses of ORR showed a greater proportion of patients with a response in the doublet group versus the control group (results not shown); however, as only 4 patients in the control group had a confirmed response, subgroup analyses should be interpreted with caution (Table 32, Appendix 3).¹⁵

Progression-Free Survival

Interim Analysis (Data Cut-Off: February 11, 2019)

At the primary analysis (data cut-off: February 11, 2019), the median duration of follow-up for PFS by BICR was 7.92 months (95% CI, 4.24 to 19.45) for the doublet group and 4.14 months (95% CI, 2.89 to 5.39) in the control group. The median PFS was 4.21 months (95% CI, 3.71 to 5.36) in the doublet group compared with 1.51 months (95% CI, 1.45 to 1.71) in the control group (< 0.0001, stratified log-rank test), resulting in a 60% reduction in progression or death (HR = 0.40; 95% CI, 0.31 to 0.52) (Figure 6).¹⁴ Based on the specified critical threshold of 0.0117 (Table 13), encorafenib plus cetuximab showed statistically significantly improved PFS compared with the control group.

Subgroup analyses of PFS were generally consistent with the results of the primary analysis and are summarized in Table 33 (Appendix 3).

Figure 6: Kaplan–Meier Plot of PFS, Doublet Group Versus Control Group (Data Cut-Off: February 11, 2019)

CETUX = cetuximab; CI confidence interval; ENCO = encorafenib; HR = hazard ratio; PFS = progression-free survival; Ref = reference.

Note: The statistical model for the HR and P value was a stratified Cox proportional hazard model and stratified log-rank test.

Source: BEACON Clinical Study Report.¹⁴

Post-Hoc Analysis (Data Cut-Off: August 15, 2019)

At the post-hoc analysis, median follow-up for PFS in the FAS was 4.11 months (range, 0.03 to 22.21) in the doublet group and 1.41 months (range, 0.03 to 13.86) in the control group. The median PFS in the doublet group was 4.27 months (95% CI, 4.07 to 5.45) compared with 1.56 months (95% CI, 1.48 to 1.91) in the control group (nominal P < 0.0001, log-rank test), resulting in a 56% reduction in risk of progression or death in the doublet group (HR = 0.44; 95% CI, 0.35 to 0.55) (Figure 7).¹⁵

Subgroup analyses were generally consistent with the results of the primary analysis and are summarized in Table 33 (Appendix 3).

Figure 7: Kaplan–Meier Plot of PFS, Doublet Group Versus Control Group (Data Cut-Off: August 15, 2019)

CETUX = cetuximab; CI confidence interval; ENCO = encorafenib; HR = hazard ratio; PFS = progression-free survival; Ref = reference.

Note: The statistical model for the hazard ratio and P value was a stratified Cox proportional hazard model and stratified log-rank test.

Post-hoc analyses were not controlled for multiplicity. Reported P value is nominal.

Source: BEACON Clinical Study Report Addendum.¹⁵

Duration of Response

Interim Analysis (Data Cut-Off: February 11, 2019)

The median DOR per BICR assessment for the 23 responders in the phase III response efficacy set for the doublet group was 6.06 months (96% CI, 4.07 to 8.28). Two patients in the control group had confirmed responders; the DOR for these 2 patients was 2.56 months and 6.93 months.¹⁴

Post-Hoc Analysis (Data Cut-Off: August 15, 2019)

The median DOR per BICR assessment for the 43 responders using the FAS was 5.55 months (95% CI, 4.14 to 8.28) in the doublet group. The DOR for the 4 patients with a confirmed response in the control group were 2.56 months, 3.09 months, 5.55 months, and 12.45 months.¹⁵

Time to Response

Interim Analysis (Data Cut-Off: February 11, 2019)

The median TTR per BICR assessment for confirmed responders in the phase III response efficacy set was 1.54 months (95% CI, 1.41 to 1.64). In the doublet group, the TTRs for confirmed responders were 1.31, 1.58, 1.71, 1.48, 1.48, and 4.17 months. Two patients in the control group with confirmed responses had a TTR of 1.41 and 1.45 months.¹⁴

Post-Hoc Analysis (Data Cut-Off: August 15, 2019)

The median TTR per BICR assessment for confirmed responders in the FAS was 1.48 months (95% CI, 1.41 to 1.54) in the doublet group. For the 4 responders in the control group, the TTR was 1.41 months, 1.45 months, 2.63 months, and 2.99 months.¹⁵

Patient-Reported Outcomes

A summary of patient-reported outcomes based on the interim analysis is provided subsequently. HRQoL data were not provided for the post-hoc analysis.

Interim Analysis (Data Cut-Off: February 11, 2019)

EORTC Quality of Life Questionnaire Core 30: Compliance for the EORTC QLQ-C30 was high in the doublet group, with greater than 80% of patients filling out the questionnaire until cycle 12; after cycle 12 there were fewer than 10 patients still on treatment eligible for completion of the EORTC QLQ-C30 tool. In the control group, greater than 80% of patients filled out the instrument until cycle 6; after cycle 10, there were fewer than 10 patients still on treatment who were eligible to complete the EORTC QLQ-C30 tool.¹⁴

Median global health status score and subscale scores were similar in both treatment groups at baseline. The median time to definitive 10% deterioration in the EORTC QLQ-C30 global health status was 4.60 months (95% CI, 3.81 to 6.11) in the doublet group versus 2.20 months (95% CI, 1.61 to 3.06) in the control group. An approximate 46% reduction in risk of definitive 10% deterioration in global health status was observed for the doublet treatment group over the control group (HR = 0.54; 95% CI, 0.43 to 0.69) (Figure 8).¹⁴

Figure 8: Kaplan–Meier Plot of Time to Definitive 10% Deterioration in EORTC QLQ-C30 Global Health Status, Doublet Group Versus Control Group

CETUX = cetuximab; CI = confidence interval; ENCO = encorafenib; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; HR = hazard ratio; Ref = reference.

Note: Definitive 10% deterioration was defined as a worsening of the corresponding scale score by at least 10% relative to baseline, with no later improvement above this threshold observed while on treatment or following death due to any cause. (Data Cut-Off: February 11, 2019)

Source: BEACON Clinical Study Report.

Functional Assessment of Cancer Therapy–Colorectal: Compliance with the FACT-C was high in the doublet group, with greater than 80% of patients filling out the instrument until cycle 14; after cycle 12, fewer than 10 patients were still on treatment and eligible to complete the instrument. In the control group, greater than 80% of patients filled out the instrument until cycle 8; after cycle 8, fewer than 10 patients were still on treatment and eligible to complete the instrument.¹⁴

Median FACT-C scores and subscale scores were similar in both treatment groups at baseline. The median time to 10% definitive deterioration in the functional well-being subscale score was 4.63 months (95% CI, 3.94 to 6.11) in the doublet group versus 2.04 months (95% CI, 1.87 to 3.22) in the control group. An approximate 43% reduction in risk of definitive 10% deterioration in the functional well-being subscale score was observed for the doublet treatment group over the control group (HR = 0.57; 95% CI, 0.45 to 0.72, Figure 9).¹⁴

Figure 9: Kaplan–Meier Plot of Time to Definitive 10% Deterioration in FACT-C Functional Well-Being Subscale, Doublet Group Versus Control Group

CETUX = cetuximab; CI = confidence interval; ENCO = encorafenib; FACT-C = Functional Assessment of Cancer Therapy–Colorectal; HR = hazard ratio; Ref = reference.

Note: Definitive 10% deterioration was defined as a worsening of the corresponding scale score by at least 10% relative to baseline, with no later improvement above this threshold observed while on treatment or following death due to any cause. (Data Cut-Off: February 11, 2019)

Source: BEACON Clinical Study Report.¹⁴

EQ-5D-5L Questionnaire: Compliance with the EQ-5D-5L was high in the doublet group, with greater than 80% of patients filling out the instrument until cycle 14; after cycle 12, fewer than 10 patients were still on treatment and eligible to complete the instrument. In the control group, greater than 80% of patients filled out the instrument until cycle 6; after cycle 8, the number of patients still on treatment who were eligible to complete the instrument was fewer than 10.¹⁴

Median EQ-5D-5L Visual Analogue Scale (VAS) scores were the same in both treatment groups at baseline. The median time to 10% definitive deterioration in the VAS scores was 5.36 months (95% CI, 4.50 to 6.37) in the doublet group versus 2.37 months (95% CI, 1.68 to 3.71) in the control group. An approximate 51% reduction in risk of definitive 10% deterioration in EQ-5D-5L VAS was observed for the doublet treatment group over the control group (HR = 0.49; 95% CI, 0.39 to 0.63) (Figure 10).¹⁴

Figure 10: Kaplan–Meier Plot of Time to Definitive 10% Deterioration in EQ-5D-5L VAS, Doublet Group Versus Control Group (Data Cut-Off: February 11, 2019)

CETUX = cetuximab; CI = confidence interval; ENCO = encorafenib; EQ-5D-5L = EuroQol 5-Dimensions 5-Levels questionnaire; HR = hazard ratio; Ref = reference; VAS = Visual Analogue Scale.

Note: Definitive 10% deterioration was defined as a worsening of the corresponding scale score by at least 10% relative to baseline, with no later improvement above this threshold observed while on treatment or death due to any cause.

Source: BEACON Clinical Study Report.¹⁴

Patient Global Impression of Change: Compliance with the PGIC was high in the doublet group, with greater than 80% of patients filling out the instrument until cycle 14; after cycle 12, the number of patients still on treatment who were eligible to complete the instrument was fewer than 10. In the control group, the proportion of patients filling out greater than 80% the PGIC instrument occurred only at cycle 4. The number of patients still on treatment who were eligible to complete the instrument in the control group was fewer than 10 after cycle 8.¹⁴

Change in PGIC during cycle 2 and cycle 4 was reported to be “much improved” or “very much improved” by more patients in the doublet group versus the control group (cycle 2: doublet = 31.0%, control = 14.9%; cycle 4: doublet = 41.7%, control = 28.3%).¹⁴

Harms

Only those harms identified in the review protocol are reported subsequently.

Adverse Events

All-grade AEs due to any cause occurred in similar frequency in both the doublet and control groups (98% versus 97%, respectively) (Table 20). The categories of frequently reported AEs were gastrointestinal disorders, skin and subcutaneous disorders, general disorders, and administration-site conditions.¹⁴ The most commonly occurring any-grade AEs were diarrhea (33.3% in the doublet group versus 48.2% in the control group), dermatitis acneiform (29.2% versus 39.4%), nausea (34.3% versus 41.5%), fatigue (30.1% versus 27.5%), vomiting (21.3% versus 29.0%), decreased appetite (26.9% versus 26.9%), abdominal pain (22.7% versus 24.9%), and asthenia (21.3% versus 35.4%).¹⁴

AEs of any grade with a difference of 10% between the doublet and control groups, and which occurred more frequently in the doublet group, included arthralgia (19.0% versus 0.5%, respectively), headache (19.4% versus 2.6%), melanocytic nevus (14.4% versus 0%), myalgia (13.4% versus 2.1%), and musculoskeletal pain (12.5% versus 1.6%).¹⁴ AEs of any grade with a difference of 10% between the doublet and control groups and which occurred more frequently in the control group included dermatitis acneiform (29.2% versus 39.4%, respectively), neutrophil count decrease (0.5% versus 10.9%), diarrhea (33.3% versus 48.2%), stomatitis (5.6% versus 2.1%), and neutropenia (0.5% versus 18.7%).¹⁴

Grade 3 or greater AEs occurred less frequently in the doublet group (50.0%) compared with the control group (60.6%) (Table 20). Most individual grade 3 or greater AEs occurred in similar frequency across both treatment groups. However, the most commonly occurring grade 3 or greater AEs were diarrhea (1.9% versus 9.8% in the doublet and control groups, respectively), neutropenia (0.5% versus 9.8%), and neutrophil count decrease (0.5% versus 8.3%), all of which occurred more frequently in the control group.¹⁴

TEAEs included AEs with a suspected relationship to the study drug; TEAEs were reported in 88.4% of patients in the doublet group and 91.2% of patients in the control group (Table 21). The most frequently reported TEAEs of any grade in the doublet group included dermatitis acneiform (27.8%), fatigue (22.7%), and nausea (20.4%). The most frequently reported TEAEs of any grade in the control group included diarrhea (44.0%), dermatitis acneiform (38.9%), nausea (36.3%), asthenia (22.3%), and stomatitis (21.2%).¹⁴

Grade 3 or greater TEAEs were less frequent in the doublet group than in the control group (19.4% versus 39.4%, respectively). Grade 3 or greater TEAEs were infrequently reported in the doublet group as each TEAE occurred at a frequency of less than 3%. The most commonly reported grade 3 or greater TEAEs in the control group included diarrhea (8.3%), neutropenia (9.3%), and neutrophil count decrease (7.8%).¹⁴

Serious Adverse Events

A summary of SAEs is provided in Table 22. In general, specific SAEs occurred infrequently and SAEs of any grade and grade 3 or greater were similar across the doublet and control groups (32.9% versus 36.8%, and 28.2% versus 33.2%, respectively). The most common SAEs of any grade were diarrhea, occurring in 0 patients in the doublet group and 10 patients (5.2%) in the control group, and intestinal obstruction, occurring in 10 patients (4.6%) and 7 patients (3.6%), respectively. The most common SAEs of any grade occurring in the doublet group included intestinal obstruction (4.6%), urinary tract infection (2.3%), and cancer pain (2.3%). The most common grade 3 or greater SAEs were diarrhea, occurring in 0 patients in the doublet group and 7 patients (3.6%) in the control group, and intestinal obstruction, occurring in 9 patients (4.2%) and 5 patients (2.6%), respectively. The most common grade 3 or greater SAEs occurring in the doublet group included intestinal obstruction (4.2%) and urinary tract infection (2.3%).¹⁴

Withdrawals Due to Adverse Events

AEs of any grade and grade 3 or greater that resulted in discontinuation of all study treatments occurred in similar frequency between the doublet group and the control group (8.3% versus 11.4% and 7.4% versus 9.3%, respectively). Any-grade TEAEs that resulted in the discontinuation of all study treatments were reported in 6 patients (2.8%) in the doublet group and 12 patients (6.2%) in the control group; grade 3 or greater TEAEs resulting in discontinuation of all study treatments were reported in 5 patients (2.3%) in the doublet group versus 9 patients (4.7%) in the control group. TEAEs of any grade and grade 3 or greater that resulted in discontinuation of any study drug were reported less frequently in the doublet group versus the control group. Dose reductions, dose interruptions, and TEAEs that required additional therapy were reported more frequently in the control group than in the doublet group (Table 23).¹⁴ A summary of specific AEs resulting in dose interruption or reduction is reported in Table 24.

AEs of any grade most commonly leading to dose interruption due to encorafenib included vomiting (4.2%), nausea (3.7%), diarrhea, and pyrexia (2.8% each); AEs leading to dose interruption due to encorafenib occurred at a frequency of less than 5% for each type of event. AEs of any grade most commonly leading to dose interruption due to cetuximab in the doublet group were from intestinal obstruction (2.8%). AEs commonly leading to dose interruption in the control group included diarrhea (5.7%), infusion-related reaction (4.1%), and neutropenia (4.1%).¹⁴

Dose reductions for encorafenib or cetuximab in both the doublet and control groups were reported infrequently. AEs resulting in dose reduction of encorafenib occurred among 8.8% of patients in the doublet group, most commonly due to asthenia, peripheral neuropathy, and musculoskeletal pain (1.4% each). AEs resulting in dose reductions of cetuximab occurred among 2.3% of patients in the doublet group and 5.75 of patients in the control group. The frequency of dose reductions due to cetuximab in the control group were due mostly to diarrhea (1.6%) and dermatitis acneiform (1.0%).¹⁴

Adverse Events of Special Interest

Adverse events of special interest (AESIs) were identified prospectively and defined as a result of signals observed from previous studies for encorafenib and binimetinib and based on known toxicities of BRAF and MEK inhibitors. In total, 130 patients (60.2%) in the doublet group experienced at least 1 AESI, of whom 26 (12.0%) had an AESI of grade 3 or greater. Conversely, 97 patients (50.3%) in the control group experienced at least 1 AESI, of whom 9 (4.7%) had an AESI of grade 3 or greater.¹⁴

The most frequently occurring AESIs in the doublet group included acneiform dermatitis (31.0%), rash (28.2%), hemorrhage (19.0%), myopathy 13.9%), skin infections (11.6%), and liver function test (LFT) abnormalities (11.1%). In the control group, the most commonly occurring AESIs included acneiform dermatitis (40.9%), rash (29.0%), skin infections (11.4%), and LFT abnormalities (10.9%). AESIs occurred in similar frequency in both the doublet and control groups, except for retinopathy (excluding retinal vein occlusion), hemorrhage, and myopathy, which occurred more often in the doublet group, and acneiform dermatitis, which occurred more frequently in the control group (Table 25).¹⁴

Mortality

On-treatment deaths were reported among 14.8% (n = 32) of patients in the doublet group and 13.5% (n = 26) of patients in the control group. Most on-treatment deaths were due to disease progression. The safety data reported for the BEACON trial included assessment of on-treatment deaths, which were deaths occurring during treatment or within 30 days of the last administered dose of the study drug. The treatments in the BEACON trial were administered both orally and through IV; in addition, while encorafenib was administered daily, chemotherapies were administered intermittently. Due to the differences in dose administration, it is possible the results of on-treatment deaths of chemotherapy regimens are underestimated. Due to this, the sponsor also assessed on-treatment deaths, defined as events up to 30 days following the investigators’ decision to terminate study treatment. Based on the modified definition for on-treatment deaths, on-treatment deaths comprised 16.7% of patients in the doublet group and 20.7% of patients in the control group, most of which were determined to be due to progression of disease. Deaths occurring during treatment or within 30 days of the last dose were considered grade 5 AEs. Seven patients (3.2%) in the doublet group and 8 patients (4.1%) in the control group had a grade 5 AE.¹⁴

Critical Appraisal

Internal Validity

The BEACON trial was an open-label phase III trial; therefore, patients and investigators were aware of treatment assignment. Due to this open-label design, bias due to the lack of blinding can affect the performance, measurement, and reporting of clinical outcomes (i.e., efficacy and safety) by both patients and investigators, potentially favouring trial results in the direction of the doublet or triplet regimens. The key efficacy end points of the BEACON trial included ORR, OS, and PFS. OS is an objective end point unlikely to be affected by biases of open-label study designs. In addition, ORR and PFS, which are subject to potential bias, as they involve assessment of patient response, were assessed by BICR, mitigating the potential biases associated with an open-label study design. Moreover, the sponsor of the trial and their designee trial team were blinded to the treatment group assignments presented to them in aggregate data summaries. During the trial, a limited number of study team members were unblinded to individual treatment assignments for the purposes of trial conduct, including for reasons of site monitoring, data management, patient emergencies, or regulatory purposes. The names and roles of team members unblinded to data were documented and these individuals did not have access to unblinded aggregate data. Further, the choice of an open-label trial was considered appropriate by the CADTH methods team based on the differences in treatment administration (i.e., schedule, oral versus IV) and management of AEs (i.e., chemotherapy versus small molecule treatments); these differences in administration and toxicities would have resulted in unblinding of treatment allocation. The sponsor implemented measures to mitigate biases associated with an open-label design. However, biases from an open-label trial remain a concern for the subjective outcomes assessed in the BEACON trial, including HRQoL. Specifically, the EORTC QLQ-C30, FACT-C, EQ-5D-5L, and PGIC tools may have been influenced by the patient’s or investigator’s knowledge of treatment assignment, which could have influenced the assessment and reporting of these outcomes. The patient-reported outcomes captured in the BEACON trial are considered exploratory and should be interpreted with caution.

In general, protocol deviations occurred in similar proportions across the doublet and control groups of the BEACON trial. However, a greater proportion of patients in the control group had deviations, which led to more exclusions from the per-protocol set than from the doublet group (19.5% versus 9.5%, respectively); the difference between groups was mainly due to the greater proportion of patients in the control group (14.0%) versus the doublet group (1.8%) who received a study treatment different from what they were randomized to; of these patients in the control group, most were not treated (12.7%), while a few received a different treatment (1.4%). It should be noted that this discrepancy may be due to differences in treatment approvals, as the US had approved treatment with encorafenib and binimetinib for patients with BRAF V600E–mutated melanoma, which resulted in off-label use of encorafenib and binimetinib for patients with mCRC; due to this, many patients randomized to the control group in the US withdrew from the trial, and the enrolment sites in the US were closed on July 15, 2018. It is not expected that this difference in removal of patients from the per-protocol set will bias the results of the efficacy analyses for the BEACON trial in any specific direction.

The sponsor pre-established a set of criteria to allow for an interim analysis that included a fallback procedure to control for type I error for the primary end points. In addition, a statistical hierarchy was established that only allowed for formal testing of key secondary end points comparing the doublet group with the control group, if ORR and OS between the triplet group and control group was found to be statistically significant. The CADTH reviewers determined that the statistical procedures specified by the sponsor for the interim and final analyses were appropriate for controlling for multiplicity and reducing the risk of type I error. Additional analyses for efficacy were conducted (data cut-off: August 15, 2019), which were not pre-specified in the protocol of the BEACON trial. Results from the post-hoc analysis (data cut-off: August 15, 2019) should be considered descriptive.

Analyses of efficacy end points were conducted using both the phase III response efficacy set and the FAS. Analyses of patients using the phase III response efficacy set included only the first 330 patients randomized into the phase III portion of the BEACON trial, whereas the FAS included all randomized patients. At the time of the primary analysis, 445 patients were enrolled and included in the FAS; the efficacy analyses based on the phase III response efficacy set included a lower number of patients overall and per treatment group. In addition, the phase III response efficacy set included a greater proportion of North American patients than the overall population (18.7% versus 13.1%); this difference is expected due to the closed US enrolment sites related to approval of encorafenib and binimetinib. Other baseline characteristics were similar between the doublet and control groups of the BEACON trial. The analysis of ORR at the updated cut-off was conducted using the FAS, which supported the initial results of ORR at the interim analysis.

The analysis of OS in the trial did not control for the subsequent therapies that patients may have received after progression. While a similar proportion of patients had any subsequent therapy in the doublet group (45.0%) and the control group (47.1%), the types of subsequent therapies differed between the 2 groups.¹⁵ For example, more patients in the doublet group received subsequent therapy with an irinotecan combination than in the control group (7.3% versus 1.8%, respectively), or received an irinotecan combination plus a vascular endothelial growth factor inhibitor (11.8% versus 5.4%), and fewer patients in the doublet group received a protein kinase inhibitor compared with the control group (6.8% versus 18.6%, respectively).¹⁵ The differences in subsequent therapies are expected to introduce confounding in the results for OS. However, the sensitivity analyses of PFS, which censored for patients who received subsequent anti-cancer therapies, continued to support the primary results, which showed statistically significant improvement in patients treated with the doublet regimen over the control group. In addition, the analysis of OS and PFS involved large amounts of censored data at the interim analysis; a total of 127 patients (57.7%) in the doublet group and 107 patients (48.4%) in the control group were censored in the analysis for OS, and 87 patients (39.5%) and 93 patients (42.1%) were censored for PFS.¹⁴ While the analyses of OS and PFS at the update data cut-off were not pre-specified and, therefore, descriptive, there were fewer instances of censoring for both OS and PFS; a total of 92 patients (41.8%) in the doublet group and 64 patients (29.0%) in the control group were censored for OS, and 53 patients (24.1%) and 74 patients (33.5) were censored for PFS.¹⁵ The continued observed benefit observed with the doublet regimen over the treatments of the control group supports the conclusion that encorafenib plus cetuximab offer improved clinical outcomes for patients.

The median duration of treatment was longer in the doublet group (19.3 weeks) compared with the control group (7.0 weeks). The relative dose intensity of treatment was also greater for treatments in the doublet regimen (87% to 88%) compared with treatments in the control group (67% to 77%).¹⁵ The longer duration of treatment in the doublet group should be considered when interpreting safety and HRQoL data, as longer exposure to treatment may influence toxicities and quality of life for patients.

The protocol of the BEACON trial was updated to allow for patients randomized to the control group to cross over to the triplet regimen. The sponsor confirmed that no patients in the BEACON trial crossed over to the doublet group. In addition, the efficacy results of the post-hoc analyses supported the primary results of the interim analysis, which supported the treatment of the doublet regimen over the treatments of the control group. Therefore, it is not expected that crossover would have affected any of the efficacy or safety analyses. A number of protocol amendments occurred that significantly changed the study design or conduct. Specifically, the protocol amendments dated September 19, 2018 introduced the addition of ORR between the triplet and control groups as a co-primary end point. The analysis of ORR between the triplet and control groups was specified to occur after certain criteria were met. In addition, boundaries for superiority and futility were added to the planned interim analysis of OS, and the planned interim analysis of OS was specified to occur during the primary analysis for ORR.

Patients in the BEACON trial were eligible to continue receiving study treatment after progression if it was believed a patient would benefit from continued treatment. A total of 104 of 141 patients with progressed disease (73.8%) in the doublet group received treatment beyond progression, compared with 37 of 116 patients with progressed disease (31.9%) in the control group.³¹ It should be noted that, since the BEACON trial used an open-label study design, the investigator’s knowledge of patient treatment may have influenced treatment decisions regarding continuation of investigational therapies. The impact of this investigator bias is unknown, although treatment groups may have been impacted differentially due to it resulting in a bias in efficacy analyses.

External Validity

The baseline characteristics of the BEACON trial were balanced mostly across the doublet and control groups. Of note, there were fewer North American patients than expected who maintained enrolment. The large amount of withdrawal of North American patients was due mainly to a large number of patients withdrawing from enrolment due to the gaining off-label access to encorafenib and binimetinib; the treatment was granted FDA approval for treatment of BRAF-mutated melanoma, which resulted in off-label use for colorectal cancer patients. In addition, a total of 7 Canadian patients were enrolled in the BEACON trial. The clinical experts consulted by CADTH for this review indicated that underrepresentation of North American patients is not expected to affect the generalizability of the efficacy of encorafenib plus cetuximab to Canadian patients.

The eligibility criteria of the BEACON trial allowed for the enrolment of patients with 1 or 2 prior therapies in the metastatic treatment setting. However, enrolled patients who had received 2 prior therapies were limited to account for no more than approximately 1-third of all patients in the trial. In total, most patients (66%) had received only 1 prior therapy, while the remaining patients (34%) had received 2 prior therapies, with 1 patient in the control group receiving more than 2 prior therapies. Patients in the control group of the BEACON trial could have been randomized to receive either cetuximab plus irinotecan or cetuximab plus FOLFIRI. Cetuximab in combination with chemotherapy for first-line treatment of mCRC in patients with wild-type KRAS was previously reviewed by CADTH and received a negative funding recommendation.⁹ However, cetuximab plus irinotecan-based regimens is funded in some provinces across Canada for use in the third line, whereas most patients in the BEACON trial were receiving treatment in the second line. Consultation with the clinical experts confirmed that for both regimens used in the control group of the BEACON trial, cetuximab plus irinotecan or FOLFIRI are used in second- or third-line therapy for patients with mCRC in Canada. Therefore, the treatment regimens in the control group were considered generalizable to the Canadian context. The eligibility criteria of the BEACON trial also excluded patients who had received prior treatment with any RAF/MEK inhibitor, cetuximab, panitumumab, or other EGFR inhibitors; this exclusion criteria are reflective of Canadian practices, which normally rely on chemotherapies with or without a biologic drug as primary therapy.

Further, regarding treatments of the control group of the BEACON trial, the clinical equivalence of cetuximab plus irinotecan and cetuximab plus FOLFIRI was considered. Direct phase III evidence to support the equivalence of the 2 regimens was not provided. However, the sponsor provided some data to suggest the equivalence of efficacy between the 2 regimens; the assumption of equivalence was also supported by the clinical experts. However, it is acknowledged that both regimens in the control group of the BEACON trial contain irinotecan, and that approximately half of patients in both the doublet and control groups of the trial were previously exposed to treatment with irinotecan. Therefore, approximately half of patients in the control group had previously progressed on a treatment regimen containing irinotecan, and were exposed to irinotecan again in the BEACON trial; re-treatment with irinotecan for patients who had previously progressed may suggest poorer clinical outcomes for patients. Results of the BEACON trial may be biased in favour of the doublet group, as patients randomized to the doublet would be receiving a treatment regimen that did not contain irinotecan and which could result in a more favourable response. Accordingly, subgroup analysis of patients showed more favourable results for OS at the interim analysis for patients without prior irinotecan use (HR = 0.50; 95% CI, 0.33 to 0.74) compared with patients with prior irinotecan use (HR = 0.75; 95% CI, 0.52 to 1.10)¹⁴; results were similar at the time of the post-hoc analysis.

Within the BEACON trial, cetuximab was administered as a 400 mg/m² IV followed by 250 mg/m² IV every week. It was noted by the clinical experts for this review that cetuximab is often not provided to patients at the dose and administration schedule specified in the BEACON trial. Cetuximab may be provided to patients at an alternative dosing schedule of 500 mg/m² every 2 weeks to address challenges with implementation (i.e., chair time, hospital resources, travel time, and inconvenience to patients). The efficacy of cetuximab provided at a dose of 250 mg/m² every week versus 500 mg/m² every 2 weeks was considered broadly similar based on a pooled analysis demonstrating noninferiority of the 2 doses and administration schedules for cetuximab.¹⁷ While no phase III evidence comparing the 2 regimens exists to support the conclusion of clinical equivalence, pharmacokinetic studies were acknowledged that support the use of cetuximab at a higher dose and less frequent administration schedule. In addition, consultation with the CADTH clinical experts supported the use of cetuximab at 500 mg/m² every 2 weeks and it was acknowledged that administration of cetuximab in clinical practice typically occurs at 500 mg/m² every 2 weeks.

Within the BEACON trial, randomization was stratified according to baseline ECOG PS (0 versus 1), prior use of irinotecan (yes versus no), and cetuximab source (US-licensed versus EU-approved). Specifically regarding cetuximab, the manufacturing of cetuximab differs between Europe and the US. The efficacy of cetuximab was considered to be no different by source of manufacturing based on a phase III, double-blind safety study comparing the 2 formulations of cetuximab in combination with platinum-based chemotherapy for patients with head and neck squamous cell carcinoma.³⁶ Based on input from the clinical experts, it was suggested that the source of cetuximab would not affect efficacy of treatment for patients.

Regarding the clinical outcomes of the BEACON trial, efficacy outcomes captured in the trial were considered clinically relevant for patients with mCRC. Regarding patient-reported outcomes, HRQoL data were not assessed based on MIDs for any of the patient-reported outcomes in the BEACON trial. Based on a CADTH literature search, no literature was found identifying established MIDs for the EQ-5D-5L and PGIC questionnaires. However, a summary of MIDs specific to patients with colorectal cancer for the EORTC QLQ-C30 and FACT-C questionnaires is provided in Appendix 4. Colorectal cancer is a common disease with an expected increase in incidence and prevalence in Canada. HRQoL tools can be useful in identifying clinically relevant differences in quality-of-life measures for patients receiving different treatments in clinical trial. While the evidence supporting the reliability and validity of HRQoL tools in the BEACON trial were considered adequate by the CADTH reviewers, additional evidence would be beneficial to aid in the interpretation of clinically meaningful differences. In addition, a TTD analysis was conducted for the HRQoL tools in the BEACON trial. TTD analyses were conducted using a threshold of 10% deterioration among patients’ HRQoL. The sponsor did not provide any justification for the use of the 10% deterioration threshold and whether this threshold was appropriate or generalizable for each of the HRQoL tools. Therefore, while results may indicate improved quality of life for patients treated with encorafenib plus cetuximab over treatments in the control group, it is unclear whether a 10% deterioration in HRQoL provides a clinically meaningful context for analysis of patient’s quality of life.

Indirect Evidence

Objectives and Methods for the Summary of Indirect Evidence

The BEACON trial compared encorafenib plus cetuximab with the investigator’s choice of cetuximab plus irinotecan or FOLFIRI for patients with mCRC with the BRAF V600E mutation after previous therapy. Other treatments exist for patients with mCRC with the BRAF V600 mutation after first- or second-line therapy. In Canada, FOLFIRI and FOLFOX are considered the most common second-line treatments for patients. The objective of this section is to summarize and critically appraise available indirect evidence comparing encorafenib plus cetuximab with relevant treatments for mCRC patients with the BRAF V600 mutation after previous therapy (as specified in the CADTH review protocol).

The sponsor conducted a systematic literature review to identify relevant literature for its submitted ITC. The search for the systematic literature review was first performed on February 7, 2019, and updated in September 24, 2019. The updated search conducted in September 2019 aimed to identify randomized controlled trial (RCT) evidence and included first-line RCT studies. The scope of the ITC for the purpose of this CADTH review involves only patients after the first line of therapy; therefore, only studies that reported results in the second line or after were included.

Description of Indirect Comparison

The sponsor-submitted ITC is summarized and appraised. A supplemental search of the medical literature for publicly available ITCs was conducted by CADTH staff; no additional ITCs were identified that evaluated the comparative efficacy and safety of encorafenib plus cetuximab for patients with mCRC with the BRAF V600 mutation after having received previous therapy.

Methods of the ITC

Objectives

The aim of the submitted ITC was to compare the efficacy and safety of second-line or later lines of treatments for adults with mCRC with a BRAF V600E mutation.

Study Selection Methods

A literature search was conducted based on details in Table 26. Studies were screened by title and abstract and then full text, resulting in the inclusion of 131 studies.

Figure 11: PRISMA Flow Diagram of Systematic Literature Review for the Sponsor’s ITC

ITC = indirect treatment comparison; PRISMA = Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

Source: Sponsor’s ITC.¹⁸

The sponsor’s systematic literature search identified 11 citations that were relevant based on pre-specified criteria. Three studies were reported as conference abstracts and involved patients with BRAF mutations. Eight citations, 1 of which was published as an abstract, reported efficacy data for subgroups of patients with BRAF mutations among patients with KRAS wild-type tumours or any mCRC. The sponsor excluded the 3 studies that involved patients with the BRAF mutation, as they were published only as conference abstracts, which are not peer-reviewed publications. Additionally, these studies were excluded based on alternate doses for encorafenib and including comparators, which were not relevant to the ITC. The third study was an abstract of the BEACON trial, which was the reference trial for the sponsor’s ITC. Among the 8 studies that assessed only subgroups of patients with BRAF mutations, 1 conference abstract was excluded, as it was not a peer-reviewed publication. In total, 7 peer-reviewed studies that reported efficacy data for at least 1 outcome of interest for a subgroup of patients with BRAF mutations receiving second-line or later treatment were identified in the sponsor’s systematic literature review.

ITC Analysis Methods

Feasibility Assessment

The sponsor conducted a feasibility assessment of the 7 studies retrieved from the systematic literature review for incorporation into its ITC. The credibility of estimates reported for BRAF-mutated subgroups in the 7 included trials was stated to be low due to small sample sizes, inadequate power, and a lack of stratification according to BRAF mutation status. In addition, the 7 studies did not include comparators common to the BEACON trial, which did not allow for connected networks through an NMA. Therefore, an NMA was considered infeasible. Instead, the sponsor conducted a grouped treatment node ITC that compared encorafenib plus cetuximab with FOLFIRI using data from the BEACON trial and trial NCT00339183 (Figure 12). In order for the comparison of encorafenib plus cetuximab with FOLFIRI to be feasible, the following assumptions were required to be made, in addition to the standard NMA assumptions:

• FOLFIRI and irinotecan are clinically equivalent

• cetuximab and panitumumab are clinically equivalent

• FOLFIRI and FOLFOX are clinically equivalent

• FOLFIRI plus cetuximab or irinotecan plus cetuximab were assumed to be clinically equivalent to FOLFIRI plus panitumumab

Figure 12: Network Diagram for ITC of Encorafenib Plus Cetuximab Versus FOLFIRI

Bini = binimetinib; CTX = cetuximab; Enco = encorafenib; FOLFIRI = folinic acid plus 5-fluorouracil and irinotecan; IRI = irinotecan; ITC = indirect treatment comparison.

Source: Sponsor’s ITC.¹⁸

ITC Methods

The Bucher method was used in the grouped treatment node ITC conducted by the sponsor. HRs with corresponding 95% CIs were provided for comparisons of encorafenib plus cetuximab with FOLFIRI. The Bucher method was chosen by the sponsor due to the limited amount of available peer-reviewed literature pertaining to patients with BRAF V600E–mutated CRC after prior therapy. In addition, the BEACON trial, the only available trial that included a patient population relevant to the ITC, did not have a treatment group that connected with any other RCTs; therefore, the sponsor could not form connected networks for indirect comparisons and conducted comparisons based on the assumptions stated earlier.

Summary of Included Studies

Assessment of Heterogeneity

An assessment of heterogeneity was conducted by the CADTH reviewers based on the trial characteristics reported in Table 27. Trial characteristics were mostly similar, in that both trials were open-label phase III trials conducted across multiple countries. However, interventions in both trials differed, and the NCT00364013 trial did not exclude patients with or without specific mutation types.

Assessment of Clinical Heterogeneity

As the pairwise comparisons of the ITC consisted of only 1 trial for each treatment group, statistical assessments of heterogeneity were stated by the sponsor to not be possible.

Baseline characteristics of patients in the BEACON trial and patients with wild-type RAS in the NCT00339183 trial are reported in Table 28. Baseline characteristics were mostly comparable. Both trials reported a median age of approximately 60 years of age. patients were mostly from North America or Europe and had an ECOG PS of 0 or 1. However, the NCT00339183 trial reported slightly more males in the trial compared with the BEACON trial (66% versus 47%, respectively) and included more White patients (97% versus 80.5%). In the BEACON trial, 2-thirds of patients had received 1 prior line of therapy compared with all of the patients in the NCT00339183 trial; approximately 1-third of patients received 2 or more lines of therapy. In addition, the NCT00339183 study included more patients with liver metastases compared with the BEACON trial (86% versus 60%, respectively). Among patients with wild-type RAS, 45 were identified as having the BRAF mutation. The baseline characteristics of those patients were not available for comparison with the BEACON trial.

Subsequent therapies in the NCT00339183 study consisted mostly of oxaliplatin, irinotecan, or 5-fluorouracil (panitumumab plus FOLFIRI: 45%; FOLFIRI: 50%), EGFR monoclonal antibodies (panitumumab plus FOLFIRI: 12%; FOLFIRI: 34%),³⁷ and bevacizumab (panitumumab plus FOLFIRI: 10%; FOLFIRI: 12%).³⁸ The use of subsequent EGFR monoclonal antibody treatments may have confounded OS and PFS results in the NCT00339183 trial. Subsequent therapies in the BEACON trial were most commonly (> 10%) reported to be irinotecan (25.4%), 5-fluorouracil (22.5), and folinic acid (12.7%) in the encorafenib plus cetuximab group (18.5%), versus irinotecan (16.8%), cetuximab (13.6%), oxaliplatin (10.3%), and vemurafenib (10.3%) in the control group.¹⁴ The use of subsequent therapies differed both across treatment groups as well as across the 2 trials. The use of subsequent therapies may impact clinical outcomes for patients in treatment groups differentially.

Assessment of Outcome Definitions Across Trials

The definitions of OS and PFS were similar across both the BEACON trial and NCT00364013 trial. Definitions of OS and PFS were the same across both trials, except for the use of RECIST v1.1 to document disease progression in the BEACON trial versus RECIST in the NCT00339183 trial (Table 29).

Risk of Bias Assessment

The sponsor conducted a risk-of-bias assessment of the 2 trials included in the ITC (BEACON and NCT00339183). The sponsor reported that both studies were large, well-run, open-label RCTs with more than 400 patients enrolled across treatment groups of relevance to the ITC. The BEACON trial enrolled patients with the presence of the BRAF V600E mutation (n = 441 across treatment groups of relevance), while the NCT00339183 study enrolled patients with mCRC without specification of the BRAF mutation; however, approximately 45 of the 421 patients (10%) enrolled in the NCT00339183 trial were patients with the BRAF mutation. Baseline characteristics were reported to be similar across both trials; however, baseline characteristics of patients with the BRAF mutation in the NCT00339183 trial were not available for comparison to baseline characteristics of the BEACON trial. Therefore, the sponsor assumed the baseline characteristics of the BRAF subpopulation were comparable between the 2 trials.

Results

Results of the sponsor’s ITC are reported in Table 30. Results suggest that both OS and PFS are superior with treatment with encorafenib plus cetuximab compared with FOLFIRI. The sponsor stated the comparisons of encorafenib plus cetuximab and FOLFOX would be expected to yield results similar to those reported in Table 30.

Critical Appraisal of the ITC

The sponsor submitted an ITC comparing encorafenib plus cetuximab with FOLFIRI or FOLFOX. Numerous issues affecting the quality of the ITC should be considered. While the sponsor conducted a systematic literature search to identify relevant literature for the ITC, some available evidence was disqualified, as it was based on published abstracts only, which are not peer reviewed. Peer review provides the opportunity for scientific communities to provide scrutiny of the validity and reliability of the scientific works conducted, ensuring work of the highest quality. However, works published only in abstract form may still contain valuable information, which may have limited the number of assumptions used by the sponsor in their analyses.

Of the 2 trials included in the ITC, the analyses of baseline characteristics revealed important differences, which may impact overall comparisons made between treatments. For example, the baseline characteristics of the NCT00339183 trial included a greater proportion of male and White patients, as well as a greater proportion of patients with liver metastases. Further, patients in the BEACON trial had received 1 or 2 previous lines of therapy, while patients in the NCT00339183 trial received only 1 line of previous therapy. Patients who have received more lines of therapy may face worse prognoses; therefore, comparisons of efficacy between patients may bias results against encorafenib plus cetuximab due to the presence of patients who have failed to respond to more than 1 therapy. In addition, the line of therapy may also impact patients’ clinical outcomes, as patients receiving earlier lines of treatment may face better prognoses compared with patients receiving treatment at later lines. Outcomes for OS and PFS are expected to be impacted by subsequent treatments across the BEACON trial as well as the NCT00339183 trial.

Most importantly, the objective of the BEACON trial was to enroll patients with the BRAF V600E mutation, whereas that was not the objective of the NCT00339183 trial. Among the patients with wild-type RAS, 45 were identified as having the BRAF mutation. The baseline characteristics of these patients were not available for comparison with the BEACON trial; therefore, it is unknown how comparable the demographic and clinical characteristics of patients with the BRAF mutation in the NCT00339183 trial are with patients in the BEACON trial. Further, the small subset of patients with the BRAF mutation in the NCT00339183 trial introduces uncertainty in the comparisons of efficacy between the 2 trials, as patients with the BRAF mutation may face worse prognoses and react to treatments differently compared with patients who do not have the BRAF mutation.

The risk of bias assessment conducted by the sponsor was not reported to be based on any accepted guidelines; the rigour of the assessment is unknown. The sponsor concluded that both the BEACON trial and the NCT00339183 trial were well conducted trials. However, the risk of bias assessment was based on the assumption the baseline characteristics between the trials were comparable, even though the BEACON trial was specific to patients with the BRAF mutation. Due to the clinical differences between patients with the BRAF mutation versus those with wild-type RAS, it is unclear whether this assumption is appropriate.

Many patients in the BEACON trial were mostly in second-line therapy (66%); however, second-line therapies for patients with mCRC in Canada typically consist of either FOLFIRI or FOLFOX. Therefore, the sponsor conducted an ITC to compare the efficacy of encorafenib plus cetuximab with FOLFIRI. A number of assumptions were made by the sponsor to conduct the ITC, including the clinical equivalence of FOLFIRI and irinotecan, cetuximab and panitumumab, FOLFIRI and FOLFOX, and FOLFIRI plus cetuximab or irinotecan plus cetuximab and FOLFIRI plus panitumumab. The sponsor provided some clinical evidence^39-42 and reference to a National Institute for Health and Care Excellence health technology assessment report for cetuximab plus panitumumab for mCRC⁴³ to support the assumptions made in their ITC. However, it should be noted that the strength of evidence provided to support the assumptions of the ITC varied and may not suggest true clinical equivalence due to small sample sizes, use of treatments in different lines of therapy, and a lack of consideration of patients with the BRAF mutation. However, it is acknowledged that literature pertaining specifically to mCRC patients with the BRAF mutation is limited. In addition, the clinical experts consulted for this CADTH review confirmed that the assumptions of the ITC made by the sponsor were reasonable. While the assumptions of clinical equivalence were considered plausible by the supportive evidence and the opinions of the clinical experts, the numerous assumptions of the analysis introduce great uncertainty affecting the overall validity of the results.

Overall, the sponsor’s ITC supported treatment with encorafenib plus cetuximab in the second line compared with FOLFIRI for patients with BRAF V600E–mutated mCRC. Based on the assumption that FOLFIRI is broadly similar to FOLFOX, the sponsor concluded that similar conclusions could be drawn to comparisons of encorafenib plus cetuximab to FOLFOX.¹⁸ The clinical experts consulted for this CADTH review confirmed the face value of the results of the sponsor’s ITC. Therefore, it is likely that encorafenib plus cetuximab provides patients with greater clinical benefit compared with FOLFIRI. However, based on the numerous issues with validity behind the analysis of the ITC, the magnitude of benefit observed from encorafenib plus cetuximab cannot be confirmed with confidence, and results should be interpreted with caution.

The sponsor’s ITC compared only the clinical efficacy of encorafenib plus cetuximab and FOLFIRI (i.e., OS and PFS). Based on the results from the BEACON trial, the doublet regimen of encorafenib plus cetuximab demonstrated statistically significantly improved clinical efficacy compared with the control group consisting of either cetuximab plus irinotecan or cetuximab plus FOLFIRI. Other important outcomes, such as safety and HRQoL, were not captured in the sponsor’s ITC. Therefore, it is not possible to know how the relative toxicities of each treatment would impact patients’ outcomes and choice of therapy.

Summary

One ITC, submitted by and conducted by the sponsor, was summarized and critically appraised. The results of the ITC indicated that treatment with encorafenib plus cetuximab was superior to FOLFIRI when considering OS and PFS. No comparisons were made for safety and HRQoL, leaving relative toxicity profiles and impact of treatment on patient-reported outcomes uncertain. Numerous assumptions regarding clinical efficacy and the equivalence of treatments were made by the sponsor. Some evidence was provided to support the assumptions made by the sponsor. In addition, opinions from clinical experts confirmed the plausibility of the assumptions made. However, the numerous assumptions made introduced uncertainty into the validity of the overall analyses and indirect effect estimates between encorafenib plus cetuximab and FOLFIRI. Thus, the direction of effect was most likely accurate in favouring treatment with encorafenib plus cetuximab compared with FOLFIRI and FOLFOX; however, due to the many issues reported with the ITC, the magnitude of effect remains uncertain.

Discussion

Summary of Available Evidence

One multi-centre, multinational, randomized, open-label, phase III study met the criteria for the CADTH systematic review. A total of 220 patients were randomized to the doublet group of the BEACON trial, and 221 patients were randomized to the control group, which included treatment with the investigators’ choice of either irinotecan plus cetuximab or FOLFIRI plus cetuximab. Enrolled patients included adults with mCRC whose tumours expressed the BRAF V600E mutation and whose disease had progressed after 1 or 2 prior regimens in the metastatic setting. Treatment was continued until disease progression, unacceptable toxicity, withdrawal of consent, initiation of subsequent anti-cancer therapy, or death. The primary outcomes for this trial were OS and ORR between the triplet group and control group. However, key secondary end points included analysis of ORR, OS, and PFS between the doublet group and control group. HRQoL was included as an exploratory end point of the trial. Baseline characteristics were similar between the doublet group and control group. Patients had a mean age of 59 years, were mostly from Europe (61%), mostly White (81%), had an ECOG PS of 0 (50%) or 1 (49%), and all patients were diagnosed with stage IV disease at study entry. The primary tumour location was in the right colon for 42% of patients, in the left colon for 34% of patients, and 56% of patients had their tumour completely resected. Two-thirds of patients had received 1 prior regimen, with the remaining patients having received 2 prior regimens; only 1 patient had received more than 2 prior regimens and this patient was randomized to the control group.¹⁴

In addition to the systematic review, 1 sponsor-submitted ITC was summarized and appraised for this review.

Interpretation of Results

Efficacy

The clinical experts consulted by CADTH for this review and input received from patient groups indicated that prolonged survival and delayed disease progression are important treatment goals for adult patients with mCRC whose tumours expressed the BRAF V600E mutation. The BEACON trial showed statistically significant improvement in OS among patients treated in the doublet group over the control group.¹⁴ The results of the BEACON trial were based on an interim analysis; the results of this interim analysis were considered clinically meaningful and supported treatment with the encorafenib and cetuximab regimen over standard chemotherapy-based regimens for patients with BRAF-mutated mCRC. A post-hoc analysis was conducted providing 6 months of additional information; while the post-hoc analysis was not pre-specified and is considered descriptive, efficacy analyses supported the results of the interim analysis. In addition, prolonged survival and delayed disease progression were highlighted as important treatment goals for patients by both the patient input and clinician input provided for this review.

Baseline characteristics were considered to be generalizable to the Canadian setting by clinical experts consulting on this CADTH review. Treatments used in the comparator group were also acknowledged to be standard treatments used in Canadian clinical practice. Two-thirds of patients in the BEACON trial had received only 1 prior therapy; however, 1 of the control-group treatment regimens (cetuximab plus irinotecan) was highlighted as being funded in only the third-line treatment setting in Canada. The clinical experts for this review confirmed that both treatment regimens in the control group of the BEACON trial were used in the second- and third-line setting. However, the clinical experts highlighted that half of patients in the doublet and control groups of the BEACON trial had been previously exposed to treatment with irinotecan. As both treatment regimens in the control group contained irinotecan, it was highlighted that patients randomized to the control group would be re-exposed to irinotecan treatment after having previously progressed on first- or second-line treatment. The clinical experts stated that in Canadian clinical practice, this would be seldomly done.

It was noted that a greater proportion of patients randomized to the control group were not treated compared with the doublet group (12.7% versus 1.8%, respectively).¹⁴ FDA approval in the US in June 2018 of encorafenib and binimetinib for the treatment of patients with BRAF-mutated melanoma resulted in off-label use of the treatment for mCRC patients. Correspondingly, a larger proportion of patients in the doublet group discontinued from the BEACON trial due to withdrawal of consent (58.2% versus 68.3%, respectively).¹⁴ The greater number of patient withdrawals from the trial and the fewer number of patients who were not treated in the control group are likely to bias efficacy analyses conservatively toward the control group. Regardless, the results of the BEACON trial were able to support the improved treatment efficacy of the doublet regimen over the control group.

Both the patient input and clinician input highlighted quality of life as an important outcome and treatment goal for patients. HRQoL was an exploratory end point in the BEACON trial. The HRQoL analyses in the BEACON trial did not involve assessment using MIDs; therefore, it is not clear whether the differences observed in the HRQoL questionnaires during the trial are clinically meaningful. However, the TTD analyses for the HRQoL questionnaires favoured treatment with encorafenib plus cetuximab over the control group. Results for patient-reported outcomes in the BEACON trial are considered exploratory and should be interpreted with caution, especially as the number of patients eligible for the completion of questionnaires steadily declined and resulted in small sample sizes over time. While TTD analyses seemed promising and suggested maintenance of patient’s quality of life, the open-label design of the trial may introduce bias, as patients were aware of their treatment assignment, potentially favouring outcomes for the intervention group.

The sponsor provided an ITC comparing the efficacy of encorafenib plus cetuximab to FOLFIRI in the second line of treatment for patients with mCRC. The results of the ITC were consistent with results of the BEACON trial, supporting treatment with the doublet over standard chemotherapy regimens for patients with the BRAF mutation. However, the sponsor’s ITC was limited in being able to inform on the clinical benefits of encorafenib plus cetuximab compared with other second-line regimens for patients with the BRAF mutation, mainly due to the lack of available published literature. To conduct their ITC, a number of assumptions regarding clinical equivalence were made. While the clinical assumptions of the ITC were considered reasonable by the clinical experts consulting for this CADTH review, their remains a lack of direct evidence comparing relevant regimens with encorafenib plus cetuximab for patients with the BRAF mutation. In addition, only 1 other trial was identified as being relevant to the sponsor’s ITC; however, this trial included only a subgroup of patients with BRAF mutation status, and the baseline characteristics of the trial sample were assumed to be the same as the characteristics of the subsample of patients with BRAF mutation status. The results of the ITC suggested that encorafenib plus cetuximab may be more efficacious for patients in the second line compared with FOLFIRI. While the analyses of the ITC are limited by the lack of published evidence and numerous assumptions, the results of the ITC were considered to be sufficient in supporting the conclusion of a superior treatment effect from encorafenib plus cetuximab over FOLFORI or FOLFOX, although the magnitude of benefit is not clear.

Harms

Almost all patients in the doublet and control groups of the BEACON trial experienced at least 1 AE (98% and 97%, respectively). The AEs frequently reported were gastrointestinal disorders, skin and subcutaneous disorders, and general disorders and administration-site conditions.¹⁴ There were differences in the frequency of some AEs between the doublet and control groups; this is expected, as encorafenib and cetuximab have different mechanisms of action compared with chemotherapies used in the control group. Specifically, the following AEs occurred more frequently in the doublet group: arthralgia, headache, melanocyte nevus, myalgia, and musculoskeletal pain. Conversely, the AEs that occurred at a greater frequency in the control group included dermatitis acneiform, neutrophil count decrease, diarrhea, stomatitis, and neutropenia.¹⁴

The patient input identified fatigue and pain as being the most important disease-related symptoms to control. The AEs related to treatment that were difficult to tolerate were varied in the patient input, but included vomiting, nausea, pain, rash, neuropathy, hair loss, and low platelets. AEs of any grade and fatigue and rash were similarly reported across the doublet and control groups. However, vomiting, nausea, diarrhea, stomatitis, neutropenia, and decreased neutrophil count occurred less frequently among patients treated with encorafenib plus cetuximab. The safety profiles for each of the treatments in the regimens of the BEACON trial were found to be consistent with the known effects of BRAF and EGFR inhibitors. More patients in the control group discontinued treatment or required dose interruptions of therapy compared with the doublet group. In addition, there was a longer duration of treatment in the doublet group compared with the control group, suggesting improved tolerability to treatment in the doublet group. Overall, most AEs observed in the BEACON were grade 1 or 2, and the toxicities of encorafenib plus cetuximab were considered manageable.

It should be noted that patients and investigators were aware of the patient’s treatment assignment due to the open-label nature of the BEACON trial. It is not clear whether the open-label design influenced the assessment or reporting of AEs in the trial. However, the clinical experts consulted by CADTH for this review confirmed the toxicities observed in the BEACON trial were expected for chemotherapy treatments, and the toxicities attributable to encorafenib were manageable.

As the sponsor’s ITC did not conduct comparisons of safety or quality of life, it is not possible to draw conclusions on the toxicity profile of encorafenib plus cetuximab compared with FOLFIRI.

Other Considerations

This current submission is for encorafenib, at a recommended dose of 300 mg orally every day in combination with cetuximab, at a recommended dose of 400 mg/m² followed by 250 mg/m² via IV infusion every week. Through consultation with clinical experts, it was acknowledged that clinical practice of administration of cetuximab may differ than what is recommended for cetuximab. Administration of cetuximab in Canadian clinical settings may involve a higher dose, at 500 mg/m², and a less frequent schedule, at every 2 weeks. A pooled analysis comparing the 2 administration schedules for cetuximab among patients with wild-type RAS supported that cetuximab provided at 500 mg/m² every 2 weeks is noninferior to cetuximab provided at 400mg/m² followed by 250 mg/m².¹⁷ The less frequent administration schedule for cetuximab may be favourable for patients and clinics, as it reduces burden on clinic resources and patients (i.e., travel time, cost, chair time). The clinical experts for this review also supported the use of cetuximab at a dose of 500 mg/m² provided every 2 weeks.

Conclusions

Patients with mCRC face poor survival rates, and patients with BRAF mutations face poorer prognoses and rapid disease progression with few available treatment options. There are currently no funded treatment options that target BRAF mutations for patients with mCRC. Based on the results of 1 phase III study (BEACON trial), encorafenib in combination with cetuximab (doublet group), compared with FOLFIRI plus cetuximab or irinotecan plus cetuximab demonstrated statistically significant improvements in OS and PFS in adult patients with mCRC with a BRAF V600E mutation, after prior therapy. ORR was also superior in the doublet group, with only a few patients achieving response in the control group. HRQoL outcomes were noted as important to patients; however, the doublet group's effect on HRQoL was uncertain due to the study's open-label design, lack of control for multiplicity, and lack of analyses based on the estimated MIDs. The CADTH reviewers did not identify direct comparative evidence for encorafenib plus cetuximab with FOLFIRI. One sponsor-submitted ITC comparing encorafenib plus cetuximab with FOLFIRI suggested that encorafenib in combination with cetuximab may be more efficacious for patients in the second line compared with FOLFIRI. However, there is uncertainty around the ITC results due to the numerous assumptions. Safety results also suggested a lower frequency of AEs and a manageable toxicity profile.

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Appendix 1: Literature Search Strategy

Note that this appendix has been formatted but not copy-edited.

Clinical Literature Search

Overview

Interface: Ovid

Databases:

• MEDLINE All (1946–present)

• Embase (1974–present)

• Note: Subject headings and search fields have been customized for each database. Duplicates between databases were removed in Ovid.

Date of Search: January 20, 2021

Alerts: Biweekly search updates until project completion

Study types: No filters were applied to limit retrieval by study type

Limits:

• Publication date limit: none

• Language limit: none

• Conference abstracts: excluded

Table 31: Syntax Guide

Multi-Database Strategy

Search Strategy:

1. (encorafenib* or braftovi* or LGX818 or LGX 818 or NVP LGX 818* or NVPLGX 818* or NVP LGX818* or NVPLGX818* or 8L7891MRB6).ti,ab,kf,ot,hw,rn,nm.

2. 1 use medall

3. *encorafenib/

4. (encorafenib* or braftovi* or LGX818 or LGX 818 or NVP LGX 818* or NVPLGX 818* or NVP LGX818* or NVPLGX818*).ti,ab,kw,dq.

5. or/3 to 4

6. 5 use oemezd

7. 6 not conference abstract.pt.

8. 2 or 7

9. remove duplicates from 8

Clinical Trials Registries

ClinicalTrials.gov

Produced by the US National Library of Medicine. Targeted search used to capture registered clinical trials.

Search terms – Braftovi/encorafenib

Health Canada’s Clinical Trials Database

Produced by Health Canada. Targeted search used to capture registered clinical trials.

Search terms – Braftovi/encorafenib

EU Clinical Trials

Register European Union Clinical Trials Register, produced by the European Union. Targeted search used to capture registered clinical trials.

Search terms – Braftovi/encorafenib

Grey Literature

Search dates: January 11, 2021 – January 20, 2021

Keywords: Braftovi/encorafenib and colorectal cancer

Limits: No limits

Updated: Search updated before meeting of the CADTH pan-Canadian Oncology Drug Review Expert Committee (pERC)

Relevant websites from the following sections of the CADTH grey literature checklist Grey Matters: A Practical Tool For Searching Health-Related Grey Literature (https://www.cadth.ca/grey-matters) were searched:

• Health Technology Assessment Agencies

• Health Economics

• Clinical Practice Guidelines

• Drug and Device Regulatory Approvals

• Advisories and Warnings

• Drug Class Reviews

• Clinical Trials Registries

• Databases (free)

• Internet Search

Appendix 2: Excluded Studies

Note that this appendix has been formatted but not copy-edited.

Table 31: Excluded Studies

Appendix 3: Detailed Outcome Data

Figure 13: Subgroup Analysis for OS, Doublet Group Versus Control Group (Data Cut-Off: February 11, 2019)

CEA = carcinoembryonic antigen; CETUX = cetuximab; Cl = confidence interval; CRP = C-reactive protein; ECOG PS = Eastern Cooperative Oncology Group Performance Status; ENCO = encorafenib; EU = European Union; F = female; HR = hazard ratio; M = male; MSI = microsatellite instability; N = no; NR = not reached; OS = overall survival; ULN = upper limit of normal; vs. = versus ; Y = yes.

Note: Statistical model used: Cox model.

Note that this appendix has been formatted but not copy-edited.

Source: BEACON Clinical Study Report.

Figure 14: Subgroup Analysis for OS, Doublet Group Versus Control Group (Data Cut-Off: August 15, 2019)

CEA = carcinoembryonic antigen; CETUX = cetuximab; Cl = confidence interval; CRP = C-reactive protein; ECOG PS = Eastern Cooperative Oncology Group Performance Status; ENCO = encorafenib; EU = European Union; F = female; HR = hazard ratio; M = male; MSI = microsatellite instability; N = no; NR = not reached; OS = overall survival; ULN = upper limit of normal; vs. = versus ; Y = yes.

Note: The HR is obtained from an unstratified Cox model. The error bars represent 95% Cl.

Source: BEACON Clinical Study Report Addendum.¹⁵

Table 32: Subgroup Analyses for Objective Response Rate in the BEACON Trial