CADTH Reimbursement Review

Trastuzumab deruxtecan (Enhertu)

Sponsor: AstraZeneca Canada Inc.

Therapeutic area: Unresectable or metastatic HER2-low breast cancer

This multi-part report includes:

Clinical Review

Pharmacoeconomic Review

Stakeholder Input

Clinical Review

Executive Summary

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

Table 1: Background Information of Application Submitted for Review

HR = hormone receptor; IHC = immunohistochemistry; ISH = in situ hybridization; NOC = Notice of Compliance.

Introduction

Breast cancer (BC) is the most common cancer affecting females in Canada. In 2022, 28,600 new cases and 5,500 cancer-related deaths due to BC in Canada were projected in women. Biological testing is standard for determining standard treatment alongside disease staging. BC was historically classified as HER2-positive or HER2-negative based on the evidence or absence of HER2 amplification and/or overexpression and/or amplification based on immunohistochemistry (IHC) or by in situ hybridization (ISH) or fluorescence in situ hybridization. HER2-negative BC was defined as IHC 0, 1+ or 2+ with a negative ISH result.^1,2 Now, IHC scores of 1+, or 2+ with a negative ISH result are defined as HER2-low BC. In Canada, prevalence estimates of HER2-low BC show that hormone receptor (HR)-positive disease is predominant (89%) compared to HR-negative disease (11%). Patients who have been historically classified as HER2-negative and HR-positive are recommended to receive first-line endocrine therapy (ET) in combination with a cyclin-dependant kinase (CDK) 4/6 inhibitor, upon progression; if refractory to ET, single-drug chemotherapy is recommended. In patients who have been historically classified as HER2-negative and HR-negative, the standard of care is sequential single-drug chemotherapy, with the addition of pembrolizumab depending on programmed death ligand 1 status.

The objective of CADTH’s Clinical Review Report is to review and critically appraise the clinical evidence submitted by the sponsor of the beneficial and harmful effects of trastuzumab deruxtecan (5.4 mg/kg IV every 3 weeks) for the treatment of unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH−) BC. The target population consists of adult patients who have received at least 1 prior line of chemotherapy in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant chemotherapy. Patients with HR-positive BC should have also received at least 1 ET and no longer be considered for further ET.

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 from 2 patient groups, Rethink Breast Cancer (Rethink) and the Canadian Breast Cancer Network (CBCN), were summarized for this CADTH review. Input from Rethink was based on meetings with BC patients and the results from an online survey of 78 patients with metastatic breast cancer (mBC) in Canada. Input received from the CBCN was obtained via online surveys that collected data from 50 patients who reported being metastatic HER2-negative before a reclassification of HER2-low. Both patient groups highlighted that disease symptom burden due to metastasis negatively affects patient quality of life noting that the disease restricts patient employment and career progress, their ability to care for children and dependents, and their ability to be social and meaningfully participate in their community. Both groups highlighted the importance of treatments that control disease progression (extend life) and manage cancer-related symptoms (improve quality of life).

Clinician Input

Input From Clinical Experts Consulted by CADTH

Two clinical experts with experience treating mBC highlighted the current unmet need for targeted therapies in the HER2-low population. The clinical experts agreed that standard outcome measures of treatment response, duration of response (DOR), survival statistics, toxicities, and quality of life measures are aligned with the outcomes used in current DESTINY-Breast04 clinical trial. The clinical experts suggested that trastuzumab deruxtecan be prescribed in a hospital setting or a specialty clinic that has the expertise and staffing to administer chemotherapy and monitor and manage treatment-related toxicities. An expert pathologist who was also consulted for the review indicated that, with increased awareness and adequate training, Canadian pathologists and oncologists will be able to correctly identify HER2-low patients.

Clinician Group Input

Input from 1 clinician group, the Ontario Health–Cancer Care Ontario (OH-CCO) Breast Cancer Drug Advisory Committee (DAC), was summarized for this review. The clinician group agreed broadly with the clinical experts consulted for this review; namely, the need for targeted treatments that patients can tolerate. The DAC also highlighted the need for access to interstitial lung disease (ILD) monitoring, a safety issue associated with the use of trastuzumab deruxtecan, and access to experts who can manage ILD in patients treated with trastuzumab deruxtecan.

Drug Program Input

The drug programs provide input on each drug being reviewed through CADTH’s reimbursement review processes by identifying issues that may affect their ability to implement a recommendation. The drug plans identified implementation issues related to relevant comparators, considerations for initiation, generalizability, funding algorithm, 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 drug plan’s implementation questions.

Clinical Evidence

Pivotal Studies and Randomized Controlled Trial Evidence

Description of Studies

DESTINY-Breast04 was a randomized, double-arm, phase III, open-label, multicentre trial to compare the safety and efficacy of trastuzumab deruxtecan versus the treatment of physician’s choice (TPC) in patients with HER2-low, unresectable, and/or mBC. A total of 557 patients were randomized in a 2:1 ratio to receive open-label treatment with trastuzumab deruxtecan or TPC. Randomization was stratified by HER2 IHC status of tissue samples assessed by a central laboratory (HER2 IHC 1+ versus HER2 IHC 2+/ISH−), number of prior lines of chemotherapy (1 versus 2), HR/CDK status (HR-positive mBC with prior CDK 4/6 inhibitor treatment versus HR-positive mBC without prior CDK 4/6 inhibitor treatment versus HR-negative mBC). The primary objective was to compare the progression-free survival (PFS) benefit of trastuzumab deruxtecan to that of TPC in a cohort of patients with HER2-low, HR-positive mBC, based on a blinded independent central review (BICR). Key secondary objectives were the PFS benefit of trastuzumab deruxtecan compared with TPC in all randomized patients regardless of hormone-receptor status (i.e., the full analysis set [FAS]) based on a BICR, the overall survival (OS) benefit of trastuzumab deruxtecan compared to TPC in patients with HER2-low, HR-positive mBC, and the OS benefit of trastuzumab deruxtecan compared to TPC in the FAS. The mean age in both cohorts of the FAS was 56.5 (standard deviation [SD] = 10.58 in the trastuzumab deruxtecan arm and 11.51 in the TPC arm). A small proportion of patients, 6.4% in the FAS trastuzumab deruxtecan arm and 4.3% in the FAS TPC arm, had baseline central nervous system (CNS) metastasis.

Efficacy Results

Overall Survival

In the HR-positive cohort, the median OS in the trastuzumab deruxtecan arm was 23.9 months (95% confidence interval [CI], 20.8 to 24.8) while in the TPC arm it was 17.5 months (95% CI, 15.2 to 22.4; P = 0.0028). The estimated hazard ratio comparing patients exposed to trastuzumab deruxtecan to patients on TPC was 0.64 (95% CI, 0.48 to 0.86).

In the FAS, the median OS in the trastuzumab deruxtecan arm was 23.4 months (95% CI, 20.0 to 24.8) while in the TPC arm it was 16.8 months (95% CI, 14.5 to 20.0; P value = 0.0010). The hazard ratio was 0.64 (95% CI, 0.49 to 0.84).

Health-Related Quality of Life

Health-related quality of life (HRQoL) results were available for the HR-positive cohort. According to the global health status parameter of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30), both treatment arms remained stable throughout the study. The mean baseline global health status was 36.26 (SD = 21.842) in the trastuzumab deruxtecan arm and 37.89 (SD = 22.511) in the TPC arm. Mean change from baseline was |||| |||||||| in the trastuzumab deruxtecan arm and |||| |||||||| in the TPC arm.

According to the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire updated breast cancer module (EORTC QLQ-BR45) (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire breast cancer module [EORTC QLQ-BR23]), the mean baseline breast symptoms scores were ||||| |||||||| in the trastuzumab deruxtecan arm and ||||| |||||||| in the TPC arm, and the mean changes from baseline were ||||| |||||||| and ||||| |||||||| in the trastuzumab deruxtecan and TPC arms, respectively.

According to the 5-Level EQ-5D (EQ-5D-5L) questionnaire, the mean baseline index scores were ||||| |||||||| in the trastuzumab deruxtecan arm and ||||| |||||||| in the TPC arm. Mean changes from baseline to end of treatment were |||||| |||||||| and |||||| |||||||| in the trastuzumab deruxtecan and TPC arms, respectively.

Progression-Free Survival

In the HR-positive cohort, the median PFS in the trastuzumab deruxtecan arm was 10.1 months (95% CI, 9.5 to 11.5) while in the TPC arm it was 5.4 months (95% CI, 4.4 to 7.1; P < 0.0001). The hazard ratio was 0.51 (95% CI, 0.40 to 0.64).

In the FAS, the median PFS in the trastuzumab deruxtecan arm was 9.9 months (95% CI, 9.0 to 11.3) while in the TPC arm it was 5.1 months (95% CI, 4.2 to 6.8; P < 0.0001). The hazard ratio was 0.50 (95% CI, 0.40 to 0.63).

Objective Response Rate

The objective response rate (ORR) of the 331 patients who received trastuzumab deruxtecan in the HR-positive cohort was 52.9% (95% CI, 47.3 to 58.4), 3.6% of whom experienced complete responses, while the 163 patients in the HR-positive cohort who received TPC had an ORR of 16.6% (95% CI, 11.2 to 23.2), 0.6% of whom experienced complete responses. In the FAS, the ORR of the 373 patients who received trastuzumab deruxtecan was 52.3% (95% CI, 47.1 to 57.4), 3.5% of whom experienced complete responses, while the 184 patients who received TPC had an ORR of 16.3% (95% CI, 11.3 to 22.5), 1.1% of whom experienced complete responses.

Duration of Response

In the 176 patients who received trastuzumab deruxtecan in the HR-positive cohort and recorded a complete or partial response, the median DOR was 10.7 months (95% CI, 8.5 to 13.7), compared to 27 patients in the TPC arm, with a median response of 6.8 months (95% CI, 6.5 to 9.9). In the FAS, the 196 patients in the trastuzumab deruxtecan arm who recorded a complete or partial response experienced a median DOR of 10.7 (95% CI, 8.5 to 13.2), compared to 30 patients in the TPC arm, with a median response of 6.8 months (95% CI, 6.0 to 9.9).

Harms Results

In total, 99.5% of patients in the trastuzumab deruxtecan arm and 98.3% of patients in the TPC arm reported at least 1 adverse event (AE). Serious adverse events (SAEs) of any grade were reported in 27.8% of patients in the trastuzumab deruxtecan arm and 25% of patients in the TPC arm. AEs leading to treatment discontinuation were reported in 16.2% of patients receiving trastuzumab deruxtecan and 8.1% in the TPC arm. Overall, 39.9% of patients in the trastuzumab deruxtecan arm and 51.2% of patients in the TPC arm had died by the January 11, 2022, data cut-off. The most common reasons leading to death in both arms were disease progression and AEs.

ILD and/or pneumonitis and left ventricular dysfunction were AEs of special interest and were more common in the trastuzumab deruxtecan arm (12.1% and 4.6%, respectively) compared to the TPC arm (0.6% and 0%, respectively).

Table 2: Summary of Key Results from Pivotal Studies and RCT Evidence

BICR = blinded independent central review; CDK = cyclin-dependent kinase; CI = confidence interval; CR = complete response; EORTC QLQ-BR23 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire breast cancer module; EORTC QLQ-BR45 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire updated breast cancer module; EORTC QLC-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; EQ-5D-5L = 5-Level EQ-5D; HR = hormone receptor; NE = not estimable; PR = partial response; RCT = randomized controlled trial; SD = standard deviation.

Note: Data cut-off: January 11, 2022.

^aBased on HR-positive cohort: trastuzumab deruxtecan group N = 331 and treatment of physician’s choice group N = 163.

^bMedian PFS or OS was from KM analysis. The CI for medians was computed using the Brookmeyer-Crowley method.

^cTwo-sided P value from a stratified log-rank test, included in the hierarchical testing structure. The prespecified interim analysis efficacy stopping boundary was 0.00748 (information fraction 59.8%).

^dHazard ratio and 95% CI from a stratified Cox proportional hazards model with stratification factors: HER2 status, number of prior lines of chemotherapy, and HR/CDK status as defined by an interactive web/voice response system.

^eHRQoL data have been updated since publication of the DESTINY-Breast04 Clinical Study Report. Following a data check, an update was made to how the last assessment/deterioration was programmed. As such, these data are reflective of the time to definitive deterioration data.

^fNot included in the hierarchical testing structure.

^gTwo-sided P value from a stratified log-rank test, included in the hierarchical testing structure.

^hBased on Clopper-Pearson method for single proportion and for the difference of 2 proportions with continuity correction.

ⁱTwo-sided P value based on a Cochran-Mantel-Haenszel test adjusted for stratification factors: HER2 status, number of prior lines of chemotherapy, HR/CDK status as defined by an interactive web/voice response system. Not included in the hierarchical testing structure.

^jMedian was from a Kaplan-Meier estimate. The CI for medians was computed using the Brookmeyer-Crowley method.

Source: DESTINY-Breast04 Clinical Study Report.³

Critical Appraisal

Patients in the DESTINY-Breast04 trial were randomized according to appropriately chosen stratification factors. Stratification was based on an interactive voice/web response system (IXRS) at the time of randomization, which differed from the electronic data capture, which corrected for mis-stratification at randomization. The overall number of patients who were mis-stratified with regard to HR status in the primary analysis was low and the impact on the conclusions of the trial was likely small. Primary and secondary end points were tested in a hierarchical sequence. OS analysis allowed for early stopping at the interim analysis. Early stopping rules preserve type I error rates of the OS significance test, but increase the possibility of overestimating the benefits. The open-label design may have resulted in an informative censoring mechanism in which certain patients exited the study before the first postbaseline tumour assessment. In the FAS analysis of PFS, 8.2% of patients in the TPC arm were censored due to the absence of a postbaseline tumour assessment, compared to only 0.8% in the trastuzumab deruxtecan arm. A post hoc sensitivity analysis was conducted to assess the impact of an alternative censoring strategy in which patients with no postbaseline tumour assessment are assumed to have not experienced a progression event until the end of the study. Results of this post hoc sensitivity analysis were consistent with those of the primary analysis.

The DESTINY-Breast04 study population was considered by the clinical experts consulted by CADTH to be representative and generalizable to the Canadian population. The investigated dose of trastuzumab deruxtecan was 5.4 mg/kg, IV, every 3 weeks, consistent with the expected Health Canada–approved dose. The clinical experts consulted for this report suggested that the basket of chemotherapies used for the TPC arm of the DESTINY-Breast04 study was appropriate and representative of Canadian practice.

Long-Term Extension Studies

No long-term extension studies were submitted as part of this review.

Indirect Comparisons

The sponsor provided a feasibility assessment for conducting an indirect treatment comparison (ITC) in the HR-negative population against the comparator sacituzumab govitecan. A network meta-analysis (NMA) was deemed infeasible due to the major differences in the clinical trial characteristics and small number of patients included. A matching adjusted indirect comparison (MAIC), while feasible, would likely produce biased and imprecise estimates due to the identified limitations.

Studies Addressing Gaps in the Pivotal and Randomized Controlled Trial Evidence

No studies addressing gaps were submitted as part of this review.

Conclusions

Evidence from the DESTINY-Breast04 trial showed statistically significant and clinically meaningful benefit in PFS and OS with trastuzumab deruxtecan 5.4 mg/kg every 3 weeks compared to TPC in patients with unresectable or metastatic HER2-low BC who have received at least 1 prior line of chemotherapy in the metastatic setting or who developed disease recurrence during or within 6 months of completing adjuvant chemotherapy. HRQoL was identified from patient input as a key end point important to patients. The evidence provided by the DESTINY-Breast04 study was not sufficient for drawing conclusions about HRQoL. An evidence gap remains for the relative efficacy comparison against sacituzumab govitecan in the HR-negative cohort of patients, although the cohort of patients for whom this comparison is relevant was small compared to the overall patient population. The clinical experts consulted for this review considered the safety profile of trastuzumab deruxtecan to be manageable and in line with their expectations.

Introduction

The objective of this report is to review and critically appraise the evidence submitted by the sponsor on the beneficial and harmful effects of trastuzumab deruxtecan, 100 mg, dosed at 5.4 mg/kg of body weight, administered by IV once every 3 weeks (21-day cycle) until disease progression or unacceptable toxicity.

Disease Background

The content of this section was informed by materials submitted by the sponsor and clinical expert input. The following have been summarized and validated by the CADTH review team.

BC is the most common cancer affecting females in Canada. In 2022, 28,600 new cases and 5,500 cancer-related deaths due to BC were projected in women according to the Canadian Cancer Statistics report.⁴ Among those assigned male at birth, 270 new cases and 55 cancer-related deaths were projected in the same year.⁴ Although BC is often detected at early stages (about 82% of cases in Canada are diagnosed at stage I and II⁵), 30% to 40% of patients diagnosed with early-stage and localized invasive disease progress to metastatic disease.^6-9 Symptoms commonly associated with metastatic disease include pain, fatigue, cognitive difficulties, and insomnia. Metastatic disease imposes financial burdens and limitations on activities of daily life,¹⁰ and significantly affects patients’ quality of life.¹¹

Biological marker testing (e.g., HER2 and HR status [i.e., progesterone receptor and estrogen receptor status, respectively]) is highly recommended at diagnosis in guidelines from the American Society of Clinical Oncology (ASCO) and College of American Pathologists (CAP) alongside disease staging, to facilitate treatment selection and disease management.¹² Historically, BC was classified as either HER2-positive or HER2-negative based on the evidence for or absence of HER2 amplification and/or overexpression and/or amplification based on IHC, ISH, or fluorescence in situ hybridization. HER2-negative BC was defined as IHC 0, 1+, or IHC 2+ with a negative ISH result.^1,2 Now, IHC scores of 1+ or 2+ with a negative ISH result are defined as HER2-low BC.

An estimated 80% to 85% of patients with BC are HER2-negative,^1,2 of whom 50% are HER2-low.^13,14 HER2-low distribution varies with HR-positive and HR-negative disease. In Canada, prevalence estimates of HER2-low BC show that HR-positive disease is predominant (89%) compared to HR-negative disease (11%).^4,15 Among cancers previously classified as HER2-negative and HR-positive BC, about 65% can now be classified as HER2-low, whereas among those previously classified as HER2-negative and HR-negative, about 37% can be now be classified as HER2-low.¹⁵ Estimates from the Alberta Health Service Registry show that about ||||| of patients diagnosed with BC in Canada (excluding Quebec) are HER2-negative,¹⁶ of whom 80.8% would be considered HER2-negative and HR-positive and 19.2% HER2-negative and HR-negative.¹⁵ The OS of HER2-negative patients varies based on HR status. The median OS for stage IV HER2-negative, HR-positive disease is approximately 35 months and only about 9 months for patients with stage IV HER2-negative and HR-negative disease.¹⁷ Patient survival also appears to decrease significantly postprogression on first-line and second-line treatments; the median OS reported in this group of patients is only about 15 months and the PFS is about 4 months.¹⁸

Other diagnostic methods used for detecting BC include blood tests, tissue biopsies, genetic testing, and imaging techniques (bilateral diagnostic mammogram, bone scan and X-ray, PET and CT scans, or ultrasound).

Standards of Therapy

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

Metastatic BC remains an incurable disease. The main goal of treatment includes extending survival and delaying progression of disease with minimal toxicity, while maintaining or improving HRQoL.^19,20 HER2-low has not been differentiated from tumours historically defined as HER2-negative; as such, patients with HER2-low tumours represent a subset of patients who would have historically been identified as HER2-negative, and current treatments align with those provided for patients with HER2-negative disease, which depends on the HR status of the tumour.

There are no Canada-specific guidelines for the treatment of BC. Oncologists in Canada typically follow guidance from international agencies, including the National Comprehensive Cancer Network (NCCN), ASCO, and the European Society of Medical Oncology. Guidelines for the management of HER2-negative mBC have been published by ASCO and NCCN for the US and by the European Society of Medical Oncology for Europe.^21-25

Patients that have been historically classified as HER2-negative and HR-positive are recommended to receive first-line ET in combination with a CDK 4/6 inhibitor (palbociclib or ribociclib). Upon progression, and if the treating physician expects further benefit, additional lines of ET can be offered. If the treating physician does not expect further benefit from ET (i.e., refractory), single-drug chemotherapy is recommended.

In patients historically classified as HER2-negative and HR-negative the standard of care is sequential single-drug chemotherapy, with the addition of pembrolizumab, depending on programmed death ligand 1 status. Standard options used are taxanes, platinum drugs, capecitabine, gemcitabine, anthracyclines, eribulin, and vinorelbine. An optimal treatment sequence has not been determined, and the treatment sequence varies by jurisdiction in Canada.²⁰ Recently, sacituzumab govitecan received a positive funding recommendation and has been approved for the treatment of adult patients with unresectable locally advanced or metastatic triple-negative BC who have received 2 or more prior therapies, with at least 1 for metastatic disease.²⁰ However, sacituzumab govitecan is currently the subject of negotiations with the pan-Canadian Pharmaceutical Alliance and is not yet widely available.

Drug Under Review

Key characteristics of trastuzumab deruxtecan are summarized in Table 3, along with other treatments available for unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH−) BC.

Trastuzumab deruxtecan, dosed at 5.4 mg/kg of body weight, is administered by IV, once every 3 weeks (21-day cycle), until disease progression or unacceptable toxicity. The approved Health Canada indication is for the treatment of adult patients with unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH−) BC who have received at least 1 prior line of chemotherapy in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant chemotherapy. Patients with HR-positive BC should have also received at least 1 prior line of ET and be no longer considered eligible for ET.

Trastuzumab deruxtecan is a HER2-targeted antibody-drug conjugate composed of a humanized anti-HER2 immunoglobin G1 monoclonal antibody and a topoisomerase I inhibitor conjugate. Trastuzumab deruxtecan binds to HER2 on tumour cells, undergoes internalization and intracellular linker cleavage by lysosomal enzymes that are upregulated in cancer cells, and inhibits the activity of topoisomerase I, thereby causing DNA damage and apoptotic cell death. Trastuzumab deruxtecan can cross the cellular membrane, killing neighbouring cells that may or may not express HER2 through a bystander effect.

Trastuzumab deruxtecan underwent a priority review via Project Orbis at Health Canada and received a Notice of Compliance on January 6, 2023. The sponsor’s reimbursement request aligns with the Health Canada indication.

Table 3: Key Characteristics of Trastuzumab Deruxtecan, Capecitabine, Eribulin, Gemcitabine, and Paclitaxel

5-fluorouracil 5-FU; BC = breast cancer; dFdCDP = difluoro-deoxycytidine metabolized intracellularly to active diphosphate; dFdCTP = difluoro-deoxycytidine metabolized intracellularly to active triphosphate; ET = endocrine therapy; IHC = immunohistochemistry; ISH = in situ hybridization; mBC = metastatic breast cancer.

^aHealth Canada–approved indication.

Sources: Trastuzumab deruxtecan product monograph,²⁶ capecitabine product monograph,²⁷ eribulin product monograph,²⁸ gemcitabine product monograph,²⁹ and paclitaxel product monograph.³⁰

Stakeholder Perspectives

Patient Group Input

This section was prepared by CADTH staff based on the input provided by patient groups. The full, original patient inputs received by CADTH have been included in the stakeholder section at the end of this report.

Input from 2 patient groups, Rethink and the CBCN, were summarized for this CADTH review. Rethink is a Canadian charity that educates, empowers, and advocates for system changes to improve the experience and outcomes of those with BC, focusing on historically underserved groups: people diagnosed at a younger age; those with mBC; and people systemically marginalized due to race, income, or other factors. The CBCN is a leading, patient-directed, national health charity committed to ensuring the best quality of care for all Canadians affected by BC through the promotion of information, education, and advocacy activities.

Input from Rethink was based on general observations and insights gathered through programming and meetings with BC patients and results from an online survey of 78 patients with mBC completed between September 2018 and April 2019, which documented the lived experience of patients and caregivers in Canada. Rethink also provided data from 2 patients in Canada and 1 patient living in the UK with HER2-low status receiving trastuzumab deruxtecan from a survey conducted in November 2022. Input received from the CBCN was obtained via online surveys (the CBCN’s 2017 Lived Experience Breast Cancer Patient Survey and the CBCN 2012 Metastatic Breast Cancer Patient and Caregiver Survey). No respondent in the CBCN survey had direct experience with trastuzumab deruxtecan. The CBCN collected survey data from 50 patients who reported being diagnosed with metastatic HER2-negative BC before the reclassification of HER2-negative into subgroups based on the presence of the HER2 gene, which includes HER2-low groups.

Both patient groups highlighted that disease symptom burden due to metastasis negatively affects patient quality of life. The Rethink group reported that younger patients with BC experience several challenges, experienced by younger patients with BC such as fertility or family-planning challenges, diagnosis during pregnancy, childcare, impact on relationships, body image, dating and sexuality, feeling isolated from peers who do not have cancer, career hiatuses, and financial insecurity. The CBCN group noted similar impacts of disease symptom and progression in mBC as the Rethink group, such as restrictions on patient employment and career, the ability to care for children and dependents, and the ability to be social and participate meaningfully in their community.

Regarding current treatment options available to patients with metastatic HER2-low disease who have progressed, the CBCN group noted that patients with metastatic HER2-low status have limited treatment line options as their disease progresses. Both groups generally expressed that patients diagnosed with mBC fear running out of treatment options (particularly patients with HER2-low metastatic disease, as there are limited lines of treatment), experience harsh side effects, and a have diminished quality of life. Rethink highlighted chemotherapy drugs such as eribulin, capecitabine, gemcitabine, nab-paclitaxel, and paclitaxel that are currently available to patients with HER2-low metastatic disease in Canada. Rethink noted that, although initial lines of therapy may provide a few months of PFS, survival decreases substantially with later lines of therapy.

Both groups emphasized the importance of treatments that control disease progression (extend life) and manage cancer-related symptoms (improve quality of life). Respondents in the CBCN survey noted that treatment effectiveness, the treatment’s ability to prolong life without sacrificing quality of life, side-effect management, cost, and treatment accessibility are important factors that influence their decisions when choosing treatments. Respondents in both groups expressed a willingness to tolerate toxicity-related effects and any impacts on their quality of life if the treatment could control their cancer.

Three respondents with HER2-low status interviewed by Rethink had experience with trastuzumab deruxtecan. The most common AEs noted by all 3 respondents were tiredness or fatigue and nausea. One of the 3 reported that “experiencing fatigue was worse than nausea.” Regarding stable disease or decrease in metastasis, both respondents interviewed in Canada reported stable disease or decreased metastasis following treatment with trastuzumab deruxtecan, while a third patient who lived in the UK and received trastuzumab deruxtecan via a clinical trial reported that they had stable disease for almost 1.5 years and had manageable side effects. The patient in the UK emphasized that fatigue and nausea were the most common events in the first couple of treatment cycles with trastuzumab deruxtecan. This patient also had sores and dry mouth, which eased off. The respondent reported experiencing a better quality of life, including freedom and the ability to work, while receiving trastuzumab deruxtecan.

Clinician Input

Input From Clinical Experts Consulted by CADTH

All CADTH review teams include at least 1 clinical specialist with expertise in the diagnosis and management of the condition for which the drug is indicated. Clinical experts are a critical part of the review team and are involved in all phases of the review process (e.g., providing guidance on the development of the review protocol, assisting in the critical appraisal of clinical evidence, interpreting the clinical relevance of the results, and providing guidance on the potential place in therapy). The following input was provided by 2 clinical specialists with expertise in the diagnosis and management of unresectable or mBC and 1 expert pathologist with experience in the diagnostic testing required for detections of HER2-low BC.

Unmet Needs

The clinical experts noted that, because no treatments are available for patients with HER2-low BC, these patients are treated as if they are HER2-negative. As such, there is an unmet need for treatments that target the HER2-low population. The expert explained that not all patients respond to available treatments and those that do respond will eventually progress. Patients who are HR-positive generally tolerate ETs; however, when they progress to chemotherapy, they experience increasing toxicities. The clinical experts noted that there is a need for therapies that are better tolerated by patients who progress in their disease.

Place in Therapy

The clinical experts suggested that trastuzumab deruxtecan would be used in alignment with the Health Canada indication and the design of the DESTINY-Breast04 trial. The clinical experts noted that most HR-positive patients would receive 1 to 2 lines of ET before receiving chemotherapy and then proceed to trastuzumab deruxtecan; however, if the treating physician anticipated that the patient would continue to benefit from ET, additional lines of ET could be offered. The clinical experts highlighted that the only time a patient with HR-positive BC would not receive ET in the first line is if the HR-positive signalling was low, mimicking an HR-negative status, or in a setting of visceral crisis. The clinical experts noted that, for patients with HR-negative disease, chemotherapy would be offered first, with trastuzumab deruxtecan offered as a second-line option. The clinical experts suggested that, for patients with HER2-low BC, trastuzumab deruxtecan may be preferred over sacituzumab govitecan in the second line, as the former is specifically targeted to the HER2 protein; however, there is no clear consensus on the sequencing of these drugs.

Patient Population

The clinical experts suggested that the patients most likely to benefit from treatment with trastuzumab deruxtecan would be those that meet the DESTINY-Breast04 study criteria. The clinical experts explained that patients suitable for treatment would be identified by the primary treating physician based on diagnosis, clinical examination (performance status), physician judgment about suitability of patient, and confirmation of clinical and/or radiographic disease progression after preceding lines of therapy. Given their advanced stage, an underdiagnosis is unlikely to occur. If it were to occur it would likely be a result of heterogeneity within tumours and receptor shift over time. The clinical experts noted that presymptomatic patients may undergo treatment to prevent cancer symptoms, or wait until they are more symptomatic to avoid treatment-related side effects but at the risk of fewer treatment options, adding that this is a clinical decision many patients and clinicians face in the real world. The clinical experts noted that there are no indicators that can be used to predict those most likely respond to trastuzumab deruxtecan; however, those who are HER2-negative (IHC 0) would not be expected to benefit.

Assessing the Response Treatment

The clinical experts reported that the outcomes used in the study were aligned with clinical practice. Responses are determined based on symptoms, laboratory markers, and radiographic scans, and tumour measurements, with scans usually performed at least every 3 months initially. Treatment is continued if the disease is either stable or responding radiographically according to Response Evaluation Criteria for Solid Tumours (RECIST) criteria. The clinical experts listed the following clinically meaningful responses:

• improvement in OS and/or PFS, noting specifically at least a 2- to 3-month survival advantage

• reduction in the frequency or severity of symptoms (e.g., pain, dyspnea)

• improvement of organ function (bone, liver, lung)

• stabilization and/or improvement of symptoms

• maintenance or improvement of performance status

• ability to maintain or increase activities of daily living

• tumour radiographic response with either stabilization of disease or response by RECIST criteria.

Discontinuing Treatment

The clinical experts listed disease progression, intolerable toxicity (ILD in particular), organ function no longer meeting treatment parameters, and patient refusal as reasons for discontinuing treatment.

Prescribing Considerations

The clinical experts suggested that trastuzumab deruxtecan be prescribed in a hospital setting or a specialty clinic that has the expertise and staff to administer chemotherapy and monitor and manage treatment-related toxicities. Treatment should be prescribed only by certified medical oncologists or an associated team physicians with expertise in cancer therapies and toxicity management.

Additional Considerations

According to the clinical experts, the benefits seen in the DESTINY-Breast04 trial are meaningful and valuable, particularly because no other therapy has demonstrated this magnitude of survival benefit in the HER2-low patient population. Given the limited treatment options and poor prognosis in those with metastatic and advanced BC, this drug would have increased uptake. The clinical experts suggested that the documented benefits commensurate with patient values and the toxicities are predictable and manageable by medical oncologists.

Clinician Group Input

This section was prepared by CADTH staff based on the input provided by clinician groups. The full original clinician group inputs received by CADTH are included in the stakeholder section at the end of this report.

Input from 1 clinician group, the OH-CCO DAC, was summarized for this review. The DAC provides timely evidence-based clinical and health system guidance on drug-related issues in support of OH-CCO’s mandate, including the Provincial Drug Reimbursement Programs and the Systemic Treatment Program. The DAC recognized needs not met by currently available treatments. The DAC pointed out that not all patients respond to available treatments, patients become refractory to current treatment options, and there are no available treatments to reverse the course of disease, creating a need for treatments that patients can better tolerate. The DAC anticipated that trastuzumab deruxtecan, if approved for public funding, could shift the currently used chemotherapy options to later lines of therapy for HER2-low patients. The DAC noted that there may be issues related to pathologic testing of specimens and identification of HER2-low status, adding that, although HER2 testing is routinely performed for all newly diagnosed BC patients, identification of the HER2-low subset of patients will require careful review by pathologists who are experts in BC. The group noted that treatment will likely be discontinued upon disease progression or treatment-related toxicity. The DAC also anticipated a need for access to ILD monitoring, a safety issue associated with the use of trastuzumab deruxtecan, and access to experts who can manage ILD for patients treated with trastuzumab deruxtecan. The DAC input generally aligns with that of the clinical experts consulted during the CADTH review.

Drug Program Input

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

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

BC = breast cancer; CDK = cyclin-dependent kinase; D5W = dextrose 5% in water; ECOG PS = European Cooperative Oncology Group Performance Status; ET = endocrine therapy; HR = hormone receptor; IHC = immunohistochemistry; ISH = in situ hybridization; mBC = metastatic breast cancer; PAG = provincial advisory group; pERC = pan-Canadian Oncology Drug Review Expert Review Committee.

Clinical Evidence

The objective of CADTH’s Clinical Review Report is to review and critically appraise the clinical evidence submitted by the sponsor of beneficial and harmful effects of trastuzumab deruxtecan (5.4 mg/kg every 3 weeks) for the treatment of unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH−) BC. The target population consists of adult patients who have received at least 1 prior line of chemotherapy in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant chemotherapy, patients with HR-positive BC should have also received at least 1 ET and no longer be considered for further ET. The focus will be placed on comparing trastuzumab deruxtecan to relevant comparators and identifying gaps in the current evidence.

A summary of the clinical evidence included by the sponsor in the review of trastuzumab deruxtecan is presented in 2 sections, and CADTH’s critical appraisal of the evidence is included after each section. The first section, the systematic review, includes pivotal studies and randomized controlled trials (RCTs) that were selected according to the sponsor’s systematic review protocol. The second section includes a summary of the indirect evidence from the sponsor.

Included Studies

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

• One pivotal study (RCT evidence)

• One feasibility assessment for conducting an ITC.

Pivotal Studies and Randomized Controlled Trial Evidence

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

Description of Studies

Characteristics of the included studies are summarized in Table 5.

DESTINY-Breast04 was a randomized, double-arm, phase III, open-label, multicentre trial to compare the safety and efficacy of trastuzumab deruxtecan versus TPC in patients with HER2-low, unresectable and/or mBC. The trial was initially designed to include only patients with HR-positive, HER2-low BC; however, after initial review of the DESTINY-Breast04 protocol by the FDA, a cohort of HR-negative, HER2-low patients was added given the high unmet need in the population with triple-negative BC (inclusive of HER2-low patients). Enrolment of HR-negative patients was capped at approximately 60 out of 540 patients (11.1%) to mimic the estimated proportion of patients with HR-negative disease in the general HER2-low population.

The primary objective was to compare the PFS benefit of trastuzumab deruxtecan to that of TPC in a cohort of patients with HER2-low, HR-positive mBC, based on a BICR. Key secondary objectives were to compare the PFS benefit of trastuzumab deruxtecan to that of TPC in all randomized patients regardless of hormone-receptor status (i.e., the FAS) based on a BICR, to compare the OS benefit of trastuzumab deruxtecan to that of TPC in patients with HER2-low HR-positive mBC, and to compare the OS benefit of trastuzumab deruxtecan to that of TPC in the FAS.

Table 5: Details of Pivotal Studies and RCT Evidence Identified by the Sponsor

ADC = antibody-drug conjugate; ASCO-CAP = American Society of Clinical Oncology–College of American Pathologists; BC = breast cancer; BICR = blinded independent central review; BOR = best overall response; CBR = clinical benefit rate; CDK = cyclin-dependent kinase; CR = complete response; DCR = disease control rate; DOR = duration of response; ECOG PS = Eastern Cooperative Oncology Group Performance Status; EORTC QLQ-BR23 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire breast cancer module; EORTC QLQ-BR45 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire modified breast cancer module; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; ET = endocrine therapy; HR = hormone receptor; IHC = immunohistochemistry; ILD = interstitial lung disease; ISH = in situ hybridization; mBC = metastatic breast cancer; mRECIST 1.1 = modified Response Evaluation Criteria in Solid Tumours Version 1.1; NCCN = National Comprehensive Cancer Network; ORR = objective response rate; OS = overall survival; PFS = progression-free survival; PFS2 = progression-free survival on the next line of therapy; PR = partial response; PR = partial response; RCT = randomized controlled trial; TPC = treatment of physician’s choice; TTR = time to response; ULN = upper limit of normal.

Note: Details from the table have been taken from the sponsor’s Summary of Clinical Evidence.

Source: DESTINY-Breast04 Clinical Study Report.³

Following screening, adult patients were enrolled from December 21, 2018, to December 31, 2021, and treated at 161 study sites, 2 of which were in Canada. A total of 557 patients were randomized in a 2:1 ratio to receive open-label treatment with trastuzumab deruxtecan or TPC. Randomization was stratified by HER2 IHC status of tissue samples assessed by a central laboratory (HER2 IHC 1+ versus HER2 IHC 2+/ISH−), number of prior lines of chemotherapy (1 versus 2), HR/CDK status (HR-positive mBC with prior CDK 4/6 inhibitor treatment versus HR-positive mBC without prior CDK 4/6 inhibitor treatment versus HR-negative mBC). The data cut-off for analyses was January 11, 2022.

Populations

Inclusion and Exclusion Criteria

Adult patients (18 years and older) with pathologically documented unresectable or mBC and a history of low HER2 expression according to the 2018 HER2 testing guidelines established by ASCO and CAP were eligible for the trial. Patients were excluded if they had received prior treatment with any drug identified as a TPC comparator in a metastatic setting or had a known contraindication to the treatment.

Interventions

Trastuzumab Deruxtecan Arm

Patients received trastuzumab deruxtecan dosed at 5.4 mg/kg of body weight, administered by IV, every 3 weeks (21-day cycle).

The initial dose of trastuzumab deruxtecan was calculated based on the patient’s body weight at screening. Dose recalculation was allowed at any point during the treatment if a patient’s weight changed by at least 10%.

Treatment of Physician’s Choice Arm

Patients received 1 of the following chemotherapy treatments under TPC, according to local or NCCN guidelines:

• Capecitabine: 1,000 mg/m² to 1,250 mg/m², orally, twice daily on days 1 to 14; cycled every 21 days

• Eribulin: 1.4 mg/m², IV, on days 1 and 8; cycled every 21 days

• Gemcitabine:

  • Option 1: 800 mg/m² to 1,200 mg/m², IV, on days 1 and 8; cycled every 21 days

  • Option 2: 800 mg/m² to 1,200 mg/m², IV, on days 1, 8, and 15; cycled every 28 days

• Paclitaxel:

  • Option 1: 175 mg/m², IV, on day 1; cycled every 21 days

  • Option 2: 80 mg/m², IV, on day 1 weekly

• Nab-paclitaxel:

  • Option 1: 260 mg/m², IV, cycled every 21 days

  • Option 2: 100 mg/m² or 125 mg/m², IV, on days 1, 8, and 15; cycled every 28 days.

Patients received trastuzumab deruxtecan or any chemotherapy treatment under the TPC arm, until disease progression, unacceptable toxicity, treatment delay of at least 28 days, withdrawal of consent, physician decision, or death, whichever occurred first.

Dose adjustments (interruptions or modifications, delay, and discontinuations) to manage drug-related toxicities of trastuzumab deruxtecan based on prespecified recommendations were outlined in the study protocol. Dose increases were not allowed for trastuzumab deruxtecan. Two dose reductions were allowed in the study (starting dose: 5.4 mg/kg; dose level 1: 4.4 mg/kg; and dose level 2: 3.2 mg/kg). Once a dose reduction due to toxicity was implemented for trastuzumab deruxtecan, all subsequent treatment cycles were administered at the lower dose, unless further dose reductions were required. A patient was permanently discontinued from the study drug if toxicity continued after 2 dose reductions. No dose re-escalations were allowed. Trastuzumab deruxtecan could be interrupted or delayed for up to 28 days from the planned date of administration. However, patients who required a dose delay of longer than 28 days were permanently discontinued from the study drug.

Dose adjustments for drugs under TPC were allowed and implemented in accordance with the local drug label guidelines in the country or in accordance with the NCCN guidelines for up to 28 days from the planned date of administration (49 days from the last infusion date). However, patients who required a dose delay longer than 28 days were permanently discontinued from the study drug and followed for survival.

Patients could withdraw from the trial for the following reasons: disease progression according to modified Response Evaluation Criteria in Solid Tumors Version 1.1 (mRECIST 1.1), clinical progression (definitive clinical signs of disease progression), AE, death, pregnancy, patient withdrew consent, patient lost to follow-up, protocol deviation reported, physician decision, and study termination by the sponsor or for other reason. Patients who discontinued study treatments were recommended to complete all protocol-specified withdrawal and follow-up procedures outlined in the study protocol.

Hematopoietic growth factors for prophylaxis or treatment were permitted at the investigator’s discretion (except within 1 week before screening), as well as prophylactic antiemetic drugs, bisphosphonates, or inhibitors of the receptor activator of nuclear factor kappa-beta ligand pathway.

Prohibited medications included other anticancer drugs such as chloroquine or hydroxychloroquine (if treatment with chloroquine or hydroxychloroquine was absolutely required for COVID-19, the study drug was required to be interrupted); radiotherapy (except for palliative radiation to known metastatic sites as long as it does not affect assessment of response or interrupt treatment for more than the maximum time specified in the dose-modification section); and chronic systemic (IV or oral) corticosteroids or other immunosuppressive medications (except drugs used to manage AEs).

Outcomes

A list of efficacy end points assessed in this clinical review report is provided in Table 6 and summarized in the following section. Included end points are based on those in the sponsor’s Summary of Clinical Evidence or identified as relevant according to clinical experts, clinician groups, or patient groups. Outcomes are presented in descending order of importance to patients, with the most important outcomes presented first.

The primary efficacy end point was PFS based on BICR, in patients with HR-positive BC. PFS was defined as the time from the date of randomization to the earliest date of the first objective documentation of radiographic disease progression via BICR according to mRECIST 1.1 or death due to any cause. Patients who were alive with no objective documentation of (radiographic) disease progression by the data cut-off date for PFS analysis were censored at the date of their last evaluable tumour assessment before the data cut-off. Patients were censored at the date of last evaluable tumour assessment if disease progression or death occurred after missing 2 or more consecutive scheduled tumour assessments or if they started a new anticancer therapy drug before progression or death.

The key secondary efficacy end points were:

• PFS, based on BICR, in all randomized patients (i.e., HER2-low HR-positive and HR-negative cohorts)

• OS in patients with HER2-low HR-positive mBC

• OS in all randomized patients, regardless of HR status.

OS was defined as the time from the date of randomization to the date of death due to any cause. If a death was not reported for a patient before the data cut-off for the OS analysis, OS was censored at the last contact date at which the patient was known to be alive.

Tumour response was assessed using mRECIST 1.1. Progressive disease was defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study); the sum must also demonstrate an absolute increase of at least 5 mm. A partial response was defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. A complete response was defined as disappearance of all target lesions with a reduction of the short axis of any pathological lymph nodes to less than 10 mm. Stable disease was defined as neither sufficient shrinkage (compared to baseline) to qualify for partial response nor sufficient increase (taking as reference the smallest sum diameters while on study) to qualify for progressive disease.

AEs that began or worsened on or after the start of study treatment until 47 days after the last dose of study drug were captured. AEs were defined as any untoward medical occurrence and were coded according to the Medical Dictionary for Regulatory Activities version 23.0³³ and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.³⁴

Table 6: Outcomes Summarized From Pivotal Studies and RCT Evidence Identified by the Sponsor

AESI = adverse event of special interest; BC = breast cancer; BICR = blinded independent central review; CR = complete response; DOR = duration of response; EORTC QLQ-BR23 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire breast cancer module; EORTC QLQ-BR45 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire updated breast cancer module; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; EQ-5D-5L = 5-Level EQ-5D; FAS = full analysis set; HR = hormone receptor; NA = not applicable; ORR = objective response rate; OS = overall survival; PFS = progression-free survival; PR = partial response; RECIST 1.1 = Response Evaluation Criteria in Solid Tumours Version 1.1; SAE = serious adverse event; TEAE = treatment-emergent adverse event.

Source: DESTINY-Breast04 Clinical Study Report.³

Patient-reported outcomes were also reported in the trial and included the following measures: EORTC QLQ-C30 and its BC module (EORTC QLQ-BR45 [QLQ-BR23]), as well as EQ-5D-5L. The EORTC QLQ-C30 and QLQ-BR45 (EORTC QLQ-BR23) were administered before infusion on day 1 of cycle 1, every 2 cycles thereafter, and at the end-of-treatment visit. Patients were followed up at day 40 (± 7 days) and at the first of the long-term survival follow-up visit 3 months after, which was the last data collection point for the questionnaires.

The EORTC QLQ-C30 is a multidimensional, cancer-specific, self-administered measure of HRQoL consisting of 30 questions across 5 multi-item functional scales, 3 multi-item symptom scales, 6 single-item symptom scales, and a 2-item global HRQoL scale; each item is evaluated using 4- and 7-point Likert scales, raw scores for each scale are computed as the average of the items that contribute to a particular scale, and each raw scale score is converted to a standardized score that ranges from 0 to 100 using a linear transformation, with a higher score reflecting better function on the function scales, worse symptoms on the symptom scales, and better HRQoL on the global quality-of-life scale.³⁵

The EORTC QLQ-BR23 consists of 23 questions related to quality of life, scored on a 4-point Likert scale (1 = not at all, 4 = very much). It is composed of questions citing the extent to which the patient has experienced symptoms or problems during the past week and during the past 4 weeks, separated into 4 functional scales (body image, sexual functioning, sexual enjoyment, future perspective), and 4 symptom scales (systemic therapy side effects, breast symptoms, arm symptoms, upset by hair loss). Time to definitive deterioration on the “breast symptoms” and “arm symptoms” subscales of the EORTC QLQ-BR45 were also assessed, with definitive deterioration defined as an increase (from baseline) of 10 points or more.³⁶

The EQ-5D-5L is a generic, preference-based measure of HRQoL consisting of 5 domains: mobility, self-care, usual activities, pain/discomfort, and anxiety and/or depression; index scores range from 0 to 1, with 0 and 1 representing the health states “dead” and “perfect health,” respectively, while EQ-5D Visual Analogue Scale (EQ VAS) scores range from 0 to 100, with 0 and 100 representing “worst imaginable health” and ”best imaginable health,” respectively.³⁷

Table 7: Summary of Outcome Measures and Their Measurement Properties

BC = breast cancer; CI = confidence interval; ECOG PS = European Cooperative Oncology Group Performance Status; EORTC QLQ-BR23 = Organisation for Research and Treatment of Cancer Quality of Life Questionnaire breast cancer module; EORTC QLQ-BR45 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire updated breast cancer module; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; EQ-5D-5L = 5-Level EQ-5D; EQ VAS = EQ-5D Visual Analogue Scale; HRQoL = health-related quality of life; ICC = intraclass correlation coefficient; ICF = International Classification of Functioning, Disability and Health; mBC = metastatic breast cancer; MID = minimal important difference.

Neither the measurement properties nor the minimal important difference (MID) of these instruments have been specifically established in patients with HER2-low mBC. However, differences in the EQ-5D-5L index score of approximately 0.037 to 0.056 in the general Canadian population, differences of approximately 7 to 12 points in the EQ VAS among advanced cancer patients, and differences of approximately 4 to 18 points in EORTC QLQ-C30 individual items and scale scores among patients with mBC are typically considered significant.^38-40 The MIDs for EORTC QLQ-BR23 individual items and scale scores are uncertain.

Statistical Analysis

Approximately 480 patients with HR-positive mBC were planned to be randomized (320 trastuzumab deruxtecan and 160 TPC). In addition, up to 60 patients with HR-negative mBC (approximately 40 trastuzumab deruxtecan and 20 TPC) were planned to be enrolled for exploratory purposes. A summary of the statistical analysis of efficacy end points is shown in Table 8.

For patients with HR-positive mBC, it was hypothesized that treatment with trastuzumab deruxtecan would result in a hazard ratio of 0.68 compared to TPC. This specified hazard ratio would correspond to a 47% improvement in hypothesized population median PFS from 4.2 months in the TPC arm to 6.2 months in the trastuzumab deruxtecan arm, if the PFS events are assumed to follow an exponential model. The final PFS analysis was to occur after approximately 318 PFS events had been documented in patients with HR-positive BC. If 318 PFS events occurred within the study, the study would have 90% power for a log-rank test to reject the null hypothesis of no difference in PFS distributions at an overall 2-sided significance level of 0.05, assuming a proportional hazards ratio of 0.68 and equal censoring distributions.⁴⁹

Statistical analysis of efficacy outcomes in the DESTINY-Breast04 trial were controlled for type I error by using a hierarchical testing strategy. The primary efficacy end point and the key secondary efficacy end points were tested hierarchically to maintain the overall 2-sided type I error rate of 0.05 or less, in the following order:

• PFS based on BICR in the HR-positive cohort

• PFS based on BICR in the FAS

• OS in the HR-positive cohort (up to 3 analyses)

• OS in the FAS (up to 3 analyses).

The statistical testing for a key secondary end point was performed only when the analyses in the hierarchy above that end point demonstrated statistical significance.

Up to 3 analyses (2 interim analyses and a final analysis) of OS were planned:

• Provided PFS was significant in both the HR-positive cohort and the FAS, the first interim analysis comparing the trastuzumab deruxtecan and TPC arms was planned at the time of the final analysis for PFS, at which point a total of 162 OS events (49% information fraction) in the HR-positive cohort were expected.

• If the first OS interim analysis was not significant, a second interim analysis for OS was planned when approximately 233 OS events (70% information fraction) in the HR-positive cohort had been documented.

• If the second OS interim analysis was not significant, a final analysis for OS was planned after approximately 333 OS events in the HR-positive cohort had been documented.

A 3-look Lan-DeMets alpha spending function with an O’Brien-Fleming–type stop boundary was used to construct the efficacy stopping boundaries with an overall 2-sided significance level of 0.05. To control for multiplicity the statical plan allowed for stopping boundaries derived separately for the HR-positive cohort and the FAS based on the actual number of OS events documented at the cut-off date, and the actual information fractions and the alpha already spent at the previous interim analyses (if the first testing of OS was not significant).

Table 8: Statistical Analysis of Efficacy End Points

BICR = blinded independent central review; CDK = cyclin-dependent kinase; CI = confidence interval; CNS = central nervous system; DOR = duration of response; ECOG PS = European Cooperative Oncology Group Performance Status; EORTC QLQ-BR23 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire breast cancer module; EORTC QLQ-BR45 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire updated breast cancer module; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; EQ-5D-5L = 5-Level EQ-5D; ET = endocrine therapy; FAS = full analysis set; HR = hormone receptor; KM = Kaplan-Meier; mBC = metastatic breast cancer; ORR = objective response rate; OS = overall survival; PFS = progression-free survival.

^aThis censoring rule was used for sensitivity analysis.

Source: DESTINY-Breast04 Statistical Analysis Plan.⁴⁹

Analysis Populations

Table 9 summarizes the analysis populations in the DESTINY-Breast04 trial. The HR-positive cohort included all HR-positive patients randomized into the study, while the FAS included all patients randomized into the study regardless of hormone status.

Table 9: Analysis Populations of DESTINY-Breast04

HR = hormone receptor.

Note: Details from the table have been taken from the sponsor’s Summary of Clinical Evidence.

Source: DESTINY-Breast04 Clinical Study Report.³

Results

Patient Disposition

A summary of the patient disposition in the DESTINY-Breast04 trial is provided in Table 10. In the FAS |||| of patients randomized to TPC were randomized but not treated compared to |||| of patients in the trastuzumab deruxtecan group. The most common reason for discontinuation beyond disease progression was an AE, with 16.2% of patients in the FAS receiving trastuzumab deruxtecan discontinuing treatment compared to 8.1% of patients in the FAS TPC arm. At the time of data cut-off in the FAS, 15.6% of patients in the trastuzumab deruxtecan arm were receiving treatment compared with 1.7% of patients in the TPC arm.

Baseline Characteristics

Baseline characteristics are summarized in Table 11. Characteristics were well balanced between treatment groups in both the HR-positive cohort and the FAS, including the IXRS stratification factors of HER2-low status, HR/previous CDK 4/6 inhibitor, and number of prior lines of chemotherapy in the metastatic setting. The mean age in both cohorts of the FAS was 56.5 (SD = 10.58 in the trastuzumab deruxtecan arm and 11.51 in the TPC arm). A small proportion of patients had baseline CNS metastasis: 6.4% in the FAS trastuzumab deruxtecan arm and 4.3% in the FAS TPC arm. The proportion of patients who had received prior lines of chemotherapy in any setting differed slightly, with 24.9%, 47.2%, and 27.9% of patients in the FAS trastuzumab deruxtecan arm having received either 1, 2, or 3 prior lines of chemotherapy, respectively, while in the FAS TPC arm the proportions were 28.3%, 38.6%, and 32.6%.

Table 10: Summary of Patient Disposition from Pivotal Studies and RCT Evidence Submitted by the Sponsor

RECIST 1.1 = Response Evaluation Criteria in Solid Tumours Version 1.1; SD = standard deviation; TPC = treatment of physician’s choice.

^aStudy duration for a patient (months) was defined as (date of last known alive minus date of randomization plus 1)/365.25 × 12.

^bThe percentage was based on the safety analysis set.

Source: DESTINY-Breast04 Clinical Study Report.³

Table 11: Summary of Baseline Characteristics of Pivotal Studies and RCT Evidence Submitted by the Sponsor

CDK = cyclin-dependent kinase; CNS = central nervous system; ECOG = Eastern Cooperative Oncology Group Performance Status; EDC = electronic data capture; ET = endocrine therapy; IHC = immunohistochemistry; IXRS = interactive web/voice response system; ISH = in situ hybridization; TPC = treatment of physician’s choice.

^aHR (based on factors from EDC): Positive = estrogen receptors negative and progesterone receptors positive; estrogen receptors positive and progesterone receptors negative; estrogen receptors positive and progesterone receptors positive; estrogen receptors positive and progesterone receptors indeterminate; estrogen receptors indeterminate and progesterone receptors positive. Negative = estrogen receptors negative and progesterone receptors negative. Indeterminate = estrogen receptors negative and progesterone receptors indeterminate; estrogen receptors indeterminate and progesterone receptors negative; estrogen receptors indeterminate and progesterone receptors indeterminate. Data presented here are based on EDC. Data from IXRS could not be modified. The derived data in EDC captured the correct status.

Sources: DESTINY-Breast04 Clinical Study Report³

Exposure to Study Treatments

Treatment exposure in the safety analysis set in the DESTINY-Breast04 study is summarized in Table 12. The mean treatment duration in the trastuzumab deruxtecan arm was ||| |||||| months while in the TPC arm it was ||| |||||| months. The mean relative dose intensity was ||||| |||||| in the trastuzumab deruxtecan arm and ranged from ||||| and |||||| across the individual chemotherapy regimens included in the TPC basket.

Table 13 summarizes the subsequent therapies received by patients in the DESTINY-Breast04 study in the FAS. In the trastuzumab deruxtecan arm, ||||| of patients received subsequent therapy with chemotherapy ||||||| representing the most common subsequent therapy. In the TPC arm, ||||| of patients received subsequent therapy with chemotherapy ||||||| representing the most common subsequent therapy.

Efficacy

Overall Survival

OS results in the HR-positive cohort are summarized in Table 14. The median OS values were 23.9 months (95% CI, 20.8 to 24.8) in the trastuzumab deruxtecan arm and 17.5 months (95% CI, 15.2 to 22.4; P = 0.0028) in the TPC arm. The estimated hazard ratio comparing patients exposed to trastuzumab deruxtecan to patients on TPC was 0.64 (95% CI, 0.48 to 0.86). The proportions of patients alive at 12 months were 80.7% (95% CI, 76.0% to 84.6%) in the trastuzumab deruxtecan arm and 69.6% (95% CI, 61.3% to 76.4%) in the TPC arm. The OS Kaplan-Meier curves for the HR-positive cohort are shown in Figure 1.

Table 12: Summary of Patient Exposure From the Safety Analysis Set in DESTINY-Breast04

SD = standard deviation.

Note: Units for drugs are mg/kg (transtuzumab deruxtecan), mg/m² (capecitabine, gemcitabine, paclitaxel, nab-paclitaxel), and mg/m² (eribulin, where 1.23 mg eribulin base = 1.4 mg eribulin mesylate). 1 month = 365.25/12 = 30.44 days. Treatment duration (months) = (date of last dose – date of first dose) + a cycle length (days)/30.44. Total patient-years of exposure = sum of treatment duration (days) of all patients (months)/12. Dose intensity (units/cycle length in weeks) = cumulative dose level (units)/(duration of treatment [days]/cycle length [days]). Relative dose intensity (%) = dose intensity/planned dose intensity × 100, where planned dose intensity (units/cycle lengths in weeks) = planned cumulative dose (units)/planned duration of exposure (days)/cycle length in day. Due to different cycle durations among the individual chemotherapy treatments, dose intensity and relative dose intensity are not presented for the overall chemotherapy arm.

Source: DESTINY-Breast04 Clinical Study Report.³

Table 13: Summary of Subsequent Treatment From Pivotal Studies and RCT Evidence Submitted by the Sponsor

RCT = randomized controlled trial.

Note: Details from the table have been taken from the sponsor’s Summary of Clinical Evidence.

Source: DESTINY-Breast04 Clinical Study Report.³

Table 14: Analysis of Overall Survival in the HR-Positive Cohort

CDK = cyclin-dependent kinase; CI = confidence interval; HR = hormone receptor.

Note: Data cut-off: January 11, 2022.

^aMedian OS was from Kaplan-Meier analysis. The CI for medians was computed using the Brookmeyer-Crowley method.

^bTwo-sided P value from stratified log-rank test, included in the hierarchical testing structure. The prespecified interim analysis efficacy stopping boundary was 0.00748 (information fraction 59.8%).

^cHazard ratio and 95% CI from a stratified Cox proportional hazards model with stratification factors: HER2 status, number of prior lines of chemotherapy, and HR/CDK status as defined by an interactive voice/web response system.

^dEstimate and CI for OS rate at the specified time point were from Kaplan-Meier analysis.

Source: DESTINY-Breast04 Clinical Study Report.³

Figure 1: Kaplan-Meier Plot of Overall Survival by Treatment Arm in the Hormone Receptor–Positive Cohort

CI = confidence interval; HR = hazard ratio; T-DXd = trastuzumab deruxtecan; TPC = treatment of physician’s choice.

Note: Stratified Cox proportional hazards model for hazard ratio and stratified log-rank test for the P value. Prespecified interim analysis efficacy stopping boundary was 0.00748 (information fraction 59.8%).

Source: DESTINY-Breast04 Clinical Study Report³

OS results in the FAS are summarized in Table 15. The median OS in the trastuzumab deruxtecan arm was 23.4 months (95% CI, 20.0 to 24.8) while in the TPC arm it was 16.8 months (95% CI, 14.5 to 20.0; P value = 0.0010). The hazard ratio was 0.64 (95% CI, 0.49 to 0.84). The proportions of patients alive at 12 months were 78.8% (95% CI, 74.3% to 82.7%) in the trastuzumab deruxtecan arm and 66.5% (95% CI, 58.8% to 73.2%) in the TPC arm. The OS Kaplan-Meier curves for the FAS cohort are shown in Figure 2.

Table 15: Analysis of Overall Survival in the Full Analysis Set

CDK = cyclin-dependent kinase; CI = confidence interval; HR = hormone receptor.

Note: Data cut-off: January 11, 2022.

^aMedian overall survival was from a Kaplan-Meier analysis. The CI for medians was computed using the Brookmeyer-Crowley method.

^bTwo-sided P value from stratified log-rank test, included in the hierarchical testing structure. Prespecified interim analysis efficacy stopping boundary was 0.00748 (information fraction 59.8%).

^cHazard ratio and 95% CI from a stratified Cox proportional hazards model with stratification factors: HER2 status, number of prior lines of chemotherapy, and HR/CDK status as defined by an interactive voice/web response system.

^dEstimate and CI for overall survival at the specified time point were from a Kaplan-Meier analysis.

Source: DESTINY-Breast04 Clinical Study Report.³

Figure 2: Kaplan-Meier Plot of Overall Survival by Treatment Arm in the Full Analysis Set

CI = confidence interval; HR = hazard ratio; T-DXd = trastuzumab deruxtecan; TPC = treatment of physician’s choice.

Note: Stratified Cox proportional hazards model for the hazard ratio and a stratified log-rank test for the P value. The prespecified interim analysis efficacy stopping boundary was 0.00748.

Source: DESTINY-Breast04 Clinical Study Report.³

Overall Survival in the HR-Negative Cohort (Exploratory End Point)

OS in the HR-negative cohort was an exploratory outcome; the reported results are from an electronic data capture, unlike the methodology used for the primary analysis. Using the electronic data capture, 40 patients in the trastuzumab deruxtecan arm were classified as HR-negative and 18 patients in the TPC arm were classified as HR-negative. The median OS values in the HR-negative cohort were 18.2 months (95% CI, 13.6 to not evaluable) in the trastuzumab deruxtecan group and 8.3 months (95% CI, 5.6 to 20.6) in the TPC group (hazard ratio = 0.48; 95% CI, 0.24 to 0.95).

Subgroup Analysis of Overall Survival in the HR-Positive Cohort

Prespecified subgroup analyses are summarized in Appendix 1, Table 28. Point estimates favoured trastuzumab deruxtecan in most subgroups, with the exception of patients with moderate renal impairment at baseline and those who had received 1 prior line of ET in the metastatic setting.

Health-Related Quality of Life

EORTC QLQ-C30 scores from the DESTINY-Breast04 study are summarized in Table 16, with the change from baseline across time points presented in Figure 3. According to the global health status parameter of the EORTC QLQ-C30, both treatment arms remained stable throughout the study. Mean baselines in global health status were 36.26 (SD = 21.842) in the trastuzumab deruxtecan arm and 37.89 (SD = 22.511) in the TPC arm. Mean changes from baseline were |||| |||||||| in the trastuzumab deruxtecan arm and |||| |||||||| in the TPC arm. The symptom scale with the greatest difference in mean change from baseline was nausea and vomiting, in favour of the TPC arm, with |||| |||||||| and ||||| |||||||| in the trastuzumab deruxtecan arm and TPC arm, respectively.

Table 16: EORTC QLQ-C30 Scores in DESTINY-Breast04 (Hormone Receptor–Positive Cohort)

EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; SD = standard deviation.

Note: Linear transformations were applied to global health status and all subscales of the EORTC QLQ-C30 such that a high score for the global health status represents a low quality of life (change of direction from raw score), a high score for a functional scale represents a low or unhealthy level of functioning, and a high score for a symptom scale or item represents a high level of symptomatology or problems.

Source: DESTINY-Breast04 Clinical Study Report.³

In the HR-positive cohort, the median times to a deterioration of 10 or more points in the global health status were 11.4 months (95% CI, 8.8 to 16.3) in the trastuzumab deruxtecan arm and 7.5 months (95% CI, 5.9 to 9.5) in the TPC arm. The hazard ratio was 0.69 (95% CI, 0.52 to 0.92).

Table 17 summarizes the EORTC QLQ-BR45 (QLQ-BR23) scores in the HR-positive cohort. The mean baseline breast symptoms score was ||||| |||||||| in the trastuzumab deruxtecan arm and ||||| |||||||| in the TPC arm, mean changes from baseline were ||||| |||||||| and ||||| |||||||| in the trastuzumab deruxtecan and TPC arms, respectively. The numbers of patients contributing to the change from baseline to end of treatment results for breast symptoms were ||| in the trastuzumab deruxtecan arm and ||| in the TPC arm.

In the HR-positive cohort, the median times to deterioration by 10 or more points according to the EORTC QLQ-BR45 (QLQ-BR23) breast symptoms were not evaluable (95% CI, 24.7 to not evaluable) in the trastuzumab deruxtecan arm and not evaluable (95% CI, not evaluable to not evaluable) in the TPC arm. The hazard ratio was 0.71 (95% CI, 0.50 to 1.01). For arm symptoms, median times to deterioration by 10 points or more were 14.4 months (95% CI, 11.9 to 23.0) in the trastuzumab deruxtecan arm and 8.7 months (95% CI, 5.6 to not evaluable). The hazard ratio was 0.62 (95% CI, 0.45 to 0.85).

Figure 3: Change From Baseline of EORTC QLQ-C30 — Global Health Status (HR-Positive Cohort)

CFB = change from baseline; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; GHS = global health status; HR = hormone receptor; T-DXd = trastuzumab deruxtecan; TPC = physician’s choice of chemotherapy.

Note: Scores range from 0 to 100; a linear transformation was applied to the raw global health status score; thus, a higher score represents lower (“worse”) global health status (overall quality of life). T-DXd and TPC treatment arms are only comparable through cycle 13 (until the number of patients with available change from baseline data fell below 10% in the TPC arm). Data in the T-DXd treatment arm are interpretable through cycle 27 (until the number of patients with available change from baseline data fell below 10%).

^a Assessment was conducted on day 1 of each cycle.

Source: Sponsor submission package.⁴⁹

Table 17: EORTC QLQ-BR45 (EORTC QLQ-BR23) Scores in DESTINY-Breast04 (HR-Positive Cohort)

EORTC QLQ-BR23 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire breast cancer module; EORTC QLQ-BR45 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire updated breast cancer module; HR = hormone receptor; SD = standard deviation.

Note: Linear transformations are applied to all subscales of the EORTC QLQ-BR23 such that a high score for functional subscales represents a low/unhealthy level of functioning (change of direction from the raw score) and a high score for a symptom scale or item represents a high level of symptomatology/problems.

Source: DESTINY-Breast04 Clinical Study Report.³

Table 18 summarizes the EQ-5D-5L index scores as well as the EQ VAS in the HR-positive cohort. The mean baseline index score was ||||| |||||||| in the trastuzumab deruxtecan arm and ||||| |||||||| in the TPC arm. Mean changes from baseline to end of treatment were |||||| |||||||| and |||||| |||||||| in the trastuzumab deruxtecan and TPC arms, respectively. The numbers of patients contributing to the change from baseline to end-of-treatment results for EQ-5D-5L index score were ||| in the trastuzumab deruxtecan arm and ||| in the TPC arm.

In the HR-positive cohort, the median times to deterioration by 10 or more points according to the EQ VAS were 12.0 months (95% CI, 9.9 to 15.2) in the trastuzumab deruxtecan arm and 6.8 months (95% CI, 4.9 to 11.4) in the TPC arm. The hazard ratio was 0.73 (95% CI, 0.54 to 0.97).

Progression-Free Survival

PFS results in the HR-positive cohort are summarized in Table 19. The median PFS in the trastuzumab deruxtecan arm was 10.1 months (95% CI, 9.5 to 11.5) while in the TPC arm it was 5.4 months (95% CI, 4.4 to 7.1; P < 0.0001). The hazard ratio was 0.51 (95% CI, 0.40 to 0.64). The proportions of patients in PFS at 12 months were ||||| |||||| || |||||| in the trastuzumab deruxtecan arm and ||||| |||||| || |||||| in the TPC arm. The PFS Kaplan-Meier curves for the HR-positive cohort are shown in Figure 4.

Table 18: EQ-5D-5L Scores in the DESTINY-Breast04 (Hormone Receptor–Positive Cohort)

EQ-5D-5L = 5-Level EQ-5D; EQ VAS = EQ-5D Visual Analogue Scale; SD = standard deviation.

Note: The EQ-5D-5L is scored according to the UK Crosswalk Value Set. The health scale is measured on a 0-to-100 mm visual analogue scale.

Source: DESTINY-Breast04 Clinical Study Report.³

Table 19: Progression-Free Survival Based on BICR in the Hormone Receptor–Positive Cohort

BICR = blinded independent central review; CDK = cyclin-dependent kinase; CI = confidence interval; HR = hormone receptor.

Note: Data cut-off: January 11, 2022.

^aMedian progression-free survival was from a Kaplan-Meier analysis. The CI for medians was computed using the Brookmeyer-Crowley method.

^bTwo-sided P value from stratified log-rank test, included in the hierarchical testing structure.

^cHazard ratio and 95% CI from stratified Cox proportional hazards model with stratification factors: HER2 status, number of prior lines of chemotherapy, and HR/CDK status as defined by the interactive voice/web response system.

^dEstimate and CI for progression-free survival rate at the specified time point are from a Kaplan-Meier analysis.

Source: DESTINY-Breast04 Clinical Study Report.³

Sensitivity analyses conducted for PFS according to the BICR in the HR-positive cohort are summarized in Table 20. Each sensitivity analysis addressed the robustness to the assumptions of the primary analysis. These analyses included testing for a difference in PFS event times without stratification, treating progression that occurred within 2 missed consecutive assessments as events, not censoring at the time of new anticancer therapy, back-dating PFS that occurred within a missed assessment, and choosing an alternative censoring for randomized but not treated patients. The benefit in favour of trastuzumab deruxtecan was consistent in all sensitivity analyses.

Table 20: Sensitivity Analysis of Progression-Free Survival in a BICR of the HR-Positive Cohort

BICR = blinded independent central review; CDK = cyclin-dependent kinase; CI = confidence interval; HR = hormone receptor; PFS = progression-free survival.

^aMedian PFS is from a Kaplan-Meier analysis. The CI for medians was computed using the Brookmeyer-Crowley method.

^bUnstratified Cox regression analysis.

^cHazard ratio and 95% CI from stratified Cox proportional hazards model using stratification factors: HER2 status, number of prior lines of chemotherapy, HR/CDK status, as defined by an interactive web/voice response system.

^dPatients were censored at the last evaluable tumour assessment date before starting the new anticancer therapy.

^eBackdated PFS event time in the case that PFS event occurred after missing 1 or more tumour assessments.

^fPFS for randomized-not-treated early censored subjects was imputed by the following algorithm: if death date is not missing, the death is imputed as PFS event, with PFS = death date -randomization date + 1. Otherwise PFS = data cut-off date − randomization date + 1.

Source: DESTINY-Breast04 Clinical Study Report.³

Figure 4: Kaplan-Meier Plot of PFS Based on BICR in the Hormone Receptor–Positive Cohort by Treatment Arm

BICR = blinded independent central review; CI = confidence interval; HR = hazard ratio; PFS = progression-free survival; T-DXd = trastuzumab deruxtecan; TPC = treatment of physician’s choice.

Note: A stratified Cox proportional hazards model was used for the hazard ratio and a stratified log-rank test for the P value. Data cut-off: January 11, 2022.

Source: DESTINY-Breast04 Clinical Study Report.³

PFS results in the FAS are summarized in Table 21. The median PFS in the trastuzumab deruxtecan arm was 9.9 months (95% CI, 9.0 to 11.3) while in the TPC arm it was 5.1 months (95% CI, 4.2 to 6.8; P < 0.0001). The hazard ratio was 0.50 (95% CI, 0.40 to 0.63). The proportions of patients in PFS at 12 months were ||||| |||||| || |||||| in the trastuzumab deruxtecan arm ||| ||||| |||||| || |||||| in the TPC arm. The PFS Kaplan-Meier curves for the FAS are shown in Figure 5.

Table 21: Progression-Free Survival Based on BICR in the Full Analysis Set

BICR = blinded independent central review; CDK = cyclin-dependent kinase; CI = confidence interval; HR = hormone receptor.

Note: Data cut-off: January 11, 2022.

^aMedian progression-free survival was from a Kaplan-Meier analysis. The CI for medians was computed using the Brookmeyer-Crowley method.

^bTwo-sided P value from stratified log-rank test, included in the hierarchical testing structure.

^cStratified Cox proportional hazards model with stratification factors: HER2 status, number of prior lines of chemotherapy, and HR/CDK status as defined by an interactive web/voice response system.

^dEstimate and CI for progression-free survival rate at the specified time point are from a Kaplan-Meier analysis.

Source: DESTINY-Breast04 Clinical Study Report.³

Progression-Free Survival Subgroup Analyses

Subgroup analysis of PFS (based on strata from the IXRS) in the HR-positive cohort was consistent with the primary efficacy analysis, showing improvement in PFS in favour of the trastuzumab deruxtecan arm, regardless of IHC status, and prior chemotherapy or CDK 4/6 inhibitor use. The hazard ratios were |||| ||||| || ||||) for patients with an HER2 status of IHC 1+ and |||| ||||| || ||||| for patients with a HER2 status of IHC 2+/ISH−. The hazard ratios were |||| ||||| || ||||| for patients who had received 1 prior line of chemotherapy and |||| ||||| || ||||| for patients who had received 2 prior lines of chemotherapy. The hazard ratios were |||| ||||| || ||||| for patients who had received prior CDK 4/6 inhibitor therapy ||| |||| ||||| || ||||| for patients who had not received prior CDK 4/6 inhibitor therapy. A full summary of all subgroup analyses is provided in Appendix 1, Table 27.

Figure 5: Kaplan-Meier Plot of PFS Based on BICR by Treatment Arm in the Full Analysis Set

BICR = blinded independent central review; CI = confidence interval; HR = hazard ratio; PFS = progression-free survival; T-DXd = trastuzumab deruxtecan; TPC = treatment of physician’s choice.

Note: Stratified Cox proportional hazard model used for hazard ratio and stratified log-rank test for the P value. Data cut-off: January 11, 2022.

Source: DESTINY-Breast04 Clinical Study Report.³

Progression-Free Survival in the HR-Negative Cohort (Exploratory End Point)

PFS in the HR-negative cohort was an exploratory outcome; results are from an electronic data capture, unlike the methodology used for the primary analysis. Using the electronic data capture, 40 patients in the trastuzumab deruxtecan arm and 18 patients in the TPC arm were classified as HR-negative. Median PFS values in the HR-negative cohort were 8.5 months (95% CI, 4.3 to 11.7) in the trastuzumab deruxtecan group and 2.9 months (95% CI, 1.4 to 5.1) in the TPC group (hazard ratio = 0.48; 95% CI, 0.24 to 0.95).

Objective Response Rate

Table 22 summarizes the ORR based on BICR in both the HR-positive cohort and the FAS. The ORR of the 331 patients who received trastuzumab deruxtecan in the HR-positive cohort was 52.9% (95% CI, 47.3 to 58.4) while the 163 patients in the HR-positive cohort who received TPC had an ORR of 16.6% (95% CI, 11.2 to 23.2). In the FAS, the ORR of the 373 patients who received trastuzumab deruxtecan in the HR-positive cohort was 52.3% (95% CI, 47.1 to 57.4) while the 184 patients in the HR-positive cohort who received TPC had an ORR of 16.3% (95% CI, 11.3 to 22.5).

Table 22: Best Overall Response and Confirmed ORR Based on BICR in the HR-Positive Cohort and the Full Analysis Set

BICR = blinded independent central review; CDK = cyclin-dependent kinase; CI = confidence interval; HR = hormone receptor; ORR = objective response rate: TPC = treatment of physician’s choice.

Note: Data cut-off: January 11, 2022.

^aOne patient in the trastuzumab deruxtecan arm who had a confirmed best overall response of complete or partial response received a baseline scan after randomization but before the first dose and was therefore considered a nonresponder in the calculation of confirmed ORR.

^bBased on the Clopper-Pearson method for single proportion and for the difference of 2 proportions with continuity correction.

^cTwo-sided P value based on the Cochran-Mantel-Haenszel-test adjusted for stratification factors: HER2 status, number of prior lines of chemotherapy, HR/CDK status as defined by an interactive web/voice response system. P value not controlled for multiplicity.

Source: DESTINY-Breast04 Clinical Study Report.³

Modi et al. (2022)⁵⁰ reports the results for the HR-negative cohort. This analysis used a more accurate electronic data capture method, differing from the methodology used for the primary analysis. In 40 patients from the HR-negative cohort who received trastuzumab deruxtecan, the ORR was 50.0% (95% CI, 33.8 to 66.2), 2.5% of whom had CRs, compared to 18 patients from the HR-negative cohort who received TPC, with an ORR of 16.7% (95% CI, 3.6 to 41.4), 5.6% of whom had CRs. Median times to response were 1.51 months in patients who received trastuzumab deruxtecan and 1.41 months in patients who received TPC.

Duration of Response

Duration of confirmed response based on the BICR is summarized in Table 23. In the 176 patients who received trastuzumab deruxtecan in the HR-positive cohort and recorded a complete or partial response, the median DOR was 10.7 months (95% CI, 8.5 to 13.7), compared to 27 patients in the TPC arm, with a median response of 6.8 months (95% CI, 6.5 to 9.9). In the FAS, 196 patients in the trastuzumab deruxtecan arm recorded a complete or partial response and the median DOR was 10.7 (95% CI, 8.5 to 13.2), compared to 30 patients in the TPC arm, with a median response of 6.8 months (95% CI, 6.0 to 9.9).

Table 23: Duration of Confirmed Response Based on BICR in the HR-Positive Cohort and the Full Analysis Set

BICR = blinded independent central review; CI = confidence interval; CR = complete response; HR = hormone receptor; PR = partial response; TPC = treatment of physician’s choice.

Note: Duration of response was defined as the time from date of the first documentation of objective response (complete or partial response) to the date of the first documentation of disease progression based on BICR or death. Percentage was calculated using number of patients with complete or partial response. Data cut-off: January 11, 2022.

^aMedian was from a Kaplan-Meier estimate. The CI for the medians was computed using the Brookmeyer-Crowley method.

Source: DESTINY-Breast04 Clinical Study Report.³

Harms

Harms data were reported for all patients who received at least 1 dose of study drug in the safety analysis set of the DESTINY-Breast04 trial. Table 24 presents detailed harms data from the DESTINYBreast-04 trial by the January 11, 2022, data cut-off.

Adverse Events

In total, 99.5% of patients in the trastuzumab deruxtecan arm and 98.3% of patients in the TPC arm reported 1 or more AEs by the January 11, 2022, data cut-off.

Serious Adverse Events

SAEs of any grade were reported in 27.8% of patients in the trastuzumab deruxtecan arm and 25% of patients in the TPC arm by the January 11, 2022, data cut-off.

Withdrawal Due to Adverse Events

AEs leading to treatment discontinuation were reported in 16.2% of patients receiving trastuzumab deruxtecan and 8.1% in the TPC arm by the January 11, 2022, data cut-off.

Mortality

Overall, 39.9% of patients in the trastuzumab deruxtecan arm and 51.2% of patients in the TPC arm had died by the January 11, 2022, data cut-off. The most common reasons leading to death in both arms were disease progression and AEs.

Notable Harms

AEs of special interest reported in the DESTINY-Breast04 trial by the January 11, 2022, data cut-off are presented in Table 24. ILD/pneumonitis and left ventricular dysfunction were more common in the trastuzumab deruxtecan arm (12.1% and 4.6%, respectively) compared to the TPC arm (0.6% and 0%, respectively).

Table 24: Summary of Harms in DESTINY-Breast04 — Safety Analysis Set

Note: Details from the table have been taken from the sponsor’s Summary of Clinical Evidence. Data cut-off: January 11, 2022.

^aAn on-treatment death was defined as a death that occurred between the start of treatment and 47 days after the last dose.

Source: DESTINY-Breast04 Clinical Study Report.³

Critical Appraisal

Internal Validity

DESTINY-Breast04 was a phase III, multicentre, randomized, double-arm, open-label, active-controlled study. Patients were randomly assigned to receive either trastuzumab deruxtecan or TPC in a 2:1 ratio. Randomization was stratified according to HER2 status, number of prior lines of chemotherapy, and HR status and/or prior exposure to CDK 4/6 inhibitors was defined by an IXRS. The stratification factors were chosen appropriately and validated by clinical experts consulted by CADTH. However, stratification was based on an IXRS at the time of randomization, which differed from an electronic data capture that corrected for mis-stratification at randomization. The overall number of patients who were mis-stratified with regards to HR status in the primary analysis was low (63 HR-negative patients in the uncorrected analysis and 58 HR-negative patients in the corrected analysis), and prespecified PFS sensitivity analyses conducted in the HR-positive cohort suggested that stratification did not have a meaningful impact on that specific end point. Additional discrepancies between the IXRS stratification and the corrected electronic data capture were found in the prior lines of chemotherapy stratification factor. In the trastuzumab deruxtecan arm, 161 patients were recorded by the IXRS as having received 2 prior lines of chemotherapy compared to the corrected value of |||. In the TPC arm, 81 patients were recorded by the IXRS as having received 2 prior lines of chemotherapy compared to the corrected value of ||. The clinical experts consulted by CADTH confirmed that, in general, heavily pretreated patients have worse expected outcomes, and because the trastuzumab deruxtecan arm was less heavily pretreated than the IXRS stratification suggests, there may be a bias in favour of trastuzumab deruxtecan, although the magnitude is unknown.

The primary end point in the study was PFS based on BICR in the HR-positive cohort, with secondary end points (PFS based on BICR in the FAS and OS in both the HR-positive cohort and FAS) tested in a hierarchical sequence. The statistical analysis plan allowed for 2 interim analyses and 1 final analysis of OS. Stopping boundaries appear to be calculated appropriately to account for multiplicity; however, the OS analysis was stopped at the first interim analysis, with an information fraction of ||||| (a measure of the amount of information present at an interim analysis in relation to the total information available). Early stopping rules preserve type I error rates of the OS significance tests but increase the possibility that benefits are overestimated.⁵¹

Although the open-label design of the study may have biased the subjective HRQoL end points in favour of trastuzumab deruxtecan, the BICR and RECIST methodologies likely reduced the impact of this bias on the PFS end point. The open-label design may have resulted in an informative censoring mechanism in which certain patients exited the study before the first postbaseline tumour assessment. In the FAS analysis of PFS with |||| of patients in the TPC arm censored due to no postbaseline tumour assessment, compared to only |||| in the trastuzumab deruxtecan arm. A post hoc sensitivity analysis was conducted to assess the impact of an alternative censoring strategy in which patients with no postbaseline tumour assessment who were assumed to have not experienced a progression event until the end of the study. Results of this post hoc sensitivity analysis were consistent with those of the primary analysis but resulted in a smaller estimated hazard ratio || |||| |||| || |||||||||||| for PFS and |||| |||| || |||||| |||||| for OS in the FAS. The directions in change of the estimated hazard ratios in the sensitivity analysis were expected and provide a conservative estimate of the hazard ratio if the differences in censoring due to withdrawal were noninformative but driven solely by the treatment assignment. No provided sensitivity analyses explored the sensitivity of the results to violations of the noninformative censoring assumption.

No HER2-low BC-specific MID studies were identified for the HRQoL outcomes. However, the clinical experts consulted by CADTH suggested that it would be reasonable to assume MIDs validated in BC patients in general would apply to the HER2-low population. MIDs for EQ-5D-5L and the EORTC QLQ-C30 validated in cancer and mBC patients aided in the interpretation and generalizability of the HRQoL outcomes in the DESTINY-Breast04 trial, although these outcomes were exploratory and not adjusted for multiplicity. As no MID studies were identified for the EORTC QLQ-BR45 (EORTC QLQBR23), results are uncertain.

External Validity

The DESTINY-Breast04 study population was considered by the clinical experts consulted by CADTH to be representative and generalizable to the Canadian population. The investigated dose of trastuzumab deruxtecan was 5.4 mg/kg, IV, every 3 weeks, consistent with the expected Health Canada–approved dose. The clinical experts consulted suggested that the basket of chemotherapies used for the TPC arm of the DESTINY-Breast04 study was appropriate and representative of Canadian practice. They also suggested that it is reasonable to infer there are no meaningful differences in efficacy between the chemotherapy options for the patient population.

In the study, 30% of HR-positive patients had not received any prior treatment with CDK 4/6 inhibitors. This is not consistent with the Canadian population given that CDK 4/6 inhibitors are a standard first-line therapy for HR-positive patients, although the clinical experts did not expect this discrepancy would affect the generalizability of the study results.

Long-Term Extension Studies

No long-term extension studies were submitted by the sponsor

Indirect Evidence

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

Objectives and Methods for the Summary of Indirect Evidence

Trastuzumab deruxtecan has been compared to TPC in patients with unresectable or metastatic HER2-low BC who have received at least 1 prior line of chemotherapy in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant chemotherapy. However, TPC did not contain any treatments targeting HER2-low patients and the trial did not examine head-to-head evidence comparing trastuzumab deruxtecan with other relevant comparators for treatment of mBC in the HER2-low population. Sacituzumab govitecan has received a conditional positive recommendation from CADTH and is currently the subject of price negotiations for an indication of metastatic triple-negative BC. As such, sacituzumab govitecan would be considered a comparator of interest for HR-negative patients in the DESTINY-Breast04 trial.

Description of Indirect Comparison

The sponsor submitted a feasibility assessment for an NMA to assess the relative effectiveness of trastuzumab deruxtecan versus relevant comparators to support reimbursement in HER2-low unresectable BC and/or mBC populations.

Table 25: Study Selection Criteria and Methods for ITC Feasibility Assessment Submitted by Sponsor

BC = breast cancer; ECOG PS = European Cooperative Oncology Group Performance Status; ET = endocrine therapy; HR = hormone receptor; mBC = metastatic breast cancer; NICE = National Institute for Health and Care Excellence; RCT = randomized controlled trial.

Note: If it was unclear whether a study meets any criterion during the level 1 screening process, the study was progressed to full-text screening to confirm its inclusion in the review.

Source: Sponsor-submitted NMA feasibility assessment.⁵²

ITC Design

Objectives

Table 26: Comparison of Treatment-Effect Modifiers Reported for Studies Included in the Networks

ECOG PS = Eastern Cooperative Oncology Group Performance Status; IHC = immunohistochemistry; NR = not reported.

^aThe full ASCENT trial was conducted in the metastatic triple negative indication. This includes both HER2-low and HER2-negative.

Source: Sponsor-submitted NMA feasibility assessment.⁵²

Summary of the Sponsor-Conducted Feasibility Assessment

The sponsor conducted a systematic review to inform an ITC feasibility assessment to evaluate the relative effectiveness of trastuzumab deruxtecan against relevant comparators in the unresectable BC and/or metastatic HER2-low BC population. Of the 17 studies identified in the review, 1 study (ASCENT 2022) met the required criteria of Table 25. The ASCENT trial was a global, open-label, randomized trial that assessed the benefit of sacituzumab govitecan versus TPC (TPC therapies included capecitabine, eribulin, vinorelbine, or gemcitabine) in HER2 IHC 0 and HER2-low metastatic triple-negativAppen BC patients. PFS and OS were the outcomes of interest for this analysis. The HER2-low subgroup of interest for the ITC was defined post hoc, and analyses were exploratory within the ASCENT trial. The sponsor subdivided the HER2-low population to HR-positive/HER2-low and HR-negative/HER2-low to assess OS and PFS outcomes. For the HR-negative/HER2-low mBC patient population, sacituzumab govitecan was the only comparator identified that was connected to trastuzumab deruxtecan with TPC as a common comparator in the network. No relevant studies were identified for the HR-positive/HER2-low population.

Although a potential network was constructed between trastuzumab deruxtecan and sacituzumab govitecan, conducting an NMA was not considered feasible due to several limitations. In particular, the sponsor noted large differences in baseline characteristics across the 2 studies, particularly in ECOG PS, race, presence of brain metastases, and prior lines of treatment (Table 26). These variables were identified by the sponsor as potential effect modifiers based on a review of the literature and expert opinion, and may have resulted in biased estimates. The clinical experts consulted during the CADTH review agreed that the observed imbalances in baseline characteristics across the 2 studies would likely affect the treatment effect in the HER2-negative patient population. The sponsor’s conclusion that this NMA was infeasible was therefore considered appropriate.

The sponsor submitted a MAIC feasibility assessment to compare trastuzumab deruxtecan to sacituzumab govitecan in the HR-negative/HER2-low mBC population. The sponsor noted that HR-negative cohorts of both trials were considered relatively small and suggested this would result in unreliable results from a MAIC due to reductions in the effective sample size. In addition, detailed patient characteristics were not reported in the ASCENT 2021 publication nor were these details provided in the subsequent HER2-low subgroup analysis. The sponsor noted that key characteristics, such as tumour location, prior lines of treatment, and presence of brain metastases, which were shown to be critical treatment-effect modifiers, were not reported. The sponsor concluded that an attempt to match the DESTINY-Breast04 trial to the ASCENT 2022 trial population would have to assume that the characteristics from the previous ASCENT 2021 publication (full triple-negative BC population inclusive of IHC 0) do not change and remain as is in the ASCENT 2022 publication (HER2-low cohort). Although the rationale provided by the sponsor does not clearly make a MAIC infeasible in this setting, the CADTH review team agreed with the sponsor that a MAIC would likely produce biased and imprecise estimates due to the identified limitations. Results from the MAIC would therefore be unlikely to informative for a reimbursement decision.

Studies Addressing Gaps in the Pivotal and Randomized Controlled Trial Evidence

No additional studies addressing gaps in the evidence were submitted by the sponsor.

Discussion

Summary of Available Evidence

The pivotal trial submitted for this review, DESTINY-Breast04 (N = 557), is a phase III, randomized, open-label, active-controlled trial of trastuzumab deruxtecan compared to TPC in patients with HER2-low unresectable or mBC. The trial included an HR-positive cohort and a FAS cohort that included a small number of patients with HR-negative, HER2-low BC. The primary end point was PFS according to a BICR in the HR-positive cohort with key secondary end points including OS in the HR-positive cohort and both PFS and OS in the FAS. Patients in the DESTINY-Breast04 study had a mean age of 56.5 years and 54.8% had an ECOG PS of 0.

The sponsor also provided a feasibility assessment for conducting an ITC in the HR-negative population against the comparator sacituzumab govitecan. An ITC was deemed infeasible due to the major differences in the clinical trial characteristics and small number of patients included.

Interpretation of Trial Results

Efficacy

In the DESTINY-Breast04 study, trastuzumab deruxtecan showed a statistically significant benefit in the primary end point of PFS in the HR-positive cohort when compared to TPC. Similar benefits were observed in the FAS, which included HR-negative patients as well. This benefit was recognized by the clinical experts as a clinically meaningful difference for patients. An OS benefit in favour of trastuzumab deruxtecan was shown in the FAS, with median OS values of 23.4 months (95% CI, 20.0 to 24.8) in the trastuzumab deruxtecan arm and 16.8 months (95% CI, 14.5 to 20.0) in the TPC arm, (hazard ratio = 0.64, 95% CI, 0.49 to 0.84, P = 0.0010). Similar benefits were observed in the HR-positive cohort. With the acknowledgement that early stopping of interim OS analyses increases the possibility of overestimating the benefits, the clinical experts consulted by CADTH considered the OS benefits to be clinically meaningful (suggesting that about 2 treatment cycles is usually interpreted as clinically meaningful) for patients, even for the most conservative estimates, based on the 95% CI. Patient input emphasized the importance of access to treatments that control disease progression, extend life, and manage cancer-related symptoms.

The design of DESTINY-Breast04 intentionally enrolled a smaller number of patients with HR-negative disease to better reflect the true distribution of patients in clinical practice. While this increases the generalizability of the FAS results to the expected Canadian population, the consequence of the design is that the HR-negative subgroup results are exploratory. Although no conclusions can be drawn directly from the HR-negative cohort results, they appear to be similar to those of the primary analysis. The clinical experts suggested that it is reasonable to assume that trastuzumab deruxtecan would have a similar benefit regardless of HR status, given that trastuzumab deruxtecan does not target the HR.

HRQoL was identified by patients as a key outcome for consideration in the treatment of mBC. As the DESTINY-Breast04 trial was not powered to detect differences in HRQoL outcomes, conclusions cannot be drawn regarding the impact that trastuzumab deruxtecan will have on the HRQoL of patients. Descriptively, there did not appear to be a deterioration in HRQoL in patients who received trastuzumab deruxtecan as the MID for the EORTC QLQ-C30 and EQ VAS were not exceeded over time. No MIDs specific to mBC were identified for the EQ-5D-5L index scores or the EORTC QLQ-BR45 (EORTC QLQ-BR23), limiting the usefulness of even descriptive comments for those outcomes.

The potential for an ITC comparing trastuzumab deruxtecan against sacituzumab govitecan was discussed by the sponsor and ultimately deemed infeasible. Sacituzumab govitecan is a comparator of interest. Given that it is indicated for triple-negative BC following treatment with chemotherapy, a subset of those patients would be classified as HER2-low in the new testing paradigm, and this subset aligns with the HR-negative cohort in the DESTINY-Breast04 trial. Sacituzumab govitecan is currently the subject of price negotiations following a conditional positive recommendation from CADTH. Given the lack of comparative evidence, the relative efficacy of trastuzumab deruxtecan against sacituzumab govitecan is unknown; however, the clinical experts suggested that, if the patient is classified as HER2-low, the use of a targeted therapy may be preferred, although it was suggested that these drugs may be used sequentially in clinical practice.

Harms

In the DESTINY-Breast04, the safety profile of trastuzumab deruxtecan was comparable to that of TPC. AEs and SAEs occurred in roughly the same proportion of patients in both treatment arms. There was a higher occurrence of nausea and ILD in the trastuzumab deruxtecan arm, with ILD resulting in a higher proportion of patients stopping treatment; however, the clinical experts consulted considered these occurrences to be manageable. The trastuzumab family of drug products has a well-defined safety profile and is used in many BC indications. There does not appear to be any evidence of additional safety concerns for the unresectable or metastatic HER2-low BC population.

Other Considerations

The impact of HER2-low on the testing paradigm for mBC in Canada was discussed with clinical experts consulted by CADTH. A pathologist expert was also consulted. HER2-low (IHC 1+ or IHC 2+/ISH−) is a new classification within the BC landscape; however, it is defined using the established 2018 ASCO and CAP testing guidelines for HER2 testing. The pathology expert consulted by CADTH confirmed that existing samples for patients already tested can be re-read to determine HER2-low status, with no need for an additional biopsy. The clinical experts further highlighted that patients may also be retested for HER2 expression following disease progression from local to metastatic disease, as HER2 expression can drift throughout the course of disease.

The pathologist expert consulted noted that, depending on calibration, some assays used in Canada may detect a higher proportion of HER2-low compared with other assays. The pathologist expert also noted that there may be interobserver discordance and lack of reproducibility when differentiating 0 and 1+ to determine HER2 IHC status, as interpretation of these 2 categories has been less rigorous historically. However, the pathologist expert indicated that, with increased awareness and adequate training, Canadian pathologists and oncologists will be able to correctly identify HER2-low patients.

Conclusion

Evidence from the DESTINY-Breast04 trial showed statistically significant and clinically meaningful benefits in PFS and OS with trastuzumab deruxtecan 5.4 mg/kg every 3 weeks compared to TPC in patients with unresectable or metastatic HER2-low BC who have received at least 1 prior line of chemotherapy in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant chemotherapy. HRQoL was identified in patient input as a key end point important to patients. The evidence provided by the DESTINY-Breast04 study was not sufficient to draw conclusions about the effect on HRQoL. There remains an evidence gap for the relative efficacy comparison against sacituzumab govitecan in the HR-negative cohort of patients, although the cohort of patients for whom this comparison is relevant is small compared to the overall patient population. The clinical experts consulted for this review described the safety profile of trastuzumab deruxtecan as manageable and in line with their expectations.

References

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