CADTH Reimbursement Review

Sacituzumab Govitecan (Trodelvy)

Sponsor: Gilead Sciences Canada, Inc.

Therapeutic area: Locally advanced or metastatic triple-negative breast cancer

This multi-part report includes:

Clinical Review

Pharmacoeconomic Review

Clinical Review

Executive Summary

An overview of the submission details for sacituzumab govitecan is provided in Table 1.

Introduction

Triple-negative breast cancer (TNBC), defined by the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), is an aggressive cancer with poor prognosis.^1,2 The disease is more common among younger women and racialized women.^1,3 Of the approximately 27,000 Canadians diagnosed with breast cancer each year,⁴ 15% will have TNBC,^1,2 which carries higher risks of early recurrence and presentation as stage 4 metastatic disease. The exact prevalence and incidence of adult patients with unresectable locally advanced TNBC or metastatic TNBC (mTNBC) who have received 2 or more prior therapies, at least 1 of them for metastatic disease, is uncertain. As noted in the CADTH pharmacoeconomic report, the sponsor estimated that the total number of patients with locally advanced TNBC or mTNBC in Canada, including incident cases of de novo mTNBC as well as prevalent cases that have recurred or spread, was 633 in 2020, and the vast majority of patients would be candidates for sacituzumab govitecan.^5,6 Median survival of locally advanced TNBC or mTNBC is approximately 12 months to 14 months.⁷ Symptoms including pain, fatigue, and insomnia impose limitations on patients’ ability to work, caregiving responsibilities, and physical activity, as well as significant financial burdens.

According to clinician and patient input, the main goals of systemic therapy for mTNBC are to extend survival and delay progression with minimal toxicity while maintaining or improving health-related quality of life (HRQoL). Immunotherapy and poly-(ADP-ribose) polymerase (PARP) inhibitors such as olaparib may induce responses in some patients, although the survival benefit is not clear, and these therapies are not currently funded. For recurrent locally advanced TNBC and mTNBC, sequential single-agent chemotherapy remains the standard of care.⁸ According to clinical experts consulted for this review, each line of therapy has diminishing response rates. The standard chemotherapies for locally advanced TNBC or mTNBC are taxanes, platinum agents, capecitabine, gemcitabine (with or without cisplatin or carboplatin), anthracyclines, eribulin, and vinorelbine. An optimal treatment sequence has not been determined, and treatment sequence varies across jurisdictions in Canada. According to clinical experts, in pre-treated patients with mTNBC, single-agent chemotherapies have low objective response rates (ORRs) (5% to 10%), as determined by tumour imaging, and low progression-free survival (PFS) (2 months to 3 months).^9,10

Sacituzumab govitecan is an antibody-drug conjugate directed against human trophoblast cell-surface marker 2 (Trop-2), a transmembrane protein involved in calcium signal transduction that is overexpressed in many epithelial cancers, including TNBC. Sacituzumab govitecan is administered at a dose of 10 mg/kg as an IV infusion on day 1 and day 8 of a 21-day treatment cycle. Sacituzumab govitecan is indicated for the treatment of adult patients with unresectable locally advanced TNBC or mTNBC who have received 2 or more prior therapies, at least 1 of them for metastatic disease. The sponsor’s reimbursement request is aligned with the Health Canada–approved indication. According to the sponsor and clinical experts consulted for this review, the treatment approach for unresectable locally advanced TNBC and mTNBC is the same, and patients with unresectable locally advanced TNBC who have been treated previously in the same manner as a metastatic patient and received at least 2 lines of systemic therapy would be eligible to receive sacituzumab govitecan in accordance with the Health Canada indication.

The objective of this report was to perform a systematic review of the beneficial and harmful effects of sacituzumab govitecan (IV injection, 10 mg/kg) for the treatment of adult patients with unresectable locally advanced TNBC or mTNBC who have received 2 or more prior therapies, at least 1 of them for metastatic disease.

Stakeholder Perspectives

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

Patient Input

Input was provided by 2 patient groups for this review: Rethink Breast Cancer and the Canadian Breast Cancer Network (CBCN). Rethink Breast Cancer conducted an online patient survey in June and July 2021. Of the 30 respondents with mTNBC (22 from the US and 6 from Canada), 4 with direct experience with sacituzumab govitecan participated in telephone interviews. The Canadian Breast Cancer Network distributed online surveys in 2012 and 2017 to patients living with breast cancer registered in the membership databases of CBCN and other patient organizations. Of the 157 respondents, data from 14 patients with mTNBC were captured in the input, and 1 Canadian patient with direct experience with sacituzumab govitecan participated in a telephone interview.

Patients highlighted the negative impacts of mTNBC, including spread to the bone, liver, lungs, and brain. Symptoms frequently included pain, fatigue, and insomnia and imposed significant financial burdens and limitations on patients’ ability to work, caregiving responsibilities, physical activity, and ability to spend time with loved ones. Patients highlighted the limited treatment options for mTNBC and their experiences with prior therapies (chemotherapy and immunotherapy), including their limited effectiveness in delaying progression, managing symptoms, and maintaining HRQoL, as well as their side effects (e.g., nausea and/or vomiting, fatigue, hand-foot syndrome). Twenty patients contacted by Rethink Breast Cancer and 1 patient contacted by CBCN had direct experience with sacituzumab govitecan. Patients felt that the drug was effective in controlling disease, extending survival, maintaining HRQoL, and reducing mTNBC symptoms (e.g., Jacksonian marches, bone pain, neuropathy) and noted that side effects (e.g., fatigue, alopecia, diarrhea, neutropenia) were manageable, although not all patients were currently able to access the drug.

Patients with mTNBC identified an important unmet need for treatments that control disease progression, prevent recurrence, and extend survival. Other needs identified by patients were treatments that maintain HRQoL, reduce symptom severity, and have a manageable safety profile.

Clinician Input

Input From Clinical Experts Consulted by CADTH

Two clinical experts with expertise in the diagnosis and management of mTNBC highlighted the poor outcomes in patients with mTNBC and the limited effective treatment options for later-line therapy (single-agent chemotherapy, optimal sequencing undefined). ORRs by objective tumour imaging are low for lines of therapy beyond anthracyclines and taxanes, many patients become refractory to treatment, and many treatments are poorly tolerated. The main goals of therapy are to extend survival and delay progression with minimal toxicity while maintaining or improving HRQoL. Sacituzumab govitecan would be administered for later-line treatment after at least 2 prior lines of chemotherapy (at least 1 taxane in the adjuvant, neoadjuvant, or advanced setting and at least 1 therapy in the metastatic setting), where it may cause a shift in the current treatment paradigm by providing an option for targeted therapy. Any patient with mTNBC who has received at least 2 prior lines of systemic therapy with adequate performance status, adequate hematological and organ function, and stable central nervous system (CNS) disease would be a candidate for sacituzumab govitecan. Treatment would be initiated in suitable patients by the primary treating physician based on pathology or biomarker assessment and imaging or biopsy results. Response to treatment is assessed by serial imaging showing stable or shrinking disease (objective responses), laboratory markers, clinical assessment, and maintained or improved HRQoL and cancer symptoms. Treatment would be discontinued in patients with progressive disease (PD) or with significant worsening of symptoms, performance status, or HRQoL, as well as in patients with significant and persistent side effects (especially diarrhea).

Clinician Group Input

Three clinician groups provided input for this review: the Ontario Health–Cancer Care Ontario Breast Cancer Drug Advisory Committee (3 medical oncologists and 1 pharmacist), the Ottawa Hospital Cancer Centre Breast Medical Oncology group (4 medical oncologists), and the Rethink Breast Cancer Scientific Advisory Committee (6 medical oncologists from across Canada). No major contrary views were presented: clinical groups echoed the lack of effective options for later-line therapy of mTNBC. Sacituzumab govitecan may change the treatment paradigm and be used before vinorelbine or gemcitabine or reuse of doxorubicin.

Drug Program Input

The Provincial Advisory Group identified the following jurisdictional implementation issues: relevant comparators, considerations for initiation of therapy, considerations for discontinuation of therapy, generalizability, care provision, system issues, and economic considerations. The clinical experts consulted by CADTH for this review weighed evidence from the included study and other clinical considerations to provide responses to the Provincial Advisory Group’s drug program implementation questions. Refer to Table 4 for more details.

Clinical Evidence

Pivotal Study and Protocol-Selected Study

Description of Study

One phase III, randomized, open-label (OL), multi-centre study (ASCENT, N = 529)^11,12 was included in the systematic review (Table 6). The primary objective of the study was to compare the efficacy of sacituzumab govitecan (10 mg/kg) with chemotherapy (the treatment of physician’s choice [TPC] selected from the following options: eribulin, capecitabine, gemcitabine, or vinorelbine) in prolonging PFS among adult patients with locally advanced TNBC or mTNBC previously treated with at least 2 systemic chemotherapy regimens (including 1 taxane in the adjuvant, neoadjuvant, or advanced setting). Of note, the study enrolled a small number of patients (approximately 3%) with locally advanced mTNBC who had not received prior therapy in the metastatic setting; according to the sponsor and clinical experts consulted for this review, the treatment approach for unresectable locally advanced TNBC and mTNBC is the same, and patients with unresectable locally advanced TNBC who had been treated previously in the same manner as a metastatic patient and received at least 2 lines of systemic therapy would be eligible to receive sacituzumab govitecan in accordance with the Health Canada indication.

Patients with acceptable performance status (Eastern Cooperative Oncology Group [ECOG] 0 or 1) and organ function were randomized 1:1 to receive sacituzumab govitecan or TPC; randomization was stratified by number of prior therapies (2 to 3 versus > 3), baseline brain metastasis (BM) status, and region (North America versus rest of world). Most patients (88.5%) were negative for BM (BM-Neg), and 11.5% were positive for BM (BM-Pos). The mean age of participants was 54.0 (standard deviation [SD] = 11.5) years, and most were White (79.0%), not Hispanic or Latino (87.0%), and from North America (65.6%; nearly all from the US). The mean number of prior systemic therapies was 4.5 (SD = 2.1); nearly all patients had received prior breast cancer–related surgery (94.9%), most had received prior non-brain radiotherapy (81.1%), and approximately one-quarter had received prior programmed cell death protein 1 (PD-1) or programmed death ligand 1 (PD-L1) therapy (28.9%).

Patients were treated until PD or unacceptable toxicity and subsequently entered survival follow-up. Crossover was not permitted. The primary outcome was PFS by blinded independent review committee (IRC) assessment in the BM-Neg population, while PFS in the intention-to-treat (ITT) set, overall survival (OS) in the BM-Neg population and ITT set, ORR in the BM-Neg population and the ITT set, and HRQoL were secondary outcomes.

Efficacy Results

A summary of key results from the ASCENT trial is shown in Table 2. The primary outcome was PFS in the BM-Neg population. Median OS was longer in patients treated with sacituzumab govitecan than in those treated with TPC (BM-Neg population: median = 12.1; 95% confidence interval [CI], 10.7 to 14.0 months versus median = 6.7; 95% CI, 5.8 to 7.7 months; P < 0.0001; ITT set: median = 11.8; 95% CI, 10.5 to 13.8 months versus median 6.9; 95% CI, 5.9 to 7.7 months; P < 0.0001). The hazard ratio (HR) for death among patients treated with sacituzumab govitecan relative to TPC was 0.476 (95% CI, 0.383 to 0.592) in the BM-Neg population and 0.508 (95% CI, 0.414 to 0.624) in the ITT set. Median (95% CI) PFS by blinded IRC assessment was statistically significantly longer in patients treated with sacituzumab govitecan than in those treated with TPC (median = 5.6; 95% CI, 4.3 to 6.3 months versus median = 1.7; 95% CI, 1.5 to 2.6 months in the BM-Neg population; median = 4.8; 95% CI, 4.1 to 5.8 months versus median = 1.7; 95% CI, 1.5 to 2.5 months in the ITT set; P < 0.0001 in both the BM-Neg population and the ITT set). The HR for progression or death among patients treated with sacituzumab govitecan relative to TPC was 0.409 (95% CI, 0.323 to 0.519) in the BM-Neg population and 0.433 (95% CI, 0.347 to 0.541) in the ITT set. Median time to progression in the sacituzumab govitecan arm compared with the TPC arm was 5.8 (95% CI, 4.8 to 6.9) months versus 2.1 (95% CI, 1.5 to 2.7) months in the BM-Neg population and 5.6 (95% CI, 4.3 to 6.2) months versus 2.1 (95% CI, 1.5 to 2.8) months in the ITT set. The ORR in the sacituzumab govitecan arm compared with the TPC arm was 34.9% (95% CI, 28.8% to 41.4%) versus 4.7% (95% CI, 2.4% to 8.3%) in the BM-Neg population and 31.1% (95% CI, 25.6% to 37.0%) versus 4.2% (95% CI, 2.1% to 7.4%) in the ITT set. Mean time to response for patients receiving sacituzumab govitecan and TPC was 2.67 (SD = 1.91) months versus 1.86 (SD = 0.92) months in the BM-Neg population and 2.66 (SD = 1.91) months versus 1.86 (SD = 0.92) months in the ITT set. Subgroup analyses were not adjusted for multiplicity and were not powered to evaluate differences in the treatment effects of sacituzumab govitecan in patients with or without BRCA1 or BRCA2 mutations, patients who had received 2 to 3 or more than 3 prior lines of therapy, or BM-Pos and BM-Neg patients. Nevertheless, the clinical experts consulted for this review felt that the results of the trial were generalizable across strata for all these subgroups.

Harms Results

Adverse events (AEs) occurred in almost all patients treated with both sacituzumab govitecan and TPC (99.6% versus 97.8%). Serious AEs (SAEs) and withdrawals due to AEs (WDAEs) occurred in similar proportions of sacituzumab govitecan– and TPC-treated patients (26.7% versus 28.1% for SAEs and 4.7% versus 5.4% for WDAEs, in sacituzumab govitecan– and TPC-treated patients, respectively). Deaths due to AEs occurred in 1 sacituzumab govitecan–treated patient (0.4%) and 3 TPC-treated patients (1.3%).

Neutropenia or febrile neutropenia occurred more frequently in patients treated with sacituzumab govitecan than with TPC (65.1% versus 44.2%), including Grade 3 neutropenia (48.4% versus 29.0%), Grade 4 neutropenia (17.8% versus 13.4%), and serious neutropenia (7.4% versus 2.7%). Diarrhea occurred more frequently in patients treated with sacituzumab govitecan than with TPC (65.1% versus 17.0%), including Grade 3 diarrhea (11.2% versus 0.9%) and serious diarrhea (3.5% versus 0%). Only 1 patient discontinued sacituzumab govitecan due to a notable harm (diarrhea), although 10.9% and 4.7% of patients required sacituzumab govitecan dose reduction due to neutropenia and diarrhea, respectively.

Critical Appraisal

Most of the notable limitations of the ASCENT trial were tied to its OL design. Although outcome assessment of PFS and OS was conducted by a blinded IRC, patient-reported HRQoL and harms outcomes may have been influenced to some degree by knowledge of treatment allocation. The decision to discontinue patients from therapy was made by investigators based on unblinded review of local imaging results and/or clinical assessments, and biased decision-making could have altered exposure to sacituzumab govitecan and/or TPC. Higher proportions of patients randomized to the TPC arm discontinued the study before receiving protocol therapy, during treatment, and during survival follow-up, and more PFS events were censored in the TPC arm due to initiation of other anticancer therapy and missed assessments. In addition, the magnitude of bias due to screening failures of unknown cause could not be evaluated as these data were not provided on a per-patient basis. The absence of formal statistical comparison and high amounts of missing HRQoL data (due to deaths and dropouts) limited interpretation of potentially important changes in this end point.

The demographic and disease characteristics of the ASCENT study population were broadly reflective of the Canadian population with mTNBC. Of note, the study enrolled small numbers of patients with locally advanced disease who had not received prior therapies in the metastatic setting (approximately 3%). According to the sponsor and the clinical experts consulted for this review, the treatment approach for unresectable locally advanced TNBC and mTNBC is the same, and patients with unresectable locally advanced TNBC who had been treated previously in the same manner as a metastatic patient and received at least 2 lines of systemic therapy would be eligible to receive sacituzumab govitecan in accordance with the Health Canada indication. Thus, enrolment of these patients in the trial would not impact generalizability. A potentially important issue limiting generalizability to Canadian patients with mTNBC was the use of granulocyte colony–stimulating factor (G-CSF) to counteract neutropenia in approximately half of patients in the sacituzumab govitecan arm. According to the clinical experts, limited access to G-CSF in Canada may mean that dose reductions would be required in higher numbers of patients; the potential impact on efficacy is unclear. Generalizability to patients not included in the study (e.g., patients with ECOG Performance Status 2, patients who have not previously received taxanes, patients receiving sacituzumab govitecan in earlier lines of therapy) could not be evaluated.

Indirect Comparisons

No indirect evidence was identified for this review.

Other Relevant Evidence

No other relevant evidence was identified for this review.

Conclusions

Evidence from the ASCENT trial suggested that compared with TPC, administration of sacituzumab govitecan (10 mg/kg on days 1 and 8 of a 21-day treatment cycle) contributed to statistically significant and clinically meaningful prolongation of PFS and OS among patients with locally advanced TNBC or mTNBC who had received at least 2 prior therapies. ORRs were higher, and time to progression was longer, in patients treated with sacituzumab govitecan than in those treated with standard chemotherapy. Analyses of European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) data could not be interpreted due to absence of formal statistical testing and high rates of missing data resulting from deaths and withdrawals. The magnitude of the observed survival benefits and the potential impact on cancer symptoms are important outcomes to patients with mTNBC. Notable harms associated with sacituzumab govitecan (including neutropenia and diarrhea) were not insignificant but manageable with appropriate supportive care (including G-CSF) and dose modification and rarely required withdrawal of treatment. Minor limitations of the available evidence included bias in favour of sacituzumab govitecan on the part of patients and investigators due to the OL design of the ASCENT trial, which may have decreased exposure to TPC relative to sacituzumab govitecan, as well as potential for higher dose reduction and discontinuation rates for Canadian patients in the absence of G-CSF.

Introduction

Disease Background

TNBC, defined by the absence of cell-surface ER, PR, and HER2, is associated with an aggressive phenotype and poor prognosis.^1,2 The disease is more common among younger women and Black women and often results in visceral metastasis.^1,3 TNBC is characterized by heterogeneous molecular and immunological characteristics¹⁴ and has worse rates of PFS and OS than other breast cancer subtypes.^1,2

More than 27,000 Canadians are diagnosed with breast cancer each year.⁴ Although the majority will be cured of their disease, up to 15% have TNBC (approximately 4,000 patients per year),^1,2 which carries a higher risk of early recurrence and presentation as stage 4 metastatic disease. The exact prevalence and incidence of adult patients with unresectable locally advanced TNBC or mTNBC who have received 2 or more prior therapies, at least 1 of them for metastatic disease, is uncertain. As noted in the CADTH Pharmacoeconomic Review, the sponsor estimated that the total number of patients with unresectable locally advanced TNBC or mTNBC was 633 in 2020. This estimation included incident cases of de novo mTNBC (calculated by applying the incidence of breast cancer in Canada according to the Canadian Cancer Statistical Advisory Committee to the population of Canada, then multiplying by the proportion with metastasis at presentation and the proportion with TNBC based on a study of Ontario women)¹⁵ as well as prevalent cases from prior years that had recurred or spread (calculated by multiplying the prevalence of breast cancer in Canada according to Statistics Canada by the annual probability of recurrence according to the Institut national d’excellence en santé et en services sociaux [INESSS] and the proportion of recurrent patients with TNBC based on a study of Ontario women). The vast majority (600) of the estimated 633 patients would be candidates for sacituzumab govitecan.^5,6 Five-year OS of TNBC following neoadjuvant therapy is approximately 64%.¹⁶ Compared with other breast cancer subtypes, TNBC is highly invasive and frequently results in locally advanced disease (spread to nearby tissues and lymph nodes) or metastatic (distant spread) disease.^1,2 Diagnosis of locally advanced TNBC or mTNBC is made by a medical oncologist based on pathological or biopsy and imaging results. Symptoms including pain, fatigue, and insomnia impose significant financial burdens as well as limitations on patients’ ability to work, caregiving responsibilities, physical activity, and ability to spend time with loved ones. Despite advances in understanding of the disease and development of new treatments, the median OS of advanced stage 4 TNBC is approximately 12 months to 14 months, which is lower than other breast cancer subtypes.⁷ Disease recurrence is often associated with metastasis to the bones, lungs, liver, and brain with significant symptomology.¹⁷ According to members of the Rethink Breast Cancer Scientific Advisory Committee (Appendix 2), this is often a debilitating and symptomatic death that occurs in younger women, and a diagnosis of mTNBC is devastating to patients and their families.

Standards of Therapy

Over the last several decades, hormone and targeted therapies have dramatically altered the landscape of other breast cancer subtypes, and multiple treatments are now available.^10,18-20 Although immunotherapies (e.g., atezolizumab, pembrolizumab) have shown great promise in other tumour types, results in TNBC have been modest and/or conflicting.²¹ In patients with BRCA1 or BRCA2 mutations, PARP inhibitors such as olaparib may induce responses, although the survival benefit is not clear. According to clinical experts consulted by CADTH for this review, immunotherapies, PARP inhibitors, and nab-paclitaxel are not available and not funded in Canada, and special access programs are now closed. Thus, for recurrent or advanced TNBC, sequential single-agent chemotherapy until all options have been exhausted remains the standard of care.⁸ Each line of therapy has diminishing response; although initial lines of therapy may provide a few months of PFS, this decreases substantially with later lines.

Neoadjuvant chemotherapy, surgery and radiation, and adjuvant chemotherapy with curative intent continue to be mainstays for treatment of more limited TNBC. However, distant recurrence within several years of treatment will occur in many patients.

According to clinical experts, standard chemotherapies for locally advanced TNBC or mTNBC include taxanes (e.g., paclitaxel, docetaxel), platinum agents, capecitabine, gemcitabine (with or without cisplatin or carboplatin), anthracyclines (doxorubicin), eribulin, and occasionally vinorelbine.²² There is jurisdictional variation in treatment sequence across Canada. In the neoadjuvant and adjuvant setting, taxanes, anthracyclines, cyclophosphamide, and/or fluorouracil with or without platinum agents are given. Patients with de novo metastasis who are treatment naive would likely receive taxanes as first-line therapy. For patients who have previously received (neo)adjuvant therapy, first-line treatment in the metastatic setting can include taxane reuse, capecitabine, or cisplatin plus gemcitabine. Most patients develop PD after first-line therapy, then receive other standard chemotherapy options in variable order (e.g., taxane or cisplatin plus gemcitabine second line; anthracycline third line). Chemotherapy regimens are usually administered until PD, unacceptable toxicity, decline in performance status, or patient discontinuation. According to the clinical experts, these treatments have disappointingly low response rates (5% to 10%), and benefit beyond the first or second line (typically anthracyclines and taxanes) has not been convincingly demonstrated. Many patients quickly become refractory to treatment. Chemotherapy does not modify the underlying disease mechanism of mTNBC but can temporarily delay progression in some patients with pre-treated mTNBC,^9,10 but often at the cost of side effects that impair HRQoL. OS in this population has not changed in 20 years.¹⁰

According to the clinical experts, the main goals of systemic therapy for mTNBC are to extend survival and delay progression with minimal toxicity while maintaining or improving HRQoL (compared with existing treatments). Additional goals of therapy are to maintain or improve organ function, reduce cancer symptoms, maintain patient independence, reduce caregiver burden, and minimize financial burdens and inconvenience for the patient. Better tolerated and more convenient therapies may help improve patient compliance.

Drug

Key characteristics of sacituzumab govitecan are shown in Table 3. Sacituzumab govitecan is administered at a dose of 10 mg/kg as an IV infusion on day 1 and day 8 of a 21-day treatment cycle. Sacituzumab govitecan is indicated for the treatment of adult patients with unresectable locally advanced TNBC or mTNBC who have received 2 or more prior therapies, at least 1 of them for metastatic disease. The sponsor’s reimbursement request is aligned with the Health Canada–approved indication. According to the sponsor and clinical experts consulted for this review, the treatment approach for unresectable locally advanced TNBC and mTNBC is the same, and patients with unresectable locally advanced TNBC who had been treated previously in the same manner as a metastatic patient and received at least 2 lines of systemic therapy would be eligible to receive sacituzumab govitecan in accordance with the Health Canada indication. Sacituzumab govitecan was approved by the FDA in 2020 with the same indication and is undergoing accelerated review by the European Medicines Agency for the indication: “for the treatment of adult patients with unresectable locally advanced or metastatic triple-negative breast cancer who have received at least two prior therapies, including at least one prior therapy for locally advanced or metastatic disease.”

Sacituzumab govitecan is an antibody-drug conjugate based on a humanized IgG1:k monoclonal antibody against Trop-2, a transmembrane protein involved in calcium signal transduction that is overexpressed in many epithelial cancers, including TNBC. The camptothecin-derived topoisomerase I inhibitor SN-38 is an active metabolite of irinotecan and is linked to the antibody by a hydrolyzable linker. The mechanism of action of sacituzumab govitecan is binding to Trop-2-expressing cancer cells followed by internalization^23,24 and subsequent release of SN-38 via hydrolysis of the linker. SN-38 interacts with topoisomerase I and prevents religation of topoisomerase I–induced single strand breaks; the resulting DNA damage leads to tumour cell death. Sacituzumab govitecan releases its SN-38 payload both intra- and extracellularly in the tumour microenvironment.^25,26 A higher amount of SN-38 is delivered to Trop-2-expressing tumours compared with conventional irinotecan therapy.²⁷ Extracellular release of SN-38 from sacituzumab govitecan also results in bystander killing of Trop-2–negative tumour cells.^28-30

Stakeholder Perspectives

Patient Group Input

This section was prepared by CADTH staff based on the input provided by patient groups. Raw patient group input can be found in Appendix 1.

Input was provided by 2 patient groups for this review: Rethink Breast Cancer and CBCN. Rethink Breast Cancer conducted online patient surveys in June and July 2021; of the 30 respondents with mTNBC (22 from the US and 6 from Canada), 4 with direct experience with sacituzumab govitecan participated in telephone interviews. CBCN distributed online surveys in 2012 and 2017 to patients living with breast cancer registered in the membership databases of CBCN and other patient organizations; of the 157 respondents, data from 14 patients with mTNBC were captured in the input, and 1 Canadian patient with direct experience with sacituzumab govitecan participated in a telephone interview.

Patients highlighted the negative impacts of mTNBC, including spread to the bone, liver, lungs, and brain. Symptoms frequently included pain, fatigue, and insomnia and imposed significant financial burdens and limitations on patients’ ability to work, caregiving responsibilities, physical activity, and ability to spend time with loved ones. Patients highlighted the limited treatment options for mTNBC and their experiences with prior therapies (chemotherapy and immunotherapy), including their limited effectiveness in delaying progression, managing symptoms, and maintaining HRQoL, as well as their sometimes-severe side effects (e.g., nausea and/or vomiting, fatigue, hand-foot syndrome). Twenty patients contacted by RBC and 1 patient contacted by CBCN had direct experience with sacituzumab govitecan. The patients felt that the drug was effective in controlling disease, extending survival, maintaining HRQoL, and reducing mTNBC symptoms (e.g., Jacksonian marches, bone pain, neuropathy) and noted that side effects (e.g., fatigue, alopecia, diarrhea, neutropenia) were manageable but that not all patients were currently able to access the drug.

Patients with mTNBC identified an important unmet need for treatments that control disease progression, prevent recurrence, and extend survival. Other needs identified by patients were treatments that maintain HRQoL, reduce symptom severity, and have a manageable safety profile.

Clinician Input

Input From Clinical Experts Consulted by CADTH

All CADTH review teams include at least 1 clinical specialist with expertise in the diagnosis and management of the condition for which the drug is indicated. Clinical experts are a critical part of the review team and are involved in all phases of the review process (e.g., providing guidance on the development of the review protocol, assisting in the critical appraisal of clinical evidence, interpreting the clinical relevance of the results, 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 adults with unresectable locally advanced TNBC or mTNBC who had received 2 or more prior therapies, at least 1 of them for metastatic disease.

Unmet Needs

Clinical experts highlighted the aggressive nature of mTNBC and its poor survival outcomes compared with other breast cancer subtypes, as well as the limited efficacy of current treatment options for later-line therapy. Unlike other subtypes of breast cancer, hormone and targeted therapies are not available to patients with mTNBC.

Place in Therapy

According to clinical experts, sacituzumab govitecan would serve as an additional line of treatment and would serve the same purpose as existing therapies (e.g., chemotherapy, immunotherapy, olaparib). Sacituzumab govitecan would not be expected to modify the underlying disease process of mTNBC but instead target Trop-2, which is present in more than 90% of tumours. Sacituzumab govitecan would be administered for later-line treatment after at least 2 prior lines of chemotherapy (at least 1 taxane in the adjuvant, neoadjuvant, or advanced setting and at least 1 therapy in the metastatic setting). However, 1 clinician suggested that for earlier-line therapy of patients who are not candidates for chemotherapy, sacituzumab govitecan might be considered. Sacituzumab govitecan would not be reserved for patients who are intolerant to other treatments or in whom other treatments are contraindicated. Clinicians expected that sacituzumab govitecan may cause a shift in the current mTNBC treatment paradigm by providing an option for targeted therapy, which is often better tolerated, after at least 2 lines of chemotherapy. Standard chemotherapies could then be considered following progression on sacituzumab govitecan.

Patient Population

Clinical experts stated that any patient with mTNBC who had received at least 2 prior lines of systemic therapy (1 taxane in the adjuvant, neoadjuvant, or advanced setting and 1 systemic therapy in the metastatic setting) with adequate performance status (ECOG 0 to 2 according to 1 expert), adequate hematological and organ function, and stable CNS disease (for patients with BM) would be a candidate for sacituzumab govitecan. Patients best suited for treatment would be identified by the primary treating physician based on pathology or biomarker assessment of ER, PR, and HER2 status and imaging or biopsy to confirm metastatic disease. Diagnosis is not challenging in routine clinical practice, and misdiagnosis or underdiagnosis is not a concern. Pre-symptomatic patients with evidence of PD following 2 lines of prior chemotherapy would also be candidates for sacituzumab govitecan. Patients who do not have mTNBC (who could receive hormone or other targeted therapies), patients with poor performance status, patients with inadequate hematological and organ function, patients with unstable CNS disease, and patients who have not yet tried taxanes would be least suited for treatment with sacituzumab govitecan. No biomarkers of response to sacituzumab govitecan are available.

Assessing Response to Treatment

Response to treatment is assessed by serial imaging demonstrating stable or shrinking disease (objective responses), laboratory markers, and clinical assessment, as well as more subjective measures such as maintained or improved HRQoL, cancer symptoms, and functional status. The outcomes used in clinical practice are the same as those used in trials. Clinically meaningful responses to treatment could be manifested by radiographic tumour response, improved survival, symptomatic stabilization, improvement or reduction in symptom frequency or severity (e.g., pain, dyspnea), stabilization of performance status, and prolonged independent ability to perform activities of daily living. Response to treatment should be assessed at each follow-up visit, with serial imaging typically performed at an 8-week to 12-week interval, with toxicity and safety assessments more often during early treatment (every 2 weeks to 4 weeks) or as needed.

Discontinuing Treatment

Treatment is usually continued in patients who have stable disease or objective responses based on tumour imaging. Treatment would be discontinued in patients with radiographically documented PD; in patients with significant worsening of symptoms, performance status, or HRQoL; and in patients with significant and persistent side effects from treatment (especially uncontrolled Grade 3 or Grade 4 diarrhea).

Prescribing Conditions

According to clinical experts, treatment with sacituzumab govitecan would be initiated by a medical oncologist or associated team physician with expertise in cancer therapies and toxicity management. Sacituzumab govitecan would be administered in a hospital setting or a specialty clinic with the expertise and staffing (chemotherapy nurses, oncology pharmacists) to administer systemic therapies and manage treatment-related toxicities.

Additional Considerations

Clinical experts emphasized that the benefits of sacituzumab govitecan demonstrated in the ASCENT trial^11,12 are meaningful and aligned with patient values. The toxicities are predictable and manageable by medical oncologists. The drug would be a valuable addition for use in heavily pre-treated, treatment-resistant patients with mTNBC.

Clinician Group Input

This section was prepared by CADTH staff based on the input provided by clinician groups. Raw clinician group input can be found in Appendix 2.

Three clinician groups provided input for this review: the Ontario Health–Cancer Care Ontario Breast Cancer Drug Advisory Committee (3 medical oncologists and 1 pharmacist), the Ottawa Hospital Cancer Centre Breast Medical Oncology group (4 medical oncologists), and the Rethink Breast Cancer Scientific Advisory Committee (6 medical oncologists from across Canada). No major contrary views were presented: Clinical groups echoed the lack of effective options for later-line therapy of mTNBC. Sacituzumab govitecan could change the treatment paradigm and be used before drugs such as vinorelbine and gemcitabine or before reuse of agents such as doxorubicin.

Drug Program Input

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

Clinical Evidence

The clinical evidence included in the review of sacituzumab govitecan is presented in the Systematic Review section and includes pivotal studies provided in the sponsor’s submission to CADTH and Health Canada, as well as those studies that were selected according to an a priori protocol. No indirect evidence was provided by the sponsor or met the selection criteria specified in the review. No additional relevant studies were identified that were considered to address important gaps in the evidence included in the systematic review.

Systematic Review: Pivotal and Protocol-Selected Studies

Objectives

To perform a systematic review of the beneficial and harmful effects of sacituzumab govitecan (IV injection, 10 mg/kg) for the treatment of adult patients with unresectable locally advanced TNBC or mTNBC who have received 2 or more prior therapies, at least 1 of them for metastatic disease.

Methods

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

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

The literature search for clinical studies was performed by an information specialist using a peer-reviewed search strategy according to the PRESS (Peer Review of Electronic Search Strategies) checklist.³³

Published literature was identified by searching the following bibliographic databases: MEDLINE All (1946‒) via Ovid and Embase (1974‒) via Ovid. All Ovid searches were run simultaneously as a multi-file search. Duplicates were removed using Ovid deduplication for multi-file searches, followed by manual deduplication in Endnote. The search strategy comprised both controlled vocabulary, such as the National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. The main search concept was Trodelvy (sacituzumab govitecan). Clinical trial registries were searched: the US National Institutes of Health’s clinicaltrials.gov, WHO’s International Clinical Trials Registry Platform search portal, Health Canada’s Clinical Trials Database, and the European Union Clinical Trials Register.

No filters were applied to limit the retrieval by study type. Retrieval was not limited by publication date or by language. Conference abstracts were excluded from the search results. See Appendix 3 for the detailed search strategies.

The initial search was completed on July 28, 2021. Regular alerts updated the search until the meeting of the CADTH pan-Canadian Oncology Drug Review Expert Committee on December 1, 2021.

Grey literature (literature that is not commercially published) was identified by searching relevant websites from the Grey Matters: A Practical Tool for Searching Health-Related Grey Literature tool.³⁴ Included in this search were the websites of regulatory agencies (the FDA and the European Medicines Agency). Google was used to search for additional internet-based materials. See Appendix 3 for more information on the grey literature search strategy.

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

Findings From the Literature

Only 1 study was identified from the literature for inclusion in the systematic review (Figure 1). The included study is summarized in Table 6. A list of excluded studies is presented in Appendix 4.

Figure 1: Flow Diagram for Inclusion and Exclusion of Studies

Description of Study

ASCENT (IMMU-132-05, N = 529)^11,12 was a phase III, randomized, OL, multi-centre study funded by Immunomedics (acquired in 2020 by the sponsor, Gilead Sciences). The primary objective of the study was to compare the efficacy of sacituzumab govitecan (10 mg/kg) with chemotherapy (TPC) in prolonging PFS among adult patients with locally advanced TNBC or mTNBC previously treated with at least 2 systemic chemotherapy regimens for unresectable locally advanced TNBC or mTNBC. Of note, the study enrolled a small number of patients with locally advanced disease who had not received prior therapy in the metastatic setting. According to the sponsor and clinical experts consulted for this review, the treatment approach for unresectable locally advanced TNBC and mTNBC is the same, and patients with unresectable locally advanced TNBC who had been treated previously in the same manner as a metastatic patient and received at least 2 lines of systemic therapy would be eligible to receive sacituzumab govitecan in accordance with the Health Canada indication. Patients (adults aged ≥ 18 years with unresectable locally advanced TNBC or mTNBC who had received at least 2 prior therapies) were enrolled from November 7, 2017, until September 2019 at 82 sites in Europe and North America (3 sites; n = 5 patients in Canada). Patients were screened for eligibility within 4 weeks of initiating protocol therapy to assess eligibility.

Patients were randomized 1:1, using an interactive web response system, to receive sacituzumab govitecan (10 mg/kg IV infusion) or TPC (1 of eribulin, capecitabine, gemcitabine, or vinorelbine). Patients with Grade 2 neuropathy were ineligible to receive vinorelbine. The randomization procedure was not explicitly stated. Randomization was stratified by number of prior therapies (2 to 3 versus > 3), BM status (BM-Pos versus BM-Neg), and region (North America versus rest of world). Baseline assessments (tumour imaging, HRQoL) were conducted within 4 weeks of starting protocol therapy. Patients were treated until progression requiring discontinuation of further treatment, unacceptable toxicity, study withdrawal, or death, whichever came first. Treatment was also discontinued due to treatment delay of more than 3 weeks for any reason, pregnancy, physician decision, or withdrawal of consent. The first determination of PD did not require treatment discontinuation if the patient still derived benefit from therapy in the opinion of the investigator (and if agreed by the sponsor). However, treatment was discontinued if subsequent imaging documented PD. Following treatment discontinuation, patients entered survival follow-up until study withdrawal, death, or data cut-off, whichever came first. Crossover was not permitted. The database was closed on March 11, 2020.

Populations

Inclusion and Exclusion Criteria

Key inclusion and exclusion criteria for the ASCENT study are summarized in Table 6. Adult patients (age ≥ 18 years) with unresectable locally advanced or metastatic (CT or MRI confirmed) TNBC (histologically or cytogenetically confirmed as per American Association for Clinical Oncology or College of American Pathologists criteria) were eligible if disease was either refractory or relapsed after at least 2 prior standard of care systemic chemotherapy regimens for unresectable locally advanced TNBC or mTNBC. Poly-(ADP-ribose) polymerase inhibitors qualified as 1 prior therapy for patients with BRCA mutations, and chemotherapy in the (neo)adjuvant setting for more limited disease qualified as 1 prior therapy if development of unresectable locally advanced TNBC or mTNBC occurred within 1 year of completing chemotherapy. Patients had to have previously received taxanes in the adjuvant, neoadjuvant, or advanced setting. Only patients with CT or MRI measurable disease according to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) and with ECOG Performance Status 0 or 1 were eligible, and for patients with baseline BM, brain MRI was required to show stable CNS disease. Other inclusion criteria were cessation of high-dose corticosteroids and prior cancer therapies, recovery from previous toxicities, eligibility for at least 1 TPC regimen, adequate hematological and organ function, and life expectancy of ≥ 3 months as judged by the investigator. Pregnant or lactating women and patients unwilling to use effective contraception were excluded, as were patients with Gilbert disease, HIV, hepatitis B virus, hepatitis C virus, active inflammatory bowel disease, and recent infections requiring antibiotic use. Patients with a history (≤ 6 months) of gastrointestinal disorders (bleeding, obstruction, or perforation), chronic obstructive pulmonary disease or other respiratory illness, or cardiac problems (unstable angina, myocardial infarction, congestive heart failure, or cardiac arrhythmia other than stable atrial fibrillation) were excluded. Patients had to be disease-free from prior malignancies — except for non-melanoma skin cancer and carcinoma of the cervix — for at least 3 years.

Baseline Characteristics

The baseline characteristics of participants in the ASCENT study are shown in Table 7. Nearly all patients were women. A total of 468 patients (88.5%) were BM-Neg, while 61 patients (11.5%) were BM-Pos. The mean (SD) age among the BM-Neg and the ITT populations was 54.1 (11.4) years and 54.0 (11.5) years, respectively. Most participants (63.7% of the BM-Neg population and 65.6% of the ITT set) were enrolled at sites in North America (US). Most participants were White (78.8% of the BM-Neg population and 79.0% of the ITT set) and not Hispanic or Latino (86.5% of the BM-Neg population and 87.0% of the ITT set). Baseline demographic characteristics were generally well balanced between study arms.

The baseline disease characteristics of participants in the ASCENT study are shown in Table 8. Approximately two-thirds of patients (68.8% of the BM-Neg population and 70.3% of the ITT set) were originally diagnosed with TNBC. The mean (SD) time from diagnosis of stage 4 TNBC to study entry was 21.44 (20.92) months in the BM-Neg population and 22.04 (20.768) months in the ITT set. Only 7.3% of the BM-Neg population and 8.1% of the ITT set were positive for either BRCA1 or BRCA2 mutations. Patients were roughly equally divided between ECOG Performance Status 0 (44.0% of the BM-Neg population and 43.3% of the ITT set) and ECOG Performance Status 1 (56.0% of the BM-Neg population and 56.7% of the ITT set). Approximately two-thirds of patients (70.5% of the BM-Neg population and 69.0% of the ITT set) had received 2 to 3 prior systemic chemotherapies, while approximately one-third had received more than 3 prior systemic chemotherapies. The mean (SD) number of prior systemic therapies received was 4.5 (2.1) in both the BM-Neg and the ITT populations. In addition to taxanes, most patients (82.1% of the BM-Neg population and 82.6% of the ITT set) had received cyclophosphamide, approximately two-thirds had received carboplatin (65.6% of the BM-Neg population and 64.8% of the ITT set), approximately two-thirds had received capecitabine (65.4% of the BM-Neg population and 66.9% of the ITT set), approximately half had received doxorubicin (51.9% of the BM-Neg population and 53.5% of the ITT set), approximately one-third had received eribulin (31.8% of the BM-Neg population and 32.7% of the ITT set), and approximately one-third had received gemcitabine (36.1% of both the BM-Neg and the ITT populations). Approximately one-fifth of patients had previously received investigational drugs (20.1% of the BM-Neg population and 20.4% of the ITT set). Approximately half of patients had received previous systemic chemotherapies in the adjuvant setting (57.5% of the BM-Neg population and 58.4% of the ITT set), approximately half had received previous systemic chemotherapies in the neoadjuvant setting (47.9% of the BM-Neg population and 47.1% of the ITT set), while nearly all had received previous systemic chemotherapies in the metastatic setting (97.6% of the BM-Neg population and 97.9% of the ITT set). A small number of patients (n = 12; 2.6% of the BM-Neg population and n = 15; 2.8% of the ITT set) had received previous systemic chemotherapies for locally advanced disease. Nearly all patients had received prior breast cancer–related surgery (94.9% of both the BM-Neg and ITT populations), most had received prior non-brain radiotherapy (81.4% of the BM-Neg population and 81.1% of the ITT set), and approximately one-quarter had received prior PD-1 or PD-L1 therapy (27.1% of the BM-Neg population and 28.9% of the ITT set).

Baseline disease characteristics were generally well balanced between study arms. Slightly higher proportions of patients in the TPC arm had previously received capecitabine (68.2% in the BM-Neg population and 69.8% in the ITT set) and gemcitabine (42.5% in the BM-Neg population and 40.5% in the ITT set) compared with patients in the sacituzumab govitecan arm (capecitabine: 62.6% in the BM-Neg population and 64.0% in the ITT set; gemcitabine: 29.8% in the BM-Neg population and 31.8% in the ITT set).

Interventions

Patients were randomized 1:1 to receive either sacituzumab govitecan or TPC. Because of the mixture of oral and IV therapies included in TPC, blinding was not possible. Both sacituzumab govitecan and TPC were administered by study personnel onsite; although not explicitly stated, capecitabine (orally twice daily for 2 weeks) was presumably self-administered. Sacituzumab govitecan was administered at a dose of 10 mg/kg based on data from the phase I/II IMMU-132-01 basket trial, suggesting that this dose had a similar safety profile to 8 mg/kg but was potentially associated with higher ORR.³⁵ Sacituzumab govitecan was administered as an IV infusion on day 1 and day 8 of a 21-day treatment cycle. For the initial sacituzumab govitecan infusion, the initial rate over the first 15 minutes was 50 mg/hour or less; this rate was increased every 15 minutes to 30 minutes by 50 mg/hour, to a maximum of 500 mg/hour. For subsequent sacituzumab govitecan infusions, the initial rate over the first 15 minutes was 100 mg/hour to 200 mg/hour; this rate was increased every 15 minutes to 30 minutes by 100 mg/hour to 200 mg/hour, to a maximum of 1,000 mg/hour.

Eribulin was administered by IV infusion over 2 minutes to 5 minutes at a dose of 1.4 mg/m² at North American sites and 1.23 mg/m² at European sites on day 1 and day 8 of a 21-day cycle. Lower doses were administered to patients with moderate hepatic impairment (Child-Pugh score, B; 0.7 mg/m² and 0.67 mg/m² for North American and European sites, respectively). Capecitabine (1,000 mg/m² to 1,250 mg/m²) was administered orally twice daily for 2 weeks, followed by a 1-week rest period, in a 21-day cycle. Gemcitabine (800 mg/m² to 1,250 mg/m²) was administered by IV infusion over 30 minutes on day 1, day 8, and day 15 of a 28-day cycle. Vinorelbine (25 mg/m²) was administered via weekly IV injections over 6 minutes to 10 minutes. For weekly vinorelbine administration, a cycle was defined as 3 weeks.

Disallowed concomitant medications included other anticancer therapy or chemotherapeutic agents, high-dose corticosteroids, and strong inhibitors or inducers of CYP3A4 (because of a known interaction with irinotecan). Palliative and/or supportive medications, such as bone-modifying medications (bisphosphonates or denosumab), and/or radiation and surgery were allowed at the investigator’s discretion. Hematopoietic growth factors and blood transfusions were permitted. Low-dose, stable doses of corticosteroids (≤ 20 mg prednisone or equivalent daily) were permitted for treatment of BM, as were topical steroids and corticosteroid inhalers.

Premedications administered as primary prophylaxis to prevent infusion reactions to sacituzumab govitecan included antipyretics as well as H₁ and H₂ blockers (antihistamines). For anaphylactic reactions, appropriate medical measures (e.g., epinephrine, antihistamines, hydrocortisone, IV fluids) were taken. Premedication with a combination regimen (e.g., dexamethasone with either a 5-HT3 receptor antagonist or an NK1 receptor antagonist, as well as other drugs as indicated) as primary prophylaxis to prevent as well as to treat chemotherapy- and sacituzumab govitecan–induced nausea and vomiting was strongly recommended. Premedications administered as secondary prophylaxis to prevent infusion reactions to sacituzumab govitecan included corticosteroids (50 mg hydrocortisone or equivalent). Appropriate premedication (e.g., atropine) was administered as secondary prophylaxis to patients who had an excessive cholinergic response to sacituzumab govitecan (e.g., abdominal cramping, diarrhea, salivation). Additional antiemetics, sedatives, and other supportive measures were administered as secondary prophylaxis if clinically indicated. Patients who experienced neutropenia were administered G-CSF for treatment and for secondary prophylaxis in subsequent infusions under the following conditions: Grade 4 neutropenia for at least 7 days; Grade 3 febrile neutropenia (absolute neutrophil count < 1,000/mm³; fever ≥ 38.5°C); or at time of scheduled treatment, Grade 3 or higher neutropenia which delays dose by 2 or 3 weeks for recovery to Grade 1 or lower neutropenia. Patients with diarrhea were treated with loperamide; additional supportive measures (fluid and electrolyte substitution) were used as clinically indicated.

The rules for sacituzumab govitecan therapy interruption, dose reduction, and discontinuation are shown in Table 9. Dose reductions for hematologic toxicity were implemented only after G-CSF was administered for treatment and as secondary prophylaxis in subsequent cycles. Patients on TPC could receive G-CSF per physician discretion, but this was not part of the recommended study protocol.

Outcomes

A list of efficacy end points identified in the CADTH review protocol that were assessed in the ASCENT study is provided in Table 10. These end points are further summarized below. A detailed discussion and critical appraisal of the HRQoL outcome measure used in the ASCENT study, EORTC QLQ-C30, is provided in Appendix 6. The EORTC QLQ-C30 has been extensively used in oncology trials and has demonstrated reliability, validity, and responsiveness to change in cancer patients, including patients with mTNBC. The consensus of several studies, including studies of patients with locally advanced TNBC and mTNBC, was that the minimally important difference (MID) on any of the instrument’s scales was approximately 5 points to 10 points.

During the treatment period (until PD or unacceptable toxicity), tumour response was assessed by CT or MRI at baseline, every 6 weeks for the first 9 months, and then every 9 weeks. BM-Pos patients underwent brain MRI at the same time points. For each patient, the same imaging modality was used to assess tumour response throughout the study. Confirmatory scans for responses observed before week 36 were obtained at the next assessment, while confirmatory scans for responses after week 36 were confirmed 36 weeks after the initial response. Patients who discontinued treatment due to toxicity continued with radiological response assessments at the protocol-required schedule until progression of disease or initiation of new therapy. Additional scans to assess disease status were performed at the discretion of the treating physician.

Designation of response was based on the response of target and non-target lesions and the appearance of any new lesions according to RECIST 1.1. PD was defined as a predefined increase (+ 20%) in the sum of target lesions or the appearance of new non-target lesions, taking as reference the smallest sum of target lesions for each patient during the study period. Partial response was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters of target lesions. Complete response was defined as the disappearance of all target lesions with reduction of the short axis of any pathological lymph nodes to less than 10 mm. Stable disease was defined as either sufficient shrinkage (compared with baseline) to qualify as partial response but not sufficient increase (taking as reference the smallest sum of diameters of target lesions while on study) to qualify as PD.

All imaging data were reviewed both by the investigator and by a blinded IRC consisting of 2 board-certified radiologists, with discrepancies evaluated by a third board-certified radiologist. Decisions to discontinue protocol therapy due to PD were made by the investigator based on local imaging scans; the decision could also be made to discontinue protocol therapy due to clinical progression, based on the judgment of the investigator, in the absence of radiological evidence. Clinical progression leading to patient discontinuation was also documented by CT or MRI scans of target lesions if possible.

The primary outcome was PFS by IRC assessment in the BM-Neg population, defined as time from randomization until PD or death, whichever came first. For patients who started other anticancer therapies before PD or death, PFS was censored at the last assessment before initiation of new therapy. PFS by IRC assessment in the ITT set was a secondary outcome, as was time to progression in both the BM-Neg population and the ITT set, defined as time from randomization until progression among patients with PD. OS was assessed as a secondary outcome in both the BM-Neg population and the ITT set and was defined as time from start of study treatment until death from any cause. Patients without documentation of death were censored at the last date known alive; OS was not censored for patients who initiated other anticancer therapies. ORR response rate (the proportion of patients with partial or complete responses according to RECIST 1.1) by IRC assessment was evaluated in both the BM-Neg population and the ITT set as a secondary outcome, as was time to response, defined as time from randomization until the first partial or complete response.

During the treatment period, HRQoL was assessed using the EORTC QLQ-C30 every 3 weeks (4 weeks for gemcitabine) on day 1 of each cycle. Following treatment discontinuation, survival follow-up occurred every 4 weeks (in person or by phone) to assess survival status and to document any subsequent anticancer therapy. Survival status was also documented from public databases if allowed by local regulations.

Harms outcomes included treatment-emergent AEs, SAEs, AEs requiring dose interruption or reduction, WDAEs, and AEs of special interest. All AEs that began or worsened on or after the start of protocol therapy until 30 days after the last dose of the study drug were captured. AE were defined as any untoward medical occurrence and were coded according to the Medical Dictionary for Regulatory Activities version 22.1 and graded according to Common Terminology Criteria for Adverse Events 4.03. Incidence was calculated at the system organ class and preferred term levels. SAEs were defined as an untoward medical occurrence that was life threatening, required inpatient hospitalization or prolongation of hospitalization, resulted in persistent or significant disability or incapacity, resulted in death, or was a congenital abnormality, or as another important medical event that required medical or surgical intervention to prevent these outcomes. Adverse events of special interest were defined as shown in Table 11 to capture all AE preferred terms considered to be potentially associated with sacituzumab govitecan treatment based on the results of the phase I/II IMMU-132-01 basket trial.³⁵ Clinical laboratory parameters, vital signs, and electrocardiograms were also monitored.

Statistical Analysis

Statistical analysis of efficacy outcomes in the ASCENT trial is summarized in Table 12. Type I error was controlled using a hierarchical testing strategy. In the 4-part hierarchy, differences in PFS by IRC assessment were tested first in the BM-Neg population. If significant, OS was tested in the BM-Neg population, followed by PFS by IRC assessment in the ITT set and then by OS in the ITT set. If fewer than 30 BM-Pos patients had been recruited, analyses in the ITT population would have been removed from the hierarchy. ORR and time to response were outside the statistical hierarchy and were evaluated in exploratory fashion.

For the primary PFS analysis, sample size was based on an HR of 0.667, corresponding to a 50% improvement in PFS, which was considered to represent a clinically meaningful improvement in this patient population. A planned interim analysis of PFS for futility was cancelled in communication with the FDA. Anticipated enrolment was 488 patients, with BM-Pos patients capped at 15% (n = 74). The primary PFS analysis would be performed when investigator-assessed PFS in 425 patients occurred in the ITT set, as long as IRC-assessed PFS had occurred in 315 or more patients in the BM-Neg population. It was assumed that a maximum of 15% of patients would be BM-Pos and that there would be 13% fewer IRC-assessed PFS events compared with investigator-assessed PFS. Given these parameters, if the true HR was 0.667 in the BM-Neg population, the study would have 95% power to detect a statistically significant improvement in PFS with a 2-sided type I error rate of 5%. Based on an average PFS estimate in this patient population of approximately 3 months in the TPC arm, and assuming a 24-month enrolment period, the primary PFS analysis would be performed after a minimum follow-up of approximately 4 months.

OS was planned to be analyzed at the time of the PFS analysis as well as after 330 deaths had occurred in the BM-Neg population. At the time of the interim OS analysis, this would yield approximately 89.5% power to detect improved OS in the BM-Neg population with a 2-sided type I error rate of 5%, assuming that 72% of the pre-specified 330 deaths (i.e., 238 deaths) had occurred and that there was a true HR of 0.7. A Lan-DeMets spending function that approximates O’Brien-Fleming stopping boundaries would be applied to the interim OS analysis.

The data monitoring committee reviewed available data when the first 95 patients were randomized and every 6 months thereafter. Following each review, the data monitoring committee made recommendations to either continue the study unchanged, to modify the study, or to terminate the study because of safety concerns. Following the meeting of March 27, 2020, the data monitoring committee recommended that the final data analysis be conducted. At this time, 302 of the 315 pre-specified PFS events and 316 of the 330 pre-specified OS events had occurred (96% for both outcomes in the BM-Neg population). The statistical analysis plan was amended to specify the number of PFS events that would be used for the final analysis and to adjust the 2-sided alpha level for the primary PFS analysis. During database cleaning, additional PFS and OS events occurred, and the originally targeted numbers of events were reached for both outcomes. Therefore, the alpha adjustment was not applicable.

For the primary analysis, PFS in the BM-Neg population was compared between the sacituzumab govitecan and TPC arms using a log-rank test stratified by randomization factors. HR and its 95% CI were based on a stratified Cox proportional hazards model, with “group” as the only covariate stratified by randomization factors. PFS was analyzed using the Kaplan-Meier (KM) method, with median PFS and its 95% CI determined by the Brookmeyer and Crowley method with log-log transformation. Milestone PFS rates at 6, 9, and 12 months were derived from KM estimates. PFS in the ITT set was analyzed using the same method.

Five sensitivity analyses of PFS in the BM-Neg and ITT population were conducted by modification of censoring rules (Table 13). In sensitivity analysis 1, objectively documented progression or death were not censored, regardless of the timing of events. In sensitivity analysis 2, the dates for censoring events were only at scheduled assessment dates. In sensitivity analysis 3, the dates of discontinuation, change of treatment, or second missed scheduled assessment were assigned as event dates. In sensitivity analysis 4, clinical progression without radiographic evidence was considered an event. In sensitivity analysis 5, the censoring rules for the primary PFS analysis were applied to the safety population.

OS and time to progression were analyzed in the BM-Neg population, and the ITT set as per the primary PFS analysis. Milestone OS rates at 12, 18, and 24 months were derived from KM estimates.

Subgroup analyses of PFS and OS were conducted for pre-specified subgroups (age < 65 versus ≥ 65 years; race; 2 to 3 versus > 3 prior therapies; region; original diagnosis of TNBC; prior breast cancer surgery; prior cancer radiotherapy; BRCA1 status; BRCA1 or BRCA2 status; prior PD-1 or PD-L1 use; Trop-2 status; baseline liver metastasis; UGT1A1 status), as per the primary analysis, but in exploratory fashion. Subgroup analyses of ORR were conducted for the same pre-specified subgroups. The study was not specifically powered to evaluate each stratum separately.

ORR was analyzed and compared between treatment arms using the Cochran-Mantel-Haenszel method stratified by randomization factors. Two-sided 95% CIs were calculated using the Clopper-Pearson exact method. A sensitivity analysis of ORR was conducted in the efficacy analyzable population, defined as randomized and treated patients who received at least 1 cycle of sacituzumab govitecan or TPC and had at least 2 post-baseline radiological assessments or only 1 post-baseline radiological assessment that was assessed as PD.

Time to response and HRQoL (EORTC QLQ-C30 scales and scores) were summarized using descriptive and summary statistics.

Analysis Populations

The screened population was defined as all patients who provided informed consent and participated in screening procedures to assess eligibility. The BM-Neg population was defined as patients without BM who were randomized to the stratum of no baseline BM. The ITT set was defined as all patients who were randomized (including BM-Neg and BM-Pos patients). The safety population was defined as all patients who received at least 1 dose of sacituzumab govitecan or TPC.

Results

Patient Disposition

In total, 730 patients were screened, of which 529 (72.5%) were randomized and 201 (27.5%) were screened but not randomized (Table 14). The proportion of patients who were screened but not randomized who were BM-Neg and BM-Pos was not provided. Reasons for screen failure were analyzed for the ITT set only and not in the BM-Neg population. The most frequent reasons for screen failure were lack of stable CNS disease for at least 4 weeks (26 of 201, 12.9%), inadequate renal and hepatic function (25 of 201, 12.4%), and absence of histologically or cytologically confirmed TNBC (24 of 210, 11.9%). The proportion of screen failures in which the reason for failure was unknown was at minimum 16.4% (33 of 201) but may have been much higher since reasons for screen failure were not provided on a per-patient basis.

Patient disposition in the ASCENT trial is summarized in Table 15. Among randomized patients, higher proportions received at least 1 dose of protocol therapy in the sacituzumab govitecan arm (97.0% in the BM-Neg population and 96.6% in the ITT set) than in the TPC arm (86.3% in the BM-Neg population and 85.5% in the ITT set), potentially because some patients in the TPC arm elected not to participate following randomization. Most patients randomized and treated eventually discontinued protocol therapy (88.5% of the BM-Neg population and 87.9% of the ITT set). The most common reason for treatment discontinuation was PD (78.0% of the BM-Neg population and 76.7% of the ITT set). Among patients who discontinued protocol therapy due to PD, a slightly higher proportion in the TPC arm were discontinued for clinical progression in the absence of radiological evidence (26 of 166 in the BM-Neg population and 28 out of 184 in the ITT set) than in the sacituzumab govitecan arm (24 out of 199 in the BM-Neg population and 24 out of 222 in the ITT set). Higher proportions of patients in the TPC arm discontinued treatment (7.3% in the BM-Neg population and 6.9% in the ITT set) and discontinued the study due to withdrawal of consent (9.9% in the BM-Neg population and 10.3% in the ITT set) compared with those in the sacituzumab govitecan arm (discontinued treatment: 1.7% of the BM-Neg population and 1.9% of the ITT set; discontinued study: 3.0% of the BM-Neg population and 3.0% of the ITT set). Only 1 patient (in the TPC arm) discontinued treatment due to unacceptable toxicity, and during the treatment phase, no patients were lost to follow-up.

Similar proportions of patients in the sacituzumab govitecan and TPC arms entered survival follow-up (78.7% and 81.1%, respectively, in the BM-Neg population; 79.8% and 80.2%, respectively, in the ITT set). The mean (SD) follow-up duration was longer in the sacituzumab govitecan arm (11.43 [5.87] months in the BM-Neg population and 11.06 [5.90] months in the ITT set) than in the TPC arm (7.26 [5.39] months in the BM-Neg population and 7.40 [5.51] months in the ITT set). Similar proportions of patients (approximately 5%) in both arms were lost to follow-up during survival follow-up. At the time of data cut-off, higher proportions of patients in the TPC arm had survival follow-up data collected at least 121 days prior (8.2% in the BM-Neg population and 8.0% in the ITT set) than those in the sacituzumab govitecan arm (2.6% in the BM-Neg population and 2.2% in the ITT set).

Protocol deviations in the ASCENT trial are shown in Table 16. Approximately one-third of patients in the ITT set had at least 1 important protocol deviation (34.5% in the sacituzumab govitecan arm and 39.7% in the TPC arm). Important protocol deviations related to informed consent were more common in the TPC arm (21.0%) than in the sacituzumab govitecan arm (10.9%). Important protocol deviations related to investigational products (primarily handling, storage, and retention of the study drug) were more common in the sacituzumab govitecan arm (6.0%) than in the TPC arm (0.4%).

Exposure to Study Treatments

Treatment exposure in the ASCENT trial safety population is shown in Table 17. Patients receiving sacituzumab govitecan had more than twice the exposure (mean = 5.77 [SD = 4.90] months, 8.5 [SD = 6.70] cycles) than those receiving eribulin (mean = 2.27 [SD = 2.18] months, 3.8 [SD = 2.97] cycles), capecitabine (mean = 2.16 [SD = 2.56] months, 3.3 [SD = 3.62] cycles), gemcitabine (mean = 2.25 [SD = 2.01] months, 3.0 [SD = 2.06] cycles), and vinorelbine (mean = 1.73 [SD = 2.31] months, 2.9 [SD = 2.97] cycles). Most protocol therapy was administered by study personnel at site visits, and thus adherence was not applicable. Although not explicitly stated, capecitabine was presumably self-administered, but no information on adherence was provided.

Concomitant medication use in the ASCENT trial is shown in Table 18. Higher proportions of patients in the sacituzumab govitecan arm received 1 or more concomitant medications (97.0% in the BM-Neg population and 96.6% in the ITT set) compared with those in the TPC arm (88.0% of the BM-Neg population and 87.0% of the ITT set). Medications used more often in the sacituzumab govitecan arm versus the TPC arm included (a) agents to prevent and treat infusion reactions (analgesics and antipyretics [76.2% versus 57.1% in the BM-Neg population; 74.5% versus 56.1% in the ITT set], corticosteroids [65.1% versus 35.2% in the BM-Neg population; 63.7% versus 35.1% in the ITT set], drugs for peptic ulcer and gastroesophageal reflux disease [67.7% versus 38.2% in the BM-Neg population; 67.0% versus 40.5% in the ITT set], and antihistamines [64.7% versus 15.9% in the BM-Neg population; 63.7% versus 16.4% in the ITT set]) and (b) agents to prevent and treat gastrointestinal symptoms (antiemetics and antinauseants [84.3% versus 53.2% in the BM-Neg population; 83.1% versus 53.8% in the ITT set] and antipropulsives [53.6% versus 9.9% in the BM-Neg population; 53.6% versus 8.8% in the ITT set]). Immunostimulants for secondary prophylaxis and treatment of myelosuppression were administered more frequently in the sacituzumab govitecan arm (46.4% of the BM-Neg population and 47.2% of the ITT set) than in the TPC arm (19.7% of the BM-Neg population and 19.8% of the ITT set).

Efficacy

Only those efficacy outcomes and analyses of subgroups identified in the review protocol are reported below. See Appendix 5 for detailed efficacy data.

Patients in the ASCENT trial were treated until PD or unacceptable toxicity. In the primary PFS analysis, censoring occurred at the time of data cut-off for patients who were still alive without PD or earlier for those who had no post-baseline tumour assessment, those who were lost to follow-up, those who withdrew consent, those who died or progressed after missing more than 1 assessment visit, or those who initiated other anticancer therapy before PD. In the OS analysis, censoring occurred at the time of data cut-off for patients who were still alive or earlier for those who were lost to follow-up or withdrew consent; however, OS was not censored at the time of initiating other anticancer therapy. Subsequent therapies were received following discontinuation of ASCENT trial protocol therapy in 47.6% of patients in the sacituzumab govitecan arm and 38.2% of patients in the TPC arm (Table 19). Specific therapies administered were similar for patients in both arms, except that more patients in the sacituzumab govitecan arm received eribulin (17.6% versus 3.8%).

OS: BM-Neg Population and ITT Set

OS by IRC assessment in the BM-Neg population and the ITT set is shown in Table 20, Figure 2, and Figure 3. Approximately two-thirds of patients in the sacituzumab govitecan arm (66.0% in the BM-Neg population and 67.0% in the ITT set) died during follow-up, while approximately 80% of patients in the TPC arm died (79.4% in the BM-Neg population and 78.6% in the ITT set). Median (95% CI) OS was 12.1 (10.7 to 14.0) months in the sacituzumab govitecan arm, compared with 6.7 (5.8 to 7.7) months in the TPC arm in the BM-Neg population, and 11.8 (10.5 to 13.8) months in the sacituzumab govitecan arm compared with 6.9 (5.9 to 7.7) months in the TPC arm in the ITT set. This difference in median OS based on tests of the KM curves was statistically significant by stratified log-rank test (P < 0.0001) in both the BM-Neg population and the ITT set. The statistical test for differences in OS for both the BM-Neg population and the ITT set were included as part of the statistical testing hierarchy in the ASCENT trial. The HR (95% CI) for death by stratified Cox regression analysis was 0.476 (0.383 to 0.592) in the BM-Neg population and 0.508 (0.414 to 0.624) in the ITT set, comparing the sacituzumab govitecan arm with the TPC arm. The percentage of patients alive at 6, 12, 18, and 24 months was higher in the sacituzumab govitecan arm (BM-Neg population: 82.4%, 50.7%, 30.5%, and not calculable, respectively; ITT set: 79.3%, 48.8%, 28.6%, and not calculable, respectively) than in the TPC arm (BM-Neg population: 54.9%, 22.2%, 12.3%, and 6.6%, respectively; ITT set: 55.4%, 23.0%, 12.9%, and 6.8%, respectively).

Figure 2: Overall Survival by IRC Assessment in the ASCENT Trial — BM-Neg Population

BM-Neg = brain metastasis–negative; CI = confidence interval; IMMU-132 = sacituzumab govitecan; IRC = independent review committee; TPC = treatment of physician’s choice.

Source: ASCENT Clinical Study Report.¹³

Figure 3: Overall Survival by IRC Assessment in the ASCENT Trial — ITT Population

CI = confidence interval; IMMU-132 = sacituzumab govitecan; IRC = independent review committee; ITT = intention to treat; TPC = treatment of physician’s choice.

Source: ASCENT Clinical Study Report.¹³

Three pre-specified subgroup analyses of OS in the ASCENT trial were of interest to this review (Appendix 5): BM at baseline (yes or no), prior therapies received (2 to 3 versus > 3) and BRCA1 or BRCA2 status. Among BM-Pos patients (n = 61), the median OS was 6.8 months in the sacituzumab govitecan arm and 7.5 months in the TPC arm (HR = 0.947; 95% CI, 0.523 to 1.716). Among patients in the ITT set who had received 2 to 3 prior therapies, the median OS was 12.1 months in the sacituzumab govitecan arm and 6.8 months in the TPC arm (HR = 0.442; 95% CI, 0.346 to 0.566). Among patients in the ITT set who had received more than 3 prior therapies, the median OS was 10.5 months in the sacituzumab govitecan arm and 7.6 months in the TPC arm (HR = 0.716; 95% CI, 0.501 to 1.022). Among BRCA1- or BRCA2-positive patients in the ITT set, the median OS was 15.6 months in the sacituzumab govitecan arm and 4.4 months in the TPC arm (HR = 0.411; 95% CI, 0.186 to 0.907); the number of BRCA1- or BRCA2-positive patients was small. Among BRCA1- or BRCA2-negative patients in the ITT set, the median OS was 10.5 months in the sacituzumab govitecan arm and 7.1 months in the TPC arm (HR = 0.595; 95% CI, 0.457 to 0.775).

HRQoL: Safety Population

HRQoL measured using the global health status or HRQoL scale of the EORTC QLQ-C30 at baseline and up to cycle 6 (n > 25 in both arms), as well as at the end of treatment, is shown in Table 21. The baseline mean global health status (on a scale of 0 to 100, with higher values signifying better HRQoL) was 61.9 (SD = 21.3) in patients treated with sacituzumab govitecan and 56.4 (SD = 22.2) in patients treated with TPC. Changes in global health status or HRQoL over time were smaller than the MID estimate of 5 points to 10 points.

Analysis of EORTC QLQ-C30 functional and symptom scales was consistent with the global health status scale (Appendix 5). Baseline values were generally slightly higher for functional scales and lower for symptom scales (indicating higher HRQoL) in the sacituzumab govitecan arm. Changes from baseline post-treatment suggested trends toward small improvements (or lesser deterioration compared with TPC) in physical functioning and role functioning, fatigue, pain, dyspnea, and insomnia. However, changes from baseline were also suggestive of worsening nausea and/or vomiting, as well as diarrhea, in patients treated with sacituzumab govitecan.

PFS: BM-Neg Population and ITT Set

PFS by IRC assessment in the BM-Neg population and the ITT set were the primary and key secondary outcomes in the ASCENT trial and are shown in Table 22, Figure 4, and Figure 5. Approximately 2-thirds of patients experienced events in both the sacituzumab govitecan arm (70.6% in the BM-Neg population and 71.2% in the ITT set) and the TPC arm (64.4% in the BM-Neg population and 65.3% in the ITT set). Among the approximately one-third of patients without events (censored), the most common reasons in the sacituzumab govitecan arm were alive without PD (15.7% in the BM-Neg population and 15.0% in the ITT set) and death after starting new anticancer therapy (11.5% in the BM-Neg population and 11.2% in the ITT set). In the TPC arm, the most common reasons for censoring were death after starting new anticancer therapy (20.2% in the BM-Neg population and 19.1% in the ITT set), lack of post-baseline tumour assessments (6.9% in the BM-Neg population and 7.6% in the ITT set), and death after missing more than 1 assessment visit (4.7% in the BM-Neg population and 4.2% in the ITT), while patients alive without PD were few (3.4% in both the BM-Neg population and the ITT set). Censoring of patients who died after starting new anticancer therapy applied to patients who were incorrectly deemed progressive by investigators and taken off protocol therapy in the absence of objective PD.

The median PFS was 5.6 (95% CI, 4.3 to 6.3) months in the sacituzumab govitecan arm, compared with 1.7 (95% CI,1.5 to 2.6) months in the TPC arm, in the BM-Neg population and 4.8 (95% CI, 4.1 to 5.8) months in the sacituzumab govitecan arm, compared with 1.7 (95% CI, 1.5 to 2.5) months in the TPC arm, in the ITT set. The differences in median PFS based on testing of the KM curves was statistically significant by stratified log-rank test (P < 0.0001) in both the BM-Neg population and the ITT set, and both statistical tests were adjusted for multiple comparisons under the hierarchical testing procedure. The HR (95% CI) for disease progression or death by stratified Cox regression analysis was 0.409 (95% CI, 0.323 to 0.519) in the BM-Neg population and 0.433 (95% CI, 0.347 to 0.541) in the ITT set, comparing the sacituzumab govitecan arm with the TPC arm. The percentage of patients alive and progression-free at 3, 6, 9, and 12 months was higher in the sacituzumab govitecan arm (BM-Neg population: 64.6%, 44.2%, 24.6%, and 17.2%, respectively; ITT set: 61.9%, 40.6%, 22.8%, and 16.2%, respectively) than in the TPC arm (BM-Neg population: 27.0%, 11.0%, 8.0%, and 6.7%, respectively; ITT set: 27.1%, 10.7%, 7.2%, and 6.0%, respectively).

Figure 4: Progression-Free Survival by IRC Assessment in the ASCENT Trial — BM-Neg Population

BM-Neg = brain metastasis–negative; CI = confidence interval; IMMU-132 = sacituzumab govitecan; IRC = independent review committee; PFS = progression-free survival; TPC = treatment of physician’s choice.

Source: ASCENT Clinical Study Report.¹³

Figure 5: Progression-Free Survival by IRC Assessment in the ASCENT Trial — ITT Population

CI: confidence interval; IMMU-132 = sacituzumab govitecan; IRC = independent review committee; ITT = intention to treat; PFS = progression-free survival; TPC = treatment of physician’s choice.

Source: ASCENT Clinical Study Report.¹³

Sensitivity analyses of PFS by IRC assessment were consistent with the primary analysis (Appendix 5). Three pre-specified subgroup analyses of PFS in the ASCENT trial were of interest to this review: BM at baseline (yes or no), prior therapies received (2 to 3 versus > 3) and BRCA1 or BRCA2 status. Among BM-Pos patients (n = 61), the median PFS was 2.8 months in the sacituzumab govitecan arm and 1.6 months in the TPC arm (HR = 0.682; 95% CI, 0.379 to 1.228). Among patients in the ITT set who had received 2 to 3 prior therapies, the median PFS was 5.4 months in the sacituzumab govitecan arm and 1.6 months in the TPC arm (HR = 0.393; 95% CI, 0.300 to 0.515). Among patients in the ITT set who had received more than 3 prior therapies, the median PFS was 4.2 months in the sacituzumab govitecan arm and 2.2 months in the TPC arm (HR = 0.533; 95% CI, 0.369 to 0.771). Among BRCA1- or BRCA2-positive patients in the ITT set, the median PFS was 7.4 months in the sacituzumab govitecan arm and 2.5 months in the TPC arm (HR = 0.421; 95% CI, 0.181 to 0.980); however, the number of BRCA1- or BRCA2-positive patients was small. Among BRCA1- or BRCA2-negative patients in the ITT set, the median PFS was 4.3 months in the sacituzumab govitecan arm and 1.6 months in the TPC arm (HR = 0.454; 95% CI, 0.341 to 0.605).

Time to Progression: BM-Neg Population and ITT Set

Time to progression among patients with PD by IRC assessment was a secondary end point in the ASCENT trial (not adjusted for multiple comparisons in the hierarchical testing structure) and is shown in Table 23. The median time to progression was 5.8 (95% CI, 4.8 to 6.9) months in the sacituzumab govitecan arm, compared with 2.1 (95% CI, 1.5 to 2.7) months in the TPC arm in the BM-Neg population and 5.6 (95% CI, 4.3 to 6.2) months in the sacituzumab govitecan arm, compared with 2.1 (95% CI, 1.5 to 2.8) months in the TPC arm, in the ITT set. The HR for progression by stratified Cox regression analysis was 0.406 (95% CI, 0.315 to 0.525) in the BM-Neg population and 0.429 (95% CI, 0.338 to 0.545) in the ITT set, comparing the sacituzumab govitecan arm with the TPC arm.

ORR: BM-Neg Population and ITT Set

ORR by IRC assessment was a secondary end point in the ASCENT trial (not adjusted for multiple comparisons in the hierarchical testing structure) and is shown in Table 24. The ORR was 34.9% (95% CI, 28.8% to 41.4%) in the sacituzumab govitecan arm versus 4.7% (95% CI,2.4% to 8.3%) in the TPC arm among the BM-Neg population and 31.1% (95% CI, 25.6% to 37.0%) versus 4.2% (95% CI, 2.1% to 7.4%) in the TPC arm among the ITT set. The odds ratio for response was 10.859 (95% CI, 5.590 to 21.095) in the BM-Neg population and 10.994 (95% CI, 5.659 to 21.358) in the ITT set, comparing sacituzumab govitecan with TPC. The proportion of patients in the sacituzumab govitecan arm achieving partial responses (BM-Neg population: 30.6%; ITT: 27.3%) was higher than that of patients in the TPC arm (BM-Neg population: 3.9%; ITT: 3.4%). The proportion of patients with stable disease was similar in the sacituzumab govitecan and TPC arms. Very few patients in either arm had complete responses.

Sensitivity analysis of ORR in the efficacy analyzable population was consistent with the primary analysis (data not shown). Three pre-specified subgroup analyses of ORR in the ASCENT trial were of interest to this review: BM at baseline (yes or no), prior therapies received (2 to 3 versus > 3) and BRCA1 or BRCA2 status. These analyses were uninformative due to the low number of responders in any of the strata.

Time to Response: BM-Neg Population and ITT Set

Time to response among patients with partial responses or complete responses by IRC assessment is shown in Table 25. Mean time to response was 2.67 (SD = 1.91) months in the sacituzumab govitecan arm, compared with 1.86 (SD = 0.92) months in the TPC arm, in the BM-Neg population and 2.66 (SD = 1.91) months in the sacituzumab govitecan arm, compared with 1.86 (SD = 0.92) months in the TPC arm, in the ITT set.

Harms

Only those harms identified in the review protocol are reported below. Refer to Table 26 for detailed harms data.

Adverse Events

Almost all patients treated with sacituzumab govitecan (99.6%) and TPC (97.8%) experienced at least 1 AE. Frequent AEs (≥ 30% in either arm) that were more common in patients receiving sacituzumab govitecan than in patients receiving TPC included diarrhea (sacituzumab govitecan: 65.1%; TPC: 17.0%), nausea (sacituzumab govitecan: 62.4%; TPC: 30.4%), fatigue (sacituzumab govitecan: 51.6%; TPC: 39.7%), alopecia (sacituzumab govitecan: 46.9%; TPC: 16.1%); neutropenia (sacituzumab govitecan: 42.6%; TPC: 25.4%), anemia (sacituzumab govitecan: 39.1%; TPC: 27.2%), constipation (sacituzumab govitecan: 37.2%; TPC: 23.2%), and vomiting (sacituzumab govitecan: 33.3%; TPC: 16.1%).

Serious Adverse Events

SAEs occurred in similar proportions of patients receiving sacituzumab govitecan (26.7%) and TPC (28.1%). Frequent SAEs (≥ 2% in either arm) that were more common in patients receiving sacituzumab govitecan than in patients receiving TPC included febrile neutropenia (sacituzumab govitecan: 5.0%; TPC: 1.8%), diarrhea (sacituzumab govitecan: 3.5%; TPC: 0%), and pneumonia (sacituzumab govitecan: 2.7%; TPC: 1.8%). Frequent SAEs that were more common in patients receiving TPC than in patients receiving sacituzumab govitecan included pyrexia (sacituzumab govitecan: 1.2%; TPC: 2.2%), dyspnea (sacituzumab govitecan: 0.8%; TPC: 3.1%), and pleural effusion (sacituzumab govitecan: 0.8%; TPC: 2.7%).

AEs Leading to Dose Interruption or Dose Reduction

AEs leading to study drug interruption were more common in the sacituzumab govitecan arm (62.8%) than in the TPC arm (38.8%). AEs leading to dose reduction occurred less frequently in the sacituzumab govitecan arm (21.7%) than in the TPC arm (26.3%).

Withdrawals Due to Adverse Events

AEs leading to discontinuation of protocol therapy occurred in similar proportions of patients receiving sacituzumab govitecan (4.7%) and TPC (5.4%).

Mortality

Most patients died due to PD either during protocol therapy or during survival follow-up. Deaths occurring within 30 days of last study drug treatment were considered deaths due to AEs. Deaths due to AEs occurred in 1 patient (0.4%) in the sacituzumab govitecan arm, who died from respiratory failure, and 3 patients (1.3%) in the TPC arm, who died from neutropenic sepsis, sepsis, and general physical health deterioration related to PD, respectively.

AEs of Special Interest

AEs of special interest occurred in almost all sacituzumab govitecan–treated patients (98.8%) and most (89.7%) TPC-treated patients.

Notable Harms

Several notable harms specified in the CADTH review protocol were more frequent in patients treated with sacituzumab govitecan than in patients treated with TPC. These included neutropenia (neutropenia, febrile neutropenia, and neutrophil count decreased) (sacituzumab govitecan: 65.1%; TPC: 44.2%); anemia (anemia and hemoglobin decreased) (sacituzumab govitecan: 39.1%; TPC: 27.7%); hypersensitivity (sacituzumab govitecan: 34.1%; TPC, 20.5%); and diarrhea (sacituzumab govitecan: 65.1%; TPC: 17.0%). Thrombocytopenia (thrombocytopenia, platelet count decreased) was more frequent in patients receiving TPC than in patients receiving sacituzumab govitecan (sacituzumab govitecan: 6.2%; TPC: 12.5%).

Among notable harms, Grade 3 neutropenia, Grade 4 neutropenia, and Grade 3 diarrhea occurred in more than 10% of patients treated with sacituzumab govitecan (48.4%, 17.8%, and 11.2% of patients, respectively) but lower proportions of patients treated with TPC. Among patients receiving sacituzumab govitecan, neutropenia and diarrhea were frequent causes of dose interruption (46.5% and 5.4% of patients, respectively) and dose reduction (10.9% and 4.7% of patients, respectively). Only 2 patients discontinued sacituzumab govitecan due to notable harms, 1 for diarrhea and 1 for thrombocytopenia.