CADTH Reimbursement Review

Sacituzumab Govitecan (Trodelvy)

Sponsor: Gilead Sciences Canada, Inc.

Therapeutic area: HR-positive, HER2-negative advanced or metastatic breast cancer

This multi-part report includes:

Clinical Review

Pharmacoeconomic Review

Stakeholder Input

Clinical Review

Executive Summary

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

Table 1: Background Information on the Application Submitted for Review

HER2 = human epidermal growth factor receptor 2; HR = hormone receptor; IHC = immunohistochemistry; ISH = in situ hybridization; NOC = Notice of Compliance.

Introduction

Breast cancer (BC) is a heterogeneous disease that most often originates in the epithelial cells lining the ducts, lobules, or other parts of breast tissue.^1,2 The presence or absence of the expression of human epidermal growth factor receptor 2 (HER2), estrogen receptors (ERs), or progesterone receptors (PRs) affects cancer cell proliferation, prognosis, treatment response, and recurrence of cancers in patients with BC.^2-4 Hormone receptor (HR)-positive tumours have both ER and PR receptors. These tumours are characterized as low grade and slow-growing, tending not to spread. However, they are known to recur in the years following treatment completion.⁵ BC that is HR-positive and HER2-negative is defined as a tumour having more than 1% immunohistochemistry (IHC) expression of ER and/or PR and a lack of HER2 expression, including HER2-low expression (i.e., an IHC score of 0, 1+ or 2+ and confirmed as negative by in situ hybridization [ISH]).^6-9

Signs and symptoms vary by disease stage, and may include swelling in the surrounding lymph nodes, nipple changes (e.g., discharges), skin changes (e.g., erythema, skin ulcers, eczema), breast pain or heaviness, or other persistent changes in the breast.^10,11 BC was the second most diagnosed cancer in Canada in 2022 and the most prevalent among females, with projected estimates of about 28,900 new cases in the overall population (about 28,600 in females and 270 in males).¹² In 2018, the 5-year prevalence of BC in females in Canada was reported to be 110,955 patients,¹³ equating to a 5-year prevalence rate of 0.73%.¹⁴ The HR-positive, HER2-negative subtypes are the most prevalent in Canada, accounting for more than 70% of all new cases. Although prognosis with HR-positive, HER2-negative BC is generally favourable when diagnosed early,² the lifetime risk of developing distant metastases ranges from 22% to 52%, and the prognosis worsens with each subsequent line of systemic therapy administered.¹⁵ The number of cases of relapse reported among newly diagnosed patients with HR-positive, HER2-negative metastatic breast cancer (mBC) who receive first-line treatment has been found to be 71%.¹⁶ The 5-year probability of distant recurrence or death among patients diagnosed with early-stage disease is 17.2% (95% credible interval, 14.6% to 20.3%).¹⁷ Survival outcomes following progression on endocrine-based therapies worsen significantly with later lines of single-drug chemotherapy, with median progression-free survival (PFS) and overall survival (OS) estimated to be as low as 3 months and 7 months, respectively.¹⁸ Metastatic, HR-positive, HER2-negative BC also negatively affects patients’ quality of life because of symptoms associated with disease progression and administered treatment. Common symptoms reported include pain, fatigue, nausea, vomiting, cognitive problems, depression, hair loss, lymphedema, sleep disturbance, loss of appetite, anxiety, and sexual dysfunction.^19-21

In Canada, the treatment algorithm for HR-positive, HER2-negative mBC outlines that standard of care systemic treatment in the first-line setting is endocrine therapy in combination with a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor. Other first-line options include endocrine monotherapy, everolimus plus exemestane, and chemotherapy. For patients with suspected visceral crisis or who are unresponsive to endocrine therapy, chemotherapy may also be used to achieve initial adequate response, with follow-up endocrine therapy in combination with a CDK4/6i.²² Following progression on first-line treatment with endocrine therapy and a CDK4/6 inhibitor, second-line options include endocrine monotherapy, chemotherapy, or everolimus with exemestane.^22,23 For patients who receive endocrine monotherapy in the first-line setting, second-line options include endocrine therapy in combination with a CDK4/6 inhibitor or chemotherapy. Patients face limited treatment options beyond the second line. There is no single standard of care, with chemotherapy recommended once patients have progressed on multiple lines of systemic therapy.²³ Available options for single-drug chemotherapy include anthracyclines, taxanes, capecitabine, eribulin, vinorelbine, platinum complexes, and other drugs.²³ The aligned input from the clinical experts consulted by CADTH regarding options for chemotherapy included capecitabine; paclitaxel; nab-paclitaxel; docetaxel; doxorubicin; epirubicin; vinorelbine; gemcitabine; eribulin; Adriamycin and cyclophosphamide; cyclophosphamide, methotrexate, and fluorouracil; gemcitabine and cisplatin; or gemcitabine and carboplatin. Chemotherapy is associated with an unfavourable toxicity profile and poor survival outcomes.^24-28

The objective of this report is to review and critically appraise the evidence submitted by the sponsor on the beneficial and harmful effects of sacituzumab govitecan, 10 mg/kg, administered as an IV infusion once weekly on days 1 and 8 of a 21-day treatment cycle for the treatment of adult patients with unresectable, locally advanced or metastatic, HR-positive, HER2-negative (IHC 0, IHC 1+, or IHC 2+, and ISH-negative) BC who have received endocrine-based therapy and at least 2 additional systemic therapies in the metastatic setting.

Sacituzumab govitecan has been previously reviewed by CADTH for other indications in the mBC setting. On February 11, 2022, a recommendation for reimbursement was issued for the treatment of adult patients with unresectable, locally advanced or metastatic, triple-negative breast cancer (mTNBC) who have already received 2 or more prior therapies, at least 1 of them for metastatic disease.²⁹

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 by clinical expert(s) consulted by CADTH for the purpose of this review.

Patient Input

The Canadian Breast Cancer Network (CBCN), Rethink Breast Cancer, Breast Cancer Canada (BCC), and the McPeak-Sirois Group (MPSG) submitted input for this review (with BCC and MPSG submitting jointly). The information from CBCN was sourced from 3 online surveys: its 2022 Triple Negative Breast Cancer Patient Survey, 2017 Metastatic Breast Cancer Patient Survey, and 2012 Metastatic Breast Cancer Patient and Caregiver Survey Report. The information submitted by BCC and MPSG was sourced from a survey that ran from July 6, 2023 to July 21, 2023, distributed through email to patients and caregivers living with recurrent mBC. Information from Rethink Breast Cancer was sourced from meetings held with patients with BC, a consultation with the Metastatic Breast Cancer Advisory Board conducted in July of 2023, an online survey of 78 patients living with mBC (which ran from September 2018 to April 2019), and a review of a 2021 survey.

The patient groups expressed that metastatic disease has significant or debilitating impacts on patients’ quality of life. BC significantly affects younger patients, especially those diagnosed in their twenties, thirties, and early forties, who may face age-specific issues such as fertility or family-planning challenges, diagnosis during pregnancy, impacts on child care, impacts on relationships, body image issues, dating and sexuality issues, feelings of isolation from peers who do not have cancer, career hiatuses, and financial insecurity. There is an unmet need for treatments in later lines due to the multirefractory drug experience in the metastatic setting. The patient groups expressed a desire for new options that control disease and extend the lives of patients living with mBC. Patients highlighted key factors that influence treatment choice, such as effectiveness, quality of life, management of side effects, cost, and accessibility. They also expressed the need for personal choice and autonomy in choosing treatments.

Two patients with mTNBC who had experience with sacituzumab govitecan for a different indication were interviewed in the CBCN survey. Feedback from 11 patients with prior experience with sacituzumab govitecan (for recurrent HR-positive, HER2-negative mBC [n = 6] and prior authorized mTNBC [n = 5]) was summarized in the joint input from BCC and MPSG, as was feedback from 3 patients in the Rethink Breast Cancer input (1 who had been diagnosed with ER-positive, HER2-negative mBC and 2 who had been diagnosed with mTNBC). Overall, patients reported manageable side effects and positive, meaningful improvements after receiving sacituzumab govitecan. Common side effects reported included hair loss, nausea, fatigue, diarrhea, rash, and headache. All respondents reported deriving benefits from sacituzumab govitecan and would recommend the drug to other patients.

Clinician Input

Input From Clinical Experts Consulted by CADTH

The experts identified multiple unmet needs among the patients of interest for this review: not all patients respond to available treatment; some become refractory to available treatment options; no treatments are available to reverse the course of disease; treatments are needed that are better tolerated once patients move past endocrine therapy; and therapies are needed to improve convenience and feasibility (e.g., fewer hospital visits and less frequent monitoring needs with imaging scans). The experts indicated that sacituzumab govitecan would fit into the current treatment paradigm for patients who have received prior endocrine-based therapy, including CDK4/6 inhibitors and 2 to 4 prior chemotherapy regimens in the metastatic setting; (neo)adjuvant therapy for early-stage disease qualified as 1 of the required prior chemotherapy regimens if the development of unresectable, locally advanced, or metastatic disease occurred within 12 months of therapy (i.e., early relapse). The experts emphasized that patients must have previously received at least 1 taxane to be considered for treatment with sacituzumab govitecan. The experts noted that the patients most likely to respond to treatment with sacituzumab govitecan are those with or without visceral metastases and an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 to 2, with expected survival of longer than 3 months (patients with brain metastases should have stable brain lesions for at least 4 weeks). According to the clinical experts, treatment should be in the hospital setting or at a specialty clinic with the expertise and staffing needed to administer systemic therapy and to monitor and manage treatment-related toxicities. Treatment responses are determined through periodic clinical assessments and serial biochemical and radiographic assessments, and are based on symptoms, laboratory markers, and radiographic scans and tumour measurements, with scans usually performed at least every 3 months initially (i.e., 1 staging scan).

Clinician Group Input

Medical oncologists from the Saskatoon Cancer Centre and the Ontario Health (Cancer Care Ontario) (OH-CCO) Breast Cancer Drug Advisory Committee (DAC) provided input for this review. Input from the Saskatchewan Cancer Agency was sourced from discussions held at multidisciplinary rounds, educational sessions, and email communications. Input from the CCO committee was gathered through videoconferencing.

The most important treatment goals highlighted by both groups were to prolong life, improve PFS, improve OS rates, delay disease progression, maintain quality of life, minimize treatment-related toxicities, and manage disease-related symptoms effectively. Current treatment paradigms for metastatic, HR-positive BC include a combination of drug and nondrug therapies; CDK4/6 inhibitors with an aromatase inhibitor (AI) are used in first-line treatment, while endocrine therapy (fulvestrant, tamoxifen), chemotherapy (capecitabine, paclitaxel), targeted therapy (alpelisib for PIK3CA mutation, olaparib for germline BRCA mutation), or clinical trial drugs (if patients are eligible) are available as second-line and subsequent treatments for patients with known progression. Both groups emphasized that sacituzumab govitecan will be a valuable option for third and later lines for patients who have exhausted other options. The patients best suited for treatment with sacituzumab govitecan will be those who have undergone prior endocrine therapy and multiple lines of chemotherapy, as indicated (similar to the inclusion criteria of the trial). Patients with poor performance status and those who have not received prior chemotherapy (at least 2 lines) will be less suitable to receive treatment, according to the clinician groups. Both groups highlighted that the end points assessed in the trial — such as OS, objective response rate (ORR), clinical benefit rate (CBR), duration of response (DoR), PFS, patient-reported outcomes (PROs), and safety — are clinically meaningful and will be used to assess treatment effectiveness in practice. Treatment will be discontinued if disease progression is observed upon radiographic imaging (i.e., tumour growth or new lesions) or in the case of unacceptable toxicity, undue toxicity, or patient preference. Sacituzumab govitecan is best administered under the guidance of a medical oncologist in an outpatient oncology clinic or in settings with clinicians that have expertise administering systemic therapy to patients with advanced disease.

Drug Program Input

Input was obtained from the drug programs that participate in the CADTH reimbursement review process. The following were identified as key factors that could potentially affect the implementation of a CADTH reimbursement for sacituzumab govitecan:

• relevant comparators

• considerations for initiation of therapy

• considerations for discontinuation of therapy

• considerations for prescribing of therapy

• generalizability

• funding algorithm

• care provision issues

• system and economic issues.

The clinical experts consulted by CADTH provided advice on the potential implementation issues raised by the drug program. Refer to Table 4 for more details.

Clinical Evidence

Systematic Review

Description of Studies

One multicentre, multinational, open-label, randomized phase III trial (TROPiCS-02) was included comparing sacituzumab govitecan with treatment of physician's choice (TPC) in patients with unresectable, locally advanced or metastatic, HR-positive, HER2-negative BC who had received endocrine-based therapy and at least 2 additional systemic therapies in the metastatic setting. To be eligible for the trial, patients must have had evidence of mBC that was HR-positive (i.e., at least 1% of the cells examined have ERs and/or PRs) and HER2-negative (i.e., IHC ≤ 2+ or fluorescence ISH-negative) confirmed by a local laboratory, been refractory to or relapsed after 2 to 4 prior systemic chemotherapy regimens for metastatic disease ([neo]adjuvant therapy for early-stage disease qualified as 1 of the required prior chemotherapy regimens if the development of unresectable, locally advanced or metastatic disease occurred within a 12-month period of time of the therapy), and been previously treated with at least 1 taxane, at least 1 prior anticancer hormonal treatment, and at least 1 CDK4/6 inhibitor in any setting.^30,31 Eligible patients (N = 543) were randomized using a 1 to 1 ratio to 1 of 2 groups: those receiving sacituzumab govitecan (n = 272) (10 mg/kg, administered as an IV infusion once weekly on days 1 and 8 of a 21-day treatment cycle) or those receiving TPC (n = 271) (eribulin, capecitabine, gemcitabine, or vinorelbine, by investigators’ choice). Patients were treated until progression requiring discontinuation of further treatment, unacceptable toxicity, study withdrawal, or death. Measures of survival (PFS, OS), tumour response to treatment (ORR, CBR, DoR), PROs (time to deterioration [TTD] in the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 [EORTC QLQ-C30] domains of global health status/quality of life [QoL], fatigue, pain, and diarrhea), and time to treatment discontinuation were compared. Harms were also reported.^30-34

At baseline, the mean ages were |||| years (standard deviation [SD] = |||||) in the sacituzumab govitecan group and |||| years (SD = |||||) in the TPC group. Nearly all patients were female (99.1%). Most patients were white (66.7%), and were from the US (42.0%), France (25.2%), Spain (12.7%), and other countries in North America and Europe. All had experienced progressive disease and extensive prior systemic treatment in the metastatic setting (median prior lines of chemotherapy = 3; 96% with 2 or more prior chemotherapies); all had received prior CDK4/6 inhibitors, reflecting the standard of care and allowing for the assessment of efficacy after CDK4/6 inhibitor treatment. Overall, most patients (95%) had visceral metastases at baseline; these are associated with particularly poor outcomes. The percentages of patients who had received at least 1 concomitant medication were similar in the sacituzumab govitecan ||||||| and TPC (||||||) groups. Most used concomitant medications, including analgesics (||||| in the sacituzumab govitecan group versus ||||| in the TPC group), antiemetics and antinauseants (||||| versus |||||), and drugs for acid-related disorders (||||| versus |||||). At any time during the study, 54.1% of patients (145 of 268 patients in the safety population) in the sacituzumab govitecan group and 34.1% of patients (85 of 249 patients in the safety population) in the TPC group used granulocyte colony-stimulating factor (G-CSF). Of these, 35.4% (n = 95) and 21.7% (n = 54) of patients in the sacituzumab govitecan and TPC groups, respectively, used it as prophylaxis for neutropenia and ||||| || | |||, while ||||| || | ||| in both groups used it to manage neutropenia.

Efficacy Results

The key efficacy results from the TROPiCS-02 trial are summarized in Table 2. The intention-to-treat (ITT) population dataset (including all randomized patients in the group to which they were randomized), which is the same as the full analysis set in this study (i.e., 272 patients in the sacituzumab govitecan group and 271 patients in the TPC group), was used for the survival and tumour response to treatment outcomes. The population datasets evaluable for health-related quality of life (HRQoL) (a subset of the ITT population, including patients with a baseline assessment and at least 1 postbaseline assessment) were used for the PROs.

Survival Outcomes

The primary efficacy end point of TROPiCS-02 was PFS per blinded independent central review (BICR) at the first interim analysis (data cut-off date: January 3, 2022; median duration of follow-up = 10.22 months [range, 0.03 months to 27.93 months]). The median PFS per BICR was 5.5 months (95% confidence interval [CI], 4.2 to 7.0) for patients treated with sacituzumab govitecan and 4.0 months (95% CI, 3.1 to 4.4) for patients treated with TPC (hazard ratio = 0.66; 95% CI, 0.53 to 0.83; P = 0.0003). As of January 3, 2022, the Kaplan-Meier (KM) estimates of the probability of PFS in the sacituzumab govitecan and TPC groups were 66.0% (95% CI, 59.6 to 71.6) versus 57.8% (95% CI, 50.8 to 64.1) at 3 months; 46.1% (95% CI, 39.4 to 52.6) versus 30.3% (95% CI, 23.6 to 37.3) at 6 months; 32.5% (95% CI, 25.9 to 39.2) versus 17.3% (95% CI, 11.5 to 24.2) at 9 months; 21.3% (95% CI, 15.2 to 28.1) versus 7.1% (95% CI, 2.8 to 13.9) at 12 months; and 13.3% (95% CI, 7.8 to 20.4) versus 7.1% (95% CI, 2.8 to 13.9) at 18 months. At the final analysis (exploratory, data cut-off date: December 1, 2022; median duration of follow-up = 12.75 months [range, 0.03 to 38.05]), the median PFSs per BICR in the sacituzumab govitecan and TPC groups were 5.5 months (95% CI, 4.2 to 6.9) versus 4.0 months (95% CI, 3.0 to 4.4) (hazard ratio = 0.65; 95% CI, 0.53 to 0.81; P = 0.0001). As of December 1, 2022, the KM estimates of the probability of PFS for sacituzumab govitecan versus TPC were 45.6% (95% CI, 38.9 to 52.0) versus 29.4% (95% CI, 22.9 to 36.2) at 6 months; 21.7% (95% CI, 15.8 to 28.3) versus 8.4% (95% CI, 4.2 to 14.5) at 12 months; and 14.4% (95% CI, 9.1 to 20.8) versus 4.7% (95% CI, 1.3 to 11.6) at 18 months.

One of the secondary end points was OS per BICR at the second interim analysis (data cut-off date: July 1, 2022; median duration of follow-up = 12.48 months [range, 0.03 to 35.48]). The median OS per BICR was 14.4 months (95% CI, 13.0 to 15.7) for patients treated with sacituzumab govitecan compared with 11.2 months (95% CI, 10.1 to 12.7) for patients treated with TPC (hazard ratio = 0.789; |||||| ||| ||||| || |||||; P = 0.020). As of July 1, 2022, the KM estimates of the probability of OS in the sacituzumab govitecan and TPC groups were 60.8% (95% CI, 54.6 to 66.4) versus 47.3% (95% CI, 41.1 to 53.2) at 12 months; 38.9% (95% CI, 32.8 to 44.9) versus 32.4% (95% CI, 26.7 to 38.2) at 18 months; and 24.6% (95% CI, 18.8 to 30.7) versus 21.4% (95% CI, 16.0 to 27.3) at 24 months. At final analysis (exploratory, data cut-off of December 1, 2022), the median OS per BICR in the sacituzumab govitecan and TPC groups was 14.5 months (95% CI, 13.0 to 16.0) versus 11.2 months (95% CI, 10.2 to 12.6) (hazard ratio = 0.788; 98.21% CI, 0.627 to 0.990; P = 0.0133). As of December 1, 2022, the KM estimates of the probability of survival for sacituzumab govitecan versus TPC were 60.9% (95% CI, 54.8 to 66.4) versus 47.1% (95% CI, 41.0 to 53.0) at 12 months; 39.2% (95% CI, 33.4 to 45.0) versus 31.7% (95% CI, 26.2 to 37.4) at 18 months; and 25.7% (95% CI, 20.5 to 31.2) versus 21.1% (95% CI, 16.3 to 26.3) at 24 months as of December 1, 2022.

Tumour Response to Treatment

At the second interim analysis (data cut-off date: July 1, 2022), the ORRs (for complete response [CR] or partial response per BICR) were 21% (57 patients of 272 patients) in the sacituzumab govitecan group and 14% (38 patients of 271 patients) in the TPC group (odds ratio = 1.63; 95% CI, 1.03 to 2.56; P = 0.03). The CBRs (for CR, partial response, or stable disease ≥ 6 months) per BICR were 34% (92 patients of 272 patients) and 22% (60 patients of 271 patients) in the sacituzumab govitecan and TPC groups, respectively (odds ratio = 1.80; 95% CI, 1.23 to 2.63; P = 0.003). Both ORR and CBR were secondary end points.

The median DoRs per BICR (secondary end point) were 8.1 months (95% CI, 6.7 to 9.1) in the sacituzumab govitecan group and 5.6 months (95% CI, 3.8 to 7.9) in the TPC group (hazard ratio and 95% CI of hazard ratio not reported), based on the data from 57 responders (CR or PR) in the sacituzumab govitecan group and 38 responders in the TPC group as of July 1, 2023.

Patient-Reported Outcomes

PROs included TTD in the EORTC QLQ-C30 global health status/QoL, fatigue, pain, and diarrhea domains at the second interim analysis (data cut-off of July 1, 2022) among the HRQoL-evaluable population.

The medians for TTD in the EORTC QLQ-C30 global health status/QoL domain (secondary end point) were 4.3 months (95% CI, 3.1 to 5.7) in the sacituzumab govitecan group and 3.0 months (95% CI, 2.2 to 3.9) in the TPC group (hazard ratio = 0.75; 95% CI, 0.61 to 0.92; P = 0.006), based on the available data from 234 patients (86%) in the sacituzumab govitecan group (272 patients at baseline) and 207 patients (76%) in the TPC group (271 patients at baseline).

The medians for TTD in the EORTC QLQ-C30 fatigue domain (secondary end point) were 2.2 months (95% CI, 1.6 to 2.8) and 1.4 months (95% CI, 1.1 to 1.9) in the sacituzumab govitecan and TPC groups, respectively (hazard ratio = 0.73; 95% CI, 0.60 to 0.89; P = 0.002), based on the available data from 234 patients (86%) in the sacituzumab govitecan group and 205 patients (76%) in the TPC group.

The medians for TTD in the EORTC QLQ-C30 pain domain (secondary end point) were 3.8 months (95% CI, 2.8 to 5.0) and 3.5 months (95% CI, 2.8 to 5.0) in the sacituzumab govitecan and TPC groups, respectively (hazard ratio = 0.918; 95% CI, 0.748 to 1.126; P = 0.415), based on the available data from 229 patients (84%) in the sacituzumab govitecan group and 202 patients (75%) in the TPC group.

The medians for TTD in the EORTC QLQ-C30 diarrhea domain (exploratory end point) were ||| |||||| |||| || |||| ||| ||| |||||| |||| || |||| in the sacituzumab govitecan and TPC groups, respectively (|||||| |||||| |||||| ||| ||| ||||| || |||||| | | ||||||), based on the available data from 232 patients (85%) in the sacituzumab govitecan group and ||| ||||| patients in the TPC group.

Time to Treatment Discontinuation

The analysis of time to treatment discontinuation was not prespecified by the sponsor; however, it was requested by the CADTH for the purpose of the certainty of evidence appraisal. The analysis of time to treatment discontinuation was performed at the final analysis (data cut-off of December 1, 2022; median duration of follow-up = ||||| months [range, |||| || |||||]). The median (95% CI) time to treatment discontinuation was ||| |||||| |||| || |||| in the sacituzumab govitecan group compared with ||| |||||| |||| || |||| in the TPC group ||||||| |||||| ||||| ||| ||| |||| || ||||| | | ||||||). The 18-month event-free rates were |||| |||| ||| ||| || |||| and |||| |||| ||| ||| || |||| for patients treated with sacituzumab govitecan and TPC, respectively.

Harms Results

The key harm results from the TROPiCS-02 trial at the second interim analysis (data cut-off of July 1, 2022) are summarized in Table 2. The safety population dataset (i.e., all patients who received at least 1 dose of the study drug, analyzed per treatment received [268 in the sacituzumab govitecan group and 249 in the TPC group]) was used for all safety outcomes.

As of July 1, 2022, adverse events (AEs) were reported in 100% and 96.0% of patients in the sacituzumab govitecan and TPC groups, respectively. The most-reported AEs by treatment group were neutropenia (70.5%), diarrhea (61.9%), and nausea (58.6%) in the sacituzumab govitecan group, and neutropenia (54.6%), nausea (34.9%), and fatigue (32.9%) in the TPC group.

The incidence of serious adverse events (SAEs) was 27.6% in the sacituzumab govitecan group compared with 19.3% in the TPC group. The most-reported SAEs were diarrhea (4.9%), febrile neutropenia (4.1%), and neutropenia (3.0%) in the sacituzumab govitecan group, and febrile neutropenia (4.0%), pneumonia (2.0%), nausea (2.0%), and dyspnea (1.6%) in the TPC group.

The incidence of AEs leading to study drug discontinuation was 6.3% in the sacituzumab govitecan; it was 4.4% in the TPC group. No trends in AEs leading to study drug discontinuation were identified in either group. AEs leading to study drug discontinuation that were reported for more than 1 patient were neutropenia, asthenia, and general physical health deterioration in the sacituzumab govitecan group, and thrombocytopenia and polyneuropathy in the TPC group.

Six patients (2.2%) in the sacituzumab govitecan group and 0 patients in the TPC group had AEs leading to death. One patient experienced an AE leading to death that was assessed by the investigator as treatment-related (i.e., septic shock due to neutropenic colitis with large intestine perforation). The AEs leading to death in the other 5 patients were assessed by the investigator as not related or unlikely to be related to sacituzumab govitecan. Upon detailed review of the AEs leading to death, no patterns were identified by the investigator regarding specific mechanism or etiology.

The most-reported AEs of grade 3 or higher were neutropenia (in 51.5% of sacituzumab govitecan patients and 39.0% of those treated with TPC), leukopenia (8.6% and 6.0%, respectively), infections (9.7% and 4.8%), diarrhea (10.1% and 1.2%), anemia (7.5% and 3.6%), febrile neutropenia (6.0% and 4.4%), fatigue (6.0% and 3.6%), neuropathies (2.6% and 3.6%), hypersensitivities (1.5% and 0.8%), and pulmonary events (0 and 0.4%).

Critical Appraisal

Randomization methods in the TROPiCS-02 trial were appropriate. There was an imbalance in the proportion of patients who were randomized but not treated (1.5% versus 8.1% in the sacituzumab govitecan and TPC groups, respectively). The presence and extent of any bias that may have been introduced could not be determined because the baseline demographic and disease characteristics of these patients were unavailable. The clinical experts commented that most of the concomitant medications were likely for the management of AEs, and the imbalances in some of them likely reflected the different incidences of AEs related to the treatments; therefore, these were less likely to affect the effect estimates in the trial. The proportion of patients with no baseline images or postbaseline evaluable was higher in the TPC group (13.7%) than in the sacituzumab govitecan group (2.9%), mainly due to the imbalance in patients who were randomized but never treated. Furthermore, for ORR and CBR, the proportion of patients who were not evaluable was higher in the TPC group (18.8%) than in the sacituzumab govitecan group (5.5%), mainly due to the imbalance in patients who were randomized but never treated and to an imbalance across groups in the proportion of patients who withdrew consent. The reasons for patients being randomized but never treated were not reported. As such, it is not possible to determine whether the results would be biased, given that it is not known whether there were imbalances in the prognostic characteristics of these patients relative to those who were randomized and treated (or to those who did or did not withdraw consent). The TROPiCS-02 trial used an open-label study design, which could potentially increase the risk of bias due to deviations from the intended interventions and measurement of the outcomes, particularly for the outcomes that were subjective in nature, including the PROs (e.g., TTD in the self-reported domains of the EORTC QLQ-C30) and some AEs (e.g., nausea, rash, diarrhea, neuropathy, and fatigue). Response outcomes (i.e., PFS, ORR, CBR, and DoR) were assessed through BICR; therefore, the risk of bias was mitigated for the measurement of these outcomes. OS and some AEs (e.g., neutropenia, febrile neutropenia, leukopenia, anemia) were objective measures with standardized criteria and/or relied on objective clinical or laboratory examination. As such, the risk of bias in the measurement of these outcomes is low. For the 4 domains of the EORTC QLQ-C30, data were analyzed for approximately 80% of the total study population (i.e., those who had baseline scores with room for at least a 10-point deterioration among the HRQoL-evaluable population). The impact of the missing data are unclear. The TROPiCS-02 trial was powered on its primary outcome. The statistical tests were appropriate, using a hierarchical testing approach to control for type I error. The stratified Cox proportional-hazards model was used for the survival outcomes. Generally, multiplicity control appeared adequate. In the time-to-event analysis for PFS, OS, DoR (among 95 responders), and time to treatment discontinuation (|| || ||| observations were excluded from the analyses due to not receiving treatment), all the patients were included in evaluation regardless of event occurrence. In general, censoring was balanced between the groups for OS, PFS, DoR, and TTD outcomes.

According to the clinical expert, no major issues were identified with respect to the generalizability of the TROPiCS-02 trial; however, the patients who did not meet the inclusion and exclusion criteria might be eligible for treatment with sacituzumab govitecan in clinical practice in Canada (e.g., it is reasonable to include patients with ECOG PS 2 or brain metastases after treatment [for those metastases] and those who have not been treated with taxanes due to a medical contraindication).

GRADE Summary of Findings and Certainty of the Evidence

Methods for Assessing the 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.^35,36 Following the GRADE approach, evidence from RCTs started as high-certainty evidence and could be rated down for concerns related to study limitations (which refer to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias.

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: PFS, OS, ORR, CBR, DoR, EORTC QLQ-C30 (global health status/QoL, fatigue, pain, and diarrhea domains), time to treatment discontinuation, and AEs of grade 3 or higher, including diarrhea, neutropenia, febrile neutropenia, leukopenia, anemia, fatigue, infections, neuropathies, hypersensitivities, and pulmonary events.

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 the evidence assessment was the presence or absence of any (non-null) effect for PFS, OS, ORR, CBR, DoR, EORTC QLQ-C30 (global health status/QoL, fatigue, pain, or diarrhea domains), time to treatment discontinuation, and AEs of grade 3 or higher, including diarrhea, neutropenia, febrile neutropenia, leukopenia, anemia, fatigue, infections, neuropathies, hypersensitivities, and pulmonary events, due to the lack of a formal minimal important difference (MID) estimate.

Results of GRADE Assessments

Table 2 presents the GRADE summary of findings for sacituzumab govitecan versus TPC in adult patients with unresectable, locally advanced or metastatic, HR-positive, HER2-negative BC who had received endocrine-based therapy and at least 2 additional systemic therapies in the metastatic setting.

Table 2: Summary of Findings for Sacituzumab Govitecan Versus TPC for Adult Patients With Unresectable, Locally Advanced or Metastatic, HR-Positive, HER2-Negative Breast Cancer

BICR = blinded independent central review; CBR = clinical benefit rate; CI = confidence interval; DoR = duration of response; ECOG = Eastern Cooperative Oncology Group; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Version 3.0; HER2 = human epidermal growth factor receptor 2; HR = hormone receptor; HRQoL = health-related quality of life; NR = not reported; OR = odds ratio; ORR = objective response rate; OS = overall survival; PFS = progression-free survival; QoL = quality of life; RCT = randomized controlled trial; SG = sacituzumab govitecan; TPC = treatment of physician’s choice.

Note: Study limitations (which refer to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias were considered when assessing the certainty of the evidence. All serious concerns in these domains that led to the rating down of the level of certainty are documented in the table footnotes.

^aAlthough the CADTH review team noted that the proportion of patients with no baseline images or postbaseline evaluable was higher in the TPC group (37 patients; 13.7%) than in the SG group (8 patients; 2.9%), mainly due to “randomized but never treated” patients (4 patients [50.0% of patients with no baseline images or who were postbaseline evaluable] in the SG group and 21 patients [56.8%] in the TPC group), the certainty of evidence was not rated down because it was not known whether these patients differed in their prognostic characteristics compared with those who were evaluated; therefore, the presence and direction of potential bias on the effect estimate was uncertain.

^bIndirectness was not rated down. Differences between the patients in the 1 RCT informing the evidence (i.e., patients with brain metastasis must have been stable for at least 4 weeks, with an ECOG Performance Status of 0 or 1, and must not have received a live vaccine within 30 days of randomization, among other inclusion and exclusion criteria) and the patients in clinical practice were noted, but not considered serious enough to result in important differences in the observed effect, according to the clinical experts consulted by CADTH. The TPC comparator was considered directly relevant to clinical practice in Canada by these clinical experts.

^cImprecision was not rated down. In the absence of available data for the between-group difference in event probabilities at clinically relevant time points, the judgment of imprecision was based on the 95% CI for the hazard ratio using the null as the threshold. The clinical importance of the between-group difference was judged based on the difference in median time to event and the input of the clinical experts consulted by CADTH for the review.

^dFor ORR and CBR, while the CADTH review team noted that the proportion of patients who were not evaluable was higher in the TPC group (51 patients; 18.8%) than in the SG group (15 patients; 5.5%), mainly due to patients who were “randomized but never treated” (4 patients [26.7% of those not evaluable] in the SG group and 22 patients [43.1%] in the TPC groups) and patients with “informed consent withdrawn” (3 patients [20.0% of those not evaluable] in the SG group and 14 patients [27.5%] in the TPC groups), the certainty of evidence was not rated down because whether these patients differed in prognostic characteristics compared with those who were evaluated was not known; therefore, the presence and effect of potential bias on the effect estimate was uncertain.

^eRated down 1 level for serious imprecision due to the small number of events. The 95% CI of the absolute effect was not available.

^fRated down 2 levels for very serious imprecision due to the small sample size. The 95% CI of the absolute effect was not available.

^gRated down 2 levels for very serious risk of bias due to the open-label nature of the study and the subjective nature of the outcome. The impact of the missing outcome data (18.8% of the total patients) is unclear.

^hRated down 2 levels for very serious risk bias of due to the open-label nature of the study and the subjective nature of the outcome. The impact of the missing outcome data (19.2% of the total patients) is unclear.

ⁱRated down 2 levels for very serious risk bias of due to the open-label nature of the study and the subjective nature of the outcome. The impact of the missing outcome data (20.6% of the total patients) is unclear.

^jRated down 1 level for serious imprecision. In the absence of available data for the between-group difference in event probabilities at clinically relevant time points, the judgment of imprecision was based on the 95% CI for the hazard ratio using the null as the threshold. The 95% CI of the hazard ratio included the “no effect” threshold of 1. The clinical importance of the between-group difference was judged based on the difference in median event rates and the input of the clinical experts consulted by CADTH for the review.

^kRated down 2 levels for very serious risk bias of due to the open-label nature of the study and the subjective nature of the outcome. The impact of the missing outcome data (19.0% of the total patients) is unclear.

^lThe analysis of time to treatment discontinuation was not prespecified by the sponsor; however, it was requested by CADTH for the purpose of the certainty of evidence appraisal.

^mRisk of bias was not rated down. Possible subjectivity in the judgment of grade 3 or higher for these AE was noted, but was not considered serious enough to result in important differences in the observed effect, based on the assessment of the CADTH review team.

ⁿRated down 2 levels for very serious imprecision due to the very small number of events. The 95% CI of the absolute effect was not available.

Sources: TROPiCS-02 Clinical Study Report (interim analysis 1);³⁰ TROPiCS-02 Clinical Study Report (interim analysis 2);³¹ sponsor’s submissions.^32,33

Long-Term Extension Studies

No long-term extension studies were identified for this review.

Indirect Comparisons

No studies with indirect evidence were identified for this review.

Studies Addressing Gaps in the Evidence From the Systematic Review

No studies addressing gaps in the pivotal and RCT evidence were identified for this review.

Conclusions

One phase III, multicentre, multinational, open-label, randomized trial (TROPiCS-02) compared sacituzumab govitecan with TPC in adult patients with unresectable, locally advanced or metastatic, HR-positive, HER2-negative BC who received endocrine-based therapy and at least 2 additional systemic therapies in the metastatic setting. Sacituzumab govitecan results in a clinically important increase in OS. Compared with TPC, sacituzumab govitecan results in an increase in PFS and time to treatment discontinuation; likely results in increases in ORR and CBR; and may result in increases in DoR and TTD in the EORTC QLQ-C30 domains of global health status/QoL and fatigue. The clinical importance of the increase in these outcomes is uncertain. Sacituzumab govitecan may result in a clinically important decrease in TTD in the EORTC QLQ-C30 diarrhea domain. The evidence is very uncertain about the effect on TTD in the EORTC QLQ-C30 pain domain compared with TPC. The evidence shows that sacituzumab govitecan likely results in an increase in neutropenia of grade 3 or higher and may result in an increase in grade 3 or higher diarrhea, febrile neutropenia, leukopenia, anemia, fatigue, and infections compared with TPC. The clinical importance of the increases in these outcomes is uncertain. Sacituzumab govitecan may result in little to no difference in neuropathies, hypersensitivities, and pulmonary events compared with TPC.

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 sacituzumab govitecan, 10 mg/kg, administered as an IV infusion once weekly on days 1 and 8 of a 21-day treatment cycle for the treatment of adult patients with unresectable, locally advanced or metastatic, HR-positive, HER2-negative (IHC 0, IHC 1+, or IHC 2+, and ISH-negative) BC who have received endocrine-based therapy and at least 2 additional systemic therapies in the metastatic setting.

Disease Background

Contents within this section have been informed by materials submitted by the sponsor and by clinical expert input. The following information has been summarized and validated by the CADTH review team.

BC was the second most diagnosed cancer in Canada in 2022 and the most prevalent among females, with projected estimates of about 28,900 new cases in the overall population (about 28,600 in females and 270 in males).¹² BC is a heterogeneous disease most often originating from epithelial cells lining the ducts, lobules, or other parts of breast tissue.^1,2 Breast cancers are classified into subtypes based on the specific cell types affected, gene expression, and receptors expressed on the surface or inside of tumour cells. For instance, the presence or absence of the expression of HER2, ERs, or PRs affects the proliferation of the cancer cells and the prognosis, treatment response, and recurrence of cancers in patients with BC.^2-4 HR-positive tumours have both ERs and PRs, are characterized as slow-growing and low grade, tending not to spread. However, they are known to recur over the years following treatment completion.⁵ HR-positive, HER2-negative BC subtypes are the most prevalent in Canada, accounting for more than 70% of all new cases. HR-positive, HER2-negative BC is defined according to criteria from the American Society of Clinical Oncology and the College of American Pathologists as a tumour having more than 1% IHC expression of ERs and/or PRs and a lack of HER2 expression (including HER2-low expression [i.e., an IHC score of 1+ or 2+, confirmed as negative by ISH] and an IHC score of 0).^6-9 Identified risk factors include age, family history, germline gene mutations (BRCA1 and BRCA2 genes), hormone therapy, genetic conditions, reproductive history (including menstrual history), and radiation exposure to breast and/or chest.^1,2 Signs and symptoms vary by disease stage and may include swelling in the surrounding lymph nodes, nipple changes (e.g., discharges), skin changes (e.g., erythema, skin ulcers, eczema), breast pain or heaviness, or other persistent changes in the breast.^10,11

The 5-year prevalence of BC in females reported in Canada in 2018 was 110,955 patients,¹³ equating to a 5-year prevalence rate of 0.73%.¹⁴ About 82% of cases at initial diagnosis are stage I to II. Patients diagnosed at stage IV, or at metastatic stages, are known to have the poorest prognoses.³⁷ A high proportion of patients diagnosed with early-stage BC will experience distant recurrence. Although the prognosis of HR-positive, HER2-negative BC is generally favourable when diagnosed early,² the lifetime risk of developing distant metastases ranges from 22% to 52%, and the prognosis worsens with each subsequent line of systemic therapy administered.¹⁵ In 1 study conducted using data from the French Epidemiological Strategy and Economics population registry, the number of cases of relapse reported among newly diagnosed patients with HR-positive, HER2-negative mBC who had received first-line treatment from 2008 to 2016 was 71%.¹⁶ The 5-year probability of distant recurrence or death among patients diagnosed with early-stage disease, based on a meta-analysis by Salvo and colleagues (2021),¹⁷ was 17.2% (95% credible interval, 14.6% to 20.3%).¹⁷ Survival outcomes following progression on endocrine-based therapies diminish significantly with later lines of single-drug chemotherapy, with median PFS and OS estimated to be as low as 3 months and 7 months, respectively.¹⁸ HR-positive, HER2-negative mBC also negatively affects patient quality of life, given that the symptoms that manifest are due to progression of disease and treatments administered. Common symptoms reported include pain, fatigue, nausea, vomiting, cognitive problems, depression, hair loss, lymphedema, sleep disturbance, loss of appetite, anxiety, and sexual dysfunction.^19-21

Diagnosis is based on the clinical presentation of lesions at mammographic screening, radiological imaging (such as ultrasound or CT), and/or physical examination.^38,39 Disease staging follows the American Joint Committee on Cancer tumour, node, metastasis system.³⁷ Tumour biopsy with pathology review and biomarker assessment (e.g., including HR and HER2 status) are completed for confirmatory diagnosis and to determine disease subtype and guide treatment decision-making.^37,40 HR and HER2 status testing are routinely conducted at initial diagnosis,⁴¹ and IHC or fluorescence ISH testing are widely available across jurisdictions in Canada.⁴⁰

Standards of Therapy

Contents within this section have been informed by materials submitted by the sponsor and by clinical expert input. The following information has been summarized and validated by the CADTH review team.

The current treatment algorithm for HR-positive, HER2-negative mBC, based on the trial findings⁴² and treatment guidelines, including the CADTH Provisional Funding Algorithms,²² the US National Comprehensive Cancer Network guidelines,⁴³ and the European Society for Medical Oncology guidelines,^23,44 is shown in Figure 1. The treatment algorithm includes publicly funded treatments as well as treatments currently under review or negotiation for public funding. In this treatment algorithm, Lynparza (olaparib) (which was withdrawn from CADTH review) and Piqray (alpelisib) (which received a “do not reimburse” recommendation)⁴⁵ are not included (Figure 1). In Canada, standard of care systemic treatment in the first-line setting is endocrine therapy in combination with a CDK4/6 inhibitor (i.e., Kisqali [ribociclib] or Ibrance [palbociclib]). The introduction of the CDK4/6 inhibitor Verzenio (abemaciclib) in the adjuvant setting may lead to additional sequencing considerations (Figure 1). Other first-line options include endocrine monotherapy, everolimus plus exemestane, and chemotherapy. For patients with suspected visceral crisis or who are unresponsive to endocrine therapy, chemotherapy may also be used to achieve initial adequate response, with follow-up endocrine therapy in combination with a CDK4/6 inhibitor.²² Following progression on first-line treatment with endocrine therapy and a CDK4/6 inhibitor, second-line options include endocrine monotherapy, chemotherapy, or everolimus with exemestane.^22,23 For patients who received endocrine monotherapy in the first-line setting, second-line options include endocrine therapy in combination with a CDK4/6 inhibitor or chemotherapy.

According to the clinical experts consulted by CADTH, generally, therapy is offered to all genders. The clinical experts shared the treatment in clinical practice as follows. If adjuvant abemaciclib is not available, the first-line treatment is an AI with a CDK4/6 inhibitor. If the disease has progressed on adjuvant AI, fulvestrant may be used to replace the AI. The second line can include endocrine monotherapy, everolimus with exemestane, or chemotherapy. If a patient has previously been treated with a first-line AI, a CDK4/6 inhibitor is then given as the second line, with fulvestrant. If adjuvant abemaciclib is given, the first-line treatment is endocrine monotherapy, everolimus with exemestane, or chemotherapy. When chemotherapy is administered, clinicians usually try capecitabine first. However, if the disease relapses after 6 months to 12 months, a CDK4/6 inhibitor and palbociclib or ribociclib can be considered. If bone metastases occur, patients would also receive palliative bisphosphonates (e.g., zoledronic acid). Nondrug treatments include palliative radiation when needed for symptomatic lesions. Re-treatment usually would not be tried after progression for some therapies (for example, endocrine monotherapy with options of letrozole, anastrozole, exemestane, tamoxifen, and fulvestrant). For premenopausal patients, treatments also include luteinizing hormone-release hormone agonists (e.g., goserelin) or consideration of oophorectomy for ovarian function suppression.

Patients face limited treatment options with prolonged efficacy beyond the second line. There is no single standard of care with respect to which chemotherapy to recommend once patients have progressed on multiple lines of systemic therapy.²³ Available options for single-drug chemotherapy include anthracyclines, taxanes, capecitabine, eribulin, vinorelbine, platinum complexes, and other drugs.²³ The aligned input from the clinical experts consulted by CADTH regarding options for chemotherapy included capecitabine; paclitaxel; nab-paclitaxel; docetaxel; doxorubicin; epirubicin; vinorelbine; gemcitabine; eribulin; Adriamycin-Cytoxan; cyclophosphamide, methotrexate, and fluorouracil; gemcitabine and cisplatin; or gemcitabine and carboplatin. The sequencing and selection of chemotherapy is usually dependent on the patient’s beforexicities. Chemotherapy is associated with an unfavourable toxicity profile and poor survival outcomes.^24-28

Enhertu (trastuzumab deruxtecan [T-DXd]) was recently approved by Health Canada for patients with HER2-low disease (i.e., IHC 1+ or IHC 2+ and ISH-negative) who have received at least 1 prior line of chemotherapy in the metastatic setting or who have developed disease recurrence during or within 6 months of completing adjuvant chemotherapy.⁴⁶ Patients should also have received, and no longer be considered eligible for, endocrine therapy. Patients without HER2 expression (i.e., IHC 0) (who represent more than 1/3 of patients with HR-positive, HER2-negative mBC), are ineligible for T-DXd.⁴⁷ T-DXd is expected to be introduced in second- and third-line metastatic settings, based on the approved indication, and it recently received a recommendation for reimbursement by CADTH “for the treatment of adult patients with unresectable or metastatic HER2-low BC if certain conditions are met.”⁴⁸

Figure 1: Current Treatment Algorithm Diagram for HR-Positive, HER2-Negative mBC

AC = Adriamycin-Cytoxan; CDK4/6i = cyclin-dependent kinase 4 and 6 inhibitor; CMF = Cyclophosphamide-Methotrexate-Fluorouracil; ET = endocrine therapy; FAC = Fluorouracil-Adriamycin-Cytoxan; FEC = 5-Fluorouracil-epirubicin-cyclophosphamide; HER2 = human epidermal growth factor receptor 2; HR = hormone receptor; IHC = immunohistochemical score.

Note: CADTH recommended that trastuzumab deruxtecan (Enhertu) “be reimbursed by public drug plans for the treatment of adult patients with unresectable or metastatic HER2-low breast cancer if certain conditions are met” on June 29, 2023. The labelling for its reimbursement status is not updated in this figure.

^a Abemaciclib in combination with ET received a recommendation for reimbursement from CADTH for the adjuvant treatment of patients with node-positive, early breast cancer at high risk of disease recurrence based on clinicopathological features and a Ki-67 score greater than or equal to 20%.

^b ET options: Options in combination with a CDK4/6i include an AI (anastrozole or letrozole) or fulvestrant; monotherapy options are either anastrozole or letrozole, exemestane, tamoxifen, fulvestrant (re-treatment is not funded if disease progression occurred during any prior fulvestrant therapy); exemestane is used in combination with everolimus.

^c Chemotherapy as first choice if visceral crisis is suspected or is not endocrine responsive; after adequate response, treatment with a CDK4/6i and ET.

^d Chemotherapy options include capecitabine, docetaxel, paclitaxel, nab-paclitaxel, doxorubicin, epirubicin, vinorelbine, gemcitabine, eribulin, FEC, FAC, AC, gemcitabine with cisplatin, and CMF.

^e Everolimus plus exemestane is under review for funding by provinces or cancer agencies based on the CADTH Provisional Funding Algorithms (2022).

^f For patients with HER2-low disease (defined as a score of 1+ on IHC analysis or as an IHC score of 2+ and negative results on in situ hybridization) who received a prior chemotherapy in the metastatic setting or developed disease recurrence during or within greater than or equal to 6 months of completing adjuvant chemotherapy. Patients must also have received and be ineligible for ET.

Source: Sponsor’s submission.⁴⁹

The treatment goal for patients with HR-positive, HER2-negative mBC is to improve survival while preserving HRQoL.²³ Patients with HR-positive, HER2-negative mBC (de novo cases or those arising from relapse) face a poor prognosis that worsens with each line of systemic therapy.⁵⁰ Once patients experience disease progression on standard of care endocrine-based therapies, remaining publicly reimbursed treatment options for the treatment of HR-positive, HER2-negative mBC are limited to single-drug chemotherapies.²³ As patients cycle through multiple lines of chemotherapy, survival deteriorates. The clinical experts pointed out that the goals of treatment are to prolong life, delay disease progression, reduce the severity of symptoms, minimize adverse effects, improve HRQoL, maintain independence, increase ability to maintain employment, and reduce burden on caregivers.

Drug Under Review

Sacituzumab govitecan is a tumour-associated calcium signal transducer 2 (Trop-2)-directed antibody–drug conjugate composed of a humanized antibody that recognizes Trop-2 covalently linked to a topoisomerase I inhibitor, SN-38, through a hydrolysable linker (CL2A). Sacituzumab govitecan binds to Trop-2-expressing cancer cells and is internalized by the subsequent release of the SN-38 through hydrolysis of the linker.⁵¹ The SN-38 interacts with topoisomerase I, preventing the relegation of topoisomerase I-induced single strand breaks. The resulting DNA damage leads to apoptosis and cell death.⁵¹ Sacituzumab govitecan is recommended as a 10 mg/kg dose, administered as an IV infusion, once weekly on days 1 and 8 of 21-day treatment cycles. Treatment should continue until disease progression or unacceptable toxicity.

Sacituzumab govitecan underwent a priority review through Project Orbis at Health Canada and received a Notice of Compliance on July 19, 2023, for the treatment of adult patients with unresectable, locally advanced or metastatic, HR-positive, HER2-negative (IHC 0, IHC 1+, or IHC 2+, and ISH-negative) BC who have received endocrine-based therapy and at least 2 additional systemic therapies in the metastatic setting. The sponsor’s reimbursement request aligns with the Health Canada indication. Sacituzumab govitecan has been approved by the FDA for the same indication as the reimbursement request and is currently under review at the European Medicines Agency.

Sacituzumab govitecan has been previously reviewed by CADTH for other indications in the mBC setting (although different from the current reimbursement request).²⁹ On February 11, 2022, a recommendation for reimbursement was issued for the treatment of adult patients with unresectable, locally advanced BC or mTNBC who have received 2 or more prior therapies, at least 1 of them for metastatic disease.²⁹ The key characteristics of sacituzumab govitecan are summarized in Table 3 along with those of other treatments available for patients with locally advanced or metastatic, HR-positive, HER2-negative (IHC 0, IHC 1+, or IHC 2+, and ISH-negative) BC who have received endocrine-based therapy and at least 2 additional systemic therapies in the metastatic setting.

Table 3: Key Characteristics of Sacituzumab Govitecan, Capecitabine, Eribulin, and Vinorelbine

AMP = adenosine monophosphate; ATPase = adenosine triphosphate-hydrolyzing enzyme; G₂/M = Gap 2/mitosis stages of cell cycle; HER2 = human epidermal growth factor receptor 2; HR = hormone receptor; IHC = immunohistochemistry; ISH = in situ hybridization; Trop-2 = tumour-associated calcium signal transducer 2.

^aHealth Canada–approved indication.

^bAccording to the clinical experts consulted by CADTH, in practice, most clinicians start with 1,000 mg/m² twice daily, due to toxicity.

Source: Product monograph, Trodelvy;⁵¹ sponsor’s summary of findings.⁴⁹

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 have been included in the Stakeholder Perspectives section of this report.

CBCN, Rethink Breast Cancer, and BCC and MPSG submitted input for this review. CBCN is a leading, patient-directed, national health charity committed to ensuring the best quality of care for all people in Canada affected by BC. It promotes information, education, and advocacy activities. Rethink Breast Cancer is a charity in Canada known for making positive change by educating, empowering, and advocating for system changes to improve the experiences and outcomes of those with BC, focusing on historically underserved groups, such as people diagnosed at a younger age, those with mBC, and people systemically marginalized due to race, income, or other factors. BCC is a national organization in Canada focused on precision oncology BC research because it believes in building on progress in therapeutic outcomes that has already been made. MPSG is a charitable organization whose vision is to bring together the main players in BC clinical research to make research accessible to many patients. BCC and MPSG submitted their input jointly.

Information from the CBCN group was sourced from 3 online surveys: the 2022 Triple Negative Breast Cancer Patient Survey, 2017 Metastatic Breast Cancer Patient Survey, and 2012 Metastatic Breast Cancer Patient and Caregiver Survey Report. The CBCN 2022 Triple Negative Breast Cancer Patient Survey enrolled 981 patients living with BC, of whom 31 had metastatic, HR-positive, HER2-negative disease. The CBCN 2017 Metastatic Breast Cancer Patient Survey assessed 180 patients living with BC, of whom 38 had metastatic, HR-positive, HER2-negative disease. The CBCN 2012 Metastatic Breast Cancer Patient and Caregiver Survey Report was conducted in collaboration with Rethink Breast Cancer and distributed to patients with metastatic disease and caregivers. In total, 71 patients and 16 caregivers in the 2012 survey participated through membership and patient organizations. Input from 2 patients with triple-negative BC who had experience with sacituzumab govitecan for a different indication were interviewed in this survey. These patients discussed the side effects and social and financial impacts of using sacituzumab govitecan. Information submitted in the joint input from BCC and MPSG was sourced from a survey that ran from July 6 to 21, 2023, distributed through email to patients living with recurrent mBC and caregivers. In total, 171 responses were submitted. Patients with mTNBC who had received sacituzumab govitecan due to their similarities with heavily pretreated patients regardless of endocrine receptor and HER2-negative status were included in the survey. Eleven patients with prior experience with sacituzumab govitecan (recurrent HR-positive, HER2-negative mBC [n = 6] and prior authorized mTNBC [n = 5]) were identified and summarized. Information from Rethink Breast Cancer was sourced from meetings held with patients with BC, including a consultation with the Metastatic Breast Cancer Advisory Board conducted in July of 2023, an online survey with 78 patients living with mBC (which ran from September 2018 and April 2019), and a review of a survey conducted in July 2021 that included 20 respondents who had received sacituzumab govitecan. One patient diagnosed with ER-positive, HER2-negative mBC and 2 patients diagnosed with mTNBC who had received sacituzumab govitecan were interviewed in the Rethink Breast Cancer input.

The 3 groups highlighted that metastatic disease poses a significant or debilitating impact on patients’ quality of life. Rethink Breast Cancer stated that BC significantly affects younger patients, especially those diagnosed in their twenties, thirties, and early forties, who face age-specific issues like fertility or family-planning challenges, diagnosis during pregnancy, child care complications, impacts on relationships, body image issues, dating and sexuality issues, feelings of isolation from peers who do not have cancer, career hiatuses, and financial insecurity. CBCN further emphasized that mBC restricts patients’ employment and careers, ability to care for children and dependents, and ability to be social and participate meaningfully in their communities. The joint input from BCC and MPSG added that chronic, long-term cancer also poses a significant financial burden on patients and caregivers in Canada, given that the majority of patients with mBC lack private third-party insurance and have to pay out of pocket, leaving them and their caregivers in financial debt.

CBCN highlighted that current treatment goals for patients with mBC include controlling the progression of the disease (i.e., extending life) and reducing cancer-related symptoms (i.e., extending or stabilizing quality of life). The organization added that patients have limited targeted treatment options, poor prognoses, and poor survival outcomes. Respondents to its 2017 survey highlighted that key factors that influenced their decisions around treatment choice included cost, accessibility, effectiveness, side effects, and ability to prolong quality of life. In the CBCN 2012 and 2017 surveys, patients with mBC also expressed the need for personal choice and autonomy in choosing treatments. Rethink Breast Cancer added that patients are aware that later-line therapies are not easy to tolerate; however, patients seek treatments that will extend their lives.

All 3 groups expressed a desire for new options that control disease and extend the lives of patients living with mBC. CBCN highlighted that current treatments for mBC are only effective in prolonging progression-free disease, and in most cases of advanced metastasis, the disease will progress, leading symptoms to worsen. They further highlighted that the level of HER2 proteins in HR-positive, HER2-negative patients is not high enough for HER2-targeted therapies to be effective. Hormone therapy is available; however, these therapies lose their effectiveness over time, and patients then have to rely on systemic treatments (chemotherapy), which are less effective and have greater side effects. The joint input from BCC and MPSG highlighted similar concerns, stating that beyond 2 or more lines of systemic therapy, there is a significant unmet need for advancement in precision chemotherapeutics and targeted therapies to improve disease control, not to mention a financial burden incurred in managing BC over long periods. There is an unmet need for treatments in later lines due to the multirefractory drug experience of patients in the metastatic setting. Rethink Breast Cancer highlighted similar limitations, stating that the options available to patients with progressed disease after the second line are limited to standard chemotherapy and that PFS decreases substantially with later lines of therapy. According to CBCN, the availability of additional treatment options that can delay disease progression, relieve cancer-related symptoms, and improve a patient’s quality of life will significantly affect patients in this setting.

Overall, patients reported manageable side effects and positive and meaningful experiences after receiving the treatment. Fifty-five percent to 66% of respondents interviewed in the joint BCC and MPSG input reported that sacituzumab govitecan had “quite a bit” of impact or “very much” impact on their quality of life while taking the therapy (depending on their endocrine status). One patient in the Rethink Breast Cancer who had ER-positive, HER2-negative mBC reported experiencing tumour shrinkage in their liver following 3 treatments with sacituzumab govitecan. Commonly reported side effects included hair loss, nausea, fatigue, diarrhea, rash, and headache. All respondents reported that they experienced benefits from receiving sacituzumab govitecan and would recommend the drug to other patients.

Clinician Input

Input From Clinical Experts Consulted by CADTH

All CADTH review teams include at least 1 clinical specialist with expertise regarding 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 BC.

Unmet Needs

The clinical experts consulted by CADTH pointed out that despite the treatment options, there are multiple unmet needs: not all patients respond to available treatments; patients become refractory to current treatment options; no treatments are available to reverse the course of disease; treatments are needed that are better tolerated once patients move past endocrine therapy; and formulations are needed to improve convenience (because many later lines are administered through IV and require frequent hospital visits).

Place in Therapy

The clinical experts indicated that sacituzumab govitecan would fit into the current treatment paradigm for patients who have received prior endocrine-based therapy, including CDK 4/6 inhibitors and 2 to 4 prior chemotherapy regimens in the metastatic setting; (neo)adjuvant therapy for early-stage disease qualified as 1 of the required prior chemotherapy regimens if the development of unresectable, locally advanced, or metastatic disease occurred within 12 months of therapy (i.e., early relapse). The clinical experts emphasized that patients must have previously received at least 1 taxane to be considered for treatment with sacituzumab govitecan.

Patient Population

The clinical experts noted that patients who are similar to those enrolled in the TROPiCS-02 trial are most likely to respond to treatment with sacituzumab govitecan — that is, patients with or without visceral metastases. (In real-world practice, patients should have an ECOG PS of 0 to 2 and an expected survival duration of longer than 3 months; those with brain metastasis should have stable brain lesions for at least 4 weeks.) According to the clinical experts, patients suitable for treatment with sacituzumab govitecan would be identified by the primary treating physician based on tissue diagnosis, clinical examination (performance status), judgment of suitability, and confirmation of clinical and/or radiographic disease progression after the preceding lines of therapy. The clinical experts indicated that companion diagnostics are not required and that underdiagnosis is not likely, given that this is a later-line study.

Assessing the Treatment Response

The clinical experts pointed out that treatment responses in clinical practice are determined through periodic clinical assessments (at every clinical visit) as well as through serial biochemical and radiographic assessments, and are based on symptoms, laboratory markers, and radiographic scans and tumour measurements, with scans usually performed at least every 3 months initially (i.e., 1 staging scan). According to the clinical experts consulted by CADTH, treatment is continued if disease is either stable or responding, based on Response Evaluation Criteria in Solid Tumours Version 1.1 (RECIST 1.1) criteria radiographically; meaningful responses include improved survival, reduction in the frequency and/or severity of symptoms (e.g., pain and dyspnea), attainment of major motor milestones, ability to perform activities of daily living, improvement or stabilization (i.e., no deterioration) in symptoms, improved organ function (e.g., bone, liver, and lung), maintenance or improvement of performance status, and tumour radiographic response, with either stabilization of disease or response as assessed using the RECIST 1.1 criteria.

Discontinuing Treatment

According to the clinical experts consulted by CADTH, the factors to be considered when deciding whether a patient should discontinue treatment with sacituzumab govitecan include disease progression, intolerable or dangerous toxicity (especially uncontrolled grade 3 or 4 diarrhea), and patient preference or refusal.

Prescribing Considerations

The clinical experts indicated that treatment with sacituzumab govitecan should be in a hospital setting or specialty clinic that has the staff and expertise (e.g., chemotherapy nurses, oncology pharmacists) to administer systemic therapy, monitor the patient, and manage treatment-related toxicities.

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 inputs received by CADTH have been included in the Stakeholder Perspectives section of this report.

Two clinician groups, the medical oncologists of the Saskatoon Cancer Centre and the OH-CCO Breast Cancer DAC, provided input for this review. The Saskatoon Cancer Centre group is composed of medical oncologists who treat breast malignancies under the Saskatchewan Cancer Agency. The OH-CCO’s cancer DAC provide timely evidence-based clinical and health system guidance on drug-related issues in support of the OH-CCO’s mandate, including the Provincial Drug Reimbursement Programs and the Systemic Treatment Program. Input from the Saskatchewan Cancer Agency was sourced from discussions held at multidisciplinary rounds and educational sessions and through email communications. Input from the OH-CCO cancer DAC was gathered through videoconferencing.

The most important treatment goals highlighted by both groups were to prolong life, improve PFS, improve OS rates, delay disease progression, maintain quality of life, minimize treatment-related toxicities, and manage disease-related symptoms effectively. The Saskatoon Cancer Centre group highlighted that ideal treatments should have the capacity to be individualized according to patients’ characteristics and preferences, to be used long-term, and to be well tolerated and convenient. Unmet needs highlighted by the Saskatoon Cancer Centre group included the availability of options for refractory patients, the availability of effective treatments for patients who progress to advanced disease, and availability of better-tolerated treatments with reduced toxicity and side effects. The OH-CCO cancer DAC noted that although patients considered ER-low (i.e., ER = 1% to 10%) would typically not be prescribed endocrine therapy, these patients should still be considered for sacituzumab govitecan.

The Saskatoon Cancer Centre group indicated that current treatment paradigms for metastatic, HR-positive BC include a combination of drug and nondrug therapies. The group added that CDK4/6 inhibitors with an AI are used in the first line, while second-line and subsequent options available to patients with known progressions include endocrine therapy (fulvestrant, tamoxifen), chemotherapy (capecitabine, paclitaxel), targeted therapy (alpelisib for PIK3CA mutation, olaparib for germline BRCA mutation), or clinical trial drugs (for eligible patients). The group noted that there is no consensus on ideal treatment sequencing for patients in the second line and beyond. Nondrug options outlined included radiation therapy, surgery, and palliative care. The group added that olaparib and T-DXd are available only through special access programs. The Saskatoon Cancer Centre group expressed the need for more effective treatments that overcome resistance mechanisms, minimize adverse effects, and provide better outcomes for patients in the metastatic setting because these patients have developed resistance to current options, especially to endocrine and chemotherapies, leading to disease progression and limited treatment options. Both groups highlighted that sacituzumab govitecan will be a valuable option for later lines (third line and beyond) for patients who have exhausted other options. The patients best suited for treatment with sacituzumab govitecan will be those who have undergone prior endocrine therapy and multiple lines of chemotherapy, as indicated; this is similar to the inclusion criteria of the trial, according to both groups. The OH-CCO cancer DAC added that ideally, eligible patients should have received an endocrine therapy; however, patients should not be required to have had a prior CDK4/6 inhibitor before initiating sacituzumab govitecan because some patients are intolerant to CDK 4/6 inhibitors. Patients with poor performance status and those who have not received at least 2 lines of prior chemotherapy are less suitable to receive treatment, according to the clinician groups.

Both groups highlighted that the end points assessed in the trial, such as OS, ORR, CBR, DoR, PFS, PROs, and safety, are clinically meaningful and will be used to assess treatment effectiveness in practice. The Saskatoon Cancer Centre group pointed out that there is no requirement for a companion diagnostic test or specific biomarker testing to predict responses to treatment for patients. Patients will typically be assessed during every cycle of treatment for toxicity, according to the OH-CCO cancer DAC. Sacituzumab govitecan will be discontinued if there is any evidence of disease progression upon radiographic imaging (i.e., tumour growth or new lesions), unacceptable toxicity, undue toxicity, or patient preference, according both groups. Sacituzumab govitecan is best administered under the guidance of a medical oncologist in an outpatient oncology clinic or in settings with clinicians who have expertise administering systemic therapy to patients with advanced disease.

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 4.

Table 4: Summary of Drug Plan Input and Clinical Expert Response

CDK4/6 = cyclin-dependent kinase 4 and 6; ECOG PS = Eastern Cooperative Oncology Group Performance Status; ER = estrogen receptor; HR = hormone receptor; IHC = immunohistochemistry; mBC = metastatic breast cancer; pERC = CADTH pan-Canadian Oncology Drug Review Expert Review Committee; PR = progesterone receptor; RECIST 1.1 = Response Evaluation Criteria in Solic Tumours Version 1.1.

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 sacituzumab govitecan 180 mg lyophilized powder for solution for injection, for IV use in the treatment of adult patients with unresectable, locally advanced or metastatic, HR-positive, HER2-negative (IHC 0, IHC 1+, or IHC 2, and ISH-negative) BC who have received endocrine-based therapy and at least 2 additional systemic therapies in the metastatic setting. The focus will be on comparing sacituzumab govitecan to relevant comparators and identifying gaps in the current evidence.

A summary of the clinical evidence included by the sponsor in the review of sacituzumab govitecan is presented in 4 sections, with CADTH’s critical appraisal of the evidence included at the end of each. 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 second section would include sponsor-submitted long-term extension studies. The third section would include indirect evidence from the sponsor. The fourth section would include additional studies that were considered by the sponsor to address important gaps in the systematic review evidence. There were no long-term extension studies (Section 2), indirect evidence (Section 3), or additional studies (Section 4) submitted by the sponsor.

Included Studies

The clinical evidence included in the CADTH review and appraised in this document is from 1 pivotal study (phase III RCT) identified in systematic review.

Systematic Review

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

Description of Studies

Characteristics of the included study are summarized in Table 5.

Table 5: Details of Study Included in the Systematic Review

AE = adverse event; BICR = blinded independent central review; CBR = clinical benefit rate; CDK4/6 = cyclin-dependent kinase 4 and 6; CNS = central nervous system; CR = complete response; DoR = duration of response; CTCAE = Common Terminology Criteria for Adverse Events; ECOG PS = Eastern Cooperative Oncology Group Performance Status; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Version 3.0; EQ-5D-5L = 5-Level EQ-5D; FA = final analysis; HR = hormone receptor; HER2 = human epidermal growth factor receptor 2; HRQoL = health-related quality of life; LIR = local investigator review; IA1 = interim analysis 1; IA2 = interim analysis 2; MedDRA = Medical Dictionary for Regulatory Activities; NCI = National Cancer Institute; ORR = objective response rate; OS = overall survival; PFS = progression-free survival; PR = partial response; PRO = patient-reported outcome; QoL = quality of life; RECIST 1.1 = Response Evaluation Criteria in Solid Tumours Version 1.1; TPC = treatment of physician’s choice; TTD = time to deterioration.

Note: Four additional reports were included: Rugo et al. (2020);⁵⁴ Rugo et al. (2022);⁵³ Rugo et al. (2023);⁵⁵ Tolaney et al. (2023).⁵²

Source: TROPiCS-02 Clinical Study Report (interim analysis 1);³⁰ TROPiCS-02 Clinical Study Report (interim analysis 2).³¹

One pivotal, multicentre, multinational, open-label, randomized phase III trial (TROPiCS-02) met the inclusion criteria for the sponsor’s systemic review, in which a total of 91 sites randomized 543 patients (Table 5). TROPiCS-02 investigated the efficacy and safety of sacituzumab govitecan compared with a TPC chemotherapy in patients with HR-positive, HER2-negative mBC (Figure 2).^30,31,53 Patient enrolment took place from May 30, 2019 to April 5, 2021. The primary (final) analysis for PFS and the first planned interim superiority analysis for OS (IA1) were conducted with a data cut-off date of January 3, 2022. The second planned interim analysis of OS, disease progression-related outcomes, and PROs (IA2) was conducted with a data cut-off date of July 1, 2022. Because statistical significance of OS was demonstrated at IA2, this was considered the final analysis of OS. A third, exploratory analysis of PFS and OS had a data cut-off date of December 1, 2022. The main body of this report presents data from the TROPiCS-02 trial as per the statistical analysis plan: PFS at IA1, and OS along with the other secondary outcomes at IA2. The exploratory PFS and OS results at the third analysis cut-off date are also presented.

Using an interactive, web-based response system,⁵⁶ patients were randomized 1 to 1 to receive either sacituzumab govitecan (N = 272) or TPC, determined before randomization (N = 271; 48% eribulin, 23% vinorelbine, 21% gemcitabine, and 8% capecitabine). Randomization was stratified by the presence of visceral metastases (yes or no), endocrine therapy in the metastatic setting (yes or no), and the number of prior lines of chemotherapy (2 versus 3 or 4). Patients were treated until progression requiring discontinuation of further treatment, unacceptable toxicity, study withdrawal, or death.⁵³ Treatment was allowed beyond progression if judged clinically beneficial by investigators.³¹ The follow-up period began the day after the end-of-treatment visit, which occurred 30 days after the last dose of the study drug. Patients were to be followed for survival and initiation of subsequent anticancer therapy. Patients who entered the follow-up period due to disease progression were treated in accordance with the local standard of care. Patients who entered the follow-up period before disease progression continued to undergo tumour assessments until documented disease progression or the initiation of subsequent anticancer therapy.

Figure 2: Study Design for the TROPiCS-02 Trial

ASCO = American Society of Clinical Oncology; BICR = blinded independent central review; CAP = College of American Pathologists; CBR = clinical benefit rate; CDK 4/6 = cyclin-dependent kinase 4 and 6; DoR = duration of response; HER2– = human epidermal growth factor receptor 2–negative; HR+ = hormonal receptor-positive; LIR = local investigator review; ORR = objective response rate; OS = overall survival; PFS = progression-free survival; PRO = patient-reported outcome; RECIST 1.1 = Response Evaluation Criteria in Solid Tumours Version 1.1; vs. = versus.

^a Disease histology based on the ASCO and CAP criteria.

^b Single-drug standard of care TPC was specified before randomization by the investigator.

Source: Sponsor’s submission.⁵²

Populations

Inclusion and Exclusion Criteria

The TROPiCS-02 trial included adult patients who had histologically confirmed, locally measurable, HR-positive, HER2-negative mBC and had received 2 to 4 prior systemic chemotherapy regimens for advanced BC. “(Neo)adjuvant therapy for early-stage disease qualified as 1 of the required prior chemotherapy regimens if the development of unresectable, locally advanced, or metastatic disease occurred within 12 months of therapy (early relapse).”⁵³ To be eligible, patients must have been previously treated with at least 1 CDK4/6 inhibitor, at least 1 anticancer hormonal treatment, and at least 1 taxane, which reflects standard practice in patient management, according to the sponsor (Table 5).^30,53,56 Among patients with a history of brain metastasis, the metastasis must have been stable for at least 4 weeks and target lesions could not be from the brain. Patients with active central nervous system metastases were excluded. Patients had to have an ECOG PS of 0 or 1.

Interventions

In the TROPiCS-02 trial, patients in both groups received study treatments until death, defined progressive disease requiring discontinuation of further treatment (as defined by RECIST 1.1), unacceptable toxicity, or study withdrawal. Treatment was allowed beyond progression if judged clinically beneficial by investigators.^30,31,53,56

Sacituzumab Govitecan

Sacituzumab govitecan 10 mg/kg was administered as a slow IV infusion on days 1 and 8 of 21-day treatment cycles. The dose was based on the patient’s body weight on day 1 of each cycle (or at each dosing day if the change in body weight was greater than 10% from the last measurement or if required by institutional policy). The initial infusion time was 3 hours. Subsequent infusions were administered over 3 hours (or over 1 to 2 hours if vital signs remained stable and no infusion reactions occurred). Dose modifications for changes in body weight of greater than or equal to 10% could be made, according to local institutional guidelines.^31,56

Visit windows of plus or minus 2 days from the scheduled infusion were permitted. Scheduled day 1 dosing could be delayed for up to 1 week for treatment-related toxicities. Day 8 dosing could be delayed for up to 1 week for treatment-related toxicities; however, if the toxicity did not resolve to grade 2 or lower within 1 week of day 8, then the scheduled day 8 dosing could be cancelled, and dosing was to resume with day 1 of the following cycle. There was a minimum of 14 days and a maximum of 21 days between the day 8 infusion and the day 1 infusion of the next cycle. No other treatment interruptions were permitted. The major toxicities of sacituzumab govitecan were expected to be gastrointestinal symptoms and hematologic suppression. Sacituzumab govitecan dose reductions and interruptions were managed based on toxicity severity as assessed by Version 5.0 of the National Cancer Institute Common Terminology for Adverse Events.⁵⁷ The sacituzumab govitecan dose must not have been re-escalated following a dose reduction.^31,56

Chemotherapy TPC

TPC was a single-drug treatment that was determined by the investigator before randomization from 1 of the 4 following choices:

• eribulin (1.4 mg/m² for North American sites, 1.23 mg/m² for European sites, or per institution) administered through IV on days 1 and 8 of a 21-day cycle

• capecitabine (1,000 mg/m² to 1,250 mg/m²) administered orally twice daily for 2 weeks, followed by a 1-week rest period, given as a 21-day cycle

• gemcitabine (800 mg/m² to 1,200 mg/m²) administered through IV on days 1, 8, and 15 of each 28-day cycle, or per institution

• vinorelbine (25 mg/m²) administered through IV on day 1 of a weekly cycle or per institution (note: patients with grade 2 neuropathy were eligible for the study, but were not to receive vinorelbine as TPC).

No combination or crossover of the 4 choices was permitted. The dosage of single-drug chemotherapy in the TPC treatment group was based on body surface area as per local standard of care and administered using the recommended doses and schedules in the locally approved prescribing information or according to National Comprehensive Cancer Network guidelines¹⁰ that were current at the time of treatment (with dose and/or schedule modifications in accordance with either locally approved prescribing information or institutional standard practices).³¹

In both treatment groups, patients also received premedications (i.e., antipyretics, H₁ blockers, and H₂ blockers) for the prevention of infusion-related reactions and a 2- or 3-drug combination regimen for the prevention and treatment of chemotherapy-induced gastrointestinal symptoms (e.g., nausea, vomiting, and diarrhea), based on the investigator’s discretion.³¹

Outcomes

A list of efficacy and harms end points assessed in this Clinical Review Report is provided in Table 6, followed by descriptions of the outcome measures in Table 7. Summarized end points are based on outcomes included in the sponsor’s Summary of Clinical Evidence as well as on any outcomes identified as important to this review, according to the clinical expert(s) consulted by CADTH and 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 most relevant to inform its 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 and included PFS, OS, ORR, CBR, DoR, and PROs that reflected patient HRQoL through the measurement of TTD in the EORTC QLQ-C30 domains of global health status/QoL, fatigue, pain, and diarrhea, and time to treatment discontinuation. Select notable harms outcomes considered important for informing CADTH’s expert committee deliberations (i.e., AEs of grade 3 or higher, including diarrhea, neutropenia, febrile neutropenia, leukopenia, anemia, fatigue, infections, neuropathies, hypersensitivities, and pulmonary events) were also assessed using GRADE.

Table 6: Outcomes Summarized From the TROPiCS-02 Trial

AE = adverse event; CR = complete response; BICR = blinded independent central review; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Version 3.0; LIR = local independent review; NA = not applicable; ORR = objective response rate; OS = overall survival; PFS = progression-free survival; PR = partial response; QoL = quality of life; RECIST 1.1 = Response Evaluation Criteria in Solid Tumours Version 1.1; SAE = serious adverse event; TTD = time to deterioration.

^aStatistical testing for these end points was adjusted for multiple comparisons (e.g., hierarchal testing).

Source: TROPiCS-02 Clinical Study Report (interim analysis 2).³¹

Tumour Assessments

Tumour assessments were performed at screening and at regular intervals during the study. Additional scans were performed as clinically indicated. Objective responses were confirmed at least 4 weeks later (e.g., generally at the next tumour assessment time point). Patients who discontinued the study drug before disease progression entered the follow-up period and continued with radiologic response assessments. Tumour assessments included CT or MRI assessments of chest and abdomen; other areas of known or newly suspected disease were assessed at screening and every 6 weeks (± 1 week) after the start of study treatment (or sooner if there was evidence of progressive disease) through 54 weeks, and then every 12 weeks (± 1 week) until the occurrence of disease progression, as determined by local independent review using RECIST 1.1. Assessment intervals were not to be changed in case of delays in dose administration. To exclude new bone metastases, bone scans (using 99m-technetium polyphosphonate scintigraphy, whole body bone MRI, or sodium fluoride and/or fluorodeoxyglucose PET) were performed at screening, during the treatment period if clinically indicated, and within a target of 1 week, but not more than 2 weeks, after a patient achieved a CR. Lesions detected on bone scans must have been followed with cross-sectional imaging. For patients with known brain metastases, a CT or MRI scan of the brain was performed at screening, during the treatment period if clinically indicated, and within a target of 1 week after a patient achieved a CR.³¹ All tumour assessment scans, as well as any unscheduled scans, were sent to a central imaging vendor designated by the sponsor. Tumour assessments were performed following guidelines provided by the central imaging vendor and as described in the independent review charter. However, if disease progression was based on the patient’s symptoms, every effort was to be made to document disease progression using objective criteria.³¹

Summary of RECIST 1.1

RECIST 1.1 defines disease progression, based on target lesions, as a 20% or greater increase in the sum of the longest diameter of target lesions and a 5 mm absolute increase, taking as reference the smallest-sum, longest denominator recorded since the baseline assessment or the appearance of 1 or more new lesions. Disease progression based on nontarget lesions is defined as the appearance of 1 or more new lesions and/or the unequivocal progression of existing nontarget lesions.⁵⁶ CR is defined as the disappearance of all target or nontarget lesions, and partial response is defined as a 30% or greater decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter. Cases with neither a sufficient shrinkage in target lesions to qualify for partial response nor a sufficient increase to qualify for progressive disease, taking as reference the smallest-sum, longest diameter since the treatment started, were categorized as stable.⁵⁶

Primary End Point (PFS per BICR)

PFS was defined as the time from date of randomization to the first observation of documented disease progression based on RECIST 1.1 or death due to any cause, whichever came first at the data cut-off date for IA1 on January 3, 2022.^6,30

Secondary End Points

Secondary end points included OS, ORR, CBR, DoR, and TTD in PRO measures.^31,56

OS was defined as the time from randomization into the study to death from any cause.

ORR was defined as the proportion of patients who had a best overall response of either CR or a partial response that was confirmed 4 weeks or more after the initial response by BICR or local independent review using RECIST 1.1. CBR was defined as the proportion of patients who had a best overall response of CR, PR, or durable stable disease (defined as stable disease with a duration of 6 months or greater after randomization). For patients who experienced a best overall response of CR or PR, DoR was calculated based on the time between the first date showing a documented response of CR or partial response and the date of progression or death, whichever occurred first.³¹

TTD was analyzed for the EORTC QLQ-C30 domains of global health status/QoL, fatigue, pain, and diarrhea, and was defined as the time from randomization to the first date on which a patient had a greater than or equal to 10-point deterioration from baseline or died due to any cause, whichever occurred first.³¹ Of these, outcome data for the EORTC QLQ-C30 diarrhea domain were provided by the sponsor, as per CADTH’s request.³³ Details of the validity, reliability, and responsiveness of the EORTC QLQ-C30 are in Table 7. The content validity of 25 of 30 items on the EORTC QLQ-C30 was endorsed by 21 health care professionals in 1 study.⁵⁸ Discriminant and convergent validity, tested among a sample of 150 patients in Canada with mBC in 1 study, showed variable results.⁵⁹ Patient-observer agreement was substantial to near-perfect across the 30 items in 1 study of patients with mBC.⁵⁹ Evidence of responsiveness to change is not available in the literature for patients with BC.^49,60 Recent studies of patients with mBC report estimated MIDs for within-group deterioration. These estimates range from –13 to –6, –11 (1 anchor-based estimate), –10 to –6, and –10 to –5 points for the global health status/QoL, pain, fatigue, and diarrhea scales, respectively.^34,61-63

Analyses of TTD in the global health status/QoL, fatigue, and pain scales were conducted for patients who had evaluable assessments of HRQoL at baseline and at least 1 evaluable assessment of HRQoL at postbaseline visits (i.e., the HRQoL-evaluable population) and who had baseline global health status/QoL scores greater than or equal to 10 as well as baseline fatigue, pain, and diarrhea scores of less than or equal to 90.^30,33,34

Time to treatment discontinuation (duration from the initiation of the study drug to treatment discontinuation due to any cause) was identified as relevant and important by the clinical experts consulted by CADTH and necessary to inform the pharmacoeconomic model. The results were provided by the sponsor, as per CADTH’s request.³²

Harms End Points

All safety analyses were conducted based on the safety population, which was defined as all patients in the ITT population who received at least 1 dose of the study drug. AE data were summarized by treatment group using descriptive statistics. AEs were coded using Medical Dictionary for Regulatory Activities Version 25.0, and AE severity was graded based on the National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0.³¹

Adverse events of special interest (AESIs) included diarrhea, neutropenia, febrile neutropenia, infections, neuropathies, hypersensitivities, and pulmonary events.³¹

Statistical Analysis

Clinical Trial End Points

The statistical analyses for trial end points are presented in Table 8.

Table 7: Summary of Outcome Measures and Their Measurement Properties

BC = breast cancer; ECOG = Eastern Cooperative Oncology Group; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Version 3.0; HRQoL = health-related quality of life; ICF = International Classification of Functioning, Disability and Health; mBC = metastatic breast cancer; MID = minimal important difference; QoL = quality of life.

Table 8: Statistical Analysis of Efficacy End Points for the TROPiCS-02 Trial

BICR = blinded independent central review; CBR = clinical benefit rate; CI = confidence interval; DoR = duration of response; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Version 3.0; ITT = intention to treat; KM = Kaplan-Meier; LIR = local independent review; ORR = objective response rate; PD = progressive disease; PFS = progression-free survival; PRO = patient-reported outcome; QoL = quality of life; SA1 = sensitivity analysis 1; SA2 = sensitivity analysis 2; SA3 = sensitivity analysis 3; SA4 = sensitivity analysis 4; TTD = time to deterioration.

Note: The analysis of TTD in the diarrhea domain of the EORTC QLQ-C30 was prespecified with the same statistical analysis for trial end points as the other 3 domains of the EORTC QLQ-C30 in this table. The analysis of time to treatment discontinuation was not prespecified by the sponsor. However, the data were requested by CADTH for the purpose of the certainty of evidence appraisal.

Source: TROPiCS-02 statistical analysis plan.⁶⁶

Sample Size and Power Calculation

The sample size was estimated based on the primary end point of PFS; it also considered OS as the main secondary end point. An overall sample size of approximately 520 patients was planned for randomization in a 1 to 1 ratio to either sacituzumab govitecan or TPC.^30,31,56,66

For PFS, assuming a hazard ratio of 0.70 (median PFS of 5.3 months for sacituzumab govitecan and 3.7 months for TPC), a total of 350 PFS events were needed to detect a statistically significant difference at a 2-sided alpha of 0.05 with 92% power. With an estimated average accrual rate of 22 patients per month, a total of 520 patients would provide approximately 350 PFS events approximately 27 months after the first patient was randomized, after accounting for events being censored because of patients missing tumour assessments or starting subsequent anticancer therapies.^30,56

The recruitment rate was assumed to be nonuniform, such that half of the patients were recruited 55% of the way through the recruitment period of approximately 24 months, reflecting the change in sample size and actual recruitment rate affected by the COVID-19 pandemic.^30,31

For OS, assuming a hazard ratio of 0.73 (median OS of 16.5 months for sacituzumab govitecan and 12 months for TPC), a total of 438 OS events were needed to detect a statistically significant difference at a 2-sided alpha of 0.05 with 86.7% power, based on a recruitment period of 24 months and a survival follow-up period of 52 months (from the time of first patient randomized).³¹

Interim Analyses

For the TROPiCS-02 trial, there was no planned interim analysis of PFS. There were 2 prespecified superiority interim efficacy analyses of the secondary end point (OS), performed when approximately 272 (62% information fraction) and 350 (80% information fraction) death events had occurred, respectively.⁶⁶ Based on the number of events that had accrued at the time of the primary analysis of PFS, the first interim analysis of OS was also performed at this time. A final, exploratory analysis of OS and PFS was also performed.

Multiplicity Control

A hierarchical testing approach was used for the analyses in this study, as depicted in Figure 3. The overall type I error rate for the TROPiCS-02 trial was strictly controlled at a 2-sided alpha of 0.05. The primary end point analysis of PFS, as assessed by BICR, served as the gatekeeper for the secondary end point analyses and was tested at a 2-sided alpha of 0.05. If the primary end point analysis of PFS was positive, the main secondary end points of OS were formally tested sequentially at a 2-sided alpha of 0.05. ORR (as assessed by BICR) and HRQoL outcomes were formally tested sequentially at a 2-sided alpha of 0.05 if the previous hypotheses in the hierarchy were statistically significant.⁶⁶ For the analysis of HRQoL end points, TTD of global health status/QoL, fatigue, and pain scales (as measured by EORTC QLQ-C30) were tested using the graphical approach of Maurer and Bretz to control multiplicity.⁶⁷ According to this approach, the hypotheses could be tested more than once, and when a particular null hypothesis was rejected, the alpha allocated to that hypothesis could be reallocated to other hypothesis tests.⁶⁷ A Bonferroni approach was used to control the type I error rate at 0.05 (2-sided) alpha for the 3 TTD hypothesis tests.⁶⁶

The Lan-DeMets alpha spending function that approximates a Pocock approach⁶⁸ was used to account for multiplicity introduced by including OS interim analyses for superiority. The first OS interim analysis was tested at a 2-sided significance level of 0.0363 if 62% of death events (272 of 438) were available at the time of the analysis. If the first OS interim analysis was not positive, the second OS interim analysis was tested at a 2-sided significance level of 0.0207 if 80% of death events (350 of 438) were available at the time of the analysis. If neither of the interim analyses was positive, the OS final analysis was to be tested at a 2-sided significance level of 0.0196. Alpha levels for the OS interim and final analyses were based on actual observed events and were adjusted accordingly.⁶⁶

Clinical event cut-offs and alpha values for each analysis are summarized in Table 9.

Figure 3: Hierarchical Testing Procedures for TROPiCS-02

BICR = blinded independent central review; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Version 3.0; IA1 = interim analysis 1; IA2 = interim analysis 2; ITT = intention to treat; ORR = objective response rate; OS = overall survival; PFS = progression-free survival; QoL = quality of life.

Note: The arrows on the diagram show how the type I error allocated to a null hypothesis that is successfully rejected will be redistributed for the testing of the other hypotheses; the arrows do not necessarily indicate the testing order.

Source: TROPiCS-02 Clinical Study Report (interim analysis 2).³¹

Table 9: Planned Analysis of Progression-Free Survival and Overall Survival in the TROPiCS-02 Trial

OS = overall survival; PFS = progression-free survival.

^aAn actual number of primary PFS events within plus or minus 10% of the target 350 events was acceptable for the primary PFS analysis (final). The full alpha was used at the final (and only) analysis for the primary end point of PFS.

^bThe boundary P values at each analysis time point are adjusted by the Lan-DeMets alpha spending function that approximates a Pocock approach.

^cBecause the statistical significance of OS was demonstrated, OS at interim analysis 2 was considered the final test for OS. The final analysis was considered descriptive only.

Sources: TROPiCS-02 Clinical Study Report (interim analysis 2);³¹ Tolaney et al. 2023.⁵²

Subgroup Analyses

To evaluate whether the treatment effect was consistent across various subgroup populations, the estimate of the between-group treatment effect with 95% CI for the primary and secondary end points was estimated and plotted graphically for the following prespecified subgroups:

• stratification factor of number of prior chemotherapy regimens for treatment of metastatic disease (2 lines versus 3 or 4 lines)

• stratification factor of visceral metastasis (yes or no)

• stratification factor of endocrine therapy in the metastatic setting for greater than or equal to 6 months (yes or no)

• age group (< 65 years or ≥ 65 years)

• race (white or others)

• screening ECOG PS (0 or 1)

• geographic region (North America, Europe, or elsewhere)

• prior CDK4/6 treatment duration (≤ 12 months or > 12 months)

• investigators’ choice of chemotherapy (eribulin, capecitabine, gemcitabine, or vinorelbine, each of which to compare with sacituzumab govitecan)

• early relapse, defined as relapse to metastatic disease within 1 year of the end of (neo)adjuvant chemotherapy (yes or no)

• baseline documented target or nontarget liver lesions per RECIST 1.1 per local independent review (yes or no)

• chemotherapy in the (neo)adjuvant setting (yes or no)

The subgroup analyses were not controlled for multiplicity.

Analysis Populations

Key analysis populations are presented in Table 10.

Table 10: Analysis Populations in the TROPiCS-02 Trial

EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Version 3.0; FAS = full analysis set; HRQoL = health-related quality of life; ITT = intention to treat; OS = overall survival; PFS = progression-free survival; QoL = quality of life; TTD = TTD = time to deterioration.

Source: TROPiCS-02 statistical analysis plan.⁶⁶

Results

Patient Disposition

Patient disposition as of the second interim analysis data cut-off date (July 1, 2022) is summarized in Table 11. Of the 776 screened patients, 543 (70%) were randomized to receive the study drug (sacituzumab govitecan = 272 patients; TPC = 271 patients). The most common reasons for screening failure were not meeting the inclusion criteria (151 patients, 64.8%), unacceptable laboratory value (18 patients, 7.7%), and meeting at least 1 exclusion criterion (16 patients, 6.9%).³⁰ A total of 26 randomized patients (4.8%) did not receive the study drug, the majority of whom were in the TPC group (8.1%, 22 patients) (versus the sacituzumab govitecan group [1.5%, 4 patients]).³¹

As of the July 1, 2022, data cut-off date, a total of 11 patients (2.0%) were continuing on the study drug (sacituzumab govitecan = 9 patients, 3.3%; TPC = 2 patients, 0.7%), and 506 patients (93.2%) had discontinued the study drug (sacituzumab govitecan = 259 patients, 95.2%; TPC = 247 patients, 91.1%). The most common reasons for discontinuation of the study drug by treatment group were as follows:³¹

• sacituzumab govitecan: progressive disease (217 patients, 79.8%), AEs (18 patients, 6.6%), and withdrawal of consent (10 patients, 3.7%)

• TPC: progressive disease (199 patients, 73.4%), withdrawal of consent (22 patients, 8.1%), and AEs (11 patients, 4.1%)

As of the July 1, 2022, data cut-off date, a total of 130 patients (23.9%) were continuing in the study (sacituzumab govitecan = 73 patients, 26.8%; TPC = 57 patients, 21.0%), and 413 patients (76.1%) had discontinued from the study (sacituzumab govitecan = 199 patients, 73.2%; TPC = 214 patients, 79.0%). The most common reason for discontinuation of the study, other than death, was withdrawal of consent (sacituzumab govitecan = 11 patients, 4.0%; TPC = 40 patients, 14.8%).³¹

Table 11: Summary of Patient Disposition in the TROPiCS-02 Trial (Screened Population; Data Cut-Off Date: July 1, 2022)

AE = adverse event; ITT = intention to treat; SAE = serious adverse event; TPC = treatment of physician’s choice.

Note: For data related to “primary reason for screening failure,” the denominator for the percentage calculation is based on the number of patients who were screened but not randomized. For data related to “treatment status,” the denominator for the percentage calculation is based on the number of patients in the safety population for each treatment group. For the rest of the data in this table, the denominator for percentages was the number of patients in the ITT population for each treatment group.

Sources: TROPiCS-02 Clinical Study Report (interim analysis 1),³⁰ TROPiCS-02 Clinical Study Report (interim analysis 2).³¹|

Patient disposition in the survival follow-up period (i.e., following the end-of-treatment visit) as of the data cut-off date (July 1, 2022) is summarized in Table 12. Overall, of the ||| patients ||||||| who entered the survival follow-up period (sacituzumab govitecan = ||| ||||||||| |||||| |||| ||| ||||||||| |||||||), 119 (21.9%) were ongoing patients who continued in the survival follow-up period (sacituzumab govitecan = 64 patients, 23.5%; TPC = 55 patients, 20.3%) after a median follow-up duration of 12.48 months (range, 0.03 to 35.48 months) at the second interim analysis cut-off on July 1, 2022.³¹

Table 12: Patient Disposition in the Survival Follow-Up Period of the TROPiCS-02 Trial (ITT; Data Cut-Off Date: July 1, 2022)

EOT = end of treatment; ITT = intention to treat; OS = overall survival; SD = standard deviation; TPC = treatment of physician’s choice.

Note: The denominator for percentages was the number of patients in the ITT population for each treatment group. Survival follow-up refers to the period after the EOT visit until the clinical cut-off date for the OS second interim analysis, unless patients died, were lost to follow-up, withdrew consent, or discontinued the study.

^aFollow-up length is the time from randomization to death date or last date known to be alive.

^bTime from last date known to be alive to data cut-off date of July 1, 2022.

^cPatients who died or whose last date known to be alive was on or after the data cut-off date were classified as current follow-up (0).

Source: TROPiCS-02 Clinical Study Report (interim analysis 2).³¹

Baseline Characteristics

The baseline characteristics outlined in Table 13 are limited to those that are most relevant to this review or that were believed to affect the outcomes or interpretation of the study results.

In general, the patient demographics and disease characteristics were similar between groups. At baseline, patients in the TROPiCS-02 study had progressive disease and extensive prior systemic treatment in the metastatic setting (median prior lines of chemotherapy = 3; 96% with 2 or more prior chemotherapies). Importantly, all patients had received a prior CDK4/6 inhibitor, reflecting the standard of care and allowing for the assessment of efficacy after CDK4/6 inhibitor treatment.^30,31,53 Overall, a high proportion of patients (95%) had visceral metastases at baseline; these are associated with particularly poor outcomes.³⁰

Table 13: Summary of Baseline Characteristics in the TROPiCS-02 Trial (ITT)

CDK4/6 = cyclin-dependent kinase 4 and 6; ECOG PS = Eastern Cooperative Oncology Group Performance Status; ITT = intention to treat; RECIST 1.1 = Response Evaluation Criteria in Solid Tumours Version 1.1; SD = standard deviation; TPC = treatment of physician’s choice.

^aIncludes American Indian or Alaska Native, Native Hawaiian, or other Pacific Islander.

^bNot reported indicates that local regulators did not allow the collection of race or ethnicity information.

^cPresence of baseline target and/or nontarget liver metastases per RECIST 1.1 by local investigator review.

^dThe reported numbers of prior therapies were miscounted at screening for some patients; 9 patients received prior chemotherapy regimens in the metastatic setting outside the per-protocol range for the inclusion criteria and were included in the ITT population.

Sources: TROPiCS-02 Clinical Study Report (interim analysis 1);³⁰ Rugo et al. (2022);⁵³ sponsor’s submissions.^33,69

Exposure to Study Treatments

The extent of patients’ exposures to the study drug (data cut-off date: July 1, 2022) is summarized in Table 14. Median treatment duration was longer in the sacituzumab govitecan group (4.11 months) versus the TPC group overall (2.33 months), as well as versus the individual single-drug chemotherapies in the TPC group, with the exception of capecitabine (||||||||| |||| ||||||| ||||||||||||| |||| ||||||| |||||||||||| |||| ||||||| |||||||||||| |||| ||||||). Median relative dose intensity was higher in the sacituzumab govitecan group (98.89%) compared to 2 TPC therapies (|||||| ||| ||||||||||||| |||||| ||| |||||||||||) but was similar to the other 2 (|||||| ||| ||||||||| ||| ||| ||| |||||||||||) (Table 14).³¹

Most patients (68.3%) in the sacituzumab govitecan group had a relative dose intensity ranging from 90% to less than 110%.³¹ A total of 5 patients, all in the sacituzumab govitecan group, experienced infusion interruptions; each of experienced 1 interruption.³¹ The proportion of patients with dose reductions was similar between the sacituzumab govitecan group (34.7%) and the TPC group (40.2% [ranging from ||||| || ||||| across the 4 single-drug chemotherapies]).³¹ For each study drug, most patients with dose reductions experienced only 1 dose reduction. The median times to first dose reduction were 1.41 months in the sacituzumab govitecan group and 0.95 months in the TPC group overall. For the individual single-drug chemotherapies in the TPC group, the median times to first dose reduction were |||| |||||| ||| ||||||||| |||| |||||| ||| ||||||||||||| |||| |||||| ||| |||||||||||| ||| |||| |||||| ||| |||||||||||, respectively.³¹

Table 14: Treatment Exposure in the TROPiCS-02 Trial (Safety Population; Data Cut-off Date: July 1, 2022)

SD = standard deviation; TPC = treatment of physician’s choice.

^aTreatment duration (in months) was calculated as the date of last treatment administration minus the date of the first treatment administration plus 1, divided by 30.4375.

^bRelative dose intensity (reported as a percentage) was calculated as the cumulative dosage received (in mg/kg) divided by the total assigned dosage (in mg/kg) multiplied by 100. The total assigned dosage (in mg/kg) for each patient was defined as the product of the assigned dose and the number of doses the patient was scheduled to receive during the treatment period (number of infusions actually received by the patient plus the number of infusions the patient missed between the first and last infusion). No dose delay information was collected for the group receiving capecitabine because the drug is administered orally.

Source: TROPiCS-02 Clinical Study Report (interim analysis 2).³¹

Concomitant Medications and Co-interventions

The most frequently reported concomitant medications for the ITT population are summarized in Table 15 (data cut-off date: July 1, 2022).³² The percentages of patients who received at least 1 concomitant medication were similar between the sacituzumab govitecan ||||||| and TPC ||||||| groups.^31,32 Concomitant medications (based on Anatomic Therapeutic Chemical classification level 2) that were taken by a higher percentage (≥ 20%) of patients in the sacituzumab govitecan group compared with the TPC group in the ITT population included analgesics (sacituzumab govitecan = ||||%; TPC = ||||%); antiemetics and antinauseants (sacituzumab govitecan = ||||%; TPC = ||||%); drugs for acid-related disorders (sacituzumab govitecan = ||||%; TPC = ||||%); otologicals (sacituzumab govitecan = ||||%; TPC = ||||%); antipruritics that include antihistamines, anesthetics, and so on (sacituzumab govitecan = ||||%; TPC = ||||%); antidiarrheals, intestinal anti-inflammatory drugs, and/or anti-infective drugs (sacituzumab govitecan = ||||%; TPC = ||||%); nasal preparations (sacituzumab govitecan = ||||%; TPC = ||||%); antihistamines for systemic use (sacituzumab govitecan = ||||%; TPC = ||||%); and immunostimulants (sacituzumab govitecan = ||||%; TPC = ||||%).³²

Per protocol, patients in the sacituzumab govitecan group also received premedications for the prevention of infusion-related reactions (i.e., antipyretics, H₁ blockers, and H₂ blockers) and a 2- or 3-drug combination regimen for the prevention and treatment of chemotherapy-induced nausea, vomiting, and diarrhea.³¹

The percentages of patients who used G-CSF at any time during the study (i.e., any G-CSF use from the first study drug dose date to 30 days after the last study drug dose date; includes G-CSF use before the first dose) were 54.1% (i.e., 145 of 268 patients in the safety patients) in the sacituzumab govitecan group and 34.1% (85 of 249 patients in the safety patients) in the TPC group. The percentages of patients who received G-CSF as prophylaxis for neutropenia were 35.4% (95 patients) in the sacituzumab govitecan group and 21.7% (54 patients) in the TPC group. The percentages of patients who received G-CSF for the management of neutropenia were ||||| ||| ||||||||| in the sacituzumab govitecan group and ||||| ||| ||||||||| in the TPC group.³¹

The percentages of patients who initiated G-CSF at any time during the study (i.e., the first date of G-CSF was from the first study drug dose date to 30 days after the last study drug dose date) were 53.7% (144 patients) in the sacituzumab govitecan group and 33.7% (84 patients) in the TPC group. The majority of these patients initiated G-CSF during cycle 1 (sacituzumab govitecan = 59.0%, 85 of 144 patients; TPC = 54.8%, 46 of 84 patients).³¹

Table 15: Summary of Concomitant Medications by ATC Classification in the TROPiCS-02 Trial (ITT; Data Cut-Off Date: July 1, 2022)

ATC = Anatomic Therapeutic Chemical; ITT = intention to treat; TPC = treatment of physician’s choice.

Note: The WHO Drug Dictionary (Version BMAR21) was used for coding. The denominator for percentages is the number of patients in the ITT population for each treatment group. Concomitant medications are defined as those taken at any time while on study treatment, including medications that were started before the first dose of study drug but were ongoing at time of first dose of study drug or initiated after the first dose of study drug and before 30 days after last dose of study drug. Patients were counted only once for each drug class and preferred drug name. Medications may appear under multiple ATC drug classes.

Source: Sponsor’s submission.³¹

Subsequent Treatment

No combination or crossover of the 4 choices in the TPC group was permitted.³¹

Patients who entered the follow-up period due to disease progression could be treated in accordance with the local standard of care. These patients were contacted every 12 weeks (± 1 week) for survival status and subsequent anticancer treatment received. Patients who entered the follow-up period before disease progression continued to undergo tumour assessments every 12 weeks (± 1 week) until documented disease progression or initiation of subsequent anticancer therapy. At that time, these patients were then to be contacted for survival status and subsequent anticancer treatment received, unless they withdrew consent for the study.³¹ A summary of anticancer therapies received is provided in Table 16.

Table 16: Summary of Subsequent Anticancer Treatment by Preferred Term in the TROPiCS-02 Trial (≥ 5% in Any Treatment Arm; Safety Population; Data Cut-Off Date: January 1, 2022)

TPC = treatment of physician’s choice.

Note: The denominator for percentages is the number of patients in the safety population for each treatment group. A patient may have taken more than 1 therapy. Therefore, the sum of therapy counts and the percentages may not equal the total counts. Multiple therapies are counted only once per patient for each preferred drug term. The WHO Drug Dictionary (Version BMAR21) was used for coding.

Source: TROPiCS-02 Clinical Study Report (interim analysis 1).³⁰

Efficacy

Efficacy results from 3 data cuts are presented here. Based on the prespecified hierarchical testing approach, the final statistical testing of PFS was completed at IA1 (data cut-off date: January 3, 2022). For all other key efficacy end points, final statistical tests were conducted at IA2 (data cut-off date: July 1, 2022). Results for PFS and OS at the final data cut (final analysis, exploratory analysis; data cut-off date: December 1, 2022) are also presented.

Survival

PFS Per BICR

PFS outcomes are summarized in Table 17.

Primary Efficacy End Point — PFS Per BICR (Data Cut-Off Date: January 3, 2022)

As of the first planned interim analysis (data cut-off date of January 3, 2022), the median duration of follow-up was 10.22 months (range, 0.03 to 27.93) (sacituzumab govitecan = 11.25 months [range, 0.03 to 27.93]; TPC = 9.79 months [range, 0.03 to 25.30]). The median PFSs, as assessed by BICR, were 5.5 months (95% CI, 4.2 to 7.0) for patients treated with sacituzumab govitecan and 4.0 months (95% CI, 3.1 to 4.4) for patients treated with TPC (hazard ratio = 0.66; 95% CI, 0.53 to 0.83; P = 0.0003) (Table 17).^30,53 The KM estimates of PFS rates in the sacituzumab govitecan and TPC groups were 66.0% (95% CI, 59.6 to 71.6) versus 57.8% (95% CI, 50.8 to 64.1) at 3 months; 46.1% (95% CI, 39.4 to 52.6) versus 30.3% (95% CI, 23.6 to 37.3) at 6 months; 32.5% (95% CI, 25.9 to 39.2) versus 17.3% (95% CI, 11.5 to 24.2) at 9 months; 21.3% (95% CI, 15.2 to 28.1) versus 7.1% (95% CI, 2.8 to 13.9) at 12 months; and 13.3% (95% CI, 7.8 to 20.4) versus 7.1% (95% CI, 2.8 to 13.9) at 18 months, respectively (Figure 4, Table 17).

Table 17: Summary of Progression-free Survival per BICR Results in the TROPiCS-02 Trial (ITT)

BICR = blinded independent central review; CI = confidence interval; ITT = intention to treat; IXRS = interactive voice and/or web response system; KM = Kaplan-Meier; NR = not reported; PD = progressive disease; PFS = progression-free survival; RECIST 1.1 = Response Evaluation Criteria in Solid Tumours Version 1.1; TPC = treatment of physician’s choice.

Note: PFS was defined as the number of months (where 1 month = 30.4375 days) from the date of randomization to the date of the first radiological disease progression per RECIST 1.1 or death due to any cause, whichever occurred first.

^aCensoring due to no baseline or no postbaseline evaluable assessment did not include a death event before the second scheduled visit postbaseline.

^bCensoring due to no baseline or no postbaseline evaluable assessment does not include a death event before the second scheduled visit postbaseline. The percentage denominator is the number of patients with PFS censored due to no baseline image or postbaseline evaluable for each treatment group.

^cThe median PFS was from the KM estimate. The CI for the median was computed using the Brookmeyer-Crowley method.

^dStratified log-rank test and stratified Cox regression adjusted for stratification factors (based on IXRS): prior chemotherapy regimens for treatment of metastatic disease (2 lines vs. 3 or 4 lines), visceral metastasis (yes or no), and endocrine therapy in the metastatic setting for at least 6 months (yes or no). The P value was not adjusted for multiple comparisons.

^eThe PFS rate was the proportion of patients alive without PD.

Sources: TROPiCS-02 Clinical Study Report (interim analysis 1);³⁰ Tolaney et al. (2023);⁵² sponsor’s submission.³²

Figure 4: KM Curves of PFS per BICR (ITT; Data Cut-Off Date: January 3, 2022)

CI = confidence interval; SG = sacituzumab govitecan; TPC = treatment of physician’s choice.

Source: TROPiCS-02 Clinical Study Report (interim analysis 1).³⁰

Sensitivity Analyses of PFS per BICR (Data Cut-Off Date: January 3, 2022)

The results from the prespecified sensitivity analyses of PFS per BICR were consistent with the primary analysis results, as shown in Table 27 (Appendix 1).

Final (Exploratory) Analysis — PFS per BICR (Data Cut-Off Date: December 1, 2022)

No further statistical testing was conducted on PFS per BICR following the first interim analysis (data cut-off date: January 3, 2022), consistent with the prespecified statistical analysis plan. At the final analysis (exploratory; data cut-off of December 1, 2022; median duration of follow-up = 12.75 months [range, 0.03 to 38.05]), the median PFSs per BICR in the sacituzumab govitecan and TPC groups were 5.5 months (95% CI, 4.2 to 6.9) versus 4.0 months (95% CI, 3.0 to 4.4) (hazard ratio = 0.65; 95% CI, 0.53 to 0.81; P = 0.0001) (Figure 4; Table 17).⁵² The KM estimates of PFS rates for sacituzumab govitecan versus TPC were 45.6% (95% CI, 38.9 to 52.0) and 29.4% (95% CI, 22.9 to 36.2) at 6 months, 21.7% (95% CI, 15.8 to 28.3) and 8.4% (95% CI, 4.2 to 14.5) at 12 months, and 14.4% (95% CI, 9.1 to 20.8) and 4.7% (95% CI, 1.3 to 11.6) at 18 months (Figure 5, Table 17).⁵² All results were consistent with those from the primary analysis.

Figure 5: KM Curves of PFS per BICR (ITT; Data Cut-Off Date: December 1, 2022)

CI = confidence interval; SG = sacituzumab govitecan; TPC = treatment of physician’s choice.

Source: Sponsor’s submission.⁵²

Subgroup Analyses of PFS by BICR (Data Cut-Off Date: January 3, 2022)

The median PFS benefit of sacituzumab govitecan over TPC was consistent across predefined subgroups, including patients with greater than or equal to 3 prior chemotherapy regimens in the metastatic setting, visceral metastases, and age greater than or equal to 65 years (Appendix 1, Figure 8).^30,53

Overall Survival

At the second planned interim analysis (data cut-off date: July 1, 2022), the median duration of follow-up was 12.48 months (range, 0.03 to 35.48) (sacituzumab govitecan = 13.80 months (range, 0.03 to 35.48); TPC = 10.68 months (range, 0.03 to 33.15).⁷⁰ Median OS was 14.4 months (95% CI, 13.0 to 15.7) for patients treated with sacituzumab govitecan compared with 11.2 months (95% CI, 10.1 to 12.7) for patients treated with TPC (hazard ratio = 0.789; 97.77% CI, ||||| || |||||; P = 0.020) (Figure 6, Table 18). The KM estimates of the 12-month OS rates were 61% (95% CI, 55 to 66) and 47% (95% CI, 41 to 53) for patients treated with sacituzumab govitecan and TPC, respectively. The KM curves for OS at the second planned interim analysis are shown in Figure 7.³¹

Table 18: Summary of Overall Survival Results in the TROPiCS-02 Trial (ITT)

CI = confidence interval; IA2 = interim analysis 2; ITT = intention to treat; IXRS = interactive voice and/or web response system; KM = Kaplan-Meier; NR = not reported; OS = overall survival; TPC = treatment of physician’s choice.

Note: OS was defined as the number of months (where 1 month = 30.4375 days) from the date of randomization to the date of death due to any cause. Patients without documentation of death were censored on the date on which they were last known to be alive. The number of OS events was 390 at the time of the OS IA2, when the 2-sided nominal alpha was 0.0223 based on the Lan-DeMets alpha spending function that approximates a Pocock approach.

^aThe median OS was from the KM estimate. The CI for the median was computed using the Brookmeyer-Crowley method.

^bStratified log-rank test and stratified Cox regression adjusted for stratification factors (based on IXRS): prior chemotherapy regimens for treatment of metastatic disease (2 lines vs. 3 or 4 lines), visceral metastasis (yes or no), and endocrine therapy in the metastatic setting for at least 6 months (yes or no).

^cThe OS rate was the proportion of patients alive.

^dThis test was not controlled for multiplicity because sacituzumab govitecan demonstrated a statistically significant OS benefit at IA2 (data cut-off date: July 1, 2022). Based on the hierarchy, the test controlled for multiplicity at the 0.0179 alpha level was to be conducted only if the OS results at IA2 were not statistically significant.

Sources: TROPiCS-02 Clinical Study Report (interim analysis 2),³¹ Tolaney et al. (2023);⁵² sponsor’s submission.³²

Figure 6: KM Curves of OS (ITT; Data Cut-Off Date: July 1, 2022)

CI = confidence interval; SG = sacituzumab govitecan; TPC = treatment of physician’s choice.

Source: TROPiCS-02 Clinical Study Report (interim analysis 2).³¹

No further formal statistical testing was conducted on OS following the second interim analysis (data cut-off date: July 1, 2022), which was consistent with the prespecified statistical analysis plan. A final, exploratory, OS analysis (data cut-off date: December 1, 2022) demonstrated continued survival benefit consistent with the second interim analysis (Figure 7, Table 18).^31,52 At data cut-off of the final analysis, 438 OS events had occurred (median follow-up = 12.75 months [range, 0.03 to 38.05]), with 47 (8.7%) new deaths in the sacituzumab govitecan group versus the TPC group (22 deaths [8.1%] versus 25 deaths [9.2%]) since the second planned interim analysis. The median OS durations per BICR in the sacituzumab govitecan and the TPC groups were 14.5 months (95% CI, 13.0 to 16.0) versus 11.2 months (95% CI, 10.2 to 12.6) (hazard ratio = 0.788; 98.21% CI, 0.627 to 0.990; P = 0.0133).³² The OS rates for sacituzumab govitecan versus TPC were 60.9% (95% CI, 54.8 to 66.4) and 47.1% (95% CI, 41.0 to 53.0) at 12 months; 39.2% (95% CI, 33.4 to 45.0) and 31.7% (95% CI, 26.2 to 37.4) at 18 months; and 25.6% (95% CI, 20.4 to 31.1) and 21.1% (95% CI, 16.3 to 26.3) at 24 months, respectively.

Figure 7: KM Curves of OS (ITT; Data Cut-Off Date: December 1, 2022)

CI = confidence interval; SG = sacituzumab govitecan; TPC = treatment of physician’s choice.

Source: Sponsor’s submission.⁵²

Tumour Response to Treatment

ORR and CBR per BICR (Data Cut-Off Date: July 1, 2022)

Because a statistically significant improvement in OS was demonstrated in the sacituzumab govitecan group versus the TPC group at the second interim analysis (data cut-off date: July 1, 2022), ORR per BICR was formally tested according to the hierarchical testing strategy (Table 19).⁷⁰ At the data cut-off, the ORRs were 21% in the sacituzumab govitecan group and 14% in the TPC group (odds ratio = 1.63; 95% CI, 1.03 to 2.56; P = 0.03). The CBRs were 34% and 22% in the sacituzumab govitecan group and TPC group, respectively (odds ratio = 1.80; 95% CI, 1.23 to 2.63; nominal P = 0.003). In the sacituzumab govitecan group, 1% of patients achieved a CR; 20% achieved a PR; and 13% achieved stable disease (i.e., lasting ≥ 6 months). No patients in the TPC group achieved a CR, while 14% achieved a partial response and 8% achieved stable disease (i.e., lasting ≥ 6 months) as of July 1, 2022.^31,70 Similar results were observed during the local independent review.³¹

Table 19: Summary of ORR and CBR per BICR in the TROPiCS-02 Trial (ITT; Data Cut-Off Date: July 1, 2022)

BICR = blinded independent central review; CI = confidence interval; CBR = clinical benefit rate; CR = complete response; ITT = intention to treat; NR = not reported; ORR = objective response rate; PD = progressive disease; PR = partial response; RD = relative difference; RECIST 1.1 = Response Evaluation Criteria in Solid Tumours Version 1.1; TPC = treatment of physician’s choice.

Note: The denominator for percentages was the number of patients in the ITT population. The exact binomial CI for proportion was based on the beta distribution. The P value was based on the Cochran-Mantel-Haenszel test stratified by the stratification factors used in randomization. Objective response was defined as the best confirmed overall response of either CR or PR. The best overall response was derived based on the tumour response per BICR at each tumour assessment according to RECIST 1.1. A response of CR and PR was confirmed no fewer than 4 weeks later. Stable disease required a minimum duration of 6 weeks to be classified as such. The clinical benefit rate was defined as the proportion of patients who had a best confirmed response as CR, PR, or durable, stable disease lasting greater than or equal to 6 months. The ORR per BICR was formally tested sequentially per hierarchical testing procedure with a 2-sided alpha equal to 0.05.

^aThe P value was not adjusted for multiple comparisons.

^bThe denominator for percentages was the number of patients with a nonevaluable response in each treatment group.

^cNonevaluable cases include those with only 1 postscreening assessment as stable disease in which the best overall response is considered not estimable because the stable disease did not meet the minimum duration requirement (≥ 35 days from randomization). There is also a case with only 1 assessment of not estimable, which is due to a partially missing postscreening assessment of a nontarget lesion and a completely missing postscreening assessment of a target lesion.

Sources: TROPiCS-02 Clinical Study Report (interim analysis 2);³¹ sponsor’s submission.³²

DoR per BICR (Data Cut-Off Date: July 1, 2022)

The median DoRs per BICR were 8.1 months (95% CI, 6.7 to 9.1) in the sacituzumab govitecan group and 5.6 months (95% CI, 3.8 to 7.9) in the TPC group (hazard ratio and 95% CI of hazard ratio not reported),³³ based on the data from 57 responders (CR or PR) in the sacituzumab govitecan group and 38 responders in the TPC group (Table 20).^31,70 Similar results were observed for DoR during the local independent review.³¹

Table 20: Summary of DoR (Confirmed CR or PR) per BICR in the TROPiCS-02 Trial (ITT;  Data Cut-Off: July 1, 2022)

BICR = blinded independent central review; CI = confidence interval; CR = complete response; DoR = duration of response; ITT = intention to treat; KM = Kaplan-Meier; NR = not reported; PD = progressive disease; PR = partial response; RD = relative difference; RECIST 1.1 = Response Evaluation Criteria in Solid Tumours Version 1.1; TPC = treatment of physician’s choice.

Note: Only patients who had a confirmed CR or PR were included in the analysis. DoR was defined as the number of months (where 1 month = 30.4375 days) from the date of initial response to the date of the event defined as the first documented progression per RECIST 1.1 or death due to any cause, whichever occurred earlier.

^aThe median DoR was from the KM estimate. The CI for the median was computed using the Brookmeyer-Crowley method.

^bThe DoR rate was the proportion of patients alive without PD after the initial response.

Source: TROPiCS-02 Clinical Study Report (interim analysis 2).³¹

Patient-Reported Outcomes

TTD in the EORTC QLQ-C30 Global Health Status/QoL, Fatigue, Pain, and Diarrhea Domains (Data Cut-Off Date: July 1, 2022)

Because a statistically significant improvement in OS was demonstrated in the sacituzumab govitecan group versus the TPC group at the second interim analysis (data cut-off date: July 1, 2022), TTD in the EORTC QLQ-C30 global health status/QoL, fatigue, and pain domains was formally tested according to the hierarchical testing strategy.³¹ The diarrhea domain was 1 of the exploratory outcomes that was identified as relevant and important by the clinical experts. TTD was defined as the time from randomization to the first date on which a patient had a greater than or equal to 10-point deterioration from baseline or died due to any cause, whichever occurred first.^31,70

For the EORTC QLQ-C30 global health status/QoL domain assessment, data were available for 234 patients (86%) in the sacituzumab govitecan group (272 patients at baseline) and 207 patients (76%) in the TPC group (271 patients at baseline) among the HRQoL-evaluable population of patients with baseline scores in this domain greater than or equal to 10.⁵⁶ The median TTDs in the global health status/QoL domain were 4.3 months (95% CI, 3.1 to 5.7) in the sacituzumab govitecan group and 3.0 months (95% CI, 2.2 to 3.9) in the TPC group (hazard ratio = 0.75; 95% CI, 0.61 to 0.92; P = 0.006) (Table 21).³¹

Data were available for 234 patients (86%) in the sacituzumab govitecan group and 205 patients (76%) in the TPC group for the EORTC QLQ-C30 fatigue domain assessment, among the HRQoL-evaluable population of patients who had baseline scores less than or equal to 90 in this domain.⁵⁶ The median TTDs in the fatigue symptom domain were 2.2 months (95% CI, 1.6 to 2.8) and 1.4 months (95% CI, 1.1 to 1.9) in the sacituzumab govitecan and TPC groups, respectively (hazard ratio = 0.73; 95% CI, 0.60 to 0.89; P = 0.002) (Table 22).³¹

Data were available for 229 patients (84%) in the sacituzumab govitecan group and 202 patients (75%) in the TPC group for the EORTC QLQ-C30 pain domain assessment, among the HRQoL-evaluable population of patients who had baseline scores less than or equal to 90 in this domain.⁵⁶ The median TTDs in the pain domain were 3.8 months (95% CI, 2.8 to 5.0) and 3.5 months (95% CI, 2.8 to 5.0) in the sacituzumab govitecan and TPC groups, respectively (hazard ratio = 0.918; 95% CI, 0.748 to 1.126; P = 0.415) (Table 23).³¹

Data were available for 232 patients (85%) in the sacituzumab govitecan group and ||| ||||| patients in the TPC group for the EORTC QLQ-C30 diarrhea domain assessment, among the HRQoL-evaluable population of patients (patients with very poor baseline scores were excluded).³³ The median TTDs in the diarrhea domain ||| ||| |||||| |||| ||| ||| || |||| and ||| |||||| |||| ||| ||| || |||| in the sacituzumab govitecan and TPC groups, respectively ||||||| |||||| |||||| ||| ||| ||||| || |||||| | | ||||||| (Table 24).³³

Table 21: TTD in EORTC QLQ-C30 Global Health Status/QoL Domain in the TROPiCS-02 Trial (HRQoL-Evaluable Population; Patients With Baseline Global Health Status/QoL Score ≥ 10; Data Cut-Off: July 1, 2022)

CI = confidence interval; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Version 3.0; HRQoL = health-related quality of life; ITT = intention to treat; IXRS = interactive voice and/or web response system; KM = Kaplan-Meier; NR = not reported; QoL = quality of life; RD = relative difference; SD = standard deviation; TPC = treatment of physician’s choice; TTD = time to deterioration.

Note: TTD was defined as the time from randomization to the first date on which a patient had a greater than or equal to 10-point deterioration from baseline or died due to any cause, whichever occurred earlier. The HRQoL-evaluable population was defined as all patients in the ITT population who had an evaluable assessment at baseline and at least 1 evaluable assessment at postbaseline visits. N is the number of patients in the HRQoL-evaluable population with a baseline global health status/QoL score greater than or equal to 10.

^aThe median TTD was from the KM estimate. The CI for the median was computed using the Brookmeyer-Crowley method.

^bStratified log-rank test and stratified Cox regression adjusted for stratification factors (based on IXRS): prior chemotherapy regimens for treatment of metastatic disease (2 lines vs. 3 or 4 lines), visceral metastasis (yes or no), and endocrine therapy in the metastatic setting for at least 6 months (yes or no).

^cAn event was defined as a greater than or equal to 10-point deterioration from baseline or death due to any cause, whichever occurred earlier.

Source: TROPiCS-02 Clinical Study Report (interim analysis 2).³¹

Table 22: TTD in EORTC QLQ-C30 Fatigue Domain in the TROPiCS-02 Trial (HRQoL-Evaluable Population; Patients With Baseline Fatigue Score ≤ 90; Data Cut-Off: July 1, 2022)

CI = confidence interval; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Version 3.0; HRQoL = health-related quality of life; ITT = intent to treat; IXRS = interactive voice and/or web response system; KM = Kaplan-Meier; NR = not reported; RD = relative difference; SD = standard deviation; TPC = treatment of physician’s choice; TTD = time to deterioration.

Note: TTD was defined as the time from randomization to the first date on which a patient had a greater than or equal to 10-point deterioration from baseline or died due to any cause, whichever occurred earlier. The HRQoL-evaluable population was defined as all patients in the ITT population who had an evaluable assessment at baseline and at least 1 evaluable assessment at postbaseline visits. N is number of patients in the HRQoL-evaluable population with baseline fatigue score of less than or equal to 90.

^aThe median TTD was from the KM estimate. The CI for the median was computed using the Brookmeyer-Crowley method.

^bStratified log-rank test and stratified Cox regression adjusted for stratification factors (based on IXRS): prior chemotherapy regimens for treatment of metastatic disease (2 lines vs. 3 or 4 lines), visceral metastasis (yes or no), and endocrine therapy in the metastatic setting for at least 6 months (yes or no).

^cAn event was defined as a greater than or equal to 10-point deterioration from baseline or death due to any cause, whichever occurred earlier.

Source: TROPiCS-02 Clinical Study Report (interim analysis 2).³¹

Table 23: TTD in EORTC QLQ-C30 Pain Domain in the TROPiCS-02 Trial (HRQoL-Evaluable Population; Patients With Baseline Pain Score ≤ 90; Data Cut-Off: July 1, 2022)

CI = confidence interval; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Version 3.0; HRQoL = health-related quality of life; ITT = intention to treat; IXRS = interactive voice and/or web response system; KM = Kaplan-Meier; NR = not reported; RD = relative difference; SD = standard deviation; TPC = treatment of physician’s choice; TTD = time to deterioration.

Note: TTD was defined as the time from randomization to the first date on which a patient had a greater than or equal to 10-point deterioration from baseline or died due to any cause, whichever occurred earlier. The HRQoL-evaluable population was defined as all patients in the ITT population who had an evaluable assessment at baseline and at least 1 evaluable assessment at postbaseline visits. N is the number of patients in the HRQoL-evaluable population with baseline pain score less than or equal to 90.

^aThe median TTD was from the KM estimate. The CI for the median was computed using the Brookmeyer-Crowley method.

^bStratified log-rank test and stratified Cox regression adjusted for stratification factors (based on IXRS): prior chemotherapy regimens for treatment of metastatic disease (2 lines vs. 3 or 4 lines), visceral metastasis (yes or no), and endocrine therapy in the metastatic setting for at least 6 months (yes or no).

^cAn event was defined as a greater than or equal to 10-point deterioration from baseline or death due to any cause, whichever occurred earlier.

Source: TROPiCS-02 Clinical Study Report (interim analysis 2).³¹

Table 24: TTD in EORTC QLQ-C30 Diarrhea Domain in the TROPiCS-02 Trial (HRQoL-Evaluable Population; Patients With Baseline Diarrhea Score ≤ 90; Data Cut-Off: July 1, 2022)

CI = confidence interval; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Version 3.0; HRQoL = health-related quality of life; ITT = intention to treat; KM = Kaplan-Meier; NR = not reported; RD = relative difference; SD = standard deviation; SG = sacituzumab govitecan; TPC = treatment of physician’s choice; TTD = time to deterioration.

Note: TTD was defined as the time from randomization to the first date on which a patient had a greater than or equal to 10-point deterioration from baseline or died due to any cause, whichever occurred earlier. The HRQoL-evaluable population was defined as all patients in the ITT population who had an evaluable assessment at baseline and at least 1 evaluable assessment at postbaseline visits. N is the number of patients in the HRQoL-evaluable population with baseline pain score of less than or equal to 90.

^aThe median TTD was from the KM estimate. The CI for the median was computed using the Brookmeyer-Crowley method.

^bThe hazard ratio and P value were estimated using a stratified Cox proportional-hazards regression analysis with treatment arm (SG vs. TPC) as a covariate and the number of prior chemotherapy regimens for treatment of metastatic disease (2 lines vs. 3 or 4 lines), visceral metastasis (yes or no), and endocrine therapy in the metastatic setting for greater than or equal to 6 months (yes or no) as stratification factors in the model. The Efron method was used to handle ties.

^cAn event was defined as a greater than or equal to 10-point deterioration from baseline or death due to any cause, whichever occurred earlier.

Source: Sponsor’s submission.^33,34

Time to Treatment Discontinuation

The analysis of time to treatment discontinuation was performed at the cut-off date of December 1, 2022 (final analysis, overall median [range] duration of follow-up: ||||| |||||| ||||| || |||||); sacituzumab govitecan: ||||| |||||| ||||| || ||||||| |||| ||||| ||||| || ||||||||^32,33 The median time to treatment discontinuation was ||| |||||| for patients treated with sacituzumab govitecan compared with ||| |||||| for patients treated with TPC (|||||| |||||| ||||| ||| ||| |||| || ||||| | | ||||||) (Table 25). The 18-month event-free rate was |||| |||| ||| ||| || |||| ||| |||| |||| ||| ||| || |||| for patients treated with sacituzumab govitecan and TPC, respectively. The KM curves for time to treatment discontinuation at the final analysis data cut-off are shown in Figure 10 (Appendix 1).³²

Table 25: Time to Treatment Discontinuation in the TROPiCS-02 Trial (Safety Population; Data Cut-Off Date: December 1, 2022)

CI = confidence interval; IXRS = interactive voice and/or web response system; KM = Kaplan-Meier; NR = not reported; RD = relative difference; TPC = treatment of physician’s choice.

Note: KM curves for time to treatment discontinuation were used for conducting parametric fittings.

^aThe data submitted for analysis included 543 observations; 26 observations were excluded because patients had not received treatment.

^bThe median time to treatment discontinuation was from the KM estimate. The CI for the median was computed using log-log transform.

^cStratified Cox regression adjusted for stratification factors (based on IXRS): prior chemotherapy regimens for treatment of metastatic disease (2 lines vs. 3 or 4 lines), visceral metastasis (yes or no), and endocrine therapy in the metastatic setting for at least 6 months (yes or no).

^dThe P value was not adjusted for multiplicity.

^eThe time to treatment discontinuation event-free rate was the proportion of patients on treatment.

Source: Sponsor’s submission.³²

Harms

All safety analyses were performed for the safety population (defined in Table 10)⁵⁶ and included data up to the cut-off date of July 1, 2022. Unless otherwise noted, all AEs and laboratory abnormalities presented were treatment-emergent and are referred to as AEs and laboratory abnormalities throughout this report. Treatment-emergent AEs were defined as any AEs that started on or after the first dose date and up to 30 days after the last dose date. The harms observed in the TROPiCS-02 trial are summarized in Table 26.³¹

Adverse Events

AEs were reported in 100% and 96.0% of patients in the sacituzumab govitecan and TPC groups, respectively. The most commonly reported AEs by treatment group were neutropenia (70.5%), diarrhea (61.9%), and nausea (58.6%) in the sacituzumab govitecan group and neutropenia (54.6%), nausea (34.9%), and fatigue (32.9%) in the TPC group.³¹

Serious Adverse Events

The incidence of SAEs was 27.6% in the sacituzumab govitecan group compared with 19.3% in the TPC group. The most commonly reported SAEs in the sacituzumab govitecan group were diarrhea (4.9%), febrile neutropenia (4.1%), and neutropenia (3.0%), and the most commonly reported SAEs in the TPC group were febrile neutropenia (4.0%), pneumonia (2.0%), nausea (2.0%), and dyspnea (1.6%).³¹

Withdrawal Due to Adverse Events

The incidence of AEs leading to study drug discontinuation was similar in the 2 groups (sacituzumab govitecan = 6.3%; TPC = 4.4%). No trends in AEs leading to study drug discontinuation were identified in either group. AEs leading to study drug discontinuation that were reported for more than 1 patient were neutropenia, asthenia, and general physical health deterioration in the sacituzumab govitecan group, and thrombocytopenia and polyneuropathy in the TPC group.³¹

Notable AEs leading to dose reduction or study drug interruption are summarized in the following section.

Deaths

Six patients (2.2%) in the sacituzumab govitecan group and 0 patients in the TPC group had AEs leading to death. One patient experienced an AE leading to death that was assessed by the investigator to have been treatment-related (septic shock due to neutropenic colitis with large intestine perforation). The AEs leading to death in the other 5 patients were assessed by the investigator as not related or unlikely to be related to sacituzumab govitecan. Upon detailed review of the AEs leading to death, no patterns were identified by the investigator regarding specific mechanism or etiology.³¹

Adverse Events of Special Interest

AESIs are summarized in this section.³¹

Diarrhea

The incidence of diarrhea was 61.9% in the sacituzumab govitecan group compared with 22.9% the TPC group. Most events of diarrhea were grade 1 or 2 in severity, nonserious, and did not lead to dose reductions (sacituzumab govitecan = 7.8%; TPC = 0%) or study drug interruptions (sacituzumab govitecan = 3.0%; TPC = 1.2%). One patient (0.4%) in the sacituzumab govitecan group and 0 patients in the TPC group discontinued treatment due to diarrhea.³¹

Neutropenia

The incidence of neutropenia was 72.8% in the sacituzumab govitecan group compared with 55.4% the TPC group. Most events of neutropenia were grade 3 or 4 in severity, nonserious, and led to study drug interruption (sacituzumab govitecan = 50.4%; TPC = 25.3%). Two patients (0.7%) in the sacituzumab govitecan group and 0 patients in the TPC group discontinued the study drug due to neutropenia.³¹

Febrile Neutropenia

The incidence of febrile neutropenia appeared similar in the 2 groups (sacituzumab govitecan = 6.0%; TPC = 4.4%). All events of febrile neutropenia were grade 3 or 4 in severity, and most were SAEs. Most events of febrile neutropenia did not lead to dose reduction (sacituzumab govitecan = 3.0%; TPC = 1.2%) or study drug interruption. No patient in either the sacituzumab govitecan or TPC group discontinued the study drug due to febrile neutropenia.³¹

Infections

The incidence of infections was 37.7% in the sacituzumab govitecan group compared with 26.9% in the TPC group. Most infections were grade 1 or 2 in severity, nonserious, and did not lead to dose reduction (sacituzumab govitecan = 0.7%; TPC = 0.4%) or study drug interruption (sacituzumab govitecan = 9.7%; TPC = 4.4%). Three patients (1.1%) in the sacituzumab govitecan group and 1 patient (0.4%) in the TPC group discontinued the study drug due to infections.³¹

Neuropathies

The incidence of neuropathies was 16.4% in the sacituzumab govitecan group compared with 24.9% in the TPC group. Most events of neuropathy were grade 1 or 2 in severity, nonserious, and did not lead to dose reduction (sacituzumab govitecan = 0.4%; TPC = 4.4%) or study drug interruption (sacituzumab govitecan = 0.4%; TPC = 1.6%). One patient (0.4%) in each group discontinued the study drug due to neuropathy.³¹

Hypersensitivities

The incidence of hypersensitivity was 26.5% in the sacituzumab govitecan group compared with 19.3% the TPC group (19.3%). Most events of hypersensitivity were grade 1 or 2 in severity, nonserious, and did not lead to dose reduction (sacituzumab govitecan = 0; TPC = 1.2%) or study drug interruption (sacituzumab govitecan = 0.7%; TPC = 0.4%). No patient in either group discontinued the study drug due to hypersensitivities.³¹

Pulmonary Events

Pulmonary events were reported for 0 patients in the sacituzumab govitecan group and 2 patients (0.8%) in the TPC group, both of whom had AEs of pneumonitis.³¹

AEs of Grade 3 or Higher

The most frequently reported AEs of grade 3 or higher included neutropenia (in 51.5% of patients treated with sacituzumab govitecan and 39.0% of those treated with TPC), leukopenia (8.6% and 6.0%, respectively), infections (9.7% and 4.8%, respectively), and diarrhea (10.1% and 1.2%, respectively), among others.³¹

Table 26: Summary of Harms Results in the TROPiCS-02 Trial (Safety Population; Data Cut-Off Date: July 1, 2022)

AE = adverse event; CI = confidence interval; MedDRA = Medical Dictionary for Regulatory Activities; NR = not reported; PT = preferred term; RD = relative difference; SAE = serious adverse event; TPC = treatment of physician’s choice.

Note: The following terms were mapped: neutrophil count decreased was mapped to neutropenia; white blood cell count decreased and was mapped to neutropenia leukopenia; lymphocyte count decreased and was mapped to neutropenia lymphopenia; hemoglobin decreased and was mapped to neutropenia anemia; red blood cell count decreased and was mapped to anemia; platelet count decreased and was mapped to thrombocytopenia. The denominator for percentages was the number of patients in the safety population for each treatment group. Treatment-emergent AEs were defined as any AEs that started on or after the first dose date and up to 30 days after the last dose date. Multiple AEs were counted only once per patient for each PT. MedDRA Version 25.0 was used for coding. PTs are presented in descending order of total frequency.

^aPatients with these AEs leading to death in the infections and infestations system organ class were not neutropenic at event onset.

^bOne patient experienced a treatment-related AE leading to death from septic shock due to neutropenic colitis with large intestine perforation.

Source: TROPiCS-02 Clinical Study Report (interim analysis 2).^31,33

Critical Appraisal

Internal Validity

Randomization in the TROPiCS-02 trial was performed using an appropriate methodology with adequate allocation concealment (i.e., an interactive, web-based response system), and randomization stratification was based on relevant prognostic factors (i.e., the presence of visceral metastases [yes or no], endocrine therapy in the metastatic setting [yes or no], and the number of prior lines of chemotherapy [2 lines versus 3 or 4]). Overall, baseline characteristics, including patient-reported HRQoL measures, were generally similar, and no imbalances in baseline characteristics of prognostic importance between the 2 groups were identified, according to the clinical experts. Notably, there was an imbalance in the proportion of patients who were randomized but not treated (4 patients [1.5%] in the sacituzumab govitecan group and 22 patients [8.1%] in the TPC group). The baseline demographic and disease characteristics of these patients were not available; as such, it was not possible to determine whether these patients differed from treated patients with respect to their prognostic factors. The presence and extent of any bias that may have been introduced could not be determined.

The proportion of patients who received at least 1 concomitant medication was high in both groups (||||| in the sacituzumab govitecan group versus ||||| in the TPC group). The clinical experts commented that most of the concomitant medications were likely for the management of AEs, and that the imbalances in some of them likely reflected the different incidences of AEs related to the treatments and were less likely to influence the effect estimates in the TROPiCS-02 trial.

The proportion of patients with no baseline images or who were not postbaseline evaluable was higher in the TPC group (37 patients; 13.7% of the total patients allocated in the TPC group) than in the sacituzumab govitecan group (8 patients; 2.9%), mainly due to the imbalance in patients who were randomized but never treated (4 patients [50.0%] among those with no baseline images or who were not postbaseline evaluable in the sacituzumab govitecan group and 21 patients [56.8%] in the TPC group) (Table 17). Furthermore, for the 2 outcomes for tumour response to treatment (ORR and CBR), the proportion of patients who were not evaluable was higher in the TPC group (51 patients; 18.8% of the total patients allocated) than in the sacituzumab govitecan group (15 patients; 5.5%), mainly due to the imbalance in patients who were randomized but never treated (4 nonevaluable patients [26.7%] in the sacituzumab govitecan and 22 nonevaluable patients [43.1%] in the TPC groups) and due to an imbalance across the groups in the proportion of patients who withdrew consent (| |||||| of the nonevaluable patients in the sacituzumab govitecan and || ||||||| in the TPC groups). The reasons for patients being randomized but never treated were not reported. As such, it is not possible to determine whether the results would be at risk of bias, because it is not known whether there were imbalances in the prognostic characteristics of these patients relative to those who were randomized and treated (or who did or did not withdraw consent).

The TROPiCS-02 trial had an open-label study design. The design could potentially increase the risk of bias due to deviations from the intended interventions and in the measurement of the outcomes, particularly for outcomes with a subjective nature, including the PROs (TTD in the self-reported domains in EORTC QLQ-C30) and some AEs (e.g., nausea, rash, diarrhea, neuropathy, and fatigue). Response outcomes (i.e., PFS, ORR, CBR, and DoR) were assessed through BICR; therefore, the risk of bias was mitigated for the measurement of these. OS and some AEs (e.g., neutropenia, febrile neutropenia, leukopenia, and anemia) were objective measures with standardized criteria and/or relied on objective clinical or laboratory examination. As such, the risk of bias in the measurement of these outcomes is low.

For PROs (i.e., the 4 domains of the EORTC QLQ-C30), data were analyzed for approximately 80% of patients in the total study population who had baseline scores with room for at least a 10-point deterioration (i.e., global health status/QoL score ≥ 10 and baseline pain, fatigue, and diarrhea scores ≤ 90) among the HRQoL population (i.e., patients who had an evaluable assessment of HRQoL at baseline and at least 1 evaluable assessment of HRQoL at postbaseline visits). As a result, there were missing outcome data for the PRO measures (18.1%, 19.2%, 20.6%, and ||||| for the global health status/QoL, fatigue, pain, and diarrhea domains, respectively). The impact of the missing data is unclear.

No significant protocol deviations were noted in either group of the TROPiCS-02 trial. The prespecified sensitivity analyses were completed and supported the effect estimate for the primary end point.

Overall, the statistical methods used in the TROPiCS-02 trial are appropriate. The trial was powered on its primary outcome; however, the subgroup analyses were likely underpowered to identify subgroup differences. The statistical tests were appropriate, using a hierarchical testing approach to control for type I error. The stratified Cox proportional-hazards model was used for the survival outcomes. In a visual inspection of the KM plots, the lines approximately followed a parallel trajectory for most outcomes. Specifically, no crossing of the 2 lines was observed for PFS at the data cut-off date of January 3, 2022 (Figure 4); for OS, the 2 lines crossed at 3 months and 28 months after treatment at the data cut-off date of July 1, 2022 (Figure 6). The missing outcome data for the HRQoL measures were not imputed; however, the patients who were not analyzed would have been censored on the last nonmissing assessment date or at the randomization date, as per the study protocol (Table 8). Generally, multiplicity control appeared adequate. For a few secondary end points (OS at the exploratory final analysis and CBR at IA2) and for the sensitivity analyses of PFS at IA1, the statistical testing was not controlled for multiplicity; therefore, there is an increased risk of false-positive results. However, these results were supportive of the primary analyses of these outcomes. In the time-to-event analysis of PFS, OS, DoR (among 95 responders), and time to treatment discontinuation (with 36 of 543 observations excluded from the analyses due to patients not receiving treatment), all the patients were included in the evaluation regardless of event occurrence. In general, censoring was balanced between the groups for the OS, PFS, DoR, and TTD outcomes.

External Validity

Patients in the TROPiCS-02 trial were enrolled in 9 countries in North America and Europe. The majority were from the US (42.0%), France (25.2%), and Spain (12.7%). One patient who was allocated to the TPC group was from Canada. A total of 66.7% of the patients were white, while 3.9% identified as Black or African American. Race or ethnicity information was not reported for 25.6% of the patients because some local regulators did not allow the collection of such information. Patients were aged 27 years to 86 years (mean, |||| ||||| |||| ||||||||). The majority of the patients were female (99.1%). The proportion of patients who had de novo mBC at baseline was 25.4%. About 70% of the patients who were screened entered the trial. The main reason for screening failure was not meeting the inclusion criteria. The clinical experts commented that the overall patient profile likely reflected the patients seen in clinical practice in Canada.

The clinical experts noted that some patients who did not meet the eligibility criteria of the TROPiCS-02 trial might still be eligible for treatment with sacituzumab govitecan in clinical practice (i.e., the trial had more stringent patient eligibility criteria). The clinical experts indicated that patients with an ECOG PS of 2 (but no greater) would likely be treated with sacituzumab govitecan in practice, and that if taxanes had not been used due to a medical contraindication, patients should still be eligible for treatment. The clinical experts also agreed that patients with brain metastases would be treated with sacituzumab govitecan following treatment for those metastases. Any differences between the patients in the TROPiCS-02 trial and those who would be treated in clinical practice in Canada were not considered serious enough to result in important differences in the observed effect, according to the clinical experts consulted by CADTH.

The clinical experts commented that the concomitant medications used in the TROPiCS-02 trial were reflective of those encountered in clinical practice in Canada and that the comparators (any of the 4 chemotherapy drugs of eribulin, capecitabine, gemcitabine, and vinorelbine) and administration of the study treatments (dosages and settings) were in line with clinical practice in Canada. Outcomes regarded as relevant and important to patients, clinicians, and drug plans were measured and reported in the trial, according to the inputs from the patient and clinician groups and clinical experts.

GRADE Summary of Findings and Certainty of the Evidence

Methods of Assessing the Certainty of the Evidence

For the pivotal studies and RCTs identified in the sponsor’s systematic review, GRADE was used to assess the certainty of the evidence for the outcomes considered most relevant to inform CADTH’s expert committee deliberations. A final certainty rating was determined as outlined by the GRADE working group:^35,36

• High certainty indicates that the group is very confident that the true effect lies close to that of the estimate of the effect.

• Moderate certainty indicates that the group is moderately confident in the effect estimate. The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. The word “likely” is used to describe evidence of moderate certainty (e.g., “X intervention likely results in Y outcome”).

• Low certainty indicates that the group’s confidence in the effect estimate is limited. The true effect may be substantially different from the estimate of the effect. The word “may” is used for evidence of low certainty (e.g., “X intervention may result in Y outcome”).

• Very low certainty indicates that the group has very little confidence in the effect estimate. The true effect is likely to be substantially different from the estimate of effect. Evidence of very low certainty is described as “very uncertain.”

Following the GRADE approach, evidence from the RCTs began as high-certainty evidence and could be rated down for concerns related to study limitations (i.e., internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias.

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. Due to the lack of a formal MID estimate and the unavailability of absolute effect estimates with CIs, the target of the certainty of evidence assessment was the presence or absence of any (non-null) effect for PFS, OS, ORR, CBR, DoR, 4 domains of the EORTC QLQ-C30 (global health status/QoL, fatigue, pain, and diarrhea), time to treatment discontinuation, and AEs of grade 3 or higher, including diarrhea, neutropenia, febrile neutropenia, leukopenia, anemia, fatigue, infections, neuropathies, hypersensitivities, and pulmonary events.

Results of GRADE Assessments

Table 2 presents the GRADE summary of findings for sacituzumab govitecan versus TPC in adult patients with unresectable, locally advanced or metastatic, HR-positive, HER2-negative BC who received endocrine-based therapy and at least 2 additional systemic therapies in the metastatic setting.

Long-Term Extension Studies

No long-term extension studies were identified for this review.

Indirect Evidence

No indirect evidence was identified for this review.

Studies Addressing Gaps in the Systematic Review Evidence

No studies addressing gaps in the pivotal and RCT evidence were identified for this review.

Discussion

Summary of Available Evidence

This systematic review included evidence of the benefits and harms from 1 pivotal trial. No open-label extension study, indirect treatment comparison, or studies addressing gaps were identified.

The pivotal study (TROPiCS-02) was a phase III, multicentre, multinational, open-label, randomized trial that compared sacituzumab govitecan with TPC in adult patients with unresectable, locally advanced or metastatic, HR-positive, HER2-negative (IHC 0, IHC 1+, or IHC 2+, and ISH-negative) BC who received endocrine-based therapy and at least 2 additional systemic therapies in the metastatic setting. Five hundred 43 eligible patients from North America and Europe (mean age = |||| years |||| ||||||| 0.9% males and 99.1% females) were randomized in a 1 to 1 ratio to either sacituzumab govitecan (10 mg/kg, administered as an IV infusion once weekly on days 1 and 8 of a 21-day treatment cycle) or TPC (1 of eribulin, capecitabine, gemcitabine, or vinorelbine, based on investigators’ choice). Patients were treated until progression requiring further treatment, unacceptable toxicity, study withdrawal, or death. Measures of survival (PFS and OS), tumour response to treatment (ORR, CBR, and DoR), PROs (TTD in the EORTC QLQ-C30 domains of global health status/QoL, fatigue, pain, and diarrhea), and time to treatment discontinuation were compared. Harms were also measured and reported.

Interpretation of Results

Efficacy

HR-positive, HER2-negative mBC is associated with a poor prognosis, particularly after endocrine resistance has developed. The treatment goal is primarily to extend patients’ lives. Patients want an enhanced or acceptable level of HRQoL, symptom relief, and manageable adverse effects of therapy. In the TROPiCS-02 study, it was demonstrated that compared to TPC in the ITT setting, sacituzumab govitecan results in an improvement in PFS (the primary end point) (median = 5.5 months versus 4.0 months) and OS (median = 14.4 months versus 11.2 months), and likely results in an increase in ORR (21.0% versus 14.0%) and CBR (33.8% versus 22.1%). According to the clinical experts, OS is an outcome of greater importance than PFS for patients, and the increase in OS with sacituzumab govitecan versus TPC is clinically significant. The clinical experts noted that, although a benefit was shown for sacituzumab govitecan in PFS, the PFS was relatively short in both groups, and the clinical meaningfulness of the between-group difference of approximately 1.5 months in median value was uncertain. One possible reason for the short PFS could be that most patients in the TROPiCS-02 trial had had the disease for a relatively long period (median months from initial metastatic diagnosis = 48.5 months in the sacituzumab govitecan group versus 46.6 months in the TPC group, respectively), had visceral metastases (95% in both groups), and had already received extensive chemotherapy in the metastatic setting (a median of 3 regimens in both groups) at baseline.⁵³ Patients with HR-positive, HER2-negative mBC eventually develop resistance to endocrine-based therapy, and there are limited options for later-line treatments.^30,31,53 According to the clinical experts consulted for this review, the profile of the patients in the TROPiCS-02 trial, all of whom had received a prior CDK4/6 inhibitor, endocrine therapy, and at least 2 lines of chemotherapy (including a taxane) for mBC, was reflective of standard of care, and it was valuable to address the efficacy of a regimen that could be used after CDK4/6 inhibitor treatment. The clinical experts also indicated that greater effects may be expected if treatment with sacituzumab govitecan was initiated earlier.

Evidence from the trial showed that relative to TPC, sacituzumab govitecan may result in an increase in TTD in the EORTC QLQ-C30 global health status/QoL and fatigue domains and a decrease in the diarrhea domain. There was uncertainty in these results due to the risk of bias arising from missing outcome data (approximately 20% of patients were not included in the analyses), the open-label nature of the trial, and the subjective nature of the outcome. The evidence for the pain domain was very uncertain due to risk of bias and imprecision. (The CI for the between-group difference included no difference.) The clinical experts commented that the effect on HRQoL in the TROPiCS-02 trial was uncertain.

Time to treatment discontinuation was identified as a relevant and important outcome by the clinical experts; it is also useful to inform the pharmacoeconomic model. It has been found that treatment discontinuation is a negative predictor of survival in patients with advanced BC or mBC, and that deterioration in patients’ global health status, physical and role functioning, and fatigue may be associated with chemotherapy discontinuation.^71,72 The TROPiCS-02 trial showed that the median time to treatment discontinuation for patients treated with sacituzumab govitecan was longer than for those treated with TPC (4.1 months versus 2.3 months), and that at various follow-up time points, higher rates of patients maintained their assigned treatment in the sacituzumab govitecan group compared to the TPC group.

Harms

In the TROPiCS-02 trial, the safety profile of sacituzumab govitecan was comparable to that of TPC. The proportions of patients who experienced at least 1 AE of any severity were comparable between the 2 treatment arms for some of the most-reported AEs (e.g., asthenia, decreased appetite, headache, and so on). Similarly low occurrences of SAEs (under 5%) were observed in both treatment arms. Six patients in the sacituzumab govitecan group versus 0 patients in the TPC group had any AE leading to death. After examining the specific AEs of these 6 patients, the trial investigators assessed 1 AE as treatment-related (septic shock due to neutropenic colitis with large intestine perforation).³¹ The clinical experts commented that the rest of those specific AEs were likely not directly induced by the treatment with sacituzumab govitecan. Higher proportions of patients had neutropenia and diarrhea in the sacituzumab govitecan group compared with the TPC group, with specific by-arm (sacituzumab govitecan versus TPC) data as follows: neutropenia of any severity (70.5% versus 54.6%), neutropenia of grade 3 or higher (51.5% versus 39.0%), diarrhea of any severity (61.9% versus 22.9%), and diarrhea of grade 3 or higher (10.1% versus 1.2%). According to the sponsor’s submission, these AEs were generally manageable with supportive medication and dose modifications.³⁰ The product monograph of sacituzumab govitecan lists severe or life-threatening neutropenia and/or severe diarrhea among the serious warnings and precautions of the drug and recommends management strategies for them, including adjusting the dose, withholding treatment, and having patients monitor for and evaluate infectious causes before reinitiating treatment.⁵¹ For the AEs of grade 3 or higher that were identified as important by the clinical experts and/or to inform the pharmacoeconomic model for this review, sacituzumab govitecan may result in an increase in diarrhea, neutropenia, febrile neutropenia, leukopenia, anemia, fatigue, and infections of grade 3 or higher, compared with TPC. The clinical importance of the increase in these outcomes is uncertain. Sacituzumab govitecan may result in little to no difference in neuropathies, hypersensitivities, and pulmonary events. Except for neutropenia of grade 3 or higher (51.5% versus 39.0% in the sacituzumab govitecan and the TPC groups, respectively), the rates of the rest of these outcomes were 0 to 10.1% in both treatment groups.

Conclusion

One phase III, multicentre, multinational, open-label, randomized trial (TROPiCS-02) compared sacituzumab govitecan with TPC in adult patients with unresectable, locally advanced or metastatic, HR-positive, HER2-negative BC who had received endocrine-based therapy and at least 2 additional systemic therapies in the metastatic setting. Sacituzumab govitecan results in a clinically important increase in OS. Compared with TPC, sacituzumab govitecan results in an increase in PFS and time to treatment discontinuation, likely results in an increase in ORR and CBR, and may result in an increase in DoR and TTD in the EORTC QLQ-C30 domains of global health status/QoL and fatigue. The clinical importance of these outcomes is uncertain. Sacituzumab govitecan may result in a clinically important decrease in TTD in the EORTC QLQ-C30 diarrhea domain. The evidence is very uncertain about the effect of sacituzumab govitecan on TTD in the EORTC QLQ-C30 pain domain compared with TPC. The evidence shows that sacituzumab govitecan likely results in an increase in neutropenia of grade 3 or higher, and may result in an increase in grade 3 or higher diarrhea, febrile neutropenia, leukopenia, anemia, fatigue, and infections when compared with TPC. The clinical importance of the increase in these outcomes is uncertain. Sacituzumab govitecan may result in little to no difference in neuropathies, hypersensitivities, and pulmonary events compared with TPC.

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