Reimbursement Review

Epcoritamab (Epkinly)

Sponsor: AbbVie Corporation

Therapeutic area: Relapsed or refractory diffuse large B-cell lymphoma

This multi-part report includes:

Clinical_Review

Pharmacoeconomic_Review

Clinical_Review

Abbreviations

Executive Summary

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

Table 1: Background Information on Application Submitted for Review

CAR chimeric antigen receptor = DLBCL = diffuse large B-cell lymphoma; NOC = Notice of Compliance; NOC/c = Notice of Compliance with conditions; SC = subcutaneous.

Introduction

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma (NHL), accounting for approximately 30% to 40% of all NHL cases in Canada.¹ DLBCLs are a heterogeneous group of aggressive B-cell malignancies that differ in clinical presentation, molecular features, prognosis, and treatment options.^1,2

The Canadian Cancer Society estimates that 11,400 people in Canada were diagnosed with NHL in 2022, with 3,000 dying from the disease.³ International studies have estimated the incidence of DLBCL in the US and England at approximately 7 cases per 100,000 persons per year.⁴ Based on statistics from 1975 to 2017, the estimated 5-year relative survival rate at diagnosis was 63.8% in US.⁵ For patients who are not chemosensitive and are ineligible for autologous stem cell transplant (ASCT), or who relapse after stem cell therapy (SCT) or chimeric antigen receptor (CAR) T-cell therapy, the prognosis is poor, and there is no standard approach to treatment. Available options are currently limited to palliative chemotherapies, including rituximab, gemcitabine, and oxaliplatin (R-GemOx), polatuzumab vedotin with bendamustine and rituximab (pola-BR), and clinical trials with novel drugs.^1,6

Epcoritamab is a humanized immunoglobulin gamma 1–bispecific antibody that binds to a specific extracellular epitope of cluster of differentiation 20 (CD20) on B-cells and to cluster of differentiation 3 (CD3) on T-cells. The activity of epcoritamab is dependent upon the simultaneous engagement of CD20-expressing cells and CD3-expressing endogenous T-cells by epcoritamab that induces specific T-cell activation and T-cell–mediated killing of CD20-expressing cells.⁷

The objective of this report is to review and critically appraise the evidence submitted by the sponsor on the beneficial and harmful effects of epcoritamab for the treatment of adult patients with relapsed or refractory (R/R) DLBCL not otherwise specified, DLBCL transformed from indolent lymphoma, high-grade B-cell lymphoma (HGBCL), primary mediastinal B-cell lymphoma (PMBCL), or follicular lymphoma grade 3B (FLG3B) after 2 or more lines of systemic therapy who have previously received or are unable to receive CAR T-cell therapy.

Stakeholder Perspectives

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

Patient Input

Two patient groups, Lymphoma Canada (LC) and the Leukemia and Lymphoma Society of Canada (LLSC), responded to CADTH’s call for patient input for the current review of epcoritamab. LC is a national Canadian registered charity that empowers the lymphoma community through education, support, advocacy, and research. LLSC is a national organization dedicated to finding a cure for blood cancers and to supporting patients and their families by funding life-enhancing research and providing educational resources, services, and support.

LC gathered information for this submission through a survey conducted from October 3, 2023 to November 20, 2023, targeting patients living with large B-cell lymphoma (LBCL). The LC survey data include information from 33 respondents. In addition, LC included a submission from France that was based on a survey regarding the use of epcoritamab for DLBCL conducted by Ensemble Leucémie Lymphomes Espoir with 9 survey respondents, supported by results of the Lymphoma Coalition's 2022 survey that included the experience of patients with DLBCL (n = 171). LLSC conducted 4 1-on-1 interviews in November 2023; 2 interviewees were patients with DLBCL, and 2 were caregivers. Three interviewees resided in Canada and 1 interviewee resided in the US.

According to the input from both groups, living with LBCL is associated with extreme fatigue, body aches, nausea, shortness of breath, lack of energy, and stress and worry, all of which have significant impacts on day-to-day activities and quality of life.

Patient groups identified a need for additional second- and third-line treatment options and described difficulties managing treatment regimens and side effects. Currently available treatments take significant mental and psychological tolls on patients and loved ones, are associated with immense financial burdens, and negatively affect the ability to work, travel long distances, and participate in daily activities. According to both inputs, patients expect new treatments to be more effective and less invasive, with fewer side effects. Patients are seeking choice in their treatment decisions and a variety of options that offer a longer life span, lengthier remission, and better quality of life.

Patients indicated that epcoritamab could offer hope and relief to those with LBCL who require a third-line treatment option; the subcutaneous (SC) administration route could mean less time in hospitals per visit, which can improve the quality of life of patients and caregivers.

Clinician Input

Input From Clinical Experts Consulted by CADTH

The clinical experts consulted by CADTH stated that the goal of treatment at this stage is palliative and generally includes maintaining health-related quality of life (HRQoL) by relieving lymphoma-related symptoms, delaying disease progression, and balancing the toxicities of therapy. There is no standard of care in this setting, but options include chemotherapy (e.g., pola-BR or rituximab-based chemoimmunotherapy [R-CIT]), radiation, and potential enrolment in clinical trials. The clinical experts stated that there is an unmet need for safe and effective treatments for patients who are palliative and not eligible for curative treatment, or for whom second-line treatment consisting of SCT or CAR T-cell therapy has not been effective, given that there are limited treatment options for disease control and that currently available options are often associated with significant toxicity that limits these options’ usefulness and applicability. Additionally, patients who relapse after transplant or CAR T-cell therapy often have poor prognoses and very poor bone marrow function, which prevents them from receiving or tolerating further cytotoxic therapy. The clinical experts also noted that there is a significant group of patients who may be eligible for intensive treatments but are unable to access them due to barriers based on location. For example, many patients are unable to travel with caregivers to specialized cellular therapy sites and choose not to have this treatment because they wish to be treated closer to home. As such, there is an additional unmet need for treatments that patients can access and receive closer to home.

After the failure of first-line therapy with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) (curative intent), treatment in the second line consists of salvage R-CIT and ASCT for patients who are transplant-eligible and chemosensitive (curative intent). Third-line therapy consists of CAR T-cell therapy (curative intent). There is no standard of care following these treatment options; patients who are transplant-ineligible in the second and third lines tend to receive either palliative R-CIT (e.g., pola-BR or R-GemOx) with noncurative intent or radiation or enrol in clinical trials. The clinical experts highlighted that there is a planned shift to the use of CAR T-cell therapy as second-line therapy for primary refractory or early relapsed DLBCL, pending funding, in Canada. The clinical experts emphasized that cytopenias are a major problem associated with palliative cytotoxic treatment options.

Acknowledging that the Health Canada–approved indication for epcoritamab limits usage to patients “who have previously received or are unable to receive CAR T-cell therapy,” the clinical experts consulted by CADTH highlighted that epcoritamab could be a beneficial treatment option in the following circumstances:

• for use after patients have received CAR T-cell therapy

• for patients who are ineligible to receive CAR T-cell therapy

• for patients who are eligible to receive CAR T-cell therapy, but did not (e.g., due to logistical challenges or choice).

The experts noted that these patients would be identified in routine practice by clinicians familiar with the treatment of lymphoma patients undergoing surveillance for relapse (clinical and/or imaging). The experts could not identify a specific subgroup of patients who would demonstrate an enhanced or reduced benefit from epcoritamab treatment. The experts highlighted that repeat biopsy is not always required in cases of suspected relapse of DLBCL unless it is a remote relapse or the patient has a history of indolent lymphoma and it is unclear which lymphoma has relapsed.

The clinical experts stated that patients’ response to treatment would be assessed using the Lugano criteria. Patients would undergo interim imaging every 3 months to confirm response, after which they would either continue or discontinue treatment. Patients are also assessed for lymphoma-related symptoms at each visit; however, the clinical experts noted that while the assessed outcomes are more subjective, these do factor into patients’ decisions to continue therapy. The experts also noted that the frequency of these assessments, and the collection of data, may vary across Canada. In terms of meaningful response to treatment, the clinical experts stated that a response lasting 6 months or longer with improved symptoms can be considered meaningful. The experts did not consider temporary shrinking of tumours beneficial to patients and believed that a meaningful partial response (PR) or complete response (CR) should have a duration of at least 6 months; otherwise, the treatment should be discontinued. Additionally, with a current median overall survival (OS) of 6 months in this population, the experts considered a benefit of at least 6 months and 3 months over the current standard of care to be clinically meaningful for OS and progression-free survival (PFS), respectively.

The clinical experts suggested that treatment with epcoritamab should be discontinued upon overt disease progression or lack of response to treatment. The experts noted that adverse events (AEs) may vary, and resolution of severe AEs can allow for the resumption of therapy; due to this variability, discontinuation should be based on physician judgment and patient request.

The clinical experts indicated that patients with R/R DLBCL are typically under the care of hematologists or oncologists who are familiar with the treatment of lymphoma patients. They also noted that the monitoring and treatment of these patients must be conducted at tertiary centres that have the means to monitor and treat cytokine release syndromes (CRSs), which may require some initial training of site staff before implementation.

Clinician Group Input

Three clinician groups — LC (3 clinicians contributing), the Ontario Health (Cancer Care Ontario) Hematology Cancer Drug Advisory Committee (7 clinicians contributing), and the LLSC Nurses Network (6 clinicians contributing) — responded to CADTH’s call for clinician group input.

According to these groups, there are poor and limited treatment options for patients with R/R DLBCL. LC indicated that for patients who are eligible for intensive curative therapies, options such as ASCT and CAR T-cell therapy are considered. Patients who have disease progression after CAR T-cell therapy, or who are unfit for this therapy for medical and/or social reasons, have the greatest unmet need for treatment because no other curative-intent therapy is readily available to them.

In contrast, those who are not eligible for curative ASCT-based or CAR T-cell therapy approaches are managed with palliative approaches, such as with pola-BR or tafasitamab (an anti–cluster of differentiation 19 antibody) in combination with lenalidomide. CADTH notes that tafasitamab in combination with lenalidomide received a do not reimburse recommendation and is not currently reimbursed by participating drug programs.⁸ A small percentage of patients might pursue allogeneic stem cell transplant, but the vast majority of patients in this setting are managed with a variety of palliative chemotherapy regimens, radiation therapy, or clinical trials. Multiple novel drugs (ibrutinib, lenalidomide, tafasitamab, and selinexor) do not have Health Canada approvals or provincial funding for R/R DLBCL.

The clinician groups noted that there is an unmet need for safe and effective treatments for patients who are not eligible for CAR T-cell therapy or for whom second-line treatment has not been effective. LC and the LLSC Nurses Network added that there are limited treatment options for disease control, and that currently, the available options are often associated with significant toxicity, side effects, and mental and physical treatment fatigue. LC stated that while ASCT or CAR T-cell therapy are considered effective for some patients, others are unable to access them due to location barriers. Only select sites are equipped to offer CAR T-cell therapy.

The most important goals of treatment for DLBCL, according to clinician groups, are to prolong survival, delay disease progression, and improve symptoms, which in turn can improve quality of life of patients and caregivers. Clinician groups agreed, in regard to the indication, that epcoritamab can be used in the third line or beyond if the patient was previously treated with CAR T-cell therapy or is ineligible for CAR T-cell therapy. LC and the LLSC Nurses Network stated that as an off-the-shelf product, this treatment could alleviate regional access issues, and that the SC injection could become a more feasible, well-favoured option than currently available treatments.

According to the clinician groups, improved survival (PFS, OS), blood work, decreased presence of cancer cells in bone marrow, and improvement in disease symptoms are outcomes used to determine whether a patient is responding to treatment. LC added that a clinically meaningful response would be PR or CR, typically determined using CT and or PET scans.

The clinician groups agreed that discontinuation of therapy should be considered in patients with disease progression or toxicity, and that epcoritamab can be given in any inpatient and outpatient setting that has expertise in managing CRS and neurotoxicity as well as the ability to admit and monitor patients receiving anticancer therapy.

Drug Program Input

The drug programs identified the following jurisdictional implementation issues: relevant comparators, considerations for initiation of therapy, considerations for discontinuation of therapy, considerations for prescribing of therapy, generalizability, funding algorithm, care provision issues, and system and economic issues. Refer to Table 7 for more details.

Clinical Evidence

Systematic Review

Description of Studies

One ongoing, phase I and II, open-label, single-arm study, the EPCORE NHL-1 study, was included in this review. The review for epcoritamab was based on the dose expansion phase of the study, which consisted of 157 patients with R/R LBCL who had relapsed after or had not responded to at least 2 prior systemic treatment regimens. Patients were excluded if they had a known primary central nervous system (CNS) lymphoma or known CNS involvement or had CAR T-cell therapy within 30 days or ASCT within 100 days before the first dose of epcoritamab, or any prior allogeneic hematopoietic stem cell transplant (HSCT). Eligible patients received treatment with epcoritamab monotherapy at the step-up recommended doses: a priming dose of 0.16 mg (cycle 1, day 1 [C1D1]), an intermediate dose of 0.8 mg (cycle 1, day 8 [C1D8]), and a full dose of 48 mg (cycle 1, day 5 [C1D15], cycle 1, day 22 [C1D22], and every 4 weeks thereafter until unacceptable toxicity or disease progression). The primary end point was objective response rate (ORR), with secondary or exploratory end points of CR, duration of response (DOR), PFS, OS, HRQoL, and safety.

The majority of patients in the intention-to-treat population of patients with LBCL had DLBCL (88.5%), with smaller subgroups who had HGBCL (5.7%), PMBCL (2.5%), or FLG3B (3.2%). Patients had received 2 (29.9%), 3 (30.6%), or 4 or more prior lines of antilymphoma therapy (39.5%), and a majority were refractory to their last prior therapy (82.8%). Prior CAR T-cell therapy was reported for 38.9% of patients, and 19.7% had received prior stem cell transplant.

Efficacy Results

Table 2 summarizes results for the efficacy end points from the EPCORE NHL-1 trial using the most recent data cut-off date (April 21, 2023).

• OS: || ||||||| patients died, resulting in a median OS of 18.5 months (95% confidence interval [CI], 11.7 to ||||). The estimated proportions of patients who remained alive at 12 months and 18 months were ||||| |||| ||| ||||| || |||||| and ||||| |||| ||| ||||| || ||||||| respectively.

• PFS: ||| ||||||| patients experienced a PFS event (disease progression or death) based on the Lugano criteria. The median PFS duration was 4.4 months (95% CI, 3.0 months to 8.8 months). The estimated percentages of patients remaining progression-free at 12 months and 18 months were ||||| |||| ||| ||||| || |||||| and ||||| |||| ||| ||||| || ||||||| respectively. Overall results for the 18 patients in the cohort of patients with other LBCL subtypes were similar to those for the cohorts of patients with LBCL and DLBCL.

• CR: The CR rate, based on Lugano criteria, was ||||| |||| ||| |||| || ||||| when determined by the independent review committee (IRC) and ||||| |||| ||| |||| || ||||| when determined by the investigator. The median duration of complete response (DOCR) was |||| |||||| |||| ||| |||| || ||| when assessed by IRC and |||| |||||| |||| ||| |||| || ||| when assessed by the investigators.

• ORR: The ORR (CR plus PR) in patients with LBCL was 63.1% (95% CI, 55.0% to 70.6%), with || ||||||| and || ||||||| patients achieving best response of CR and PR, respectively.

• DOR: For patients who had achieved PR or CR || | |||| the median DOR was |||| |||||| |||| ||| ||| || ||||| when assessed by IRC using Lugano criteria. The estimated percentages of patients still responding at 12 months and 18 months were ||||| |||| ||| ||||| || |||||| and ||||| |||| ||| ||||| || ||||||| respectively. The median DOR was |||| |||||| (95% CI, 13.0 to 26.5) when assessed by the investigators using Lugano criteria.

• Functional Assessment of Cancer Therapy–Lymphoma (FACT-Lym) total score: 140 patients completed the FACT-Lym, and the mean score at baseline was 118.4 (standard deviation [SD] = 25.47). At cycle 5, day 1 (n = 66) and cycle 7, day 1 (n = 52), the mean changes from baseline in total score were ||| ||||||| and |||| |||||||| respectively. At the end-of-treatment assessment (n = 54), the mean change from baseline in total score was |||| |||||||.

• Functional Assessment of Cancer Therapy–General (FACT-G) total score: 140 patients completed the FACT-G, and the mean score at baseline was 76.2 (SD = 16.86). At cycle 5, day 1 (n = 66) and cycle 7, day 1 (n = 52), the mean changes from baseline in total score were ||| ||||||| and ||| |||||||, respectively. At the end-of-treatment assessment || | |||, the mean change from baseline in total score was |||| ||||||||.

• Functional Assessment of Cancer Therapy–Lymphoma Subscale (FACT-LymS): The sponsor evaluated 6 questions from the FACT-Lym that were related to the symptoms of lymphoma: body pain (P2), severe fever (BRM3), night sweats (ES3), lack of energy (GP1), tires easily (BMT6), and weight loss (C2). One hundred and 40 patients completed the FACT-LymS, and the mean score at baseline was 42.2 (SD = 9.98). At cycle 5, day 1 (n = 66) and cycle 7, day 1 (n = 52), the mean changes from baseline in total score were ||| |||||| and ||| ||||||| respectively.

Harms Results

As of the data cut-off date (April 21, 2023), ||| ||||||| patients with LBCL had experienced at least 1 treatment-emergent adverse event (TEAE). A total of ||| ||||||| patients experienced grade 3 or higher TEAEs. The most frequent TEAEs (experienced by at least 20% of patients) by preferred term (PT) were CRS (80 patients [51.0%]), pyrexia (not attributed to CRS; || |||||||), fatigue (|| |||||||), neutropenia (|| |||||||||), nausea) (|| |||||||||), anemia (|| |||||||||), and diarrhea (|| |||||||). The most common grade 3 or 4 TEAEs (experienced by ≥ 5% of patients) by PT in patients with LBCL (N = 157) were neutropenia (|| ||||||| patients), anemia (|| ||||||| patients), neutrophil count decrease (|| |||||| patients), COVID-19 (|| |||||| patients), and thrombocytopenia (| |||||| patients). Serious TEAEs were reported in ||| ||||||| patients. The most frequent serious TEAEs (experienced by ≥ 2% of patients) by PT in patients with LBCL were CRS (|| |||||||||); COVID-19 (|| |||||| patients); COVID-19 pneumonia (| |||||| patients); pleural effusion (| ||||||||); pneumonia (| |||||| patients); pyrexia (not attributed to CRS); sepsis; immune effector cell–associated neurotoxicity syndrome (ICANS); and febrile neutropenia (| |||||| patients each). ||||| patients experienced at least 1 TEAE that led to treatment discontinuation, and ||||| of patients had at least 1 TEAE that led to delayed dosing.

CRS: Eighty patients (51.0%) had at least 1 CRS event. The majority of these were grade 1 (50 patients out of 80 patients) and occurred most frequently after the first full dose of epcoritamab (65 patients out of 80 patients). Grade 2 and grade 3 events occurred in 25 patients and 5 patients, respectively, out of 80 patients. There were no grade 4 or 5 events. The CRS symptoms resolved in || || || ||||||| patients.

ICANS: ICANS events were reported in 10 patients (6.4%); of these, 7 patients (4.5%) had grade 1 ICANS, 2 patients (1.3%) had grade 2 ICANS, and 1 patient (0.6%) had grade 5 (fatal) ICANS. | ||||||| patients experienced ICANS events that led to dose delay, and in | ||||||| patient, this event led to treatment discontinuation.

Clinical tumour lysis syndrome (CTLS): Two patients (1.3%) experienced CTLS events. Both were grade 3 in severity. ||||||| ||||| ||| |||||||| ||||| || ||| ||||||||| |||||| ||||| ||| || ||||||| ||||||||||||||.

Critical Appraisal

The EPCORE NHL-1 trial is an ongoing, phase I and II, multicentre, open-label, single-arm study of epcoritamab. The trial is being conducted as part of a clinical trial program, including the ongoing comparative phase III trial, EPCORE DLBCL-1. The single-arm trial was justified considering that the study was designed as an early-phase I and II study in which an internal comparator group is not required; it is also justified given the severity of illness for patients at this stage (i.e., those with refractory or relapsed illness after at least 2 lines of prior systemic therapy). However, the decision to conduct a single-arm study has implications for the overall strength and interpretability of the results. There is an increased risk of bias in the estimation of treatment effects due to the potential for confounding related to natural history and prognostic factors. The potential influence of selection bias is also difficult to ascertain in a single-arm study. Additionally, time-to-event end points cannot be adequately assessed in a single-arm trial because all patients receive the same treatment. As such, the effect of epcoritamab on time-to-event end points, such as PFS, OS, and DOR, is uninterpretable, and can be considered as exploratory and supportive only.

Health Canada issued a Notice of Compliance with conditions (NOC/c) for epcoritamab based on promising results from the EPCORE NHL-1 trial. In the absence of a comparator group in the trial, assessing the comparative clinical value of epcoritamab relies on indirect treatment comparisons (i.e., unanchored, matching-adjusted indirect comparisons [MAICs]), which rely on numerous assumptions about the comparability of treatment groups, thereby increasing the uncertainty related to the comparative efficacy. The uncertainty in the comparative efficacy of epcoritamab versus relevant comparators was acknowledged by Health Canada, which has specified that the sponsor must provide phase III trial results showing that epcoritamab improves the OS of patients with DLBCL compared to investigator's choice of either bendamustine plus rituximab (BR) or R-GemOx. In addition to the single-arm design, the study was administered in an open-label manner: the investigator and study participants were aware of their treatment status, potentially increasing the risk of detection and performance biases. As such, the open-label trial design limits the interpretability of the subjective study outcomes, such as tumour response, patient-reported outcomes (PROs) (including HRQoL), and AEs. To mitigate the impact of this bias, PFS and ORR were assessed by both the IRC and investigator using the Lugano classification criteria for the response.

The EPCORE NHL-1 study was an international, multicentre study, and the clinical experts consulted by CADTH had no concerns regarding the generalizability of its results to the Canadian setting. The experts noted that the baseline characteristics were a reasonable reflection of the patient population for whom epcoritamab could be considered an appropriate treatment in clinical practice in Canada. The proportion of patients with an Eastern Cooperative Oncology Group (ECOG) Performance Status of 2 was relatively low (3.2%); the clinical experts noted that this could be greater in clinical practice, especially given that the indication is limited to those who are ineligible for CAR T-cell therapy. The clinical experts noted that 40% of patients with prior CAR T-cell therapy exposure is a reasonable reflection of the target population in Canada (although percentages would vary across jurisdictions), and that the overall proportion of patients with stem cell transplant could be slightly lower than might be anticipated in routine practice in Canada for patients for whom 2 or more lines of systemic therapy have not been effective. The treatment regimen used in the EPCORE NHL-1 trial aligns with the recommendations on the Health Canada–approved product monograph for epcoritamab (i.e., a priming dose of 0.16 mg, an intermediate dose of 0.8 mg, and a full dose of 48 mg thereafter).⁷ The clinical experts consulted by CADTH noted that the dosages of epcoritamab and the medications used to manage AEs during the treatment period are reflective of the regimen that would be administered in practice in Canada.

GRADE Summary of Findings and Certainty of the Evidence

For the pivotal studies and randomized controlled trials (RCTs) identified in the sponsor’s systematic review, Grading of Recommendations Assessment, Development and Evaluation (GRADE) was used to assess the certainty of the evidence for the outcomes considered most relevant to inform CADTH’s expert committee deliberations, and a final certainty rating was determined as outlined by the GRADE Working Group.^9,10 Although GRADE guidance is not available for noncomparative studies, the CADTH review team assessed pivotal single-arm trials for study limitations (which refers to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias to present these important considerations. Because the lack of a comparator arm does not allow a conclusion to be drawn on the effect of the intervention versus any comparator, the certainty of evidence for single-arm trials started at very low certainty, with no opportunity for rating up.

The selection of outcomes for GRADE assessment was based on the sponsor’s Summary of Clinical Evidence, consultation with clinical experts, and input received from patient and clinician groups and public drug plans. The following list of outcomes was finalized in consultation with expert committee members: median OS, median PFS, change from baseline in HRQoL, and clinical response (i.e., CR, ORR, and median DOR). For time-to-event outcomes, landmark analyses at 12 months and 18 months were also of interest.

When possible, certainty was rated in the context of the presence of an important (nontrivial) treatment effect; if this was not possible, certainty was rated in the context of the presence of any treatment effect (i.e., the clinical importance is unclear). In all cases, the target of the certainty of evidence assessment was based on the point estimate and its location relative to the threshold for a clinically important effect (when a threshold was available) or to the null.

The target of the certainty of evidence assessment was the presence of a clinically important improvement in survival (OS and PFS) and HRQoL, which were considered the most important outcomes of treatment by the clinical experts consulted by CADTH, the clinician group, and patient groups. According to the clinical experts consulted by CADTH, clinically important thresholds for the outcomes of OS and PFS were a benefit of at least 6 months and 3 months over current standard of care for OS and PFS, respectively. Additionally, response to treatment (CR, ORR, and DOR) was included in the certainty of evidence assessment based on the potential translation to long-term survival outcomes.

Table 2: Summary of Findings on Epcoritamab for Patients With R/R DLBCL

CFB = change from baseline; CI = confidence interval; CR = complete response; DLBCL = diffuse large B-cell lymphoma; DOR = duration of response; FACT-G = Functional Assessment of Cancer Therapy–General; FACT-Lym = Functional Assessment of Cancer Therapy–Lymphoma; HRQoL = health-related quality of life; IRC = independent review committee; NR = not reported; ORR = objective response rate; OS = overall survival; PFS = progression-free survival; R/R = relapsed or refractory; SD = standard deviation.

Note: All serious concerns with respect to study limitations (which refer to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias are documented in the table footnotes.

^aIn the absence of a comparator group, conclusions about efficacy relative to any comparator cannot be drawn, and the certainty of evidence is started at very low.

^bIn the EPCORE NHL-1 trial, statistical testing for this outcome was not adjusted for multiplicity. The results are considered as supportive evidence.

^cRated down 1 level for serious imprecision due to the low number of events and the small sample size.

^dRated down 1 level for serious risk of bias due to potential for bias arising from the open-label nature of the study and the subjective nature of the outcome.

^eDespite the study limitations resulting in the certainty of evidence starting as “very low,” the outcomes of CR and ORR are demonstrative of an antitumour effect, which is supported by regulatory authorities (FDA, Health Canada, and European Medicines Agency). As such, given the effect size, which was believed to be large and clinically important, the CADTH review team considered the certainty of this evidence to be higher. Note that the outcome could be rated down 1 level for serious indirectness because a surrogate outcome (ORR) was used as the primary outcome in the place of OS and PFS.

Source: Sponsor’s clinical submission.¹¹

Indirect Treatment Comparisons

Description of Studies

One sponsor-submitted, indirect treatment comparison (ITC) was summarized and critically appraised by CADTH. The MAICs focused on 3 patient populations: the overall population of patients with LBCL; the population of patients with LBCL with no prior CAR T-cell therapy; and the population of patients with LBCL without prior CAR T-cell therapy who were considered eligible to receive CAR T-cell therapy. The ITCs of interest for the CADTH review were epcoritamab versus pola-BR and R-CIT. The sponsor-submitted ITC included comparisons against 3 CAR T-cell therapy regimens: axicabtagene ciloleucel, tisagenlecleucel, and lisocabtagene maraleucel. Given that the Health Canada–approved indication for epcoritamab states that the drug is approved for use only in patients “who have previously received or are unable to receive CAR T-cell therapy,” CADTH does not consider CAR T-cell therapies to be relevant comparators for the current review. The approach is consistent with applications that have been filed in the same therapeutic area. Outcomes evaluated in the MAIC included OS, PFS, ORR, and CR.

Efficacy Results

Epcoritamab Versus Polatuzumab Vedotin With Rituximab, With or Without Bendamustine (Overall Population of Patients With LBCL)

In the adjusted overall population of patients with LBCL, the sponsor reported that epcoritamab was associated with significant improvements in both PFS |||| |||||| ||| ||| ||||| || |||||| | | |||||| and OS |||| |||||| ||| ||| ||||| || |||||| | | |||||| compared to polatuzumab vedotin with rituximab, with or without bendamustine (pola-B/R). The sponsor also reported a significant improvement with epcoritamab versus pola-B/R in both CR rate ||||||| ||| ||| ||||| || |||||| |||||||| and ORR ||||||| ||| ||| |||| || |||||| | | ||||||.

Epcoritamab Versus Pola-BR (Patients Without Prior CAR T-Cell Therapy)

Compared with pola-BR in the analysis for patients with prior CAR T-cell therapy, the sponsor reported no significant difference in PFS |||| |||||| ||| ||| ||||| || |||||| | | ||||||, OS |||| |||||| ||| ||| ||||| || |||||| | | ||||||, or CR rate ||||||| ||| ||| |||||| || |||||| | | ||||||. The sponsor reported that epcoritamab was associated with an improvement in ORR versus pola-BR ||||||| ||| ||| |||| || |||||| | | ||||||.

Epcoritamab Versus Chemoimmunotherapy (Patients Without Prior CAR T-Cell Therapy)

PFS could not be reported for the comparison versus R-CIT in the population of patients with LBCL with no prior CAR T-cell therapy. Compared to chemoimmunotherapy (CIT), the sponsor reported that epcoritamab was associated with significant improvements in OS |||| |||||| ||| ||| ||||| || |||||| | | ||||||; CR rate ||||||| ||| ||| ||||| || |||||| | | ||||||; and ORR ||||||| ||| ||| ||||| || |||||| | | ||||||.

Critical Appraisal

Given the lack of direct evidence comparing epcoritamab to relevant treatments in the R/R DLBCL third-line setting, the sponsor’s decision to conduct an ITC (i.e., unanchored MAIC) was justified. There were important differences in the design of the included studies and the cohorts evaluated that limit the ability to draw strong conclusions about the efficacy of epcoritamab compared with pola-BR and R-CIT. The EPCORE NHL-1 study of epcoritamab was a phase I and II, single-arm study, whereas the GO29365 study was a comparative, phase Ib and II randomized, open-label study; the SCHOLAR-1trial was a retrospective research study; and Liebers et al. (2021) was a real-world study. In addition, all the comparisons involved the use of subgroup data from 1 or both of the studies included in the ITC.

In addition to differences in study design, there were notable differences in the eligibility criteria of the included studies, resulting in heterogeneity in baseline characteristics across populations. The sponsor provided a comprehensive list of likely prognostic factors and treatment-effect modifiers (identified through consultation with clinical experts). However, adjustment of all these factors could not be achieved due to differences in reporting across the various studies and a lack of access to patient-level data (other than for those enrolled in the EPCORE NHL-1 trial). It is unclear if the lack of adjustment for differences in baseline characteristics (particularly those that may be prognostic. such as primary refractory disease) would have an impact on the results of the MAIC. A key limitation of the sponsor-submitted MAICs, which is a limitation inherent to all unanchored MAICs, is that it assumes that all effect modifiers and prognostic factors are accounted for in the model. This assumption is largely considered impossible to meet, according to the National Institute for Health and Care Excellence (NICE) Decision Support Unit Technical Guidance report on the methods for population-adjusted indirect treatment comparisons (ITCs).

Overall, CADTH concluded that there were multiple limitations in the sponsor-submitted MAICs, including differences in inclusion and exclusion criteria, heterogeneity in baseline characteristics across studies, and notable reductions in sample sizes due to matching and weighting. There was also significant uncertainty about the overall generalizability of the results to the population in Canada. Additionally, wide 95% CIs led to imprecision and uncertainty in the results.

CADTH notes that the Haute Autorité de Santé (HAS) in France similarly concluded that no formal conclusions can be drawn from the sponsor’s MAICs, citing methodological limitations that include uncertainty regarding the quality of the data (particularly the real-world evidence [RWE]), significant heterogeneity between the populations included in the different studies, and residual differences across the various treatments after weighting. However, NICE acknowledged that, despite the uncertainty associated with the sponsor’s MAICs, epcoritamab was likely to be more effective than R-CIT based on the sponsor’s MAIC. Clinical experts consulted by NICE noted that epcoritamab could plausibly be more effective than pola-BR; however, the NICE expert committee noted that there was too much uncertainty with the ITC and concluded that an assumption of equal efficacy would be more appropriate to inform the economic evaluation.

Long-Term Extension Studies

Not applicable.

Studies Addressing Gaps in the Evidence From the Systematic Review

Not applicable.

Consideration for a Time-Limited Recommendation

A time-limited reimbursement (TLR) recommendation is a recommendation by the CADTH expert committee to publicly fund a drug or drug regimen for a certain period of time based on the condition that the sponsor will conduct 1 or more clinical studies that address uncertainty in the clinical evidence. CADTH would subsequently conduct a reassessment of the additional evidence and issue a final reimbursement recommendation within a defined period of time. Based on the preliminary assessment by CADTH, epcoritamab meets the criteria to be considered by the expert committee for a TLR recommendation.

The basis for the TLR recommendation and subsequent reassessment would be the ongoing EPCORE DLBCL-1 phase III study, which is comparing epcoritamab monotherapy with investigator’s choice of either BR or R-GemOx for improvement in the OS of patients with DLBCL. The primary end point is OS, and the NOC/c Qualifying Notice from Health Canada states that the sponsor should acknowledge that authorization may be revoked if the trial fails to show an OS benefit for epcoritamab over BR or R-GemOx. The clinical experts consulted by CADTH expressed concerns regarding the choice of comparator in the EPCORE DLBCL-1 trial (i.e., BR or R-GemOx) because it was felt that the efficacy data from the EPCORE NHL-1 trial were compelling and that BR and R-GemOx would be associated with significant toxicities for patients. The experts noted that patients at this stage of disease would likely have already received R-CIT in the course of disease and been shown to be refractory to the treatment; as such, the experts expressed concerns regarding clinical equipoise in the trial, with a belief that those randomized to BR or R-GemOx would be receiving an inferior treatment option. The clinical experts noted that more appropriate comparators would be newer therapies that have recently emerged in the second- and third-line setting, such as pola-BR and CAR T-cell therapy. CADTH noted that the curative potential of CAR T-cell therapy would typically make this the preferred option for many patients. This could pose challenges in the design and conduct of a comparative clinical trial.

In its comments on the draft report, the sponsor clarified that at the start of the EPCORE DLBCL-1 study (January 2021), neither CAR T-cell therapy nor pola-BR were widely used. Therefore, R-CIT was considered the most appropriate comparator, and CIT remains a treatment option in practice in Canada for the treatment of R/R LBCL. CADTH agrees with the sponsor’s assessment regarding the choice of comparator at the time of initiating the EPCORE DLBCL-1 trial. (The final CADTH recommendation for pola-BR was issued in April 2021, 4 months after the trial began.)

Conclusions

One phase I and II, single-arm, open-label trial, the EPCORE NHL-1 trial, provided evidence for the efficacy and safety of epcoritamab in adult patients with R/R LBCL who have relapsed after or have not responded to at least 2 prior systemic therapies. Clinicians and patients highlighted the need for accessible, alternative treatment options for patients in this treatment setting. Improvements in survival were considered the most important outcomes of treatments by patients and clinicians. Although OS and PFS were evaluated in the EPCORE NHL-1 trial, the single-arm design precludes the ability to accurately evaluate the impact of epcoritamab treatment on these important end points. Nonetheless, the study demonstrated that ||||| of patients achieved CR, which was considered a clinically important result by the clinical experts consulted by CADTH. HRQoL is an outcome that is important to patients, and many patients in the EPCORE NHL-1 trial demonstrated improvements from baseline after initiating the treatment; however, due to the noncomparative design, high patient attrition rates, and open-label administration of the treatment, the effect of epcoritamab on HRQoL remains uncertain. Overall, the clinical experts consulted by CADTH believe the results demonstrated that epcoritamab offers clinically meaningful improvements for this heavily pretreated patient population and may help address an unmet medical need for a treatment that may extend life, improve symptoms, and be considered tolerable by patients.

Harms associated with epcoritamab were largely consistent with the mechanism of action, including a high frequency of patients experiencing CRS (50.1%) and serious infections (|||||||). All patients received pretreatment with standardized medications (i.e., prednisolone, diphenhydramine, and acetaminophen) to mitigate the risk of CRS. The majority of patients recovered from the CRS events, and the product monograph provides detailed guidance on grading and managing these events in practice. The clinical experts consulted by CADTH noted that patients will likely require hospitalization for a 24-hour monitoring period after the first full dose of epcoritamab (because outpatient monitoring may be challenging) and that this requirement may pose important challenges for the health system and could limit the adoption of the treatment.

There were important limitations with the sponsor-submitted ITCs that were used to inform the comparative effectiveness of epcoritamab versus R-CIT and pola-BR (which were the comparators considered most relevant for this review, given the Health Canada–approved indication for epcoritamab). Results for the MAICs varied across the comparisons for epcoritamab versus pola-B/R, with the sponsor claiming significant improvements in PFS, OS, CR rate, and ORR in the overall population of patients with LBCL and no significant difference in PFS, OS, or CR rate in the population without prior CAR T-cell therapy. CADTH considered the analyses of epcoritamab versus pola-BR to be associated with significant uncertainty due to small sample sizes and heterogeneity across the studies and patient populations. The sponsor’s MAIC suggested that epcoritamab was superior to CIT for patients with no prior exposure to CAR T-cell therapy. The clinical experts consulted by CADTH felt that it was plausible that treatment with epcoritamab could offer greater clinical benefits for patients in comparison to R-CIT for the target patient population on the basis that these patients have already demonstrated disease progression and drug resistance following exposure to their initial R-CIT regimen (typically R-CHOP) and that the potential toxicity of R-CIT regimens at this stage of disease can limit the regimens’ clinical utility. However, important limitations with the MAIC make it challenging to quantify the magnitude of potential added benefit and preclude the ability to draw evidence-based conclusions regarding the comparative effectiveness of epcoritamab versus R-CIT. Given that the sponsor has been mandated by Health Canada to conduct a head-to-head trial against R-CIT in the relevant patient population, there will be direct evidence to inform the comparative clinical benefit. This evidence could be included in a reassessment application as part of a TLR.

Introduction

The objective of this report is to review and critically appraise the evidence submitted by the sponsor on the beneficial and harmful effects of epcoritamab for the treatment of adult patients with R/R DLBCL not otherwise specified, DLBCL transformed from indolent lymphoma, HGBCL, PMBCL, or FLG3B after 2 or more lines of systemic therapy who have previously received or are unable to receive CAR T-cell therapy.

Disease Background

The contents of this section were informed by materials submitted by the sponsor and by clinical expert input. These have been summarized and validated by the CADTH review team.

DLBCL is the most common type of NHL, accounting for 30% to 40% of all NHL cases in Canada.¹ DLBCLs are a heterogeneous group of aggressive B-cell malignancies that differ in clinical presentation, molecular features, prognosis, and treatment options. Some types of indolent B-cell lymphomas (e.g., follicular lymphoma) can transform into DLBCL.^1,2

Patients with DLBCL typically present with enlarged symptomatic masses in the lymph nodes, typically in the neck, chest, or abdomen; however, widespread DLBCL can also arise in tissues outside the lymph nodes (i.e., extranodal involvement), such as in the bone marrow, bones, brain, and gastrointestinal tract, among others. DLBCL can also cause systemic B symptoms (i.e., unexplained fever, weight loss, and night sweats) and elevated serum lactate dehydrogenase.⁴

DLBCL is an aggressive disease that is typically diagnosed in more advanced stages; however, 30% to 40% of patients are diagnosed when the disease is localized (stage I or II).² It is diagnosed through surgical or core needle biopsy, usually of an involved lymph node or extranodal site. Histological evaluation is performed in accordance with the WHO classification of lymphoid neoplasms, which categorizes lymphomas on the basis of cytology, immunophenotype, and genetic and clinical features.¹² A morphological diagnosis of the cell of origin to distinguish between activated B-cell type (25% to 30% of DLBCL cases) and germinal centre B-cell (GCB) type (approximately 60% of DLBCL cases) is generally confirmed by immunohistochemistry or flow cytometry and has been considered a major prognostic factor in the first-line treatment of DLBCL.^6,13-16 Other molecular subtypes with prognostic implications have been identified, including double-hit lymphoma (with concurrent translocations of MYC and either BCL2 or BCL6), a particularly aggressive, high-risk subtype with poor prognosis.^12,17 Double-expressor lymphoma (with overexpression of MYC and BCL2) is not considered a separate entity, and has also been associated with a worse prognosis.^18,19 However, the prognostic significance of these biomarkers remains controversial, and optimal clinical management has not been established.^19-22

Disease staging is crucial for determining the appropriate treatment and assessing the prognosis. The gold standard for staging patients with DLBCL is PET or CT scan. Patients are initially divided into 2 groups by stage: limited or advanced. The extent of DLBCL is determined using the Ann Arbor staging classification system, which further categorizes the disease into 4 stages according to the extent of lymph node and extranodal sites involvement. For prognostic purposes, the International Prognostic Index (IPI) is calculated to assign a prognosis to patients undergoing treatment with chemotherapeutic regimens.²³

There are limited estimates of DLBCL incidence and prevalence in Canada. The Canadian Cancer Society estimated that 11,400 people in Canada were diagnosed with NHL in 2022 (with approximately 40% of cases being DLBCL), with 3,000 dying from the disease.^1,3 International studies have estimated the incidence of DLBCL in the US and UK at approximately 7 cases per 100,000 persons per year.⁴

Although the cure rate of DLBCL is high, 30% to 50% of patients will relapse after or be refractory to treatment with standard, first-line R-CHOP or a similar regimen.^16,24 The estimated 5-year relative survival at diagnosis with DLBCL was 63.8% in the US, based on statistics from 1975 through 2017.⁵ Until the recent approval of CAR T-cell therapy, treatment for patients not eligible for SCT or who relapsed after SCT had been largely palliative, with median survival being approximately 6 months.²⁵

Standards of Therapy

The contents of this section were informed by materials submitted by the sponsor and clinical expert input. These have been summarized and validated by the CADTH review team.

First-line treatment for DLBCL is relatively standardized across Canada, with most patients receiving R-CHOP once every 3 weeks.^6,26 While most patients respond well to R-CHOP, 30% to 50% of patients will either be refractory to or relapse following first-line therapy. Patients who relapse early (within 12 months)¹ and patients with refractory disease have worse prognoses than those who do not relapse within 12 months, even with second-line therapy.^26,27

Patients requiring second-line treatment for R/R DLBCL are classified based on their eligibility to receive SCT. Based on the Canadian Evidence-Based Guideline for the Treatment of R/R DLBCL, for patients who are refractory to R-CHOP or who relapse after 12 months of R-CHOP, the standard approach consists of salvage, platinum-based chemotherapy followed by high-dose chemotherapy and ASCT (for patients with chemosensitive disease who meet the eligibility criteria for transplant). In patients who are ineligible for SCT, second-line treatment options include pola-BR or chemotherapy, with or without rituximab.^1,6

Currently, CAR T-cell therapy is approved in Canada for patients with R/R DLBCL following 2 or more lines of therapy. As such, CAR T-cell therapy is the standard treatment approach for patients with R/R DLBCL who do not respond to salvage chemotherapy (i.e., who are transplant-ineligible) or who relapse after SCT.^1,6 Though currently not adopted, CAR T-cell therapy may be offered as second-line treatment to eligible patients.²⁸

For patients who are not chemosensitive and are ineligible for ASCT and relapse after SCT or CAR T-cell therapy, the prognosis is poor, and there is no standard treatment approach. Available options are currently limited to palliative chemotherapies — including R-GemOx, pola-BR, and tafasitamab with lenalidomide — or clinical trials with novel drugs.^1,6 Tafasitamab with lenalidomide received a “do not reimburse” recommendation from CADTH and is not currently reimbursed by participating drug programs.⁸

Based on input from the clinician groups, novel drugs — including ibrutinib, lenalidomide, tafasitamab, and obinutuzumab — are available through compassionate access programs in Canada, but generally do not have Health Canada approvals or provincial funding for the treatment of R/R DLBCL.

Drug Under Review

Mechanism of Action

Epcoritamab is a humanized immunoglobulin gamma-1–bispecific antibody that binds to a specific extracellular epitope of CD20 on B-cells and to CD3 on T-cells. The activity of epcoritamab is dependent upon the simultaneous engagement of CD20-expressing cells and CD3-expressing endogenous T-cells by epcoritamab, which induces specific T-cell activation and T-cell–mediated killing of CD20-expressing cells.⁷

Dosing and Administration

Epcoritamab is administered through SC injection at step-up doses of 0.16 mg, 0.8 mg, and 48 mg according to the following schedule:

• Cycle 1: 0.16 mg (priming dose) on day 1; 0.8 mg (intermediate dose) on day 8; 48 mg (full dose) on day 15

• Cycles 2 and 3: 48 mg once per week over a 28-day period (days 1, 8, 15, and 22 of a 28-day cycle)

• Cycles 4 through 9: 48 mg once every 2 weeks (days 1 and 15 only of each cycle)

• Cycle 10 and onward: 48 mg once every 4 weeks (day 1 only of each 28-day cycle)⁷

Table 3: Dosing Schedule for Epcoritamab

Source: Epcoritamab product monograph.⁷

Recommended Premedication for CRS

The product monograph recommends that prophylaxis be initiated against Pneumocystis jirovecii pneumonia (PJP) and herpes virus infections before starting treatment with epcoritamab. Epcoritamab should be administered only under the supervision of a health professional experienced in the treatment of cancer patients who has access to appropriate medical support to manage severe reactions, such as CRS and ICANS. Recommended premedications for CRS are summarized in Table 4.⁷

Table 4: Recommended Premedications for CRS

CRS = cytokine release syndrome.

^aPatients will be permanently discontinued from epcoritamab after a grade 4 CRS event.

Source: Epcoritamab product monograph.⁷

Approved Indication and Reimbursement Request

Epcoritamab has been approved by Health Canada for the treatment of adult patients with R/R DLBC not otherwise specified, DLBCL transformed from indolent lymphoma, HGBCL, PMBCL, or FLG3B after 2 or more lines of systemic therapy who have previously received, or are unable to receive, CAR T-cell therapy. The sponsor has requested that epcoritamab be reimbursed in accordance with the indication approved by Health Canada. Figure 1 summarizes the sponsor’s proposed place in therapy for epcoritamab.

Figure 1: Sponsor’s Proposed Place in Therapy for Epcoritamab for LBCL

ASCT = autologous stem cell transplant; BR = bendamustine plus rituximab; CAR = chimeric antigen receptor; CIT = chemoimmunotherapy; LBCL = large B-cell lymphoma; pola-BR = polatuzumab vedotin with bendamustine and rituximab; R-CHOP = rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone.

^a Alternate rituximab-based chemotherapy regimens.

^b Pola-BR is funded only for patients with DLBCL who are ineligible for ASCT and have received at least 1 prior therapy.

^c CAR T-cell therapy options include lisocabtagene maraleucel, tisagenlecleucel, and axicabtagene ciloleucel.

^d For patients who have previously received or are unable to receive CAR T-cell therapy.

Source: Sponsor submission materials.

CAR T-Cell Therapy Considerations

The Health Canada–approved indication for both epcoritamab and glofitamab limits the approved usage to patients “who have previously received or are unable to receive CAR T-cell therapy.” This indication is more restrictive than the approved labels from the FDA, European Medicines Agency, and UK Medicines and Health care products Regulatory Agency^29-31 and the proposed indication currently under review by the Therapeutic Goods Administration in Australia. None of these organizations has included the condition that patients have previously received CAR T-cell therapy or are unable to receive CAR T-cell therapy.

CADTH sought clarification from the sponsor regarding the rationale for the wording in the indication because patients in the EPCORE NHL-1 trial were not required to have previously received CAR T-cell therapy or be unable to receive CAR T-cell therapy (i.e., this was not stated in the eligibility criteria for the trial). The sponsor stated that Health Canada provided advance feedback indicating that, to qualify for the NOC/c review process, AbbVie should modify the proposed indication to focus on populations with high unmet medical needs (e.g., patients who have received CAR T-cell therapy). Following the feedback from Health Canada, AbbVie proposed wording for the indication that met the NOC/c criteria of unmet medical need (i.e., “…where patient is unable to receive or has previously received CAR T-cell therapy.”)

The sponsor noted that from a clinical perspective, the current Health Canada–approved indication allows for use by patients:

• after CAR T-cell therapy

• who are ineligible to receive CAR T-cell therapy

• who are eligible to receive CAR T-cell therapy, but did not (e.g., due to logistical challenges or choice).

The clinical experts consulted by CADTH agreed with the sponsor’s interpretation of the indication, identified these patient groups as potential candidates for epcoritamab, and similarly noted that the approved indication is not reflective of the trial population for the EPCORE NHL-1 study. In addition, the clinical experts noted that some patients who are ineligible to receive CAR T-cell therapy at the time of initiating treatment with epcoritamab may subsequently become eligible for CAR T-cell therapy if their disease status changes or other barriers to CAR T-cell therapy access cease to apply.

The clinical experts noted that the treatment landscape for R/R LBCL in Canada may shift toward earlier usage of CAR T-cell therapy because axicabtagene ciloleucel (Yescarta) received a favourable recommendation from CADTH for use as a second-line option based on the results of the ZUMA-7 trial. Axicabtagene ciloleucel was under review by the pan-Canadian Pharmaceutical Alliance at the time of this review and was not funded by any of the participating drug programs (refer to Figure 1).

As part of the NOC/c requirements, AbbVie will file confirmatory evidence of efficacy in the setting of R/R DLBCL in the form of a Supplement to a New Drug Submission – Confirmatory (SNDS-C). Upon approval of this SNDS-C, conditions associated with the NOC would be removed by Health Canada.

Non-DLBCL Forms of Aggressive NHL

Health Canada considered the small number of patients enrolled in the EPCORE NHL-1 trial who had forms of aggressive B-cell non-Hodgkin lymphoma (aNHL) other than DLBCL (i.e., those with HGBCL, PMBCL, and FLG3B) and noted that adequately powered clinical studies would be problematic to conduct given the rarity of these subtypes. After an examination of response rates in these patients, Health Canada concluded that epcoritamab demonstrated efficacy and that these patients are treated in the same manner as those with DLBCL in clinical practice.³² This included patients living with HGBCL, a more aggressive form of aNHL than DLBCL. The approved indication for epcoritamab specifically identifies approval for use in HGBCL, which is different from the indications for the other Health Canada–approved regimens for R/R LBCL (i.e., glofitamab, polatuzumab vedotin, pembrolizumab, and tafasitamab).^7,33-36 Keytruda (pembrolizumab) has been approved for use in the treatment of adult and pediatric PMBCL and in patients who have relapsed after 2 or more lines of therapy. The sponsor recently declined to file a submission to CADTH for this indication. The clinical experts consulted by CADTH noted that the evidence supports the efficacy of epcoritamab for patients with rarer forms of lymphoma.

Table 5: Health Canada–Approved Indications for Use in R/R LBCL

DLBCL = diffuse large B-cell lymphoma; FLG3B = follicular lymphoma grade 3B; HGBCL = high-grade B-cell lymphoma; LBCL = large B-cell lymphoma; NOS = not otherwise specified; PMBCL = primary mediastinal B-cell lymphoma; pola-BR = polatuzumab vedotin with bendamustine and rituximab; R//R = relapsed or refractory.

^aReceived a draft recommendation from CADTH in favour of reimbursement.

^bReceived a final recommendation from CADTH in favour of reimbursement.

^cSome participating jurisdictions provide reimbursement for pola-BR for this population.

^dPolatuzumab vedotin with rituximab, cyclophosphamide, doxorubicin, and prednisone is indicated for the treatment of adult patients with previously untreated LBCL, including diffuse DLBCL NOS, HGBCL, Epstein-Barr virus–positive DLBCL NOS, and T-cell or histiocyte-rich LBCL.

^eSponsor declined to file a submission with CADTH for this indication.

Conditional Regulatory Approval

Health Canada issued an NOC/c for epcoritamab with the following key confirmatory requirements regarding efficacy:

• The sponsor should commit to the submission of a clinical trial for the purposes of providing confirmatory evidence of efficacy in the setting of R/R DLBCL. Specifically, the primary analyses of Study GCT3013 to 05: A Randomized, Open-Label, Phase 3 Trial of Epcoritamab vs Investigator’s Choice Chemotherapy in Relapsed/Refractory Diffuse Large B-cell Lymphoma (EPCORE DLBCL-1) should be submitted to Health Canada as an SNDS-C.

• The primary efficacy objective of the EPCORE DLBCL-1 phase III study is to demonstrate that epcoritamab monotherapy improves the OS of patients with DLBCL compared to investigator’s choice of either BR or R-GemOx. The sponsor should acknowledge that authorization may be revoked if the trial fails to show an OS benefit for epcoritamab over investigator’s choice of therapy. The sponsor should provide an estimated date of completion of the primary analyses for the study as well as an estimated date for the submission of the study to Health Canada.

Characteristics of Drugs for Patients With R/R LBCL

Epcoritamab has not been previously reviewed by CADTH. Its key characteristics are summarized in Table 6 along with those of other treatments available for R/R LBCL.

Table 6: Key Characteristics of Epcoritamab, Glofitamab, and Combination Chemotherapy

ADC = antibody-drug conjugate; CAR = chimeric antigen receptor; CD3 = cluster of differentiation 3; CD20 = cluster of differentiation 20; CD79b = cluster of differentiation 79b; CRS = cytokine release syndrome; DLBCL = diffuse large B-cell lymphoma; FLG3B = follicular lymphoma grade 3B; HBV = hepatitis B virus; HGBCL = high-grade B-cell lymphoma; ICANS = immune effector cell–associated neurotoxicity syndrome; mAb = monoclonal antibody; MMAE = monomethyl auristatin E; NA = not applicable; PMBCL = primary mediastinal B-cell lymphoma; PML = progressive multifocal leukoencephalopathy; pola-BR = polatuzumab vedotin with bendamustine and rituximab; R-GDP = rituximab plus gemcitabine, dexamethasone, cisplatin; R-GemOx = rituximab, gemcitabine, and oxaliplatin; R-ICE = rituximab plus ifosfamide, carboplatin, etoposide; R/R = relapsed or refractory; SC = subcutaneous; TLS = tumour lysis syndrome; trFL = follicular lymphoma.

Source: Product monographs for epcoritamab,⁷ glofitamab (Columvi) for injection,³³ polatuzumab vedotin (Polivy) for injection,³⁴ and rituximab (Rituxan) for injection.³⁷

Stakeholder Perspectives

Patient Group Input

This section was prepared by the CADTH review team based on the input provided by patient groups. The full original patient inputs received by CADTH are included in the Stakeholder Perspectives section of this report.

Two patient groups, LC and LLSC, responded to CADTH’s call for patient input for the current review of epcoritamab. LC is a national Canadian registered charity that empowers the lymphoma community through education, support, advocacy, and research. LLSC is a national organization dedicated to finding a cure for blood cancers and supporting patients and their families by funding life-enhancing research and providing educational resources, services, and support.

LC gathered information for this submission through a survey from October 3, 2023 to November 20, 2023, targeting patients living with LBCL. The LC survey data included 33 respondents. The LC information included a submission from France that was based on a survey regarding the use of epcoritamab for DLBCL conducted by Ensemble Leucémie Lymphomes Espoir, with 9 survey respondents; this was supported by the results of the Lymphoma Coalition's 2022 survey, which included the experiences of patients with DLBCL (n = 171). LLSC conducted 4 1-on-1 interviews in November 2023; 2 interviewees were patients with DLBCL, and 2 were caregivers. Three interviewees resided in Canada, and 1 resided in the US.

According to both inputs, living with LBCL is associated with extreme fatigue, body aches, nausea, shortness of breath, lack of energy, and stress and worry, all of which have a significant impact on day-to-day activities and patients’ quality of life.

From the LC input, the majority of 15 patients indicated that they had received 1 to 3 or more lines of treatment, such as R-CHOP as first-line treatments; rituximab-based chemotherapy and radiation as second-line treatments; and CAR T-cell therapy and pola-BR as a third-line therapy. While most patients (67%) in the LC survey indicated that they were satisfied with their front-line treatment options, respondents from both surveys stated that there is a lack of second- and third-line treatment options and described difficulties managing treatment regimens and side effects. Currently available treatments take significant mental and psychological tolls on patients and their loved ones, are associated with immense financial burdens, and negatively affect people’s ability to work, travel long distances, and participate in daily activities.

Both inputs indicated that patients expect new treatments to be more effective and less invasive with fewer side effects. Patients are seeking choice in their treatment decisions and would like a variety of options that offer a longer life span, lengthier remission, and better quality of life.

In the LC input, 1 patient from the survey and 8 patients from the French Health Technology Assessment (HTA) submission indicated they were treated with epcoritamab. In the LLSC input, 1 caregiver spoke about their experience with epcoritamab. According to both inputs, patients experienced fewer side effects, and only 1 patient discontinued the treatment due to side effects. Patients indicated that this treatment option could offer hope and relief to many third-line patients. In addition, the SC administration of the drug results in less time spent in hospital per visit, which can improve the quality of life of patients and caregivers.

Clinician Input

Input From 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 LBCL.

Unmet Needs

R/R LBCL is associated with a poor prognosis, and in patients who are not eligible for or who did not respond to cellular therapy (i.e., CAR T-cell therapy and/or ASCT), the outcomes are poor (i.e., OS < 6 months). The clinical experts indicated that the goal of treatment at this stage is palliative and generally includes maintaining HRQoL by relieving lymphoma-related symptoms, delaying disease progression, and balancing the toxicities of therapy. There is no standard of care in this setting, but options include chemotherapy (e.g., pola-BR), radiation, and clinical trials. The experts noted that there is an unmet need for safe, effective treatments for palliative patients who are not eligible for curative treatment (including those who are clinically ineligible or unable to receive treatments for other reasons) or who have not responded to second-line treatment consisting of SCT or CAR T-cell therapy, given that there are limited treatment options for disease control and that currently available options are often associated with significant toxicity, limiting these options’ usefulness and applicability. Additionally, after transplant and CAR T-cell therapy, patients often have a poor prognosis and very poor bone marrow function, which prevents them from receiving or tolerating further cytotoxic therapy.

Input from the experts suggested that there is also a significant group of patients who may be eligible for intensive treatments but unable to access them due to barriers based on geographic location and capacity limitations within the health care system. Many patients are unable to travel with caregivers to specialized cellular therapy sites and choose not to have this treatment because they wish to be treated closer to home. As such, there is an additional unmet need for treatments that patients can access and receive closer to home.

Place in Therapy

First-line treatment for patients with LBCL is administered with curative intent and consists of R-CHOP (or a reduced dose of R-CHOP for patients aged 75 years or older or who have significant comorbid illnesses). Second-line treatment consists of salvage R-CIT and ASCT for transplant-eligible, chemosensitive patients (i.e., curative intent). Third-line therapy can include CAR T-cell therapy (i.e., curative intent). There is no standard of care following these treatment options, and transplant-ineligible patients in the second- and third-line settings tend to receive palliative R-CIT (e.g., pola-BR, rituximab plus gemcitabine, dexamethasone, and cisplatin, or R-GemOx) with noncurative intent, radiation, and/or consideration for enrolment in clinical trials for investigative therapies. The clinical experts highlighted that there is a planned shift in Canada to use CAR T-cell therapy as second-line therapy for primary refractory or early relapsed LBCL, pending funding. The clinical experts emphasized that cytopenias are an important problem with currently available palliative treatment options.

The experts highlighted that epcoritamab should be restricted to patients who are not eligible for curative therapies, have already received CAR T-cell therapy, or would not be able to receive epcoritamab later (i.e., whether as third-line therapy after CAR T-cell therapy or because they are ineligible); they envisioned epcoritamab occupying the same therapeutic space as pola-BR. The clinical experts noted that some patients could be considered for CAR T-cell therapy after receiving treatment with epcoritamab and subsequently experiencing disease progression, including:

• patients who were considered eligible for CAR T-cell therapy and had previously chosen not to receive the treatment, but remain candidates for the therapy after receiving epcoritamab

• patients whose clinical status made them borderline candidates for CAR T-cell therapy due to tumour burden or underlying comorbidity and whose condition improves after receiving epcoritamab to a point where they can be considered candidates for CAR T-cell therapy.

The clinical experts noted that the fixed-dose SC administration of epcoritamab would offer efficiencies for both patients and health care providers compared with the IV administration required for the existing comparator options. In addition, epcoritamab is given as monotherapy, whereas all comparator regimens are administered as combinations. This may reduce the time required for patients to spend at cancer treatment centres, offering improvements in quality of life for patients and their caregivers as well as reductions in the time needed for health care providers to administer the treatments.

Patient Population

The experts noted that these patients would be identified in routine practice by clinicians familiar with the treatment of lymphoma patients undergoing surveillance for relapse (clinical and/or imaging).

In accordance with the indication approved by Health Canada, the clinical experts noted that patients with R/R LBCL requiring third-line or later treatment who are not eligible for or who did not respond adequately to intensive cellular therapies (i.e., SCT or CAR T-cell therapy) would be considered for epcoritamab. The experts could not identify a specific subgroup of patients who would demonstrate an enhanced or reduced benefit from epcoritamab treatment based on available evidence. However, it was noted that patients who cannot receive CAR T-cell therapy because of logistical or geographic reasons could be candidates.

Patients who may not be suitable for epcoritamab could include those who do not want continuous treatment (given that epcoritamab does not have a limited number of cycles and would be administered until disease progression or unacceptable toxicity); those who develop CRS that does not resolve following the first cycle of treatment; and those who are able and willing to receive CAR T-cell therapy. The experts also noted that patients with impaired B-cell or T-cell immunity (e.g., those with hypogammaglobulinemia from multiple previous lines of immune therapies) may have exhausted their T-cells, making a response to epcoritamab less likely.

The experts highlighted that repeat biopsy is generally not required in cases of suspected relapse of LBCL unless it is a remote relapse or the patient had a history of indolent lymphoma and it was unclear which lymphoma had relapsed. Similar to glofitamab, no companion diagnostic test is required for epcoritamab.

The clinical experts noted that epcoritamab could help address an unmet need for patients who may be ineligible for or unwilling to receive additional chemotherapeutic regimens in the third-line setting (e.g., either pola-B/R or R-CIT). The experts noted that third-line CIT would not be expected to have significant response rates among patients who have been heavily pretreated, including with prior exposures to R-CIT in the first-line setting, as well as salvage chemotherapy before ASCT and/or bridging therapy before CAR T-cell therapy. As such, the different mechanism of action offered by bispecific T-cell engagers (i.e., epcoritamab or glofitamab) would be an attractive option for these patients. However, the experts noted that the potential need for hospital admission to monitor for CRS and ICANS could lessen some of the enthusiasm for these new treatment options.

Assessing the Response to Treatment

The clinical experts stated that response to treatment would include standard assessment of lymphoma response using the Lugano criteria. Patients would undergo interim imaging every 3 months to confirm response, which would lead either to ongoing treatment or to discontinuation. Patients are also assessed for lymphoma-related symptoms at each visit; the clinical experts noted that these outcomes are more subjective but do factor into patients’ decisions about continuation of therapy. The experts also noted that the frequency of these assessments and collection of data may vary across Canada.

In terms of meaningful response to treatment, the clinical experts stated that a response of 6 months or more with improved symptoms can be considered meaningful. The experts did not consider temporary shrinking of tumours beneficial to patients. They believed that initial responses (PR or CR) should exceed 6 months; otherwise, treatment should be discontinued.

Additionally, with a current median OS of 6 months in this population, the experts considered a benefit of at least 6 months and 3 months over current standard of care to be clinically meaningful for OS and PFS, respectively.

The experts noted the need to ensure careful monitoring for serious adverse reactions, given that these could negate the potential benefits of the treatment.

Discontinuing Treatment

The clinical experts suggested that treatment with epcoritamab should be discontinued upon disease progression, lack of response, or unacceptable toxicity.

Prescribing Considerations

The clinical experts indicated that patients with R/R LBCL are typically under the care of hematologists or oncologists who are familiar with the treatment of lymphoma patients. They also noted that the monitoring and treatment of these patients must initially be conducted at tertiary centres that have the means to monitor and treat CRS, which may require some initial training of site staff before implementation. Following the first few cycles, the clinical experts noted that treatment may continue at regional centres because the risk of CRS decreases.

Clinician Group Input

This section was prepared by the CADTH review team based on the input provided by clinician groups. The full original clinician group input(s) received by CADTH have been included in the Stakeholder section of this report.

Three clinician groups — LC (3 clinicians contributing), the Ontario Health (Cancer Care Ontario) Hematology Cancer Drug Advisory Committee (7 clinicians contributing), and the LLSC Nurses Network (6 clinicians contributing to the input) — responded to CADTH’s call for clinician group input.

According to these groups, there are poor and limited treatment options for patients with R/R DLBCL. LC indicated that for patients who are eligible for aggressive curative intensive therapies, options such as ASCT and CAR T-cell therapy are considered. Those who have disease progression after CAR T-cell therapy, or who are unfit for this therapy for medical and/or social reasons, have the greatest unmet need for treatment because no other curative-intent therapy is readily available for them.

In contrast, those who are not eligible for curative ASCT-based or CAR T-cell therapy approaches are managed with palliative approaches, such as pola-BR or tafasitamab (an anti–cluster of differentiation 19 antibody) in combination with lenalidomide. CADTH notes that tafasitamab in combination with lenalidomide received a do not reimburse recommendation and is not currently reimbursed by participating drug programs.⁸ A small percentage of patients might pursue allogeneic stem cell transplant, but the vast majority of patients in this setting are managed with a variety of palliative chemotherapy regimens, radiation therapy, or clinical trials. Multiple novel drugs (ibrutinib, lenalidomide, tafasitamab, and selinexor) do not have Health Canada approvals or provincial funding for R/R DLBCL.

The clinician groups noted that there is an unmet need for safe and effective treatments for patients who are not eligible for CAR T-cell therapy or for whom second-line treatment has not been effective. LC and the LLSC Nurses Network added that there are limited treatment options for disease control, and that currently, the available options are often associated with significant toxicity, side effects, and mental and physical treatment fatigue. LC stated that while ASCT or CAR T-cell therapy are considered effective for some patients, others are unable to access them due to location barriers. Only a select sites are equipped to offer CAR T-cell therapy.

The most important goals of treatment for DLBCL, according to clinician groups, are to prolong survival, delay disease progression, and improve symptoms, which in turn can improve the quality of life of patients and caregivers. Clinician groups agreed, in regard to the indication, that epcoritamab can be used in the third line or beyond if the patient was previously treated with CAR T-cell therapy or is ineligible for CAR T-cell therapy. LC and the LLSC Nurses Network stated that as an off-the-shelf product, this treatment could alleviate regional access issues, and that the SC injection could become a more feasible, well-favoured option than currently available treatments.

According to the clinician groups, improved survival (PFS, OS), blood work, decreased presence of cancer cells in bone marrow, and improvement in disease symptoms are outcomes used to determine whether a patient is responding to treatment. LC added that a clinically meaningful response would be PR or CR, typically determined using CT and or PET scans.

The clinician groups agreed that discontinuation of therapy should be considered in patients with disease progression or toxicity and that epcoritamab can be given in any inpatient and outpatient setting that has the ability to admit and monitor patients who are receiving anticancer therapy and has expertise in managing CRS and neurotoxicity.

Drug Program Input

The drug programs provide input on each drug being reviewed through CADTH’s Reimbursement Review processes by identifying issues that may affect their ability to implement a recommendation. The implementation questions and corresponding responses from the clinical experts consulted by CADTH are summarized in Table 7.

Table 7: Summary of Drug Plan Input and Clinical Expert Response

BR = bendamustine plus rituximab; CAR = chimeric antigen receptor; CNS = central nervous system; CRS = cytokine release syndrome; DLBCL = diffuse large B-cell lymphoma; ICANS = immune effector cell–associated neurotoxicity syndrome; LBCL = large B-cell lymphoma; NOS = not otherwise specified; PAG = Provincial Advisory Group; PMBCL = primary mediastinal B-cell lymphoma; pola-BR = polatuzumab vedotin with bendamustine and rituximab; R-CIT = rituximab-based chemoimmunotherapy; R-GemOx = rituximab, gemcitabine, and oxaliplatin; R/R = relapsed or refractory; SC = subcutaneous.

Clinical Evidence

The objective of CADTH’s Clinical Review Report is to review and critically appraise the clinical evidence submitted by the sponsor on the beneficial and harmful effects of epcoritamab (5 mg/mL and 60 mg/mL) for SC injection in the treatment of adult patients with R/R DLBCL not otherwise specified, DLBCL transformed from indolent lymphoma, HGBCL, PMBCL, or FLG3B after 2 or more lines of systemic therapy who have previously received or are unable to receive CAR T-cell therapy. The focus will be on comparing epcoritamab to relevant comparators and identifying gaps in the current evidence.

A summary of the clinical evidence included by the sponsor in the review of epcoritamab is presented in 4 sections, with CADTH’s critical appraisal of the evidence included at the end of each section. The first section, the systematic review, includes pivotal studies and RCTs that were selected according to the sponsor’s systematic review protocol. CADTH’s assessment of the certainty of the evidence in this first section using the GRADE approach follows the critical appraisal of the evidence. The next section includes indirect evidence from the sponsor. No sponsor-submitted long-term extension studies or additional studies that were considered by the sponsor to address important gaps in the systematic review evidence were submitted.

Included Studies

Clinical evidence from the following has been included in the CADTH review and appraised in this document:

• 1 pivotal study identified in the systematic review (the EPCORE NHL-1 study)

• 1 ITC (a MAIC).

Systematic Review

The contents of this section were informed by materials submitted by the sponsor. The following information has been validated by the CADTH review team.

Description of Studies

Characteristics of the EPCORE NHL-1 study are summarized in Table 8.

Table 8: Details of Studies Included in the Systematic Review

AE = adverse event; ASCT = autologous stem cell transplant; AST = aspartate aminotransferase; ALT = alanine transaminase; aNHL = aggressive B-cell non-Hodgkin lymphoma; BOR = best objective response; CAR = chimeric antigen receptor; CD3 = cluster of differentiation 3; CD20 = cluster of differentiation 20; C1D1 = cycle 1, day 1; C1D8 = cycle 1, day 8; C1D15 = cycle 1, day 15; C1D22 = cycle 1, day 22; CNS = central nervous system; CR = complete response; DH = double hit; DLBCL = diffuse large B-cell lymphoma; DOCR = duration of complete response; DOR = duration of response; ECOG = Eastern Cooperative Oncology Group; FACT-Lym = Functional Assessment of Cancer Therapy–Lymphoma; FDG = fluorodeoxyglucose; FLG3B; HGBCL = high-grade B-cell lymphoma; HSCT = hematopoietic stem cell transplant; IRC = independent review committee; LBCL = large B-cell lymphoma; mAb = monoclonal antibody; MRD = minimum residual disease; ORR = objective response rate; OS = overall survival; PD = progressive disease; PFS = progression-free survival; PK = pharmacokinetic; PMBCL = primary mediastinal B-cell lymphoma; PR = partial response; q.w. = once weekly; q.2.w. = once every 2 weeks; RP2D = recommended phase II dose; TH = triple hit; TTCR = time to complete response; TTR = time to response; ULN = upper limit of normal.

^aThe EPCORE NHL-1 trial was a phase I and II trial with a dose escalation part and a dose expansion part. Unless otherwise specified, the details provided are for the dose expansion part (aNHL cohort), given that this is the focus of the CADTH submission.

Source: Sponsor’s Summary of Clinical Evidence.¹¹

One study was included in the review. The EPCORE NHL-1 study is an ongoing, phase I and II, multicentre, open-label, single-arm study of epcoritamab monotherapy in patients with R/R with DLBCL (de novo or transformed from all indolent subtypes, including Richter’s transformation), including patients diagnosed with double-hit or triple-hit DLBCL, with MYC and BCL2 and/or BCL6 rearrangements, or other LBCL (including PMBCL, HGBCL, or FLG3B). The study was divided into 2 parts: part 1 (a phase I dose escalation study) and part 2 (a phase II dose expansion study). The primary objective of the EPCORE NHL-1 study was to evaluate the efficacy, safety, and tolerability of escalating doses of epcoritamab monotherapy. The overall study design of the EPCORE NHL-1 trial is shown in Figure 2.

Results from the January 2022 data cut-off formed the basis for approval by Health Canada and were published by Thieblemont et al. (2023).³⁹ The final analysis was recently completed with a data cut-off of April 21, 2023, and this analysis is the focus of the CADTH submission.

Figure 2: Study Design for the EPCORE NHL-1 Study

Source: Clinical Study Report.⁴³

The epcoritamab recommended phase II dose (RP2D) regimen was selected based on results from the dose escalation part of the trial and consisted of an initial priming dose of 0.16 mg (C1D1), an intermediate dose of 0.8 mg (C1D8), and a full dose of 48 mg at C1D15, C1D22, and thereafter. In the expansion part of the trial, epcoritamab was administered as monotherapy by SC injection weekly during cycles 1 to 3, every 2 weeks during cycles 4 to 9, and every 4 weeks during cycle 10 and beyond (until unacceptable toxicity, PD, or withdrawal of consent).⁴⁴

The aNHL cohort in the expansion part of the trial was conducted in 2 stages. In stage 1, patients with DLBCL were enrolled. Following an interim futility analysis, additional patients with DLBCL and other LBCL subtypes were enrolled for stage 2 as summarized here:⁴⁴ The aNHL cohort consisted of 128 to (a planned maximum size of) 158 patients with R/R aNHL (also referred to as LBCL). In stage 1, there were 28 patients with DLBCL. In stage 2, there were 100 additional patients with DLBCL and less than or equal to 30 patients with other LBCL subtypes (HGBCL, PMBCL, FLG3B). The planned maximum sample size for the aNHL expansion cohort was 158 patients. A total of 157 patients, including 139 with DLBCL and 18 patients with other LBCL subtypes, were treated with the epcoritamab RP2D regimen.⁴⁴

The primary end point was ORR by the IRC using Lugano criteria.⁴⁵ Secondary end points included DOR, CR rate, DOCR, PFS, time to response per IRC, and OS. In addition, minimum residual disease and PROs for HRQoL were assessed as exploratory end points.³⁹

Populations

Inclusion and Exclusion Criteria

The key inclusion and exclusion criteria for the EPCORE NHL-1 study are summarized in Table 4. Briefly, patients eligible for the cohort of interest to this review (i.e., dose expansion) consisted of adults (i.e., at least 18 years of age) diagnosed with DLBCL or other aggressive NHL (including PMBCL, HGBCL, or FLG3B) R/R disease who had previously been treated with at least 2 prior lines of systemic therapy, including at least 1 anti-CD20–containing regimen, and who had not responded to, or were ineligible for, ASCT. Patients were required to have an ECOG Performance Status of 0, 1, or 2. Relapsed disease was defined as recurrence at least 6 months after completion of therapy, and refractory disease was defined as progression either during therapy or within 6 months of completion of therapy. Patients with prior CAR T-cell therapy were eligible if it had been 30 days or more since their last treatment. There were no requirements related to minimum life expectancy or absolute leukocyte count.^39,44

Interventions

The EPCORE NHL-1 trial was an open-label, single-arm trial in which patients received epcoritamab until unacceptable toxicity, PD, or withdrawal of consent.⁴⁴

Epcoritamab

A step-up dosing approach was employed, primarily to mitigate the development of serious CRS. Planned doses for the dose escalation part ranged from 0.0128 mg to 60 mg. Patients received a priming dose on day 1 of cycle 1 and an intermediate dose on day 8 of cycle 1 before receiving full doses for the remainder of the treatment period. Epcoritamab was administered SC in 28-day cycles starting with once-weekly dosing, then moving to biweekly dosing and finally once every 4 weeks.⁴⁶

From the dose escalation part, a dose of 48 mg was identified as the RP2D based on the safety data, together with pharmacokinetic and pharmacodynamic modelling and exposure-response and exposure-safety analyses. Therefore, this dose was investigated in the phase II dose expansion part.³⁹

In the dose expansion part, epcoritamab was administered by SC injection in treatment cycles of 4 weeks (i.e., every 28 days). The preferred injection site was the lower part of the abdomen or thigh. Changing the injection site from the left to right side or vice versa was recommended, especially during weekly administration.

During the expansion part of the trial, the RP2D regimen, which included a priming dose of 0.16 mg (C1D1), an intermediate dose of 0.8 mg (C1D8), and a full dose of 48 mg (C1D15, C1D22, and thereafter), was administered according to the following schedule:⁴⁴

• Cycles 1 to 3: days 1, 8, 15, and 22 (weekly)

• Cycles 4 to 9: days 1 and 15 (every 2 weeks)

• Cycle 10 and beyond until unacceptable toxicity, PD, or withdrawal of consent: day 1 (every 4 weeks)

During the expansion part, hospitalization was only required for a minimum of 24 hours after the first full dose of epcoritamab in cycle 1.⁴⁴ Epcoritamab was taken according to the schedule shown in Figure 3 until disease progression or unacceptable toxicity.

Figure 3: Epcoritamab Dosing Schedule

Note: Epcoritamab doses in cycle 1 were as follows: day 1, 0.16 mg (priming dose); day 8, 0.8 mg (intermediate dose); day 15, 48 mg (full dose); day 22, 48 mg. Epcoritamab doses in cycle 2 and onward were 48 mg.

Source: Product monograph.⁷

Premedication Prior to Epcoritamab Administration

Patients were premedicated with corticosteroids, antihistamines, and antipyretics 30 minutes to 120 minutes before the first 4 doses of epcoritamab. For subsequent doses of epcoritamab, premedication and CRS prophylaxis were optional.⁴⁴

Prophylactic Corticosteroids Following Epcoritamab Administration

Corticosteroids were administered following epcoritamab administration on day 2, day 3, and day 4 in conjunction with all 4 doses of epcoritamab in cycle 1 (i.e., priming, intermediate, and first 2 full doses). If CRS greater than or equal to grade 2 occurred following the fourth administration of epcoritamab on day 22 of cycle 1, corticosteroid administration on the day of and for 3 days following epcoritamab administration was continued for subsequent epcoritamab doses until a dose was given after which no CRS occurred. Otherwise, 4-day consecutive corticosteroids were administered following epcoritamab dosing only for cycle 1 and for any repriming cycles.⁴⁴ Based on the investigator’s evaluation, the corticosteroid daily dose requirement could be reduced to mitigate possible side effects from high-dose steroid administration.⁴⁴

Permitted Concomitant Therapy

Concomitant medications were allowed to provide adequate patient care and were given as clinically indicated, except for antilymphoma therapy. All concomitant medications were recorded except for vitamins and nutrient supplements. Supportive medications, such as premedication, antiviral medication, and anti–interleukin-6 receptor (IL-6R) were provided at the trial site.⁴⁴ For treatment of CRS, patients were recommended to receive supportive care, including infusion of saline, systemic glucocorticoids, antihistamines, antipyretics, support for blood pressure (vasopressin, vasopressors), support for low-flow and high-flow oxygen, and positive pressure ventilation and/or monoclonal antibodies against IL-6R (e.g., IV tocilizumab).⁴⁴ Patients considered to be at increased risk for CTLS were recommended to receive hydration and prophylactic treatment with a uric acid-lowering drug. If signs of CTLS occurred, supportive therapy, including rasburicase, was allowed.⁴⁴ Prophylactic antibiotic, antiviral, and antifungal therapies were allowed unless medically contraindicated. The use of growth factors for neutropenia, such as granulocyte colony-stimulating factor, was allowed during treatment with epcoritamab. In case of recurring greater than or equal to grade 3 neutropenia, use of growth factors was mandated.⁴⁴

Outcomes

A list of efficacy end points assessed in this Clinical Review Report is provided in Table 9, followed by descriptions of the outcome measures. Summarized end points are based on outcomes included in the sponsor’s Summary of Clinical Evidence as well as any outcomes identified as important to this review by the clinical experts consulted by CADTH and in the stakeholder input from patient and clinician groups and public drug plans. Using the same considerations, the CADTH review team selected end points that were considered to be most relevant to inform CADTH’s expert committee deliberations and finalized this list of end points in consultation with members of the expert committee. All summarized efficacy end points were assessed using GRADE. Select notable harms outcomes considered important for informing CADTH’s expert committee deliberations were also assessed using GRADE.

Table 9: Outcomes Summarized From the Studies Included in the Systematic Review

CR = complete response; CRS = cytokine release syndrome; DOR = duration of response; FACT-Lym = Functional Assessment of Cancer Therapy–Lymphoma; HRQoL = health-related quality of life; ICANS = immune effector cell–associated neurotoxicity syndrome; ORR = objective response rate; OS = overall survival; PFS = progression-free survival.

Source: Sponsor’s Summary of Clinical Evidence.

Efficacy Outcomes

According to the clinical expert input, patient group input, and clinician group input received by CADTH, patients for whom second- and third-line treatments have not been effective have few safe and effective treatment options, and currently available therapies are palliative. Patients typically have poor survival (e.g., OS less than 6 months). Therefore, outcomes related to survival were included as outcomes to be assessed using GRADE. In the EPCORE NHL-1 study, these included OS and PFS.

The clinical experts consulted by CADTH noted that clinical response, particularly CR rate in R/R LBCL, is an important outcome of treatment; thus, CR and ORR were included in the GRADE assessment. Further to CR and ORR alone, the clinical experts suggested that DOR may demonstrate greater treatment effect than response rates alone; thus, this was included in the GRADE assessment.

HRQoL was identified as an important outcome in patients with R/R LBCL; thus, the change from baseline in HRQoL outcomes, including FACT-Lym total score, were included in the GRADE assessment.

Primary Efficacy Outcome

The primary efficacy end point of the EPCORE NHL-1 trial was ORR rate, defined as the proportion of patients whose best overall response was CR or PR based on IRC assessment of PET and/or CT scans using Lugano criteria. Patients who achieved a PR or CR after a PD event had been reported were included in the analysis of ORR || | |||.

Secondary Efficacy Outcomes

Secondary end points are summarized in Table 8 and included additional response outcomes (e.g., ORR and CR assessed according to lymphoma response to immunomodulatory therapy criteria [LYRIC] criteria), time-to-event outcomes (OS and PFS), response durations (DOR and DOCR), and HRQoL outcomes.

Assessment of Disease Response and PD

Response assessments according to the imaging assessment were performed by the site investigators to inform decisions regarding continuation of treatment for the patient. Response was assessed according to both Lugano and LYRIC criteria (with LYRIC including an assessment of indeterminate response). The response assessments and disease progression for the primary and secondary study end points were determined by an IRC according to the study protocol. The IRC workflow included the multistep evaluation presented here.

1. Radiology review:

   • Time point-by-time point radiology review: Each imaging time point for a patient was assessed by 2 independent reviewers, who assessed tumour burden at baseline and determined an overall tumour assessment at each postbaseline time point according to the Lugano criteria and LYRIC. Both PET-CT or CT-MRI and fluorodeoxyglucose PET 5-point scoring assessments per both criteria were performed when both modalities were available.

   • Global radiology review: The same independent reviewers globally assessed the reviewed time points and confirmed or updated their previous overall tumour assessments according to the Lugano criteria and separately according to LYRIC.

   • Radiology adjudication review: This was required if the independent radiologists’ results for a global radiology review conflicted. An independent radiologist who did not participate in the earlier reviews for the patient chose the independent radiologist with whom they agreed most as the final assessment and provided justifying comments separately for the Lugano criteria-based and LYRIC-based overall tumour assessment s.

2. Oncology review: Following the radiology review, an independent oncologist (single read) reviewed the final radiology review assessments and available pertinent clinical data and provided the final overall tumour assessment per visit per Lugano criteria, and separately by LYRIC.

3. Secondary radiology review: The time point-by-time point radiology review and global radiology review for a subset of patients was repeated. The secondary radiology review was used for the determination of intrareader agreement for that subset of patients and did not alter the original read.

Patient-Reported Outcomes

PROs in the EPCORE NHL-1 trial included the FACT-Lym, FACT-G, and EQ-5D-3L.

• FACT-Lym: A questionnaire used to assess quality of life in lymphoma patients. It consists of a general quality of life instrument (i.e., FACT-G) and a condition-specific module called “Lym.” The sponsor reports that FACT-Lym is a validated quality of life questionnaire for patients with lymphoma. FACT-G consists of 27 statements categorized by 5 subscales (Physical Well-Being, Social/Family Well-Being, Emotional Well-Being, Functional Well-Being, and Additional Concerns). Patients score each statement using a 5-point scale, with responses ranging from “not at all” to “very much.” The Lym module consists of 15 statements that score using an identical 5-point scale as that applied the FACT-G.⁴⁷

• FACT-Lym symptoms: The sponsor evaluated 6 questions from the FACT-Lym that were related to the symptoms of lymphoma: P2 (body pain), BRM3 (fever), ES3 (night sweats), GP1 (lack of energy), BMT6 (tires easily), and C2 (weight loss). Changes from baseline in these questions were evaluated as secondary end points in the EPCORE NHL-1 trial. The sponsor reported that compliance was |||| at most study time points, and lower than this at |||| |||||||| ||||| |||||||| ||| ||| |||||||| |.

• EQ-5D-3L: The EQ-5D-3L consists of a descriptive system and EQ visual analogue scale (EQ VAS). The descriptive system consists of 5 dimensions (mobility, self-care, usual activities, pain and/or discomfort, and anxiety and/or depression), with 3 levels (no health problems, moderate health problems, and extreme health problems). The EQ VAS records self-rated health on a scale ranging from 0 (worst imaginable health state) to 100 (best imaginable health state).⁴⁷ The sponsor reported that the minimal important difference can be approximated at 0.08 for change from baseline in EQ-5D-3L health utility scores and a change from baseline in EQ VAS score of 7 points (citing a retrospective analysis from Pickard et al. [2007] conducted in patients living with advanced cancer).⁴⁸

Table 10: Summary of Outcome Measures and Corresponding Measurement Properties

ECOG = Eastern Cooperative Oncology Group; FACT-G = Functional Assessment of Cancer Treatment–General; FACT-Lym = Functional Assessment of Cancer Therapy–Lymphoma; HRQoL = health-related quality of life; ICC = intraclass correlation coefficient; LymS = lymphoma subscale; MCS = Mental Component Summary; MID = minimal important difference; NHL = non-Hodgkin lymphoma; PCS = Physical Component Summary; POMS = Profile of Mood States; PS = Performance Status; SF-36 = Short Form (36) Health Survey.

Harms Outcomes

All safety analyses were conducted using the safety analysis set, which included 157 patients with LBCL who received at least 1 dose of epcoritamab in the EPCORE NHL-1 study. The adverse events of special interest (AESIs) for the EPCORE NHL-1 trial were CRS, CTLS, and ICANS. All AEs were graded by the investigator according to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0, except for CRS, ICANS, and CTLS. Events of CRS and ICANS were graded according to American Society for Transplantation and Cellular Therapy criteria,⁵⁰ and CTLS events were graded according to Cairo-Bishop.⁵¹

Statistical Analysis

Clinical Trial End Points

The statistical analyses of the trial end points are presented in Table 11.⁵²

Table 11: Statistical Analysis of Efficacy End Points in the EPCORE NHL-1 Trial Dose Expansion Part

AE = adverse event; BOR = best overall response; CI = confidence interval; CR = complete response; DLBCL = diffuse large B-cell lymphoma; DOR = duration of response; DOCR = duration of complete response; EQ VAS = EQ visual analogue scale; FACT-G = Functional Assessment of Cancer Therapy–General; FACT-Lym = Functional Assessment of Cancer Therapy–Lymphoma; FAS = full analysis set; IRC = independent review committee; KM = Kaplan-Meier; LBCL = large B-cell lymphoma; LYRIC = lymphoma response to immunomodulatory therapy criteria; MID = minimum important difference; mRES = modified response-evaluable set; NA = not applicable; ORR = objective response rate; OS = overall survival; PFS = progression-free survival; PP = per protocol; RES = response-evaluable set; SD = stable disease; TOI = Trial Outcome Index.

^aSecondary response end points included determination by both Lugano criteria and LYRIC as assessed by IRC.

Source: EPCORE NHL-1 Statistical Analysis Plan⁵² and Clinical Study Report (April 2023 data cut-off).⁴³

Sample Size and Power Calculation

In total, up to 158 patients were planned for enrolment.⁵² Assuming a nonevaluable rate of 10%, a sample size of 128 patients in the DLBCL group would provide approximately 90% power to detect the alternative hypothesis of at least 50% ORR while ensuring a 2-sided significance level of 0.05 using a 1-sample exact binomial test under the null hypothesis of at most 35% ORR. The probability of futility at the end of stage 1 was approximately 30% under the null and 2.1% under the alternative.⁵²

Statistical Testing

For continuous variables, descriptive statistics included the number of nonmissing values (n), mean, SD, median, and minimum and maximum values. In addition, 25th percentile and 75th percentile were provided for some outcomes.⁵² Time-to-event variables were analyzed using Kaplan-Meier estimates (median time, first and third quartiles), with the number and percentage of patients with event or censoring reported. If specified, 95% CIs were provided using the Brookmeyer and Crowley method with log-log transformation. Landmark event-free rates were also presented together with the 95% CIs for some end points.⁵²

The primary analysis was conducted based on a data cut-off of January 31, 2022. The April 21, 2023 analysis is the most recent analysis and is the focus of the CADTH submission.

Subgroup Analyses

As per the prespecified statistical analysis plan, ORR and CR rates based on IRC assessment per Lugano criteria in the full analysis set (FAS) were summarized within the subgroups listed along with 95% exact CIs in a forest plot for DLBCL and LBCL. For any subgroup that included fewer than 20 patients, either the analysis for was not carried out or combining of subgroups was considered.⁵² The subgroups were:

• age (< 65 years, 65 years to < 75 years, ≥ 75 years)

• gender (male, female)

• race (white, Asian, Black, or other)

• region (North America, Europe, other)

• baseline ECOG Performance Score (0, 1, 2, or higher)

• baseline weight (< 65 kg, 65 kg to < 85 kg, ≥ 85 kg)

• number of prior antilymphoma therapies (2, 3, 4, or more than 4)

• time from last anti-CD20 therapy until first dose of epcoritamab (< median, ≥ median)

• prior CAR T-cell therapy experience (yes, no)

• prior ASCT (yes, no)

• prior antilymphoma therapy status (primary refractory, other)

• most recent prior anti-CD20 containing therapy (refractory, relapse)

• chromosomal abnormality (double hit, triple hit, other)

• Ann Arbor staging (I or II; III or IV)

• IPI (0 to 2; ≥ 3)

• DLBCL disease state (de novo, transformed)

• molecular classification (GCB, non-GCB)

• molecular classification (activated B-cell)

• overall presence of antidrug antibodies (positive or nonpositive)

• As per the prespecified statistical analysis plan, forest plots of median PFS (both primary and secondary definitions) based on IRC assessment per Lugano criteria along with 95% CIs were also produced for each level of each of these subgroups for the FAS.⁵² OS was also assessed.

In addition to the prespecified analyses previously listed, key analyses of ORR, CR, PFS, and OS were conducted for the following subgroups: primary refractory disease; refractory to prior CAR T-cell therapy; and elevated lactate dehydrogenase.⁴³

Analysis Populations

Analysis populations in the EPCORE NHL-1 trial are summarized in Table 12.

Table 12: Analysis Populations of the EPCORE NHL-1 Trial

DOR = duration of response; ORR = overall response rate.

Sources: EPCORE NHL-1 Statistical Analysis Plan;⁵² sponsor’s Summary of Clinical Evidence.

Results

Patient Disposition

The disposition of patients in the EPCORE NHL-1 trial dose expansion part is summarized in Table 13. A total of ||| patients were screened; 157 patients were enrolled and received at least 1 dose of epcoritamab. At the time of the April 21, 2023, data cut-off, || ||||||| patients were still receiving epcoritamab treatment and ||| ||||||| patients had discontinued. The most frequently reported reasons for discontinuation were disease progression (|| |||||||) and AEs (|| |||||||). The sponsor reported that | |||||| patients discontinued epcoritamab after deciding to proceed to transplant after having CR (| | |) or PR (| | |) to the treatment. A total of || ||||||| permanently discontinued the trial, with death being the most common reason (|||||).

Table 13: Patient Disposition in the EPCORE NHL-1 Trial Dose Expansion Part (FAS)

aNHL = aggressive B-cell non-Hodgkin lymphoma; DLBCL = diffuse large B-cell lymphoma; LBCL = large B-cell lymphoma.

^aProgressive disease includes both clinical progression and documented radiographic disease progression.

^b“Withdrawal by patient” includes: 2 patients who refused to come to the site for the end-of-treatment visit before completing cycle 1 and died due to disease progression on day 46 and day 91; 1 patient who was in complete response following cycle 14 and did not want to come into the hospital frequently anymore; 1 patient who opted for hospice and died from disease progression the day after discontinuing treatment; and 1 patient whose treatment discontinuation occurred 5 days after their last lymphoma assessment showing disease progression (the specific reason for the patient’s decision to discontinue treatment cannot be established).

^c“Other” includes: 2 patients due to investigator decision (not further specified); 1 patient who proceeded to chimeric antigen receptor T-cell therapy following a partial response to epcoritamab; 1 patient due to adverse events and good response to treatment; and 1 patient who was too frail to continue further therapy and likely approaching end of life.

Source: Sponsor’s Summary of Clinical Evidence.¹¹

Baseline Characteristics

The baseline characteristics are outlined in Table 14. The median age was 64.0 years, with 48 patients (30.6%) aged 65 years to under 75 years and 29 patients (18.5%) aged greater than or equal to 75 years. Most patients had a baseline ECOG Performance Status of 0 (47.1%) or 1 (49.7); 3.2% had an ECOG Performance Status of 2. Most (139 patients [88.5%]) had DLBCL histology, with 97 patients (69.8%) with DLBCL having de novo disease and 40 patients (28.8%) having transformed disease. Patients with other LBCL subtypes included 9 patients (5.7%) with HGBCL, 5 patients (3.2%) with FLG3B, and 4 patients (2.5%) with PMBCL.

Table 15 summarizes the treatment history for those enrolled in the EPCORE NHL trial. The median number of prior lines of antilymphoma therapy was 3.0 (range, 2 to 11), with 47 patients (29.9%) having received 2 prior lines of therapy, 48 patients (30.6%) having received 3 lines, and 62 patients (39.5%) having received greater than or equal to 4 lines. Overall, 61 patients (38.9%) had received prior CAR T-cell therapy and 31 patients (19.7%) had prior ASCT.

Table 14: Summary of Baseline Characteristics From the EPCORE NHL Trial Dose Expansion Part (FAS)

ABC = activated B-cell; CrCl = creatinine clearance; DLBCL = diffuse large B-cell lymphoma; ECOG = Eastern Cooperative Oncology Group; FISH = fluorescence in situ hybridization; FL = follicular lymphoma; GCB = germinal centre B-cell; HGBCL = high-grade B-cell lymphoma; IPI = International Prognostic Index; LBCL = large B-cell lymphoma; MZL = marginal zone lymphoma; NCI = National Cancer Institute; PMBCL = primary mediastinal large B-cell lymphoma; SLL = small lymphocytic lymphoma.

^aOther includes HGBCL (n = 9), FL grade 3B (n = 5), and PMBCL (n = 4).

^bPatients who had results from local laboratory analysis collected as medical history.

Source: EPCORE NHL-1 Clinical Study Report (April 21, 2023)⁴³ and sponsor’s Summary of Clinical Evidence.¹¹

Table 15: Summary of Treatment History in the EPCORE NHL Trial Dose Expansion Part (FAS)

aNHL = aggressive B-cell non-Hodgkin lymphoma; ASCT = autologous stem cell transplant; CAR = chimeric antigen receptor; CD19 = cluster of differentiation 19; CD20 = cluster of differentiation 20; DLBCL = diffuse large B-cell lymphoma; FL = follicular lymphoma; HGBCL = high-grade B-cell lymphoma; LBCL = large B-cell lymphoma; PMBCL = primary mediastinal B-cell lymphoma; SCT = stem cell transplant.

^aOther includes HGBCL (n = 9), FL grade 3B (n = 5), and PMBCL (n = 4).

^bConsidered primary refractory if refractory to front-line antilymphoma therapy.

^cConsidered refractory if experienced disease progression or stable disease as best response or disease progression within 6 months after therapy completion.

^dConsidered relapsed if experienced disease progression more than 6 months after last treatment.

Source: Clinical Study Report for the EPCORE NHL-1 study.⁴³

Exposure to Study Treatments

Patients with LBCL in the study received epcoritamab for a mean duration of ||| months and ||| cycles, with an average of |||| doses administered. Epcoritamab exposure and treatment compliance are summarized in Table 16. The median number of cycles initiated was ||| ||||||| | || ||| and the median duration of treatment was ||| months ||||||| | || ||||.⁴³

A total of || ||||||| patients with LBCL initiated cycle 4 treatment, providing a close estimation of patients who received at least 3 months of treatment. Similarly, || ||||||| patients with LBCL initiated cycle 7, approximating at least 6 months of treatment; || ||||||| patients with LBCL initiated cycle 10, approximating at least 9 months of treatment; and || ||||||| patients with LBCL initiated cycle 13, approximating at least 12 months of treatment. || |||||||| ||||| initiated cycle 26, approximating at least 2 years of treatment. As of the data cut-off date of 21 April 2023, || ||||||| patients with LBCL were continuing on epcoritamab treatment.⁴³

Overall, || ||||||| patients with LBCL required at least 1 dose delay during the trial, including || ||||||| patients who required a dose delay due to an AE and || |||||| patients who required a dose delay for another reason, including COVID-19 control measures (Table 16). Dose reductions were not allowed in this trial.⁴³

The median relative dose intensity for patients with LBCL was |||| ||||||| ||| |||| in cycle 1 to cycle 3 (weekly dosing), |||| ||||||| ||| |||| in cycle 4 to cycle 9 (with dosing every 2 weeks), and ||||| ||||||| ||| |||| in cycle 10 and beyond (dosing every 4 weeks). For cycle 1 to cycle 3, relative dose intensity was greater than or equal to 90% for ||| ||||||| patients; for cycle 4 to cycle 9, relative dose intensity I was greater than or equal to 90% for more than ||| of patients; and for cycle 10 and beyond, relative dose intensity was greater than or equal to 90% for ||| of patients. The exposure to the study drug allowed adequate assessment of safety and efficacy in the trial population.⁴³

A dose delay referred to a delay in the administration of epcoritamab relative to the per-protocol schedule per investigator. A dose repriming cycle consists of a weekly schedule of a priming dose, an intermediate dose, and 2 full doses.⁴³

As of the data cut-off date, || |||||| patients required epcoritamab repriming. For 9 of these patients, the reason for repriming was dose delay (due to AEs in ||| patients, ||| of which were related to COVID-19 infection and ||| of which were due to COVID-19 control measures). No specified reason was given for the remaining patient who was reprimed. In all ||| patients, the repriming occurred late in the treatment cycle (i.e., after cycle 11), and no patient experienced CRS after repriming.⁴³

Table 16: Epcoritamab Exposure and Compliance in the EPCORE NHL-1 Study Dose Expansion Part (Safety Analysis Set)

FL = follicular lymphoma; HGBCL = high-grade B-cell lymphoma; LBCL = large B-cell lymphoma; PMBCL = primary mediastinal large B-cell lymphoma; SD = standard deviation.

^aOther includes 9 patients with HGBCL, 5 patients with FL grade 3B, and 4 patients with PMBCL.

^bDuration of treatment was calculated as last dose date minus first dose date plus 1.

^cActual dose intensity is calculated as the actual dose administered on and after the first full dose divided by duration of dosing period in a 28-day cycle. Relative dose intensity is calculated as actual dose intensity divided by planned full dose intensity in the analysis period.

^dPatients may experience multiple times of dose delay.

^eIncludes patients who had dose delays due to COVID-19 control measures.

Source: EPCORE NHL-1 Clinical Study Report (April 21, 2023)⁴³ and sponsor’s Summary of Clinical Evidence.

Concomitant Medications and Cointerventions

Concomitant medications used by greater than or equal to 20% of patients in the aNHL expansion cohort are summarized in Table 17.⁴³ For treatment of CRS, patients were recommended to receive supportive care, including saline infusion, systemic glucocorticoids, antihistamines, antipyretics, support for blood pressure (vasopressin, vasopressors), support for low-flow and high-flow oxygen and positive pressure ventilation, and/or monoclonal antibodies against IL-6R (e.g., IV administration of tocilizumab).⁴³ Patients considered to have an increased risk of CTLS were recommended to receive hydration and prophylactic treatment with a uric acid-lowering drug. If signs of CTLS occurred, supportive therapy, including rasburicase, was allowed.⁴³

Prophylactic antibiotic, antiviral, and antifungal therapies were allowed unless medically contraindicated. The use of growth factors for neutropenia, such as granulocyte colony-stimulating factor, was allowed during treatment with epcoritamab. In case of recurring neutropenia of greater than or equal to grade 3, use of growth factors was mandated.⁴³ All 157 patients received corticosteroids before and after epcoritamab administration, per the criteria specified in the protocol. Overall, || ||||||| patients received concomitant allopurinol, and || ||||||| patients received concomitant rasburicase; these medications were used mostly as prophylactic measures in patients with high risk factors for CTLS.⁴³

Table 17: Concomitant Medications in at Least 20% of Patients Overall in the EPCORE NHL-1 Study Expansion Cohort (Safety Analysis Set)

ATC = anatomic therapeutic chemical; LBCL = large B-cell lymphoma.

Note: ATC code level 2 IS presented only where at least 1 generic name met the cut-off of 20% in that category.

^aOther includes 9 patients with high-grade B-cell lymphoma, 5 patients with follicular lymphoma grade 3B, and 4 patients with primary mediastinal B-cell lymphoma.

Source: EPCORE NHL-1 Clinical Study Report (April 21, 2023).⁴³

Subsequent Treatment

Subsequent antilymphoma therapies used by patients with LBCL are summarized in Table 18. A total of || ||||||| patients with LBCL went on to receive a subsequent antilymphoma therapy. The most common subsequent systemic therapy received was rituximab (||| ||||||| patients). In addition, || ||||||| patients received subsequent radiotherapy and || |||||| patients received subsequent CAR T-cell therapy.⁴³ A total of | |||||| patients received a subsequent allogeneic HSCT, and | |||||| patient received a subsequent ASCT. ||||| of these patients had a best overall response of CR (including the patient who received ASCT); ||| patient had PR; and ||| patient had stable disease per IRC using Lugano criteria. ||||| patients were alive as of the data cut-off date; ||| patient died after coding (i.e., had a cardiac arrest) in the emergency department; ||| patient died of respiratory failure; and ||| ||||||| ||| |||||||| |||| |||| ||| || ||||||| |||||||||||.⁴³

Table 18: Subsequent Antilymphoma Therapies in the EPCORE NHL-1 Study Dose Expansion Part (FAS)

ATC = anatomic therapeutic chemical; CAR = chimeric antigen receptor; LBCL = large B-cell lymphoma.

Note: Patients are counted at most 1 time within each generic name, and at most 1 time per ATC level.

^aWhere incidence for LBCL was greater than 5.0%.

Source: EPCORE NHL-1 Clinical Study Report (April 21, 2023).⁴³

Efficacy

Efficacy results from the April 2023 cut-off date for the EPCORE NHL-1 study are summarized in Table 19.

Table 19: Summary of Key Efficacy Results From the EPCORE NHL-1 Study

CI = confidence interval; CR = complete response; ctDNA = circulating tumour DNA; IRC = independent review committee; MRD = minimum residual disease; ORR = overall response rate; PD = progressive disease; PFS = progression-free disease; PR = partial response; SD = standard deviation.

^aORR is equal to CR plus PR.

^bBased on the Clopper-Pearson method.

^cBased on Kaplan-Meier estimate.

^dThe primary definition of PFS accounted for the initiation of subsequent antilymphoma therapy and censored PFS at the last evaluable tumour assessment on or before the date of subsequent antilymphoma therapy. The subsequent antilymphoma therapies for PFS censoring consist of systemic antilymphoma therapy and curative-intent radiotherapy on 1 and only target lesion.

Source: EPCORE NHL-1 Clinical Study Report (April 2023 data cut-off).⁴³

Overall Survival

OS was a secondary end point of the EPCORE NHL-1 study. Results for OS at the clinical cut-off date (April 21, 2023) in the primary efficacy population are summarized in Table 19 and displayed visually in Figure 4. By the clinical cut-off date, || ||||||| patients had died, resulting in a median OS of 18.5 months (95% CI, 11.7 months to |||| months). The estimated proportions of patients who remained alive at 12 months and 18 months were ||||| |||| ||| ||||| || |||||| and ||||| |||| ||| ||||| || ||||||| respectively.

Figure 4: Kaplan-Meier Plot of OS — Patients With LBCL, EPCORE NHL-1 Study Dose Expansion Part (FAS) [Redacted]

CI = confidence interval; CR = complete response; LBCL = large B-cell lymphoma; PR = partial response.

Source: Adapted from data in the EPCORE NHL-1 Clinical Study Report (April 2023 data cut-off)⁴³

Progression-Free Survival

Results for PFS based on IRC assessment (Lugano criteria) are summarized in Table 19 and displayed visually in Figure 5. ||| ||||||| patients experienced a PFS event (i.e., disease progression or death) according to the primary definition. The median PFS (primary definition) was 4.4 months (95% CI, 3.0 months to 8.8 months). The estimated percentages of patients remaining progression-free at 12 months and 18 months were ||||| |||| ||| ||||| || |||||| ||| ||||| |||| ||| ||||| || ||||||| Overall results for the 18 patients in the cohort of other LBCL subtypes were similar to those for the LBCL and DLBCL cohorts. Similar PFS rates were observed using the secondary definition (i.e., median PFS was ||| |||||| |||| ||| ||| || ||||).

Similar to DOR, for PFS based on IRC assessment (primary definition), there was a higher number of censored patients when evaluated using LYRIC compared with Lugano criteria. Consequently, median PFS was longer using LYRIC (|||| |||||| for LBCL) than with Lugano criteria (||| |||||| for LBCL).

Figure 5: Kaplan-Meier Plot of PFS (Primary Definition) Based on IRC Assessment, Lugano Criteria — Patients With LBCL, EPCORE NHL-1 Study Dose Expansion Part (FAS) [Redacted]

CI = confidence interval; IRC = independent review committee; LBCL = large B-cell lymphoma.

Source: Adapted from data in the EPCORE NHL-1 Clinical Study Report (April 2023 data cut-off).⁴³

Figure 6: EPCORE NHL-1 Study — Kaplan-Meier Plot, Stratified by Response, for PFS in Patients with LBCL [Redacted]

LBCL = large B-cell lymphoma.

Source: EPCORE NHL-1 Clinical Study Report (April 2023 data cut-off).⁴³

Clinical Response

Results for all clinical response outcomes of interest, including CR, PR, ORR, and DOR, are summarized in Table 16.

CR Rate

The CR rates, based on Lugano criteria, were ||||| |||| ||| |||| || ||||| when determined by the IRC and ||||| |||| ||| |||| || ||||| when determined by the investigator. The median DOCRs were |||| |||||| |||| ||| |||| || ||| when assessed by IRC and |||| |||||| |||| ||| |||| || ||| when assessed by the investigators. The CR rate was ||||| |||| ||| |||| || ||||| when assessed by the IRC using LYRIC, with a median DOCR of |||| |||||| |||| ||| |||| || |||||.

Overall Response Rate

The ORR (CR plus PR) in patients with LBCL (N = 157) was 63.1% (95% CI, 55.0% to 70.6%), with || ||||||| and || ||||||| patients achieving best responses of CR and PR, respectively. Patients with a response in the primary analysis included || patients with a PR or CR (using Lugano criteria) after assessment of PD. These responses were also included in the analysis of the secondary end points, such as CR rate, DOR, DOCR, TTR, time to CR, and PFS.

Duration of Response

For patients who had achieved PR or CR || | |||| the median DOR was |||| |||||| |||| ||| ||| || ||||| when assessed by IRC using Lugano criteria. The estimated percentages of patients remaining in response at 12 months and 18 months were ||||| |||| ||| ||||| || |||||| and ||||| |||| ||| ||||| || ||||||| respectively. The median DORs were |||| |||||| |||| ||| |||| || ||||| when assessed by the investigators using Lugano criteria and |||| |||||| |||| ||| |||| || ||||||.

Table 20: Summary of Subgroup Analyses From the EPCORE NHL-1 Study

ASCT = autologous stem cell transplant; CAR = chimeric antigen receptor; CI = confidence interval; CR = complete response; DLBCL = diffuse large B-cell lymphoma; ECOG = Eastern Cooperative Oncology Group; ORR = objective response rate; OS = overall survival; R-IPI = revised International Prognostic Index.

Source: EPCORE NHL-1 Clinical Study Report (April 2023 data cut-off).⁴³

Patient-Reported Outcomes

PROs from the EPCORE NHL-1 trial are summarized in Table 21, Table 22, and Table 23. The collection of PROs (i.e., FACT-Lym and EQ-5D-3L) was prespecified up to cycle 9. PRO data at the end of treatment assessment refer to patients who progressed and discontinued therapy.⁴³

FACT-Lym Total Score

At baseline, a total of 140 patients completed the FACT-Lym, and the mean score at baseline was 118.4 (SD = 25.47). At cycle 5, day 1 (n = 66) and cycle 7, day 1 (n = 52), the mean changes from baseline in total score were ||| ||||||) and |||| |||||||| respectively. At the end-of-treatment assessment (n = 54), the mean change from baseline in total score was |||| |||||||.⁴³

FACT-G Total Score

At baseline, a total of 140 patients completed the FACT-G, and the mean score at baseline was 76.2 (SD = 16.86). At cycle 5, day 1 (n = 66) and cycle 7, day 1 (n = 52), the mean changes from baseline in total score were ||| ||||||| and ||| |||||||, respectively. At the end-of-treatment assessment (| | ||), the mean change from baseline in total score was |||| ||||||||⁴³

FACT-LymS

The sponsor evaluated 6 questions from the FACT-Lym that were related to the symptoms of lymphoma: P2 (body pain), BRM3 (fever), ES3 (night sweats), GP1 (lack of energy), BMT6 (tires easily), and C2 (weight loss). At baseline, a total of 140 patients completed the FACT-LymS, and the mean score at baseline was 42.2 (SD = 9.98). At cycle 5, day 1 (n = 66) and cycle 7, day 1 (n = 52), the mean changes from baseline in total score were ||| |||||| and ||| ||||||, respectively. At the end-of-treatment assessment (n = |||), the mean change from baseline in total score was ||| ||||||. Table 21 summarizes the proportion of patients who reported at least a 1-category improvement in any of the 6 key lymphoma symptoms (i.e., body pain, fever, night sweats, lack of energy, tires easily, and weight loss, with each assessed using a 5-point severity response scale ranging from “not at all” to “very much”) without worsening in the other 5 symptoms, from baseline through cycle 9, day 1.⁴³

Table 21: Summary of FACT-Lym Total Score, FACT-G Total Score, and FACT-LymS

BL = baseline; C1 = cycle 1; C3 = cycle 3; C5 = cycle 5; C7 = cycle 7; C9 = cycle 9; D1 = day 1; EOT = end of treatment; FACT-G = Functional Assessment of Cancer Therapy–General; FACT-Lym = Functional Assessment of Cancer Therapy–Lymphoma; FACT-LymS = Functional Assessment of Cancer Therapy–Lymphoma Subscale; SD = standard deviation.

Sources: EPCORE NHL-1 Clinical Study Report (April 21, 2023)⁴³ and sponsor’s Summary of Clinical Evidence.¹¹

Table 22: Summary of FACT-Lym — Lymphoma Symptoms From the EPCORE NHL-1 Study

BL = baseline; C2 = cycle 2; C3 = cycle 3; C5 = cycle 5; C7 = cycle 7; C9 = cycle 9; D1 = day 1; FACT-Lym = Functional Assessment of Cancer Therapy–Lymphoma.

Sources: EPCORE NHL-1 Clinical Study Report (April 21, 2023)⁴³ and sponsor’s Summary of Clinical Evidence.¹¹

EQ-5D-3L

At baseline, a total of ||| patients completed the EQ-5D-3L. The mean (SD) utility score at baseline was ||||| ||||||||. At cycle 5, day 1 (n = |||) and cycle 7, day 1 (n = |||), the mean changes from baseline in total score were ||||| |||||||| and ||||| ||||||||| respectively. At the end-of-treatment assessment (n = |||), the mean change from baseline in total score was |||||| |||||||||⁴³ The mean (SD) score in EQ VAS at baseline was |||||| |||||||||. At cycle 5, day 1 (n = |||) and cycle 7, day 1 (n = |||), the mean changes from baseline in total score were ||||| ||||||||| and |||||| |||||||||, respectively. At the end-of-treatment assessment (n = |||), the mean change from baseline in total score was |||||| ||||||||||

Table 23: Summary of EQ-5D-3L From the EPCORE NHL-1 Study

BL = baseline; C1 = cycle 1; C3 = cycle 3; C5 = cycle 5; C7 = cycle 7; C9 = cycle 9; D1 = day 1; EOT = end of treatment; EQ VAS = EQ visual analogue scale; SD = standard deviation.

Source: EPCORE NHL-1 Clinical Study Report (April 21, 2023)⁴³ and sponsor’s Summary of Clinical Evidence.¹¹

Harms

Refer to Table 24 for harms data. As of the data cut-off date (April 21, 2023), ||| ||||||| patients with LBCL had experienced at least 1 TEAE. Serious TEAEs were reported in ||| ||||||| patients. A total of ||| ||||||| patients experienced grade 3 or higher TEAEs, and ||| ||||||| patients had grade 3 or higher TEAEs considered related to epcoritamab by the investigator.⁴³

Table 24: Summary of Harms Results From Studies Included in the Systematic Review

PT = preferred term; SOC = system organ class; TEAE = treatment-emergent adverse event.

^aOne patient died due to fatal TEAEs related to COVID-19 pneumonia and myocarditis.

Source: EPCORE NHL-1 Clinical Study Report (April 2023 data cut-off).⁴³

Adverse Events

In patients with LBCL (N = 157), the most frequent (i.e., noted in at least 20% of patients) TEAEs by PT were CRS (80 patients [51.0%]), pyrexia (not attributed to CRS; || |||||||), fatigue (|| |||||||), neutropenia (|| |||||||), nausea (|| |||||||), anemia (|| ||||||| patients), and diarrhea (|| |||||||). Grade 3 or 4 TEAEs were reported for ||| ||||||| patients with LBCL. The most common grade 3 or grade 4 TEAEs (≥ 5%) by PT in patients with LBCL (N = 157) were neutropenia (|| |||||||), anemia (|| |||||||), neutrophil count decrease (||| ||||||), COVID-19 (|| ||||||), and thrombocytopenia (| ||||||).⁴³

Serious Adverse Events

Serious TEAEs were reported in ||| ||||||| patients with LBCL. The most frequent (≥ 2%) serious TEAEs by PT in patients with LBCL were CRS (|| |||||||); COVID-19 (|| ||||||); COVID-19 pneumonia (| ||||||); pleural effusion (| ||||||); pneumonia (| ||||||); and pyrexia (not attributed to CRS), sepsis, ICANS, and febrile neutropenia (| |||||| each).⁴³

Withdrawal or Interruption Due to Adverse Events

In patients with LBCL (N = 157), || ||||||| patients experienced at least 1 TEAE that led to treatment discontinuation. The most common of these were COVID-19 pneumonia (| ||||||), COVID-19 (| ||||||), and myelodysplastic syndrome (| ||||||). Other TEAEs that led to treatment discontinuation in this group, occurring in 1 patient each, were pneumonia, bacterial pneumonia, progressive multifocal leukoencephalopathy, anogenital warts, malignant lung neoplasm, myocardial infarction, myocarditis, chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids, ICANS, fatigue, and CRS.⁴³

There were || ||||||| patients with LBCL who had TEAEs leading to dose delay, and for || |||||||| In patients with LBCL (N = 157), the most common (≥ 2% overall) TEAEs leading to dose delay were COVID-19 (19 patients [12.1%]); CRS (11 patients [7.0%]); neutropenia (| |||||||| thrombocytopenia (5 patients [3.2%]); and pyrexia (not attributed to CRS), upper respiratory tract infection, and pleural effusion (| |||||| each).⁴³

Mortality

Table 25 provides a summary of deaths reported in the EPCORE NHL-1 trial for the population of patients with LBCL. Deaths were reported for || ||||||| patients with LBCL, || ||||||| patients with DLBCL, and || ||||||| patients with other LBCL subtypes. The majority of deaths were attributed to disease progression (||||| of patients).⁴³

Table 25: Summary of Mortality From the EPCORE NHL-1 Study

DLBCL = diffuse large B-cell lymphoma; LBCL = large B-cell lymphoma.

Source: Clinical Study Report.⁴³

Notable Harms

Table 39 provides a summary of the notable harms from the EPCORE NHL-1 trial, including CRS events, ICANS events, and serious infections.

Cytokine Release Syndrome

The AESI of CRS was analyzed and summarized at the patient level and event level. In the patient-level analysis, patients with multiple CRS events were counted only once, but may have been counted in more than 1 dosing period. In the event-level analysis, all CRS events are counted, including multiple episodes experienced by the same patient. In patients with LBCL, 80 patients (51.0%) had at least 1 CRS event. The majority of these were grade 1 events (|| | of 80 patients) and occurred most frequently after the first full dose of epcoritamab on C1D15 (||| of 80 patients). Grade 2 and grade 3 events occurred in ||| and ||| of 80 patients, respectively. There were no grade 4 or 5 events. The most common symptom was fever (||| of 80 patients). The most common treatment reported for CRS was anticytokine therapy using tocilizumab (||| of 80 patients); no other anticytokines were used. Events of CRS were treated with corticosteroids (beyond those scheduled for mandatory CRS prophylaxis) for ||| of 80 patients who experienced CRS. Oxygen was used to treat ||| of 80 patients who experienced CRS.

The median time to first CRS onset was ||||| days (range, || ||) correlating with the first full dose of epcoritamab on C1D15. The median time to CRS resolution was |||| days (range, || ||). Of the | | CRS events that occurred for the priming doses, most (|||) were grade 1, and only 2 were grade 3; no grade 3 events were observed with the priming doses. The CRS symptoms resolved in ||| of 80 patients (||||||). For most dosing periods, CRS resolved for all patients. The exception was the second full dose: CRS was unresolved for 2 patients of 7 patients within that dosing period.

Immune Effector Cell–Associated Neurotoxicity

ICANS symptoms were monitored at every visit and daily for patients who were hospitalized because of CRS. All but 1 of the reported ICANS events occurred in patients with DLBCL. ICANS events of were reported in 10 patients (6.4%); | ||||||| patients had grade 1 ICANS, | ||||||| patients had grade 2 ICANS; and | ||||||| patient had grade 5 (fatal) ICANS.

The fatal episode of ICANS, in a 72-year-old female patient with DLBCL, was an on-treatment event with onset on day 12, which was 4 days after the patient’s most recent dose of the study drug. The episode was considered related to the study drug. This event was confounded with long-standing cardiovascular comorbidities, grade 3 pancreatitis, and multifocal cerebral and splenic infarcts. The patient had received only the priming and intermediate doses.

Three patients (|||||) experienced ICANS events that led to dose delays, and in | ||||||| patient, the event led to treatment discontinuation. The median time to first onset was |||| |||| ||||||| || ||||, correlating with the period shortly following the first full dose of epcoritamab on C1D15. As of the data cut-off date, ICANS events had resolved for | ||||||| patients, with the median time to resolution of ||| |||| ||||||| || ||. Of the 10 patients with LBCL with an ICANS event, ||| patients received at least 1 concomitant medication as treatment. The only medications used to treat ICANS for more than | |||||||| were dexamethasone (||| patients) and levetiracetam (||| patients).

Clinical Tumour Lysis Syndrome

Among patients with LBCL, there were 2 patients (1.3%) who experienced CTLS events; both events were considered treatment-related in the disease progression setting. Both were grade 3 in severity. Neither had resolved before the patients’ deaths (both due to disease progression).

Serious Infections

Forty-six patients (29.3%) experienced at least 1 serious infection during the EPCORE NHL-1 trial. The majority of patients who had serious infections had at least 1 event that was classified as grade 3 (|||||), with grade 4 and 5 events reported for ||| and ||| patients, respectively.

Critical Appraisal

Internal Validity

Trial design: The EPCORE NHL-1 phase I and II trial was the only study included in this review. The study is an ongoing phase I and II, multicentre, open-label, single-arm study of epcoritamab. The choice to conduct a single-arm trial was justified by the sponsor on the basis that the study was designed as an early-phase I and II study in which an internal comparator group is not required; the severity of illness for patients at this stage (i.e., those with R/R illness following at least 2 lines of prior systemic therapy) was also a justification. However, the decision to conduct a single-arm study has implications for the overall strength and interpretability of the results. As a single-arm study, there is an increased risk of bias in the estimation of treatment effects due to the potential for confounding related to natural history and prognostic factors. The potential influence of selection bias is also difficult to ascertain in a single-arm study. Additionally, time-to-event end points cannot be adequately assessed in a single-arm trial because all patients receive the same treatment. As such, the effects of epcoritamab on time-to-event end points, such as PFS, OS, and DOR, are uninterpretable, and can only be considered as exploratory and supportive.

Lack of comparator: In the absence of a comparator group in the EPCORE NHL-1 study, an assessment of the comparative clinical value of epcoritamab relies on ITCs (i.e., unanchored MAICs), which rely on numerous assumptions about the comparability of treatment groups, thereby increasing the uncertainty related to the comparative effectiveness (refer to the Indirect Evidence section for details). The uncertainty in the comparative efficacy of epcoritamab versus relevant comparators was acknowledged by Health Canada, which has specified that the sponsor must provide phase III trial results showing that epcoritamab improves the OS of patients with LBCL compared to investigator's choice of either BR or R-GemOx.

Open label: In addition to the single-arm design, the EPCORE NHL-1 study was administered in an open-label manner whereby the investigator and study participants were aware of their treatment status, potentially increasing the risk of detection bias and performance bias. As such, the open-label trial design limits interpretability of the subjective study outcomes, such as tumour response and PROs, including HRQoL and AEs. However, to mitigate the impact of this bias, PFS and ORR were assessed by both IRC and the investigator using the Lugano classification criteria for the response. For response outcomes, there was generally a low discordance rate between IRC- and investigator-assessed responses in the EPCORE NHL-1 trial. Discordance between IRC- and investigator-assessed responses and the potential influence on outcomes are well documented, including guidance from the FDA to industry.⁵³ Given the open-label design of the trial, it is possible that the IRC provided less potentially biased tumour assessments compared with investigator’s assessments.

Sample size: A limited number of patients were included in the primary efficacy population (N = 157). Although the EPCORE NHL-1 study was powered for the primary end point, the magnitude of the treatment-effect estimates observed in a relatively small study sample may not be replicable in a larger study sample.

Outcomes: The clinical experts consulted by CADTH and the regulatory authorities indicated that the outcomes studied in the EPCORE NHL-1 trial were those typically assessed for the target population. Health Canada reviewers noted that the median follow-up times for patients enrolled in the EPCORE NHL-1 trial are similar to those of other therapies that have been studied in the population of patients with R/R LBCL. Despite PFS and OS results that were considered clinically meaningful by the clinical experts consulted by CADTH, the results for survival end points should only be considered supportive of the overall antitumour effect of epcoritamab due to the single-arm design and the secondary nature of the outcomes. Quality of life outcomes, which were identified as important to patients in their input to CADTH, were also secondary end points of the EPCORE NHL-1 study.

The primary end point of ORR in the EPCORE NHL-1 study does not appear to be aligned with regulatory guidance from the FDA⁵³ regarding hematologic cancers, which cites CR as opposed to ORR as a direct measure of the drug’s antitumour activity in oncology clinical trials. Health Canada similarly questioned the choice of ORR as the primary efficacy outcome rather than CR rate, which their review team considered to be the more informative outcome measure in the population of patients with R/R LBCL. Health Canada noted that the DOR was relatively short for those with a best overall response of PR (refer to PFS Figure 6).³² In response to Health Canada’s question regarding the use of ORR as the primary end point, the sponsor provided the following as justification that ORR is a clinically meaningful surrogate end point in the context of single-arm trials that are intended to support market authorization for treatment that is intended to fulfill the unmet medical needs of patients with R/R LBCL:

• ORR was chosen as the primary efficacy outcome based on benchmark studies that led to recent approvals in R/R LBCL that also used ORR as the primary efficacy end point: Minjuvi (tafasitamab); Kymriah (tisagenlecleucel); and Breyanzi (lisocabtagene maraleucel).

• CR was a secondary end point in the EPCORE NHL-1 study, with a CR rate of ||||||.

• Response-stratified analyses demonstrated that those who achieved a CR had the highest PFS and OS benefit and those who achieved a PR (|||||| achieved longer median PFS ||| |||||| and OS |||| ||||||) than those of nonresponders (||| months PFS and ||| months OS).⁵⁴

In a retrospective analysis of the GOYA trial⁵⁵ and a meta-analysis of studies of LBCL,⁵⁶ the prognostic value of PET in assessing CR with respect to PFS and OS was evaluated. Although the results of these studies suggest that end-of-treatment CR was a predictor of PFS and OS, and that CR could be an effective surrogate end point for survival, these studies were conducted in previously untreated patients; thus, it remains unclear whether there is an association between CR rate and survival in patients receiving third-line treatment for LBCL. Recent literature has highlighted that the correlation between response rates and survival is variable and that there are gaps in understanding the strength of response as a surrogate outcome in hematologic malignancy trials.^57-59 Overall, the clinical experts consulted by CADTH felt that the clinical trial end points were appropriate for the target population. In addition, data from the phase II trials of glofitamab and epcoritamab demonstrated that CR responses were durable and that patients who experienced CR survived longer than those who did not respond to treatment or whose best response was PR. The sponsor also noted that an analysis of patients in Denmark (N = 130) who received treatment with a bispecific T-cell engager (glofitamab or epcoritamab) in phase I and II clinical trials reported that 73% of patients with CR remained in complete remission after 3 years.⁶⁰

Statistical approach: There were no methods incorporated to account for multiple testing; thus, all secondary end points were considered supportive and should be interpreted with respect to type I error. There was also no control for multiplicity across the cohorts selected for inclusion in the review.

External Validity

Trial location and setting: The EPCORE NHL-1 study was an international, multicentre study that included sites in Australia, South Korea, US, France, Netherlands, Spain, Denmark, Germany, UK, Poland, Singapore, Italy, and Canada (1 site with 1 patient enrolled). The clinical experts consulted by CADTH had no concerns regarding the generalizability of the study results to the setting in Canada. Patients in the EPCORE NHL-1 trial were hospitalized for at least 24 hours after receiving the first full dose of epcoritamab. The clinical experts consulted by CADTH noted that this is reflective of how this drug will be used in practice in Canada.

Intervention: The treatment regimen used in the EPCORE NHL-1 trial aligns with the recommendations shown on the Health Canada–approved product monograph for epcoritamab (i.e., a priming dose of 0.16 mg; an intermediate dose of 0.8 mg; and full doses of 48 mg thereafter).⁴⁴ The pretreatment and posttreatment medications (e.g., prednisolone) used to reduce the risk of CRS in the EPCORE NHL-1 trial are reflective of those recommended in the product monograph, as were the therapies used to manage the more severe CRS events (i.e., tocilizumab or additional corticosteroids). The clinical experts consulted by CADTH noted that dosing of epcoritamab and the medications used for the management of AEs throughout the peritreatment period are reflective of the regimen that would be administered in practice in Canada.

Outcomes: Outcomes included in the EPCORE NHL-1 trial were relevant in the management of R/R LBCL and were identified as important to patients and clinicians. For tumour response and disease progression, measurement using the Lugano criteria is standardized across jurisdictions. However, it was noted in the clinician group input that PET and/or CT are not available in all jurisdictions. While the experts considered response outcomes to be important in the treatment of R/R LBCL and believed that the responses observed in the EPCORE NHL-1 trial study were better than they would expect to observe from other currently available treatments, they noted that survival and the prevention of progression are of greatest importance to patients at this stage. As previously mentioned, the estimates of PFS and OS may be overestimated due to the relatively small information fraction and overall immaturity of the data, which may affect the generalizability of the results to the population of patients with R/R LBCL in Canada. The patient group input also highlighted the importance of treatments that improve HRQoL and provide the ability to engage in usual activities. However, as identified for PFS and OS, the EPCORE NHL-1 trial was not adequately designed to assess the effects of epcoritamab on HRQoL and related outcomes.

Population: The clinical experts consulted by CADTH noted that the inclusion and exclusion criteria used in the EPCORE NHL-1 trial were a reasonable reflection of the patient population for whom epcoritamab could be considered an appropriate treatment in clinical practice in Canada. Although patients who had received ASCT and were refractory or experienced relapse relatively rapidly were excluded from the EPCORE NHL-1 trial, the clinical experts noted that these patients could be considered candidates for epcoritamab. (That is, the exclusion from the EPCORE NHL-1 trial of patients who had received ASCT within 100 days before the first dose of epcoritamab may not be reflective of clinical practice, and these patients could be considered for treatment.) Overall, the clinical experts concluded that the baseline characteristics of those enrolled in the EPCORE NHL-1 trial were reflective of the target population in Canada.

The proportion of patients with an ECOG Performance Status of 2 included in the EPCORE NHL-1 trial was relatively low (3.2%). The clinical experts noted that the proportion could be greater in clinical practice, especially given that the indication is limited to those who are ineligible for CAR T-cell therapy.

Prior CAR T-cell therapy: The clinical experts noted that 40% of patients with prior CAR T-cell therapy exposure is a reasonable reflection of the target population for epcoritamab in Canada (while noting that the figure would vary across jurisdictions). They also noted that the overall proportion of patients with a history of stem cell transplant could be slightly lower than might be anticipated in routine practice in Canada for patients for whom 2 or more lines of systemic therapy have not been effective. Both the clinical experts consulted by CADTH and the participating drug programs noted that the treatment landscape for R/R LBCL in Canada may shift toward earlier usage of CAR T-cell therapy, given that axicabtagene ciloleucel (Yescarta) received a recommendation to reimburse with conditions from CADTH for use as a second-line option, based on the results of the ZUMA-7 trial. Axicabtagene ciloleucel was under review by the pan-Canadian Pharmaceutical Alliance at the time of this review and was not funded by any of the participating drug programs for any line of therapy (refer to Figure 1).

Concomitant treatments: The clinical experts noted that the type and distribution of concomitant medications were a reasonable reflection of what would be administered in practice in Canada in the R/R LBCL setting.

Subsequent Treatments: The clinical experts consulted by CADTH noted that the distribution of subsequent antilymphoma therapies received after the discontinuation of epcoritamab was a reasonable reflection of what could be expected in routine practice in Canada. The clinical experts noted that ||| of the patients in the EPCORE NHL-1 trial received no subsequent antilymphoma therapy, which is an indication of how severe the baseline level of disease was in this trial (i.e., epcoritamab was the final therapy before patients died). A total of |||| of patients (n = |||) received subsequent CAR T-cell therapy in the EPCORE-1 NHL trial. The clinical experts noted that they would anticipate similar rates in practice in Canada of patients receiving potentially curative therapies after treatment with epcoritamab (e.g., CAR T-cell therapy or stem cell transplant), and they emphasized that epcoritamab could provide a useful option as a bridging therapy for those awaiting CAR T-cell infusion (acknowledging that such usage would be off-label, based on the current indication approved by Health Canada). Similarly, the clinical experts consulted by CADTH noted that patients who do not respond or progress following epcoritamab could be considered candidates for CAR T-cell therapy (acknowledging that the Health Canada–approved indication for epcoritamab would suggest that the treatment should be initiated only in those who could not receive CAR T-cell therapy at the time of initiating therapy with epcoritamab).

Tolerability: The clinical experts noted that similar rates of discontinuation and the reasons for discontinuation were aligned with the expectations for the target patient population in Canada.

GRADE Summary of Findings and Certainty of the Evidence

Methods for Assessing the Certainty of the Evidence

For pivotal studies and RCTs identified in the sponsor’s systematic review, GRADE was used to assess the certainty of the evidence for outcomes considered most relevant to inform CADTH’s expert committee deliberations, and final certainty ratings were determined as outlined by the GRADE Working Group:^9,10

• High certainty: We are very confident that the true effect lies close to that of the estimate of the effect.

• Moderate certainty: We are moderately confident in the effect estimate. This means the true effect is likely to be close to the estimate of the effect, but there is a possibility that it may be substantially different. We use the word “likely” for evidence of moderate certainty (e.g., “X intervention likely results in Y outcome”).

• Low certainty: Our confidence in the effect estimate is limited. This means the true effect may be substantially different from the estimate of the effect. We use the word “may” for evidence of low certainty (e.g., “X intervention may result in Y outcome”).

• Very low certainty: We have very little confidence in the effect estimate. This means the true effect is likely to be substantially different from the estimate of effect. We describe evidence of very low certainty as “very uncertain.”

Although GRADE guidance is not available for noncomparative studies, the CADTH review team assessed pivotal, single-arm trials for study limitations (which refers to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias to present these important considerations. Because the lack of a comparator arm does not allow for a conclusion to be drawn on the effect of the intervention versus any comparator, the certainty of evidence for single-arm trials started at very low certainty, with no opportunity for rating up.

When possible, certainty was rated in the context of the presence of an important (nontrivial) treatment effect; if this was not possible, certainty was rated in the context of the presence of any treatment effect (i.e., the clinical importance is unclear). In all cases, the target of the certainty of evidence assessment was based on the point estimate and where it was located relative to the threshold for a clinically important effect (when a threshold was available) or to the null.

The target of the certainty of evidence assessment was the presence of a clinically important improvement in survival (PFS and OS) and HRQoL, which were considered the most important treatment outcomes by the clinical experts consulted by CADTH as well as the clinician and patient group inputs. According to the clinical experts consulted by CADTH, clinically important thresholds for the outcomes of PFS and OS were a benefit of at least 6 months and 3 months over current standard of care for OS and PFS, respectively. Additionally, response to treatment (CR, ORR, DOR) was included in the certainty of evidence assessment based on the potential translation to long-term survival outcomes.

The EPCORE NHL-1 trial, a phase I and II, single-arm, open-label study of epcoritamab monotherapy, was the only study included in the GRADE assessment.

Results of GRADE Assessments

Table 2 presents the narrative GRADE summary of findings for epcoritamab monotherapy from the EPCORE NHL-1 study.

Long-Term Extension Studies

No long-term extension studies were submitted to CADTH or identified in the literature.

Indirect Evidence

The contents of this section were informed by materials submitted by the sponsor. The following information has been summarized and validated by the CADTH review team.

Objectives for the Summary of Indirect Evidence

Given the single-arm nature of the EPCORE NHL-1 trial, there is no direct head-to-head evidence comparing epcoritamab against the following comparators for patients with R/R LBCL or R/R DLBCL with exposure to at least 2 prior therapies:

• CIT

• pola-BR

• pola-B/R

• axicabtagene ciloleucel

• tisagenlecleucel

• lisocabtagene maraleucel.

ITC Design

Objectives

The objective of the sponsor-provided ITC was to compare epcoritamab against comparator drug therapies (i.e., CIT, pola-BR, axicabtagene ciloleucel, tisagenlecleucel, and lisocabtagene maraleucel) for patients with R/R LBCL or R/R DLBCL with exposure to at least 2 prior therapies.

Study Selection Methods

Eligibility criteria for the systematic literature review (SLR) are summarized in Table 26. The sponsor conducted the SLR to identify, extract, and analyze relevant clinical evidence for greater than or equal to third-line therapies in R/R LBDC or R/R DLBCL. The technical report notes that the studies were selected in accordance with the approved indication for epcoritamab; however, this appears more accurate for the international context, in which the approved indication has not been restricted to patients who have already received or are unable to receive CAR T-cell therapy. Specifically, the sponsor included CAR T-cell therapies as comparators in the MAICs, but these cannot be considered comparators in the context of the Health Canada–approved indication.

Table 26: Study Selection Criteria and Methods for ITCs Submitted by the Sponsor

CR = complete response; CRD = Centre for Reviews and Dissemination; DLBCL = diffuse large B-cell lymphoma; HR = hazard ratio; IRC = independent review committee; ITC = indirect treatment comparison; LBCL = large B-cell lymphoma; MAIC = matching-adjusted indirect comparison; ORR = overall response rate; OS = overall survival; PFS = progression-free survival; pola-B/R = polatuzumab vedotin with rituximab, with or without bendamustine; pola-BR = polatuzumab vedotin with bendamustine and rituximab; pola-R = polatuzumab vedotin with rituximab; QA = quality assessment; R-CIT = rituximab-based chemoimmunotherapy; R/R = relapsed or refractory; RCT = randomized controlled trial; RWE = real-world evidence; SLR = systematic literature review.

^aAn exception is the 5-year follow-up from the ZUMA-1 trial of axicabtagene ciloleucel, which was included in the MAIC of the epcoritamab April 2023 data cut-off.

Source: Sponsor’s indirect comparison.¹¹

ITC Analysis Methods

Unanchored MAICs were determined to be the most appropriate analysis method, given that network meta-analysis generation was determined infeasible due to the single-arm nature of the EPCORE NHL-1 study. For each MAIC, patient-level data from the EPCORE NHL-1 trial data were reweighted using a propensity scoring approach to match the comparator trial data based on the availability of common patient characteristics. Under the counterfactual conditions of the comparator trial characteristics, the unanchored MAIC for survival were formed by calculating the logarithm of the hazard ratio of the reweighted epcoritamab survival curve versus the comparator’s digitized survival curve. The log estimates were then exponentiated and presented on the natural scale of the hazard ratio. Similarly, the mean difference between the predicted response for the reweighted epcoritamab arm and the comparator’s simulated patient-level data were calculated.

Analysis Populations for the ITC

To account for differing data availability across epcoritamab and the comparators, the sponsor identified 3 distinct populations (refer to Table 27).

Table 27: ITC Analysis Populations

CAR = chimeric antigen receptor; ITC = indirect treatment comparison; ITT = intention to treat; MAIC = matching-adjusted indirect comparison; pola-BR = polatuzumab vedotin with bendamustine and rituximab; R-CIT = rituximab-based chemoimmunotherapy; RCT = randomized controlled trial.

Source: Sponsor’s indirect comparison.¹¹

Characteristics Included in Propensity Matching

The sponsor stated that variables for adjustment in the propensity matching were selected using the following approaches: literature review, empirical testing of prognostic status in the EPCORE NHL-1 trial, and clinical expert input as to whether patient characteristics are important to adjust for in the population of patients with R/R LBCL and R/R DLBCL. The sponsor selected the following final characteristics:

• Age (≥ 65 years)

• Gender

• DLBCL histology (including transformed follicular lymphoma) versus not DLBCL

• Primary refractoriness

• Refractory to greater than or equal to 2 consecutive lines of therapy

• Refractory to last prior anti-CD20 drug

  • Refractoriness to last treatment when information on last prior anti-CD20 or primary refractoriness is not available

• Prior CAR T-cell therapy

• Prior ASCT

• Relapse within 12 months of ASCT

• ECOG Performance Status greater than 1

• Disease stage III to IV

  • It was considered unnecessary to adjust for IPI score if the stage was included, given that IPI score correlates with disease stage

Characteristics Not Included in Propensity Matching

The sponsor reported that the following core adjustment characteristics were considered, but not included: bridging therapy use, secondary CNS involvement, lactate dehydrogenase blood level before treatment, and the exact number of prior therapy lines. Additional characteristics adjusted for in scenario analyses included tumour burden, bulky disease, IPI score, extranodal disease, and creatinine clearance. Characteristics were excluded due to being inapplicable and/or not present in the EPCORE NHL-1 trial data, not being prognostic as per the analysis of the data, or not being relevant, as per clinical expert opinion. The exact number of prior therapy lines was specifically not adjusted for due to variability in the number of earlier lines of therapy in each trial.

Propensity Score Weighting

Propensity score weighting was performed for the EPCORE NHL-1 trial data: the data were reweighted to match the baseline characteristics of those reported in the comparator trial using the method of moments as described by Signorovitch et al.⁶¹ such that the weighted means of key baseline characteristics from the EPCORE NHL-1 study exactly matched those in the study being compared and such that each individual patient’s weight was equal to their estimated odds of being in the comparator trial versus the EPCORE NHL-1 trial. Whenever indicated — and to improve the accuracy and precision of final parameter estimates — adjustment weights were incrementally truncated at the following thresholds of the weights’ distribution to reduce the occurrence of extreme weights (i.e., generally higher than 5 or 6 or lower than 0.1) while preserving the resulting balance in adjusted baseline characteristics, as previously recommended:

• || and |||

• |||| and |||||

• || and |||

The final decision concerning which distribution cut-off point was appropriate for the particular ITC was driven by whether the next broader cut-off selection substantially imbalanced the baseline characteristics of epcoritamab and the comparator. Therefore, for different ITC analyses, different cut-off points were deemed optimal. The impact of reweighting is that there is less statistical information in the reweighted trial data, which is reflected in the effective sample size (ESSs). The maximum ESS is equal to the original trial size and occurs when the patient characteristics of the EPCORE NHL-1 trial and the comparator are identical.

Table 28: ITC Analysis Methods

CR = complete response; NICE = National Institute for Health and Care Excellence; ORR = overall response rate; OS = overall survival; PFS = progression-free survival.

Source: Sponsor’s Summary of Clinical Evidence.¹¹

Pola-BR has been previously reviewed by CADTH and received a recommendation to reimburse with conditions as a second- or third-line option. The recommendation from CADTH was based on the results of the GO29365 study, a phase Ib and II, open-label RCT in which pola-BR demonstrated improvements in CR rate, ORR, PFS, and OS compared with BR alone. The sponsor for epcoritamab elected not to include the GO29365 study in the submitted MAIC estimating the comparative efficacy of epcoritamab versus pola-BR for the overall population of patients with LBCL, opting instead to use RWE from Liebers et al. (2021). The sponsor cited the following reasons for concluding that the GO29365 and EPCORE NHL-1 trials were not sufficiently similar for the ITC:

• Lines of therapy: Approximately 30% of patients in the GO29365 trial had prior exposure to only 1 prior line of therapy; the sponsor suggested that the patients enrolled in the GO29365 study were less ill than those enrolled in the EPCORE NHL-1 trial (who were more heavily pretreated at the time of enrolment). CADTH notes that the sponsor is correct with respect to the number of prior lines of therapy that patients received in the GO29365 study compared with the EPCORE NHL-1 trial. Specifically, those in the EPCORE NHL-1 trial had received a median of 3 prior lines of therapy compared with a median of 2 lines of prior therapy in the GO29365 study.

• Prior exposure to CAR T-cell therapy: No patients enrolled in the GO29365 study had received prior treatment with CAR T-cell therapy, whereas 39% of those enrolled in the EPCORE NHL-1 trial had. CADTH notes that prior exposure to CAR T-cell therapy is an important prognostic factor and would make the GO29365 study inappropriate for comparisons with the overall cohort of patients with LBCL in the EPCORE NHL-1 trial or with the cohort of patients with prior CAR T-cell exposure.

• Real-world efficacy: The sponsor stated that clinical experts had stated that the efficacy of pola-BR does not seem as promising in the real world versus the GO29365 trial. CADTH notes that evaluating efficacy in short-term clinical trials can overestimate the clinical benefit of drugs versus the real-world setting. However, this potential bias would apply to all early-phase clinical trial settings, not just the GO29365 trial. As with other HTA agencies (i.e., NICE and HAS), CADTH considered the approach of comparing data derived from a clinical trial for 1 drug against data derived from a real-world world setting for the comparator to be associated with uncertainty, given the differences in patient selection and data collection.

The sponsor did use subgroup data from the GO29365 trial for the comparison of epcoritamab versus pola-BR for patients with no prior CAR T-cell exposure (specifically extracting data for patients who had not responded to 2 prior lines of therapy).

Comparisons Versus CIT

The sponsor was able to conduct an ITC of epcoritamab versus CIT only for patients with no prior CAR T-cell therapy exposure (due to an absence of data for CIT in the target population). Hence, the subgroup of patients from the EPCORE NHL-1 trial (n = 96) was compared against a subgroup of patients from the SCHOLAR-1 study. The SCHOLAR-1 study was a retrospective cohort analysis with data drawn from 4 sources: observational cohorts from the MD Anderson Cancer Center; the Molecular Epidemiology Resource of the University of Iowa/Mayo Clinic Lymphoma Specialized Program of Research Excellence; the phase III Canadian Cancer Trials Group study; and the phase III CORAL study. The specific subgroup of patients from the SCHOLAR-1 study used by the sponsor was derived from a published ITC of axicabtagene ciloleucel versus CIT in which patients from the ZUMA-1 trial were matched against those from the SCHOLAR-1 dataset.

Comparisons Versus CAR T-cell Therapies

The sponsor-submitted ITC included comparisons against 3 CAR T-cell therapy regimens: axicabtagene ciloleucel, tisagenlecleucel, and lisocabtagene maraleucel. Given that the Health Canada–approved indication for epcoritamab states that the drug is approved for use only in patients “who have previously received or are unable to receive CAR T-cell therapy,” CADTH does not consider CAR T-cell therapies to be relevant comparators for the current review. The approach is consistent with applications that have been filed in the same therapeutic area. The sponsor’s results are presented in this section of the CADTH report but are not otherwise appraised or interpreted by CADTH.

ITC Results

Summary of Included Studies

Table 29 summarizes selected patient and study characteristics for the trials included in the sponsor’s MAICs.

Table 29: Characteristics of the Trials Included in the ITC

ASCT = autologous stem cell transplant; BR = bendamustine plus rituximab; CAR = chimeric antigen receptor; CIT = chemoimmunotherapy; CR = complete response; DLBCL = diffuse large B-cell lymphoma; ECOG = Eastern Cooperative Oncology Group; HR = hazard ratio; IRC = independent review committee; LOT = lines of therapy; NA = not applicable; NR = not reported; OL = open label; ORR = overall response rate; OS = overall survival; PFS = progression-free survival; pola-B = polatuzumab vedotin with bendamustine; pola-B/R = polatuzumab vedotin with rituximab, with or without bendamustine; pola-BR = polatuzumab vedotin with bendamustine and rituximab; pola-R = polatuzumab vedotin with rituximab; RWE = real-world evidence; Tx = treatment.

^aThe sponsor included the results for all 54 patients included in the salvage chemotherapy group of Liebers et al., which required pooling of patients who received pola-BR (n = 32 [59.3%]), pola-R (n = 20 [37.0%]), pola-B (n = 1 [1.85%]), and pola-R with gemcitabine (n = 1 [1.85%]).

^bFifty-four patients were included in the salvage treatment cohort.

Table 30: Assessment of Homogeneity for MAIC Comparing Epcoritamab to Pola-B/R for Overall Population of Patients With LBCL

ASCT = autologous stem cell transplant; CAR = chimeric antigen receptor; CR = complete response; DLBCL = diffuse large B-cell lymphoma; ECOG = Eastern Cooperative Oncology Group; FAS = full analysis set; IRC = independent review committee; LBCL = diffuse large B-cell lymphoma; MAIC = matching-adjusted indirect comparison; pola-B = polatuzumab vedotin with bendamustine; pola-B/R = polatuzumab with rituximab, with or without bendamustine; pola-BR = polatuzumab vedotin with bendamustine and rituximab; pola-R = polatuzumab vedotin with rituximab; PR = partial response; PS = Performance Status; R/R = relapsed or refractory.

Source: Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Table 31: Assessment of Homogeneity for MAIC Comparing Epcoritamab to Pola-BR for Population Without Prior CAR T-Cell Therapy

ASCT = autologous stem cell transplant; BR = bendamustine and rituximab; CAR = chimeric antigen receptor; ECOG = Eastern Cooperative Oncology Group; IRC = independent review committee; MAIC = matching-adjusted indirect comparison; pola-BR = polatuzumab vedotin with bendamustine and rituximab; PS = Performance Status; RCT = randomized controlled trial.

Source: Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Results

Table 32 summarizes the association strength of several patient characteristics of interest with 12-month PFS and OS in the EPCORE NHL-1 trial. Across the literature and results from the empirical test for whether patient characteristics were prognostic, the following features came up as possible variables that need to be adjusted for: age, sex, ECOG Performance Status, histology, IPI score, disease stage, primary refractoriness, response to recent prior therapy, number of prior lines of therapy, prior ASCT, and prior CAR T-cell therapy.

Table 32: Association of Patient Characteristics With PFS and OS in the EPCORE NHL-1 Study