CADTH Reimbursement Review

Trastuzumab Deruxtecan (Enhertu)

Sponsor: AstraZeneca Canada Inc.

Therapeutic area: Metastatic HER2-positive 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.

Introduction

Breast cancer is the most common cancer and the leading cause of cancer mortality among women.² Amplification and/or overexpression of the human epidermal growth factor 2 (HER2) occurs in approximately 15% to 20% of breast cancers.³ The disease is most often detected at relatively early stages⁴ when cure is possible via surgical resection, radiation, chemotherapy, and HER2-targeted therapies.⁵ However, some patients treated at earlier stages of disease will relapse⁶ and others are diagnosed de novo with stage IV HER2-positive unresectable or metastatic breast cancer (MBC).⁷ Symptoms of MBC, including pain, fatigue, and insomnia, impose significant financial burdens as well as limitations on the activities of daily living.⁸ Especially in its later stages, HER2-positive MBC severely negatively impacts health-related quality of life (HRQoL) due to the impacts of metastases.⁹ The sponsor estimated that approximately 562 patients per year would be eligible for trastuzumab deruxtecan in Canada outside of Quebec.¹ Median overall survival (OS) of HER2-positive MBC is approximately 4 to 6 years from diagnosis.^10,11

According to the clinical experts consulted by CADTH for this review, most patients who develop HER2-positive MBC have been previously diagnosed with an earlier stage of breast cancer and have previously received adjuvant or neoadjuvant systemic therapy consisting of chemotherapy plus trastuzumab (sometimes with pertuzumab added, if covered by private insurance). Patients who have residual invasive disease at the time of surgery are switched to adjuvant trastuzumab emtansine. For patients who have received no prior systemic therapy or if HER2-positive MBC occurs 6 months or longer after adjuvant or neoadjuvant therapy, the standard first-line treatment in the metastatic setting is taxane chemotherapy plus trastuzumab and pertuzumab. However, in patients who progress to MBC during or less than 6 months following adjuvant or adjuvant therapy, trastuzumab emtansine is given as the first line of treatment in the metastatic setting. A minority of patients may be considered for first-line endocrine therapy in the metastatic setting. According to the clinical experts, the standard second-line treatment in the metastatic setting is trastuzumab emtansine and, although not yet publicly funded and only accessible through patient access programs, the standard third-line treatment is likely to become tucatinib plus capecitabine and trastuzumab. There are no well-defined guidelines beyond these lines of therapy and options include chemotherapy alone or in combination with trastuzumab as well as other drugs, dependent on local funding. According to the clinical experts, the main goals of treatment of HER2-positive MBC are to prolong survival, delay disease progression, maintain or improve HRQoL, optimize performance status (PS), and minimize disease symptoms.

Trastuzumab deruxtecan is a HER2-targeted antibody drug conjugate consisting of the humanized monoclonal antibody trastuzumab covalently linked to the topoisomerase I inhibitor deruxtecan. The relevant Health Canada indication for trastuzumab deruxtecan is for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received at least 1 prior anti-HER2-based regimen either in the metastatic setting, or in the neoadjuvant or adjuvant setting and developed disease recurrence during or within 6 months of completing neoadjuvant or adjuvant therapy. The drug is dosed at 5.4 mg/kg by IV infusion once every 3 weeks until disease progression or unacceptable toxicity.

The objective of this report was to perform a systematic review of the beneficial and harmful effects of trastuzumab deruxtecan (5.4 mg/kg by IV infusion every 21 days) for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received at least 1 prior anti-HER2-based regimen in the metastatic setting, or those who have received anti-HER2 therapies in the neoadjuvant or adjuvant setting and have developed disease recurrence during or within 6 months of completing systemic neoadjuvant or adjuvant therapy.

Stakeholder Perspectives

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

Patient Input

Two patient groups, the Canadian Breast Cancer Network (CBCN) and Rethink Breast Cancer (RBC) provided input for this review. CBCN collected patient input via 2 online surveys (survey 1, 2017, n = 31 patients living in Canada with HER2-positive MBC; survey 2, 2012, n = 71 patients in Canada and n = 16 caregivers of patients in Canada with MBC regardless of HER2 status; no respondents had direct experience with trastuzumab deruxtecan), telephone interviews with key informants (2021 and 2022, n = 7 patients in Canada with HER2-positive MBC who had direct experience with trastuzumab deruxtecan as third-line treatment in the metastatic setting), and a literature review. The input from RBC was based on general observations and insights gathered through various activities (e.g., patient blogs, virtual support groups, working groups, patient advisory boards, peer-support networks, Instagram, and scientific advisory committee meetings), email interviews (2022, n = 3 patients with HER2-positive MBC who had direct experience with trastuzumab deruxtecan), and written correspondence (2020, n = 1 patient with HER2-positive MBC seeking access to trastuzumab deruxtecan). Patients highlighted the negative impacts of HER2-positive MBC symptoms such as fatigue, insomnia, and pain, as well as the more severe symptoms associated with metastasis to the bones, lungs, liver, brain, and skin; together, these symptoms impose a heavy physical, emotional, psychosocial, and financial toll and negatively impact HRQoL. It was acknowledged in the input from patient groups that currently available treatments for HER2-positive MBC are only shown to prolong the progression-free period, and that there are decreasing response rates with later lines of therapy; while the disease will eventually progress, patients seek to live their remaining months and years with the best possible HRQoL. Patients identified an unmet need for new treatments for HER2-positive MBC that can prolong survival, delay disease progression, and control cancer symptoms (especially those associated with metastasis) while having an acceptable toxicity profile, although they indicated that they would be willing to tolerate treatment side effects for therapies that are effective in controlling disease. Patients who had direct experience with trastuzumab deruxtecan treatment felt that the drug had contributed to controlling their disease; improving their HRQoL; and had tolerable side effects, including nausea, vomiting, stomach pain or other stomach issues, loss of appetite, fatigue, and hair loss.

Clinician Input

Input From the Clinical Experts Consulted by CADTH

Two clinical specialists with expertise in the diagnosis and management of HER2-positive MBC provided input for this review. The clinical experts stated that although many patients with HER2-positive MBC will benefit from the available HER2-targeted therapies, response rates beyond the first line of treatment are generally low, with progression usually occurring within months. Although the available therapies for HER2-positive MBC are generally well tolerated, drugs with fewer toxicities would be highly desirable. The clinical experts stated that the most appropriate place in therapy for trastuzumab deruxtecan would be the position currently occupied by trastuzumab emtansine; displacement of trastuzumab emtansine by trastuzumab deruxtecan may therefore result in a shift in the current treatment paradigm of HER2-positive MBC in the metastatic setting. Thus, trastuzumab deruxtecan would be offered as second-line treatment in the metastatic setting after taxane chemotherapy plus trastuzumab and pertuzumab (for patients who have received no prior systemic therapy or if HER2-positive MBC occurs 6 months or longer after adjuvant or neoadjuvant therapy) or as first-line treatment in the metastatic setting (for patients who progress to MBC during or less than 6 months from adjuvant or neoadjuvant therapy). The clinical experts emphasized that in patients who progress following trastuzumab deruxtecan, optimal sequencing of subsequent therapies remains unclear; however, in the absence of contrary evidence, many clinicians would choose to use trastuzumab emtansine as third-line therapy in the metastatic setting following trastuzumab deruxtecan. The clinical experts clarified that currently, trastuzumab deruxtecan would not be used in the place of trastuzumab emtansine as adjuvant therapy for patients who have residual invasive disease at the time of surgery after systemic neoadjuvant therapy as the 2 drugs have not been compared in this setting. In patients who previously received adjuvant trastuzumab emtansine, the clinical experts acknowledged that the role of trastuzumab deruxtecan in the metastatic setting is unclear due to a lack of clinical trial evidence; however, the clinical experts believed that there is presently no reason to think that these patients would not derive benefit from trastuzumab deruxtecan. Of note, in the DESTINY-Breast03 study, prior adjuvant or neoadjuvant treatment with trastuzumab emtansine was only allowed if disease progression had not occurred within 12 months of the end of adjuvant therapy.

The clinical experts relayed that the patients most likely to tolerate and respond to trastuzumab deruxtecan are those with good PS, no cardiovascular or pulmonary contraindications, and no active central nervous system (CNS) metastases. Response to trastuzumab deruxtecan would be assessed via serial radiological imaging (every 2 to 3 months) as well as via bloodwork and clinical evaluation (every 3 weeks or as needed). Clinically meaningful responses to treatment would be reflected by tumour shrinkage, stable metastatic disease, prolongation of survival, and improvement or stabilization of disease symptoms, PS, and HRQoL. Trastuzumab deruxtecan would be discontinued in patients who experience disease progression, who develop a serious toxicity (e.g., symptomatic interstitial lung disease [ILD]) and are unable to tolerate the drug despite dose modifications, whose PS declines such that palliative care measures alone are required, and by patient preference.

Clinician Group Input

Three clinician groups provided input for this review: the Ontario Health-Cancer Care Ontario Breast Cancer Drug Advisory Committee (3 medical oncologists), the RBC Scientific Advisory Committee (6 medical oncologists), and a group of medical oncologists from The Ottawa Hospital Cancer Centre and across Canada (11 medical oncologists). No major contrary views from those provided by the clinical experts consulted by CADTH for this review were presented. The clinician groups echoed the relatively low response rates of available treatment options for HER2-positive MBC beyond the first line in the metastatic setting and highlighted that with increasing use of HER2 drugs in the adjuvant or neoadjuvant settings, treatment resistance may develop rapidly in pretreated patients in the metastatic setting. Additional treatment options are needed in the second and subsequent lines in the metastatic setting, and trastuzumab deruxtecan could shift the current treatment paradigm by becoming the new standard second-line treatment.

Drug Program Input

The Provincial Advisory Group identified the following jurisdictional implementation issues: considerations for initiation of therapy, funding algorithm, care provision issues, and system and economic issues. 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 program’s implementation questions.

Clinical Evidence

Pivotal Studies and Protocol Selected Studies

Description of Studies

One phase III, multicentre, open-label (OL) randomized controlled trial designed to compare the efficacy and safety of trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive MBC previously treated with taxane chemotherapy plus trastuzumab contributed evidence to this review (DESTINY-Breast03, N = 524).¹² The primary objective of the study was to compare the progression-free survival (PFS) benefits per blinded independent central review (BICR) of trastuzumab deruxtecan versus trastuzumab emtansine in pretreated patients with HER2-positive MBC, and the key secondary objective (hierarchically tested) was to compare the OS benefits of the 2 drugs. Other secondary objectives included comparison of PFS per investigator assessment (IA), objective response rate (ORR) per BICR and IA, and duration of response (DOR) per BICR and IA, while changes in patient-reported HRQoL were evaluated as a health economics and outcome research (HEOR) analysis. Adult patients (age 18 years and older) with HER2-positive MBC that was previously treated with trastuzumab plus taxane chemotherapy in the metastatic setting (or who had progressed within 6 months after neoadjuvant or adjuvant treatment involving a regimen including trastuzumab and taxane) were enrolled at 169 centres in 15 countries (1 site, n = 2 patients in Canada). Patients were randomized 1:1 to receive OL trastuzumab deruxtecan (5.4 mg/kg by IV infusion every 21 days) or OL trastuzumab emtansine (3.6 mg/kg by IV infusion every 21 days) until disease progression according to modified Response Criteria for Evaluation of Solid Tumours (mRECIST) v. 1.1 or unacceptable toxicity. Randomization was stratified by hormone receptor status (positive or negative), prior treatment with pertuzumab (yes or no), and history of visceral disease (yes or no). Following treatment discontinuation, patients were followed for survival every 3 months until death.

Patients had to have an Eastern Cooperative Oncology Group (ECOG) PS of 0 or 1 and adequate hematological and organ function; patients previously treated with an anti-HER2 antibody drug conjugate were excluded (unless treatment was in the adjuvant or neoadjuvant setting and progression had not occurred within 12 months of the end of adjuvant therapy), as were patients with spinal cord compression or clinically active CNS metastases and patients with clinically significant cardiovascular or pulmonary disease. The mean age at study was 54.4 years, approximately 60% of patients were Asian, and only 2 patients were male. Approximately 63% of patients had an ECOG PS of 0 and approximately 37% had an ECOG PS of 1. Approximately half of patients had hormone receptor positive disease (approximately half of patients had estrogen receptor positive disease, while approximately one-third had progesterone receptor positive disease). Approximately 73% and 70% of patients had visceral metastases at baseline or a reported history of visceral metastases, respectively, and approximately 16% and 22% of patients had CNS metastases at baseline or a reported history of CNS metastases, respectively. All patients had received at least 1 prior systemic therapy for breast cancer and the mean number of prior regimens received was 3.3 (standard deviation [SD] = 2.33 regimens). Approximately 60% of patients had received prior pertuzumab. Approximately 72% of patients had received fewer than than 3 lines of prior systemic therapy, excluding hormone therapies, while approximately 28% had received 3 lines of systemic therapy excluding hormone therapies or more. Approximately 40% of patients had received 1 prior line of therapy in the metastatic setting, while approximately 60% had received 2 or more prior lines of therapy in the metastatic setting; note that the definition of lines of prior systemic therapy in the metastatic setting included patients for whom the therapy was intended to treat locally advanced and/or metastatic or palliative disease and patients for whom the therapy was intended as neoadjuvant, adjuvant, or maintenance therapy, and whose disease progressed within 6 months from the end of therapy (12 months for pertuzumab). Approximately 87% of patients had received prior systemic therapy with the intent-to-treat metastatic disease.

Efficacy Results

Key efficacy results of the DESTINY-Breast03 study are summarized in Table 2.

Overall Survival

As of the May 21, 2021, data cut-off date, OS events had occurred in 33 (12.6%) patients in the trastuzumab deruxtecan arm and 53 (20.2%) patients in the trastuzumab emtansine arm. Median OS and its 95% confidence interval (CI) could not be estimated in either treatment arm. The hazard ratio (HR) for OS comparing trastuzumab deruxtecan with trastuzumab emtansine was 0.5546 (95% CI, 0.3587 to 0.8576) in favour of trastuzumab deruxtecan; however, the stratified log-rank P value of 0.007172 did not cross the prespecified boundary for the interim analysis (P < 0.000265) calculated based on 86 OS events.

Progression-Free Survival

As of the May 21, 2021, data cut-off date, PFS events per BICR had occurred in 87 (33.3%) patients in the trastuzumab deruxtecan arm and 158 (60.1%) patients in the trastuzumab emtansine arm. Median PFS per BICR had not yet been reached in the trastuzumab deruxtecan arm but the lower limit of the 95% CI was 18.5 months, while the median PFS per BICR was 6.8 months in the trastuzumab emtansine arm (95% CI, 5.6 months to 8.2 months) (P < 0.0001). The HR for PFS per BICR comparing trastuzumab deruxtecan with trastuzumab emtansine was 0.2840 (95% CI, 0.2165 to 0.3727) in favour of trastuzumab deruxtecan.

As of the May 21, 2021, data cut-off date, PFS events per IA had occurred in 78 (29.9%) patients in the trastuzumab deruxtecan arm and 168 (63.9%) patients in the trastuzumab emtansine arm. Median PFS per IA was 25.1 months (95% CI, 22.1 months to not estimable) in the trastuzumab deruxtecan arm and 7.2 months (95% CI, 6.8 months to 8.3 months) in the trastuzumab emtansine arm. The HR for PFS per IA comparing trastuzumab deruxtecan with trastuzumab emtansine was 0.2649 (95% CI, 0.2011 to 0.3489) in favour of trastuzumab deruxtecan. Note that this analysis was not part of the statistical hierarchy and not adjusted for multiplicity.

Health-Related Quality of Life

Changes in European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30), 5-Level EQ-5D (EQ-5D-5L), and European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Breast Cancer 45 (EORTC QLQ-BR45) scores from baseline to the end of treatment were evaluated as an HEOR analysis. The interpretation of changes in patient-reported HRQoL outcomes was limited by high rates of missing data at later times post baseline.

Objective Response Rate

The ORR per BICR was 79.7% (95% CI, 74.3% to 84.4%) in the trastuzumab deruxtecan arm and 34.2% (95% CI, 28.5% to 40.3%) in the trastuzumab emtansine arm. The ORR per IA was 77.0% (95% CI, 71.4% to 82.0%) in the trastuzumab deruxtecan arm and 36.9% (95% CI, 31.0% to 43.0%) in the trastuzumab emtansine arm. The difference in ORR per BICR was 45.5% (95% CI, 37.6% to 53.4%) in favour of trastuzumab deruxtecan. Note that this analysis was not part of the statistical hierarchy and not adjusted for multiplicity.

Duration of Response

Among patients who achieved objective responses to treatment, median DOR per BICR was not yet reached in either treatment arm (trastuzumab deruxtecan 95% CI, 20.3 months to not estimable; trastuzumab emtansine 95% CI, 12.6 months to not estimable). Among patients who achieved objective responses to treatment, median DOR per IA was not yet reached in either treatment arm (trastuzumab deruxtecan 95% CI, 20.8 months to not estimable; trastuzumab emtansine 95% CI, 14.1 months to not estimable). Note that this analysis was not part of the statistical hierarchy and not adjusted for multiplicity.

Harms Results

Key harms results of the DESTINY-Breast03 study are summarized in Table 2. Almost all patients treated with trastuzumab deruxtecan (99.6%) and trastuzumab emtansine (95.4%) experienced at least 1 adverse event (AE). Serious AEs (SAEs) occurred overall at similar rates in patients treated with trastuzumab deruxtecan (19.1%) and trastuzumab emtansine (18.0%). Withdrawals due to AEs (WDAEs) occurred in 13.6% of patients treated with trastuzumab deruxtecan and 7.3% of patients treated with trastuzumab emtansine. AEs leading to study drug interruption occurred in 44.0% of patients treated with trastuzumab deruxtecan and 23.4% of patients receiving trastuzumab emtansine. Five patients (1.9%) in each of the treatment groups had AEs associated with an outcome of death. The study protocol-defined AEs of special interest of ILD, decreased left ventricular (LV) ejection fraction, and LV dysfunction occurred more frequently in patients receiving trastuzumab deruxtecan (10.9%, 2.3%, and 0.4%, respectively) than in patients receiving trastuzumab emtansine (1.9%, 0.4%, and 0%, respectively).

Table 2: Summary of Key Results From the DESTINY-Breast03 Study

AE = adverse event; CI = confidence interval; CTCAE = Common Terminology Criteria for Adverse Events; FAS = full analysis set; HR = hazard ratio; ILD = interstitial lung disease; LV = left ventricular; LVEF = left ventricular ejection fraction; MedDRA = Medical Dictionary for Regulatory Activities; NE = not estimable; OS = overall survival; PFS = progression-free survival; SAE = serious adverse event; WDAE = withdrawal due to adverse event.

Note: AEs were defined and graded using MedDRA version 23.0 and CTCAE version 5.0. All events are within 47 days of the last dose of the study drug unless otherwise indicated.

^aFrom a Kaplan-Meier analysis.

^bTwo-sided P value is from the stratified log-rank test; HR and 95% CI are from the stratified Cox proportional hazards model with hormone receptor status, prior pertuzumab, and history of visceral disease stratification factors.

Source: DESTINY-Breast03 Clinical Study Report.¹³

Critical Appraisal

A major limitation of the DESTINY-Breast03 study was immaturity of the OS analysis as of the May 21, 2021, data cut-off; only 86 OS events had been observed, and the prespecified boundary for statistical significance at the interim analysis was not crossed. In addition, analysis of OS did not consider treatment switching and crossover, which were imbalanced between arms and may have important impacts on the results. Thus, no conclusions regarding the relative impacts of trastuzumab deruxtecan and trastuzumab emtansine on OS could be reached. Other potential limitations of the study included its OL design and associated potential biases in outcome assessment due to knowledge of treatment allocation. Although disease progression was objectively evaluated using mRECIST 1.1 criteria per BICR, patients were discontinued from protocol therapy based on assignment of progressive disease per IA. Comparison of response evaluation per BICR and per IA suggested that a subset of patients may have been selectively continued on trastuzumab deruxtecan post progression per BICR and a subset of patients may have been discontinued from trastuzumab emtansine inappropriately due to an incorrect assignment of progressive disease per IA; this bias would be directional and in favour of trastuzumab deruxtecan, but according to the clinical experts consulted by CADTH for this review, would be unlikely to have major impacts on the PFS analysis. ORR, DOR, and HRQoL (evaluated as an HEOR analysis) were not part of the statistical hierarchy and statistical tests for these outcomes were not adjusted for multiplicity.

The DESTINY-Breast03 study excluded patients with active or symptomatic CNS metastases, and as a result provided no evidence on the efficacy of trastuzumab deruxtecan in these patients. Only 6.5% of patients in the study were from North America and 59.9% of the patients were Asian, which is not reflective of the Canadian patient population with HER2-positive MBC. No patients previously exposed to anti-HER2 antibody drug conjugates were included in the study, so the influence of use of these drugs for adjuvant or neoadjuvant therapy on responses in later lines was uncertain. Several of the subsequent therapies received in the study after discontinuation of protocol therapy are not available to patients in Canada with HER2-positive MBC in this setting and may limit the generalizability of the OS findings to Canadian practice.

Indirect Comparisons

No indirect evidence was identified for this review.

Other Relevant Evidence

No other relevant evidence was identified for this review.

Conclusions

Evidence from the DESTINY-Breast03 study suggested that, compared with trastuzumab emtansine, administration of trastuzumab deruxtecan contributed to improved PFS per BICR among patients with HER2-positive MBC who had previously received taxane chemotherapy plus trastuzumab. Definitive conclusions could not be reached for OS due to immaturity of the data and non-statistically significant OS differences at a prespecified boundary for the interim analysis. Analyses of PFS per IA, ORR, and DOR also numerically favoured trastuzumab deruxtecan, although they were not part of the statistical hierarchy and were supportive of the primary analysis of PFS per BICR. Results for patient-reported HRQoL and symptom scores (i.e., EQ-5D-5L, EORTC QLQ-C30, and EORTC QLQ-BR45) could not be interpreted due to the absence of multiplicity control in formal statistical testing, the potential for bias in an OL trial, and high rates of missing data at later time points post baseline. Dose interruption, dose reduction, treatment discontinuation, and ILD occurred more commonly in patients receiving trastuzumab deruxtecan than in those receiving trastuzumab emtansine. The observed PFS benefits, consistent numeric improvements in other efficacy outcomes, and toxicity profile considered manageable by clinical experts were aligned with outcomes identified as important to patients with HER2-positive MBC who are seeking additional treatment options to delay progression and prolong survival with an acceptable HRQoL.

Introduction

Disease Background

Breast cancer is the most common cancer and the leading cause of cancer mortality among women.² Amplification and/or overexpression of HER2 occurs in approximately 15% to 20% of breast cancers and contributes to an aggressive tumour phenotype characterized by rapid growth and spread, high rates of resistance to chemotherapies, and frequent visceral and CNS metastases.³ The disease is most often detected at relatively early stages (approximately 29% in stage I, approximately 43% in stage II, and approximately 21% in stage III)⁴ and in many of these patients, cure is possible via surgical resection, radiation, chemotherapy, and HER2-targeted therapies.⁵ However, approximately 10% to 20% of patients diagnosed with early-stage HER2-positive breast cancer will experience recurrence within 5 years,⁶ and approximately 5% of patients are diagnosed with stage IV HER2-positive unresectable breast cancer or MBC.⁷ Symptoms including pain, fatigue, cognitive difficulties, and insomnia impose significant financial burdens as well as limitations on patients’ ability to work, caregiving responsibilities, social activities, and ability to spend time with loved ones.⁸ Especially in the later stages of disease, HER2-positive MBC severely negatively impacts HRQoL and can lead to a symptomatic death, often in younger women, due to the impacts of visceral and CNS metastases.⁹

Based on estimates of the incidence (21 to 23 cases per 100,000 population) and 10-year prevalence (552 cases per 100,000 population) of breast cancer, the proportion of tumours that are HER2-positive (14.3%), the proportion of patients who are diagnosed with MBC (4.9%), who progress to MBC from earlier stages of disease (5.7%), or who progress during or within 6 months of completing adjuvant or neoadjuvant therapy (2.8%) each year, and the proportions of patients who receive first-line (81.3%) and second-line (40.5%) treatment in the metastatic setting, the sponsor calculated that as of 2022, approximately 562 patients per year would be eligible for trastuzumab deruxtecan in Canada outside of Quebec.¹ Median OS of HER2-positive MBC is approximately 4 to 6 years from diagnosis,^10,11 which is made by a medical oncologist based on biopsy and imaging results as well as molecular testing for HER2 overexpression and/or amplification.

Standards of Therapy

According to the clinical experts consulted by CADTH for this review, most patients who develop HER2-positive MBC have been previously diagnosed with an earlier stage of breast cancer and have previously received adjuvant or neoadjuvant systemic therapy consisting of chemotherapy plus trastuzumab. The addition of pertuzumab to adjuvant or neoadjuvant therapy may improve rates of tumour pathologic complete responses without a clear survival benefit; thus, the drug is not currently funded in the adjuvant or neoadjuvant settings in Canada, although some patients may receive it if covered by private medical insurance. The clinical experts relayed that patients who have residual invasive disease in the breast and/or axilla at the time of surgery are switched to adjuvant trastuzumab emtansine and in this group of patients, optimal first-line treatment following progression to MBC is unknown but the standard first-line treatment described in the following would be considered depending on the disease-free interval. For patients who have received no prior systemic therapy or if HER2-positive MBC occurs 6 months or longer after adjuvant or neoadjuvant therapy, the standard first-line treatment in the metastatic setting is taxane chemotherapy plus trastuzumab and pertuzumab. However, in patients who progress to MBC in 6 months or less from time of adjuvant or adjuvant therapy, trastuzumab emtansine is given as the first line of treatment in the metastatic setting. A minority of patients may be considered for first-line endocrine therapy in the metastatic setting (for instance, if they have hormone receptor positive disease and have contraindications to chemotherapy). According to the clinical experts, the standard second-line treatment in the metastatic setting is trastuzumab emtansine, and although not yet publicly funded and only accessible through patient access programs, the standard third-line treatment is likely to become tucatinib plus capecitabine and trastuzumab. There are no well-defined guidelines beyond these lines of therapy; options include chemotherapy alone or in combination with trastuzumab as well as other drugs (e.g., lapatinib, neratinib, margetuximab) dependent on local funding.

According to the clinical experts, the main goals of treatment of HER2-positive MBC are to prolong survival, delay disease progression, maintain or improve HRQoL, optimize PS, and minimize disease symptoms. The clinical experts relayed that the choice of systemic treatment for patients with HER2-positive MBC depends on PS, presence of comorbidities, previous treatments, the disease-free interval between adjuvant therapy and development of MBC, and patient preference.

Drug

The key characteristics of trastuzumab deruxtecan are shown in Table 3. Trastuzumab deruxtecan is dosed at 5.4 mg/kg by IV infusion once every 3 weeks until disease progression or unacceptable toxicity. The relevant Health Canada indication for trastuzumab deruxtecan is for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received at least 1 prior anti-HER2-based regimen either in the metastatic setting, or in the neoadjuvant or adjuvant setting and developed disease recurrence during or within 6 months of completing neoadjuvant or adjuvant therapy. In 2021, the drug received a Notice of Compliance with Conditions from Health Canada for another indication (for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received prior treatment with trastuzumab emtansine) and has not been previously reviewed by CADTH. The mechanism of action of trastuzumab deruxtecan is binding to HER2, internalization, and inhibition of topoisomerase I leading to DNA damage and apoptotic cell death. The sponsor’s reimbursement request is the same as the Health Canada indication. The drug is undergoing priority review at Health Canada under Project Orbis.

Table 3: Key Characteristics of Trastuzumab Deruxtecan and Trastuzumab Emtansine

ADCC = antibody-dependent cellular cytotoxicity; ECD = extracellular domain; HER2 = human epidermal growth factor 2; ILD = interstitial lung disease.

^aHealth Canada–approved indication or proposed Health Canada indication.

Sources: Product monograph for trastuzumab deruxtecan¹⁴ and product monograph for trastuzumab emtansine.¹⁵

Stakeholder Perspectives

Patient Group Input

This section was prepared by CADTH staff based on the input provided by patient groups. The original patient group submissions can be found at the end of this report.

Two patient groups, CBCN and RBC, provided input for this review. CBCN collected patient input via 2 online surveys (survey 1, 2017, n = 31 patients in Canada with HER2-positive MBC; survey 2, 2012, n = 71 patients in Canada and n = 16 caregivers of patients in Canada with MBC regardless of HER2 status; no respondents had direct experience with trastuzumab deruxtecan), telephone interviews with key informants (2021 and 2022, n = 7 patients in Canada with HER2-positive MBC who had direct experience with trastuzumab deruxtecan as third-line treatment in the metastatic setting), and a literature review. The input from RBC was based on general observations and insights gathered through various activities (e.g., patient blogs, virtual support groups, working groups, patient advisory boards, peer-support networks, Instagram, and scientific advisory committee meetings), email interviews (2022, n = 3 patients with HER2-positive MBC who had direct experience with trastuzumab deruxtecan), and written correspondence (2020, n = 1 patient with HER2-positive MBC seeking access to trastuzumab deruxtecan). Patients highlighted the negative impacts of HER2-positive MBC symptoms such as fatigue, insomnia, and pain, as well as the more severe symptoms associated with metastasis to the bones, lungs, liver, brain, and skin; together, these symptoms impose a heavy physical, emotional, psychosocial, and financial toll and negatively impact HRQoL. It was acknowledged in the input from patient groups that currently available treatments for HER2-positive MBC are only shown to prolong the progression-free period and highlighted the decreasing response rates in later lines of therapy; while the disease will eventually progress, patients seek to live their remaining months and years with the best possible HRQoL. Patients identified an unmet need for new treatments for HER2-positive MBC that can prolong survival, delay disease progression, and control cancer symptoms (especially those associated with metastasis) while having an acceptable toxicity profile, although they indicated that they would be willing to tolerate treatment side effects for therapies that are effective in controlling disease. Patients who had direct experience with trastuzumab deruxtecan treatment felt that the drug had contributed to controlling their disease, improving their HRQoL, and had tolerable side effects, including nausea, vomiting, stomach pain or other stomach issues, loss of appetite, fatigue, and hair loss.

Clinician Input

Input From the Clinical Experts Consulted by CADTH

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

Unmet Needs

According to the clinical experts consulted by CADTH for this review, although many patients with HER2-positive MBC will benefit from the available HER2-targeted therapies, many eventually develop resistance to these drugs; moreover, beyond the first line of treatment in the metastatic setting, responses are generally short-lived and progression usually occurs within months. Although the available therapies for HER2-positive MBC are generally well tolerated, their toxicities (e.g., diarrhea, palmar-plantar erythrodysesthesia, ILD, cardiotoxicity) can be difficult for patients, and drugs with fewer toxicities would be highly desirable. The clinical experts highlighted that approximately half of patients with HER2-positive MBC will develop intracranial metastases and that while tucatinib can elicit tumour responses within the brain, there is an unmet need for additional drugs that can target CNS metastases (for instance, in patients with symptomatic brain metastases or leptomeningeal disease) in earlier lines of therapy.

Place in Therapy

The clinical experts stated that the most appropriate place in therapy for trastuzumab deruxtecan would be the position currently occupied by trastuzumab emtansine; displacement of trastuzumab emtansine by trastuzumab deruxtecan would therefore result in a shift in the current treatment paradigm. Thus, trastuzumab deruxtecan would be offered as second-line treatment in the metastatic setting after taxane chemotherapy plus trastuzumab and pertuzumab (for patients who have received no prior systemic therapy or if HER2-positive MBC occurs 6 months or longer after adjuvant or neoadjuvant therapy) as well as first-line treatment in the metastatic setting (for patients who progress to MBC during or less than 6 months after adjuvant or adjuvant therapy).

The clinical experts emphasized that in patients who progress following trastuzumab deruxtecan, optimal sequencing of subsequent therapies remains unclear; however, in the absence of contrary evidence, many clinicians would choose to use trastuzumab emtansine as third-line therapy in the metastatic setting following trastuzumab deruxtecan. However, the clinical experts also acknowledged that based on the results of the phase II DESTINY-Breast01 study,¹⁶ use of trastuzumab deruxtecan as third-line treatment in the metastatic setting following trastuzumab emtansine appears to be associated with high ORRs and prolonged PFS; thus, patients who receive trastuzumab emtansine as second-line treatment in the metastatic setting are likely to derive clinical benefit from trastuzumab deruxtecan.

The clinical experts clarified that currently, trastuzumab deruxtecan would not be used in the place of trastuzumab emtansine as adjuvant therapy for patients who have residual invasive disease at the time of surgery after systemic neoadjuvant therapy as the 2 drugs have not been compared in this setting. In patients who previously received adjuvant trastuzumab emtansine, the clinical experts acknowledged that the role of trastuzumab deruxtecan in the metastatic setting is unclear due to a lack of clinical trial evidence; however, the clinical experts believed that there is presently no reason to think that these patients would not derive benefit from trastuzumab deruxtecan. Of note, in the DESTINY-Breast03 study, prior adjuvant or neoadjuvant treatment with trastuzumab emtansine was only allowed if disease progression had not occurred within 12 months of the end of adjuvant therapy.

Patient Population

The clinical experts consulted by CADTH for this review relayed that the patients most likely to tolerate and respond to trastuzumab deruxtecan are those with good PS, no cardiovascular or pulmonary contraindications, and no active CNS metastases. Patients most in need of treatment (i.e., those with rapidly progressing, symptomatic MBC) would be identified by a medical oncologist. The only biomarker of response is HER2 expression status, which is routinely determined at the time of diagnosis.

Assessing Response to Treatment

According to the clinical experts consulted by CADTH for this review, response to trastuzumab deruxtecan would be assessed via serial radiological imaging, bloodwork, and clinical evaluation. Clinically meaningful responses to treatment would be reflected by tumour shrinkage; stable metastatic disease; prolongation of survival; and improvement or stabilization of disease symptoms, PS, and HRQoL. Imaging assessments would be conducted every 2 to 3 months, while clinical assessments would be performed more regularly (e.g., every 3 weeks) during early treatment or as needed.

Discontinuing Treatment

The clinical experts consulted by CADTH for this review stated that trastuzumab deruxtecan would be discontinued in patients who experience disease progression, who develop a serious toxicity (e.g., symptomatic ILD) and are unable to tolerate the drug despite dose modifications, whose PS declines such that palliative care measures alone are required, and by patient preference.

Prescribing Conditions

According to the clinical experts consulted by CADTH for this review, trastuzumab deruxtecan would be administered in outpatient settings at facilities with those who have experience in the delivery of cancer therapies and that is equipped to monitor and manage AEs such as ILD and infusion reactions. Appropriate treatment settings would have access to a respirology service. However, the clinical experts emphasized that even in community settings, a medical oncologist would identify and monitor patients receiving trastuzumab deruxtecan.

Clinician Group Input

This section was prepared by CADTH staff based on the input provided by clinician groups. The original clinician group submissions can be found at the end of this report.

Three clinician groups provided input for this review: the Ontario Health-Cancer Care Ontario Breast Cancer Drug Advisory Committee (3 medical oncologists), the RBC Scientific Advisory Committee (6 medical oncologists), and a group of medical oncologists from The Ottawa Hospital Cancer Centre and across Canada (11 medical oncologists). No major contrary views from those provided by the clinical experts consulted by CADTH for this review were presented. The clinician groups echoed the relatively low response rates of the available treatment options for HER2-positive MBC beyond the first line in the metastatic setting and highlighted that with increasing use of HER2 drugs in the adjuvant or neoadjuvant settings, treatment resistance may develop rapidly in pretreated patients in the metastatic setting. Additional treatment options are needed in the second and subsequent lines in the metastatic setting, and trastuzumab deruxtecan could shift the current treatment paradigm by becoming the new standard second-line treatment.

Drug Program Input

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

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

ADC = antibody drug conjugate; D5W = dextrose 5% in water; ECOG = Eastern Cooperative Oncology Group; HER2 = human epidermal growth factor 2; ILD = interstitial lung disease; ISMP = Institute for Safe Medication Practices; OS = overall survival; PAG = Provincial Advisory Group; pERC = CADTH pan-Canadian Oncology Drug Review Expert Review Committee; PS = performance status.

Clinical Evidence

The clinical evidence included in the review of trastuzumab deruxtecan is presented a single section, the Systematic Review, which includes pivotal studies provided in the sponsor’s submission to CADTH and Health Canada as well as those studies that were selected according to an a priori protocol. No indirect evidence was identified for this review. No additional studies contributing other relevant evidence that addressed important gaps in the evidence included in the systematic review were identified.

Systematic Review (Pivotal and Protocol Selected Studies)

Objectives

To perform a systematic review of the beneficial and harmful effects of trastuzumab deruxtecan (5.4 mg/kg by IV infusion every 21 days) for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received at least 1 prior anti-HER2-based regimen in the metastatic setting, or those who have received an anti-HER2 treatment in the neoadjuvant or adjuvant setting and have developed disease recurrence during or within 6 months of completing systemic neoadjuvant or adjuvant therapy.

Methods

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

The literature search for clinical studies was performed by an information specialist using a peer-reviewed search strategy according to the PRESS Peer Review of Electronic Search Strategies checklist.¹⁷ Published literature was identified by searching the following bibliographic databases: MEDLINE All (1946–) via Ovid and Embase (1974–) via Ovid. All Ovid searches were run simultaneously as a multi-file search. Duplicates were removed using Ovid deduplication for multi-file searches, followed by manual deduplication in EndNote. The search strategy comprised both controlled vocabulary, such as the National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. The main search concepts were Enhertu and trastuzumab deruxtecan. The following clinical trials registries were searched: the US National Institutes of Health’s clinicaltrials.gov, WHO’s International Clinical Trials Registry Platform (ICTRP) search portal, Health Canada’s Clinical Trials Database, and the European Union Clinical Trials Register. No filters were applied to limit the retrieval by study type. Retrieval was not limited by publication date or by language. Conference abstracts were excluded from the search results. The initial search was completed on April 14, 2022. Regular alerts updated the search until the meeting of the CADTH pan-Canadian Oncology Drug Review Expert Committee (pERC) on August 10, 2022. Refer to Appendix 1 for the detailed search strategies.

Grey literature (literature that is not commercially published) was identified by searching relevant websites from the Grey Matters: A Practical Tool For Searching Health-Related Grey Literature resource.¹⁸ Included in this search were the websites of regulatory agencies (US FDA and European Medicines Agency). Google was used to search for additional internet-based materials. Refer to Appendix 1 for more information on the grey literature search strategy.

These searches were supplemented by reviewing bibliographies of key papers and through contacts with appropriate experts. In addition, the manufacturer of the drug was contacted for information regarding unpublished studies. Two CADTH clinical reviewers independently selected studies for inclusion in the review based on titles and abstracts, according to the predetermined protocol. Full-text articles of all citations considered potentially relevant by at least 1 reviewer were acquired. Reviewers independently made the final selection of studies to be included in the review, and differences were resolved through discussion.

Findings From the Literature

Two reports of a single study^12,13 were identified from the literature for inclusion in the systematic review (Figure 1). The included study is summarized in Table 6.

Figure 1: Flow Diagram for Inclusion and Exclusion of Studies

Table 6: Details of the Included Study

ADC = antibody drug conjugate; ANC = absolute neutrophil count; aPTT = activated partial thromboplastin time; ASCO = American Society of Clinical Oncology; BICR = blinded independent central review; CAP = College of American Pathologists; CBR = clinical benefit rate; CNS = central nervous system; COPD = chronic obstructive pulmonary disease; CrCL = creatinine clearance; DOR = duration of response; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EORTC QLQ-BR45 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Breast Cancer 45; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; EQ-5D-5L = 5-Level EQ-5D; HBV = hepatitis B virus; G-CSF = granulocyte colony-stimulating factor; HCV = hepatitis C virus; HER2 = human epidermal growth factor receptor 2; IA = investigator assessment; ILD = interstitial lung disease; INR = international normalized ratio; LV = left ventricle; mAb = monoclonal antibody; mRECIST = modified Response Evaluation Criteria in Solid Tumours; NYHA = New York Heart Association; OL = open label; ORR = objective response rate; OS = overall survival; PCR = polymerase chain reaction; PFS = progression-free survival; PFS2 = progression-free survival on the next line of therapy; PS = performance status; PT = prothrombin time; PTT = partial thromboplastin time; QTc = corrected QT interval; RCT = randomized controlled trial; RNA = ribonucleic acid; TBIL = total bilirubin; TTR = time to response; ULN = upper limit of normal.

Note: One additional report was included (the DESTINY-Breast03 Clinical Study Report).

^aThe first informed consent was signed on 09 August 2018 according to the DESTINY-Breast03 Clinical Study Report.

^bG-CSF administration was not allowed within 1 week of screening assessment.

^cPlatelet transfusion was not allowed within 1 week of screening assessment.

^dRed blood cell transfusion was not allowed within 1 week of screening assessment.

Source: DESTINY-Breast03 Clinical Study Report.¹³

Description of Studies

The key characteristics of the DESTINY-Breast03 study are summarized in Table 6. DESTINY-Breast03 was a phase III, multicentre, OL randomized controlled trial (RCT) designed to compare the efficacy and safety of trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive MBC previously treated with taxane chemotherapy plus trastuzumab (N = 524).¹² The primary objective of the study was to compare the PFS benefits per BICR of trastuzumab deruxtecan versus trastuzumab emtansine in pretreated patients with HER2-positive MBC, and the key secondary objective (hierarchically tested) was to compare the OS benefits of the 2 drugs.

Following screening, adult patients (aged 18 years or older) with HER2-positive MBC that was previously treated with trastuzumab plus taxane chemotherapy in the metastatic setting (or who had progressed within 6 months after neoadjuvant or adjuvant treatment involving a regimen including trastuzumab and taxane) were enrolled from July 20, 2018, to June 23, 2020, at 169 centres in 15 countries (1 site, n = 2 patients in Canada). Patients were randomized on a 1:1 ratio using an Interactive Web and Voice Response System to receive OL trastuzumab deruxtecan (5.4 mg/kg by IV infusion every 21 days) or OL trastuzumab emtansine (3.6 mg/kg by IV infusion every 21 days) until disease progression or unacceptable toxicity. Randomization was stratified by hormone receptor status (positive or negative), prior treatment with pertuzumab (yes or no), and history of visceral disease (yes or no). Following treatment discontinuation, patients were followed for survival every 3 months until death. Enrolment was complete and the study was ongoing at the time this report was prepared; the data cut-off for the results presented in this report was May 21, 2021. The study was funded by Daiichi Sankyo, who jointly developed and commercialized the drug with the sponsor.

Populations

Inclusion and Exclusion Criteria

Key eligibility criteria for the DESTINY-Breast03 study are summarized in Table 6. Adult patients (age 18 years or older) with pathologically documented MBC that was HER2-positive according to American Society for Clinical Oncology-College of American Pathologists criteria and was previously treated with taxane chemotherapy plus trastuzumab in the metastatic setting (or progressed within 6 months of neoadjuvant or adjuvant therapy with taxane chemotherapy plus trastuzumab) were eligible if documented disease progression occurred during or after the most recent treatment (or within 6 months of completing adjuvant therapy), at least 1 measurable lesion was present, and the patient had an ECOG PS of 0 or 1, with adequate hematological, renal, and hepatic function. Patients who had previously been treated with an anti-HER2 antibody drug conjugate in the metastatic setting were excluded; however, prior treatment in the adjuvant or neoadjuvant setting was allowed if disease progression had not occurred within 12 months of the end of adjuvant therapy. Patients with spinal cord compression or clinically active CNS metastases (untreated, symptomatic, or requiring treatment with corticosteroids; patients with inactive or asymptomatic brain metastases were eligible) or a history of clinically significant cardiovascular disease or ILD were excluded.

Baseline Characteristics

The baseline demographic characteristics of patients in the DESTINY-Breast03 study are shown in Table 7. The mean age was 54.4 years (SD = 11.47 years), approximately 60% of patients were Asian, and only 2 patients were male. Only 6.5% of patients were from North America.

The baseline disease characteristics of patients in the DESTINY-Breast03 study are shown in Table 8. In the trastuzumab deruxtecan arm, 59.0% of patients had an ECOG PS of 0 and 40.6% had an ECOG PS of 1, while in the trastuzumab emtansine arm, 66.5% of patients had an ECOG PS of 0 and 33.1% of patients had an ECOG PS of 1. Approximately half of patients had hormone receptor positive disease (approximately half of patients had estrogen receptor positive disease, while approximately one-third had progesterone receptor positive disease). Approximately 60% of patients had received prior pertuzumab, approximately 73% and 70% had visceral metastases at baseline or a reported history of visceral metastases, respectively, and approximately 16% and 22% had CNS metastases at baseline or a reported history of CNS metastases, respectively. Approximately 90% of patients had 3 or higher HER2 expression by immunohistochemistry. Approximately 72% of patients had received 2 lines or fewer prior systemic therapies excluding hormone therapies, while approximately 28% had received 3 or more lines of systemic therapy.

A more detailed summary of prior systemic therapies for breast cancer in the DESTINY-Breast03 study are shown in Table 9. All patients had received at least 1 prior systemic therapy for breast cancer and the mean number of prior regimens received was 3.3 (SD = 2.33 regimens). Approximately 40% of patients had received 1 prior line of therapy in the metastatic setting, while approximately 60% had received 2 or more prior lines (note that the definition of lines of prior systemic therapy in the metastatic setting included patients for whom the therapy was intended to treat locally advanced, metastatic, or palliative disease and patients for whom the therapy was intended as neoadjuvant, adjuvant, or maintenance therapy and whose disease progressed within 6 months from the end of therapy [12 months for pertuzumab]). Approximately 87% of patients had received prior systemic therapy meant to treat metastatic disease.

Table 7: Summary of Baseline Demographic Characteristics in the DESTINY-Breast03 Study (FAS)

BMI = body mass index; FAS = full analysis set; SD = standard deviation.

^aAge in years was calculated using the date of birth and the date of informed consent.

Source: DESTINY-Breast03 Clinical Study Report.¹³

Table 8: Summary of Baseline Disease Characteristics in the DESTINY-Breast03 Study (FAS)

AST = aspartate transaminase; CNS = central nervous system; ECOG = Eastern Cooperative Oncology Group; EDC = electronic data capture; FAS = full analysis set; HER2 = human epidermal growth factor receptor; IHC = immunohistochemistry; ISH = in situ hybridization; IXRS = interactive web/voice response system; PS = performance status; SD = standard deviation; ULN = upper limit of normal.

^aHormone receptors were classified as positive if estrogen receptors and/or progesterone receptors were positive; were classified as negative if estrogen receptors and progesterone receptors were negative; and were classified as indeterminate if neither estrogen receptors nor progesterone receptors were positive and either estrogen receptors or progesterone receptors were indeterminate. Derived data are those reported from EDC.

^bBaseline visceral disease was determined with any target or non-target tumour in defined lesion locations.

^cDuring tissue screening, tissue samples were first tested for HER2 IHC. Only samples with HER2 IHC 2 or higher were tested for HER2 gene amplification (ISH).

^dNormal renal function was classified as creatinine clearance of 90 mL per minute or more; mild renal impairment was classified as creatinine clearance of 60 mL per minute or more but less than 90 mL per minute; moderate renal impairment was classified as creatinine clearance of 30 mL per minute or more but less than 60 mL per minute; severe renal impairment was classified as creatinine clearance of 15 mL per minute or more but less than 30 mL per minute; and end-stage renal disease was classified as creatinine clearance of less than 15 mL per minute.

^eNormal hepatic function was classified as total bilirubin less than or equal to the ULN (and AST less than or equal to the ULN) except for patients with Gilbert syndrome, or total bilirubin less than or equal to 3.0 times the ULN (and AST less than or equal to the ULN) in patients with Gilbert syndrome; mild hepatic dysfunction was classified as total bilirubin greater than the ULN but less than or equal to 1.5 times the ULN (any AST) except for patients with Gilbert syndrome, or total bilirubin greater than the ULN but less than or equal to 3.0 times the ULN (and AST greater than the ULN) for patients with Gilbert syndrome, or total bilirubin less than or equal to the ULN (and AST greater than the ULN) regardless of Gilbert syndrome; moderate hepatic dysfunction was classified as total bilirubin greater than 1.5 times the ULN but less than or equal to 3.0 times the ULN (any AST) except for patients with Gilbert syndrome; and severe hepatic dysfunction was classified as total bilirubin greater than 3.0 times the ULN (and any AST) regardless of Gilbert syndrome.

Source: DESTINY-Breast03 Clinical Study Report.¹³

Table 9: Summary of Prior Breast Cancer Systemic Therapy in the DESTINY-Breast03 Study (FAS)

FAS = full analysis set; SD = standard deviation.

^aPrior cancer systemic therapy case report form pages were not completed for 2 patients who were mistakenly randomized but not treated.

^bThe definition of “lines of prior systemic therapy in the metastatic setting” included patients for whom the therapy was intended to treat locally advanced, metastatic, or “other” (palliative) disease and patients for whom the therapy was intended as neoadjuvant, adjuvant, or maintenance and whose disease progressed within 6 months from the end of therapy (12 months for pertuzumab), only if the date of the end of therapy and the date of progression were present after imputation.

^cPatients may have received more than 1 type of therapy.

^dPercentages are based on the number of patients with the corresponding prior cancer systemic therapy.

^ePercentages are based on the number of patients who received trastuzumab as prior cancer systemic therapy.

Source: DESTINY-Breast03 Clinical Study Report.¹³

Interventions

Trastuzumab deruxtecan (starting dose 5.4 mg/kg) was administered as an IV infusion over 90 minutes for the first dose and over a minimum of 30 minutes for subsequent doses on day 1 of a 21-day treatment cycle. Trastuzumab emtansine (starting dose of 3.6 mg/kg) was administered in a similar manner. Treatment was continued until disease progression (per IA), unacceptable toxicity, treatment delay of 4 weeks or longer, withdrawal of consent, physician decision, or death, whichever occurred first.

Prophylactic treatment of drug-related nausea and vomiting was permitted at the investigator’s discretion per institutional guidelines. It was recommended that patients receive prophylactic antiemetic drugs before infusion of trastuzumab deruxtecan and on subsequent days. Hematopoietic growth factors could be used for prophylaxis or treatment at the investigator’s discretion. Use of other anticancer therapies (except for bisphosphonates or RANKL pathway inhibitors for the prevention or treatment of skeletal-related events), chloroquine or hydroxychloroquine, investigational drugs, radiotherapy (except for palliative radiation to metastatic sites if it did not affect response assessment or interrupt treatment for longer than 4 weeks), and long-term use of corticosteroids or other immunosuppressive medications were prohibited during the treatment period.

Guidelines for dose modification of trastuzumab deruxtecan due to toxicity are provided in Appendix 2. Does modifications of trastuzumab emtansine due to toxicity were made based on the locally approved label. Two dose reductions were permitted for each treatment arm (trastuzumab deruxtecan: starting dose of 5.4 mg/kg, first dose reduction to 4.4 mg/kg, second dose reduction to 3.2 mg/kg; trastuzumab emtansine: starting dose of 3.6 mg/kg, first dose reduction to 3.0 mg/kg, second dose reduction to 2.4 mg/kg). Once the dose of the study drug was reduced due to toxicity, all subsequent cycles were administered at that lower dose level unless further dose reduction was required. No dose re-escalations were allowed. If toxicity continued after 2 dose reductions, then the patient was withdrawn from the study drug. The dose could have been interrupted for up to 28 days from the planned date of administration. If a patient was assessed as requiring a dose delay of longer than 28 days, they were permanently discontinued from the study treatment.

Outcomes

A list of efficacy end points identified in the CADTH review protocol that were assessed in the clinical trial included in this review is provided in Table 10. These end points are further summarized in the following text. A detailed discussion and critical appraisal of the outcome measures is provided in Appendix 3.

Table 10: Summary of Outcomes of Interest Identified in the CADTH Review Protocol

BICR = blinded independent central review; CR = complete response; DOR = duration of response; EORTC QLQ-BR45 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Breast Cancer 45; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; IA = investigator assessment; mRECIST = modified Response Evaluation Criteria in Solid Tumours; NA = not applicable; ORR = objective response rate; OS = overall survival; PFS = progression-free survival; PR = partial response.

Source: DESTINY-Breast03 Clinical Study Report.¹³

OS, PFS, ORR, and DOR are standard and broadly accepted outcome measures in oncology trials for the treatment of MBC (refer to Table 10 and Table 11 for outcome definitions and censoring rules). Tumour assessment by CT/MRI of the chest, abdomen, pelvis, and any other sites of disease was performed during screening (within 4 weeks of cycle 1 day 1). CT or MRI of the brain was also performed during screening. During the treatment period, tumour imaging was performed every 6 weeks as well as within 1 week of study drug discontinuation; brain imaging was mandatory on the same schedule for patients with baseline stable brain metastases and was conducted if clinically indicated in other patients. Involvement of all sites of disease identified during screening and any additional newly suspected sites of progressive disease was assessed. For patients who discontinued treatment for reasons other than disease progression, tumour assessments were to be continued until disease progression. The same imaging modality was used for each patient throughout the study. Anonymized copies of all scans were sent for BICR.

Tumour response was assessed using mRECIST version 1.1.¹⁹ Progressive disease was defined as a predefined increase in the sum of diameters of target lesions (at least 20%), taking as reference the smallest sum of diameters on study, in target lesions or the appearance of new non-target lesions; the sum must also have demonstrated an absolute increase of at least 5 mm. Partial response was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Complete response was defined as the 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 of diameters while on study) to qualify for progressive disease. Under the mRECIST version 1.1 criteria, assessment of response by investigators was based on local imaging scans as well as clinical evaluation (e.g., using skin caliper measurements). An initial indication of response was confirmed at the next scheduled assessment.

Decisions to discontinue protocol therapy due to progressive disease were made by the investigator based on local imaging scans and clinical evaluation to assess clinical deterioration in the absence of radiological evidence. Patients who discontinued treatment without documented progressive disease continued to have radiological assessments every 6 weeks until progressive disease, death, or the date of study termination. Following disease progression, patients were followed up for survival every 3 months until death.

Patient-reported HRQoL was assessed using the EQ-5D-5L, EORTC QLQ-C30, and EORTC QLQ-BR45 instruments on day 1 of cycles 1, 2, 3, and then every 2 cycles thereafter as well as at the time of study drug discontinuation. For a detailed description of the measurement properties of these instruments, refer to Appendix 3. Neither the measurement properties nor the minimal important difference (MID) of these instruments have been specifically established in patients with HER2-positive 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 visual analogue scale (VAS) among cancer patients, and differences of approximately 4 to 18 points in the EORTC QLQ-C30 individual items and scale scores among patients with MBC are typically considered significant. MIDs for EORTC QLQ-BR45 individual items and scale scores are uncertain.

• The EQ-5D-5L²⁰ is a generic, preference-based measure of HRQoL consisting of 5 domains: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression; index scores range from 0 to 1, with 0 and 1 representing the health states “dead” and “perfect health,” respectively, while EQ VAS scores range from 0 to 100, with 0 and 100 representing “worst imaginable health” and ”best imaginable health,” respectively.

• The EORTC QLQ-C30²¹ 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, higher symptoms on the symptom scales, and better HRQoL on the global quality of life scale.

• The EORTC QLQ-BR45²² is a 45-item patient-reported, breast cancer-specific, HRQoL questionnaire; each item is evaluated using 4-point Likert scales, where 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, higher symptoms on the symptom scales, and better HRQoL on the global quality of life scale.

Harms outcomes included treatment-emergent AEs, SAEs, AEs requiring dose reduction, WDAEs, adverse events of special interest (AESIs), and deaths. AESIs were defined as ILD or pneumonitis and LV dysfunction. AEs that began or worsened on or after the start of protocol therapy until 47 days after the last dose of the study drug were captured. AEs were defined as any untoward medical occurrence and were coded according to Medical Dictionary for Regulatory Activities, version 23.0,²³ and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0.²⁴

Statistical Analysis

The statistical analysis of efficacy outcomes in the DESTINY-Breast03 study is summarized in Table 11. Randomization stratification factors were used in the primary efficacy analysis of PFS per BICR, sensitivity analyses of PFS per BICR, analysis of OS, analysis of PFS per IA, and analysis of ORR per BICR. In addition, the following key prognostic factors were used in a Cox regression model as covariates for PFS per BICR assessment as well as treatment arm: ECOG PS (0 or 1), lines of prior systemic therapy not including hormone therapy (< 3 or ≥ 3), clinically inactive CNS metastases at baseline (yes or no), and age (< 65 or ≥ 65 years). Missing or dropout data were not imputed unless otherwise specified.

Planned Analyses and Multiplicity Control

In the initial version of the protocol, the primary efficacy end point of PFS by BICR was to be analyzed when approximately 331 BICR-assessed PFS events had been observed. The primary efficacy end point, PFS, and the key secondary efficacy end point, OS, would be tested hierarchically to maintain the overall 2-sided type I error rate to 0.05 or less.

Protocol Changes

Based on emergent data from the DESTINY-Breast01 study,¹⁶ the sponsor believed there was a strong rationale to evaluate the primary efficacy end point of PFS at an earlier time point. Therefore, the protocol was amended to add an interim analysis of PFS, which was to be conducted after approximately 234 BICR-assessed PFS events (70% information fraction) had been observed. If the study was not statistically significant at this interim analysis, the final PFS analysis was to be performed after observing 335 BICR-assessed PFS events. A group sequential design, using a 2-look Lan-DeMets alpha spending function with O’Brien-Fleming efficacy boundary, would be used to control the type I error rate for the primary efficacy analysis with an overall 2-sided significance level of 0.05.

To ensure that the study would be declared positive only if the results from the PFS interim analysis were robust enough to demonstrate not only statistical strength of evidence but also a highly clinically relevant magnitude of benefit compared with the control arm, the final version of the protocol changed the efficacy boundaries from the O’Brien-Fleming to the Haybittle-Peto efficacy boundaries with a 2-sided P value of 0.000204 for the interim analysis. A subsequent protocol change allowed up to 2 planned interim PFS analyses and a final analysis of OS, provided PFS was statistically significant. The final OS analysis was planned after approximately 250 OS events had been documented. A group sequential design, using a 3-look Lan-DeMets alpha spending function with an O’Brien-Fleming efficacy boundary, was used to construct the efficacy stopping boundaries for OS with an overall 2-sided significance level of 0.05. If PFS was significant in the interim analysis for PFS, an interim analysis for OS was also to be performed. This guaranteed the protection of the overall significance level across the 2 hypotheses and the repeated testing of the OS hypotheses in the interim and the final analyses.

Power for Interim and Final Analyses

Assuming a median PFS of 9.6 months in the trastuzumab emtansine arm (based on the results of the EMILIA study²⁵), it was hypothesized that treatment with trastuzumab deruxtecan would result in an HR of 0.7, corresponding to an improvement in median PFS from 9.6 months in the trastuzumab emtansine arm to 13.7 months in the trastuzumab deruxtecan arm under the exponential model assumption. A total of approximately 500 patients were planned to be randomized (250 patients to trastuzumab deruxtecan and 250 patients to trastuzumab emtansine). An interim analysis allowing the study to declare superiority for the primary PFS end point was planned after approximately 234 (70%) of the targeted PFS events were documented. The final PFS analysis would occur after approximately 335 PFS events had been documented, but only if superiority was not demonstrated at the interim analysis. With 335 PFS events, the study would have approximately 90.4% power to detect an HR of 0.70 in PFS at an overall 2-sided significance level of 0.05 to reject the null hypothesis (HR = 1) using a log-rank test and a 2-look group sequential design with Haybittle-Peto efficacy boundary.

OS would be compared between the 2 treatment groups provided that the test of the primary end point PFS was statistically significant at either the interim analysis or final analysis. Assuming a median OS of 29.9 months in the trastuzumab emtansine arm based on the results of the EMILIA study, it was hypothesized that treatment with trastuzumab deruxtecan would result in an HR of 0.7 for OS, corresponding to an improvement in median OS from 29.9 months in the trastuzumab emtansine to 42.7 months in the trastuzumab deruxtecan arm under the exponential model assumption. With 250 OS events, the study would have approximately 80% power (conditional on PFS being statistically significant) to detect an HR of 0.70 in OS at an overall 2-sided significance level of 0.05 to reject the null hypothesis (HR = 1) using a log-rank test and a 3-look group sequential design with Lan-DeMets alpha spending function with an O’Brien-Fleming efficacy boundary. If the true HR was 0.7, it was estimated that approximately 96 (38.4%) and 153 (61.2%) of the targeted OS events would be documented at the timing of the 2 OS interim analyses (when PFS interim and final analyses were performed).

Analytical Techniques

For the primary end point (PFS per BICR) and key secondary end point (OS), the trastuzumab deruxtecan and trastuzumab emtansine arms were compared using a 2-sided stratified log-rank test. The HR comparing treatment arms was calculated from stratified Cox proportional hazards model with treatment as the sole covariate. Stratification factors for these analyses were hormone receptor status, prior pertuzumab, and visceral disease. CIs adjusted for the corresponding significance level (95%) of the HR were calculated. The PFS and OS functions were estimated using the Kaplan-Meier (KM) product limit method; 2-sided 95% CIs for median survival were obtained by log-rank transformation. PFS and OS rates at fixed time points and their 95% CIs were derived from KM analysis. Analysis of PFS per IA as a secondary outcome and analysis of DOR was performed in the same manner as the primary analysis. Note that the primary analysis of PFS per BICR was not censored due to initiation of other anticancer therapy following study drug discontinuation (although censoring was incorporated in a sensitivity analysis of PFS per BICR). Similarly, OS was not censored at the time of initiating new anticancer therapy following study drug discontinuation.ORR and its exact 95% CI was calculated in each treatment group using the Clopper-Pearson method. The differences in ORRs between treatment groups and corresponding 95% CIs were calculated using the Cochran-Mantel-Haenszel methodology adjusted by stratification factors used for randomization. Stratified ORs and their 95% CIs were calculated using the Mantel-Haenszel estimator. Patients who discontinued the study and tumour assessments before objective response were counted as nonresponders. Patient-reported HRQoL data (i.e., EQ-5D-5L index score, EQ VAS, EORTC QLQ-C30, and EORTC QLQ-BR45) were presented as descriptive and summary statistics.

Sensitivity analyses for the primary analysis of PFS per BICR included unstratified analysis with stratification factors as covariates, stratified analysis in the per-protocol set, analysis including censoring of PFS at the initiation of new anticancer therapy, analysis of PFS with back-dating progression for PFS events that occurred after the patient missed 1 or more tumour assessments, and multiple Cox regression analyses with additional covariates (set 1: age, ECOG PS, lines of prior systemic therapy not including hormone therapy, baseline CNS metastases; set 2: age, ECOG PS, lines of prior systemic therapy not including hormone therapy, history of CNS metastases).

Subgroup analyses of prespecified subgroups (by hormone receptor status, estrogen receptors, progesterone receptors, prior treatment with pertuzumab, lines of prior systemic therapy not including hormone therapy, renal impairment at baseline, hepatic impairment at baseline, baseline visceral disease, baseline lung metastases, baseline liver metastases, baseline CNS metastases, reported history of CNS metastases, age, race, region, and ECOG PS) were conducted per the primary analysis in exploratory fashion. The study was not specifically powered to evaluate outcomes in individual strata, and testing for interactions were not conducted.

Analysis Populations

The full analysis set (FAS) included all randomized patients; following the intent-to-treat principle, patients were analyzed according to the treatments and strata to which they were assigned at randomization. The per-protocol set included all patients from the FAS who complied sufficiently with the protocol with respect to exposure to study treatment, availability of tumour assessments, and absence of major protocol deviations likely to affect efficacy outcomes (requirements were to have received at least 1 dose of the study drug intended, as per randomization; at least 1 evaluable post-baseline tumour assessment per BICR or died within 14 weeks of first dose; absence of major protocol deviations). The safety analysis set included all randomized patients who received at least 1 dose of the study treatment; patients were summarized according to the treatment they actually received.

Results

Patient Disposition

Patient disposition in the DESTINY-Breast03 study is summarized in Table 12. A total of 699 patients were screened, of which 175 (25.0%) were categorized as screen failures. An analysis of reasons for screen failure was not provided. The remaining 524 patients were randomized to the trastuzumab deruxtecan (n = 261) and trastuzumab emtansine (n = 263) arms for OL treatment. The vast majority of participants (98% in the trastuzumab deruxtecan arm and 99.2% in the trastuzumab emtansine arm) received at least 1 dose of the study drug. The mean study duration was months (SD = |||||| months) in the trastuzumab deruxtecan arm and |||||| months (SD = |||||| months) in the trastuzumab emtansine arm. As of the May 21, 2021, data cut-off, approximately 49% and 82% of patients in the trastuzumab deruxtecan and trastuzumab emtansine arms, respectively, had discontinued treatment. The most common reasons for treatment discontinuation were progressive disease (trastuzumab deruxtecan = 25.7%; trastuzumab emtansine = 60.5%) and AEs (trastuzumab deruxtecan = 13.6%; trastuzumab emtansine = 6.5%). In the trastuzumab deruxtecan arm, 5.1% of patients discontinued treatment due to patient withdrawal and 1.6% discontinued treatment due to clinical progression per IA, while in the trastuzumab emtansine arm, 4.2% of patients discontinued treatment due to patient withdrawal and 4.6% discontinued treatment due to clinical progression per IA.

Table 12: Patient Disposition in the DESTINY-Breast03 Study

AE = adverse events; FAS = full analysis set; mRECIST = modified Response Evaluation Criteria in Solid Tumours; PP = per protocol; SD = standard deviation.

^aStudy duration (months) was defined as (end of study participation date – randomization date + 1)/365.25 × 12.

^bThe percentage was based on the number of patients in the safety analysis set (257 patients in the trastuzumab deruxtecan arm and 261 patients in the trastuzumab emtansine arm).

^cTwo patients were off the study drug for more than 28 days.

^dOne patient was noncompliant, 1 patient had a persistent tumour at the gamma knife site in the brain, 1 patient withdrew due to patient decision, 1 patient was off the study drug for more than 28 days, and 1 patient had hepatic failure.

^ePatients withdrew consent for tumour assessments but were followed for survival.

Source: DESTINY-Breast03 Clinical Study Report.¹³

Major protocol deviations during the DESTINY-Breast03 study (those that had the potential to impact patient safety, substantially alter risks to patients, affect the integrity of study data, influence the conduct of the study, or affect the patient’s willingness to participate in the study) are summarized in Table 13. Major protocol deviations occurred in 26 (10.0%) patients randomized to the trastuzumab deruxtecan arm and 22 (8.4%) patients randomized to the trastuzumab emtansine arm.

Exposure to Study Treatments

Treatment exposure in the DESTINY-Breast03 study is summarized in Table 14. Treatment compliance was assessed by site personnel during IV infusion of the study drug at each visit. As of the May 21, 2021, data cut-off date, the mean duration of treatment was ||||| months (SD = ||||| months) in the trastuzumab deruxtecan arm and |||| months (SD = ||||| months) in the trastuzumab emtansine arm. The mean relative dose intensity approached 100% in both treatment arms.

Anticancer therapies received after discontinuation of the study treatment in the DESTINY-Breast03 study are summarized in Table 15. As of the May 21, 2021, data cut-off date, smaller proportions of patients randomized to the trastuzumab deruxtecan arm had initiated new radiation, surgery, or systemic therapy for cancer (3.8%, 0.8%, and 29.9%, respectively) following discontinuation of the study drug compared with the trastuzumab emtansine arm (9.5%, 3.8%, and 62.4%, respectively). Following study drug discontinuation, higher proportions of patients randomized to receive trastuzumab deruxtecan received trastuzumab emtansine as subsequent therapy compared with patients randomized to receive trastuzumab emtansine (16.5% versus 6.5%). By contrast, following study drug discontinuation, lower proportions of patients randomized to receive trastuzumab deruxtecan versus trastuzumab emtansine received trastuzumab (8.8% versus 25.1%), trastuzumab deruxtecan (0% versus 11.4%), pertuzumab (4.2% versus 9.5%), taxane chemotherapy (1.9% versus 6.1%), taxane chemotherapy plus trastuzumab (1.1% versus 5.7%), other anti-HER2 drugs (6.1% versus 27.8%), hormone therapy (5.0% versus 8.0%), and other systemic therapy (15.3% versus 47.9%).

Table 13: Protocol Deviations in the DESTINY-Breast03 Study (FAS)

FAS = full analysis set.

Note: For each category and deviation, patients were counted only once, regardless off the number of events in that category of deviation.

Source: DESTINY-Breast03 Clinical Study Report.¹³

Table 14: Treatment Exposure in the DESTINY-Breast03 Study (Safety Set)

SD = standard deviation.

^aTreatment duration = (last dose date – first dose date + 21) × 12/365.25 (interruptions included).

^bDose intensity (mg/kg per 3 weeks) = total amount of drug taken / (treatment duration [days]/21).

^cRelative dose intensity (%) = dose intensity/planned dose intensity × 100.

Source: DESTINY-Breast03 Clinical Study Report.¹³

Table 15: Subsequent Therapies in the DESTINY-Breast03 Study Received Following Study Drug Discontinuation (FAS)

ADC = antibody drug conjugate; FAS = full analysis set; HER2 = human epidermal growth factor receptor 2; TKI = tyrosine kinase inhibitor.

^aDenominator is the full analysis set.

Note: Patients may have received more than 1 subsequent treatment.

Source: Cortés et al. (2022).¹²

Note that the primary analysis of PFS per BICR was not censored due to initiation of other anticancer therapies following study drug discontinuation (although censoring was incorporated into a sensitivity analysis of PFS per BICR). Similarly, OS was not censored at the time of initiating a new anticancer therapy following study drug discontinuation. Crossover from trastuzumab deruxtecan to trastuzumab emtansine (trastuzumab deruxtecan arm = 16.5%), crossover from trastuzumab emtansine to trastuzumab deruxtecan (trastuzumab emtansine arm = 11.4%), and post-progression re-treatment with trastuzumab emtansine (trastuzumab emtansine arm = 6.5%) were imbalanced between treatment arms.

Efficacy

Only those efficacy outcomes and analyses of subgroups identified in the review protocol are reported in the following. Refer to Appendix 3 for detailed efficacy data (sensitivity and subgroup analyses of PFS per BICR and OS).

Table 16: OS in the DESTINY-Breast03 Study (FAS)

CI = confidence interval; FAS = full analysis set; HR = hazard ratio; NE = not estimable; OS = overall survival.

^aFrom Kaplan-Meier analysis.

^bTwo-sided P value is from the stratified log-rank test; HR and 95% CI are from the stratified Cox proportional hazards model with hormone receptor status, prior pertuzumab, and history of visceral disease stratification factors.

Source: DESTINY-Breast03 Clinical Study Report.¹³

Overall Survival

An analysis of the hierarchically tested key secondary outcome of OS in the DESTINY-Breast03 study is summarized in Table 16 and Figure 2. As of the May 21, 2021, data cut-off date, OS events had occurred in 33 (12.6%) patients in the trastuzumab deruxtecan arm and 53 (20.2%) patients in the trastuzumab emtansine arm. |||||||| patients |||||||| in the trastuzumab deruxtecan arm and |||||||| patients (||||||||) in the trastuzumab emtansine arm had been lost to follow-up. Median OS and its 95% CI could not be estimated in either treatment arm. The HR for OS comparing trastuzumab deruxtecan with trastuzumab emtansine was 0.5546 (95% CI, 0.3587 to 0.8576) in favour of trastuzumab deruxtecan; however, the stratified log-rank P value of 0.007172 did not cross the prespecified boundary for the interim analysis (P < 0.000265) calculated based on 86 OS events. The 12-month OS rate was 94.1% (95% CI, 90.3% to 96.4%) in the trastuzumab deruxtecan arm and 85.9% (95% CI, 80.9% to 89.7%) in the trastuzumab emtansine arm.

Subgroup analyses of OS by hormone receptor status, estrogen receptors, progesterone receptors, prior treatment with pertuzumab, lines of prior therapy not including hormone therapy, baseline visceral disease, baseline CNS metastases, and history of CNS metastases were consistent with the main analysis across all strata (refer to Appendix 2). A subgroup analysis of OS by time from neoadjuvant or adjuvant therapy to development of MBC (less than 6 months versus 6 months or longer) was not conducted. Sensitivity analyses of OS were not conducted because the prespecified boundary for the interim analysis was not crossed. OS results from a more recent data cut were requested but not provided, although the sponsor confirmed that the trigger for the next interim analysis of OS (approximately 153 OS events) had not yet been reached.

Figure 2: Kaplan-Meier Plot of OS in the DESTINY-Breast03 Study (FAS)

CI = confidence interval; FAS = full analysis set; HR = hazard ratio; IA = investigator assessment; NE = not estimable; OS = overall survival; PFS = progression-free survival; T-DM1 = trastuzumab emtansine; T-DXd = trastuzumab deruxtecan.

Note: HR is from a stratified Cox proportional hazard model and P value is from the stratified log-rank test.

Source: DESTINY-Breast03 Clinical Study Report.¹³

Progression-Free Survival per Blinded Independent Central Review

Analysis of the primary outcome of PFS per BICR in the DESTINY-Breast03 study is summarized in Table 17 and Figure 3. As of the May 21, 2021, data cut-off, PFS events per BICR had occurred in 87 (33.3%) patients in the trastuzumab deruxtecan arm and 158 (60.1%) patients in the trastuzumab emtansine arm. The most common reasons for censoring of PFS per BICR were treatment ongoing without event (49.0% and 18.6% of the trastuzumab deruxtecan and trastuzumab emtansine arms, respectively) and adequate tumour assessments no longer available (10.3% and 11.8% of the trastuzumab deruxtecan and trastuzumab emtansine arms, respectively). Median PFS per BICR had not yet been reached in the trastuzumab deruxtecan arm but the lower limit of the 95% CI was 18.5 months, while the median PFS per BICR was 6.8 months in the trastuzumab emtansine arm (95% CI, 5.6 to 8.2 months; P < 0.0001). The HR for PFS per BICR comparing trastuzumab deruxtecan with trastuzumab emtansine was 0.2840 (95% CI, 0.2165 to 0.3727) in favour of trastuzumab deruxtecan. The 12-month PFS per BICR rate was 75.8% (95% CI, 69.8% to 80.7%) in the trastuzumab deruxtecan arm and 34.1% (95% CI, 27.7% to 40.5%) in the trastuzumab emtansine arm.

Subgroup analyses of PFS per BICR by hormone receptor status, estrogen receptors, progesterone receptors, prior treatment with pertuzumab, lines of prior therapy not including hormone therapy, baseline visceral disease, baseline CNS metastases, and history of CNS metastases were consistent with the main analysis across all strata (refer to Appendix 3). In addition, a post- hoc subgroup analysis of PFS per BICR by time from neoadjuvant or adjuvant therapy to development of MBC (less than 6 months versus 6 months or longer) was consistent with the main analysis across both strata. Sensitivity analyses of PFS per BICR, including an analysis with censoring at the time of initiating a new anticancer therapy if this occurred before progression per BICR, were consistent with the main analysis (refer to Appendix 2). Only ||||| patients (|||||in the trastuzumab deruxtecan arm and ||||| in the trastuzumab emtansine arm) had PFS censored due to initiation of a new anticancer therapy before progression per BICR.

Table 17: PFS per BICR in the DESTINY-Breast03 Study (FAS)

BICR = blinded independent central review; CI = confidence interval; FAS = full analysis set; HR = hazard ratio; NE = not estimable; PFS = progression-free survival.

^aPatients whose last tumour scan was more than 14 weeks before the data cut-off date.

^bFrom a Kaplan-Meier analysis.

^cTwo-sided P value is from the stratified log-rank test; HR and 95% CI are from the stratified Cox proportional hazards model with hormone receptor status, prior pertuzumab, and history of visceral disease stratification factors.

Source: DESTINY-Breast03 Clinical Study Report.¹³

Figure 3: Kaplan-Meier Plot of PFS per BICR in the DESTINY-Breast03 Study (FAS)

BICR = blinded independent central review; CI = confidence interval; FAS = full analysis set; HR = hazard ratio; NE = not estimable; PFS = progression-free survival; T-DM1 = trastuzumab emtansine; T-DXd = trastuzumab deruxtecan.

Note: HR is from a stratified Cox proportional hazard model and P value is from the stratified log-rank test.

Source: DESTINY-Breast03 Clinical Study Report.¹³

Progression-Free Survival per Investigator Assessment

An analysis of the secondary outcome of PFS per IA in the DESTINY-Breast03 study is summarized in Table 18 and Figure 4. Note that this analysis was not part of the statistical hierarchy and not adjusted for multiplicity. As of the May 21, 2021, data cut-off date, PFS events per IA had occurred in || ||||||| patients in the trastuzumab deruxtecan arm and ||| ||||||| patients in the trastuzumab emtansine arm. The most common reasons for censoring of PFS per IA were treatment ongoing without event (||||| and ||||| of the trastuzumab deruxtecan and trastuzumab emtansine arms, respectively) and adequate tumour assessments no longer available (|||| and |||| of the trastuzumab deruxtecan and trastuzumab emtansine arms, respectively). Median PFS per IA was 25.1 months (95% CI, 22.1 months to not estimable) in the trastuzumab deruxtecan arm and 7.2 months (95% CI, 6.8 months to 8.3 months) in the trastuzumab emtansine arm. The HR for PFS per IA comparing trastuzumab deruxtecan with trastuzumab emtansine was 0.2649 (95% CI, 0.2011 to 0.3489) in favour of trastuzumab deruxtecan. The 12-month PFS per IA rate was 76.3% (95% CI, 70.4% to 81.2%) in the trastuzumab deruxtecan arm and 34.9% (95% CI, 28.8% to 41.2%) in the trastuzumab emtansine arm.

Table 18: PFS per IA in the DESTINY-Breast03 Study (FAS)

CI = confidence interval; FAS = full analysis set; HR = hazard ratio; IA = investigator assessment; NE = not estimable; PFS = progression-free survival.

^aPatients whose last tumour scan was more than 14 weeks before the data cut-off date.

^bFrom a Kaplan-Meier analysis.

^cTwo-sided P value is from the stratified log-rank test (note that this test is outside the statistical hierarchy and the P value is not adjusted for multiplicity); HR and 95% CI are from the stratified Cox proportional hazards model with hormone receptor status, prior pertuzumab, and history of visceral disease stratification factors.

Source: DESTINY-Breast03 Clinical Study Report.¹³

Figure 4: Kaplan-Meier Plot of PFS per IA in the DESTINY-Breast03 Study (FAS)

CI = confidence interval; FAS = full analysis set; HR = hazard ratio; IA = investigator assessment; NE = not estimable; PFS = progression-free survival; T-DM1 = trastuzumab emtansine; T-DXd = trastuzumab deruxtecan.

Note: HR is from a stratified Cox proportional hazard model and P value is from the stratified log-rank test (note that this test is outside the statistical hierarchy and the P value is not adjusted for multiplicity).

Source: DESTINY-Breast03 Clinical Study Report.¹³

Health-Related Quality of Life

All patient-reported HRQoL instruments had completion rates of 82% or higher among patients still receiving protocol therapy in both treatment arms from cycles 3 to 27 (weeks 9 to 81).

An analysis of EORTC QLQ-C30 scores in the DESTINY-Breast03 study is summarized in Table 19. Among patients with available data in the trastuzumab deruxtecan arm, the mean changes from baseline to end of treatment in global health status, physical functioning, emotional functioning, and social functioning were 1.98 (SD = 21.340), ||||||||||||||||||||||||||||||, and |||||||||||||||||||| respectively. Among patients with available data in the trastuzumab emtansine arm, the mean changes from baseline to end of treatment in global health status, physical functioning, emotional functioning, and social functioning were 4.07 (SD = 22.048), ||||||||||||||||||||||||||||||, and ||||||||||||||||||||||||||||||, respectively.

An analysis of the EQ-5D-5L scores in the DESTINY-Breast03 study is summarized in Table 20. Among patients with available data in the trastuzumab deruxtecan arm, the mean changes from baseline to end of treatment in EQ-5D-5L index scores and EQ VAS scores were |||||||||||||||||||| and ||||||||||||||||||||, respectively. Among patients with available data in the trastuzumab emtansine arm, the mean changes from baseline to end of treatment in EQ-5D-5L index scores and EQ VAS scores were |||||||||||||||||||| and ||||||||||||||||||||, respectively.

An analysis of EORTC QLQ-BR45 breast symptoms scale scores in the DESTINY-Breast03 study is summarized in Table 21. Among patients with available data in the trastuzumab deruxtecan arm, the mean change from baseline to end of treatment was ||||||||||. Among patients with available data in the trastuzumab emtansine arm, the mean change from baseline to end of treatment was ||||||||||.

Table 19: EORTC QLQ-C30 Scores in the DESTINY-Breast03 Study (FAS)

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

Note: Linear transformations are applied to global health status and all subscales of the EORTC QLQ-C30. A high score for global health status represents a low HRQoL; a high score for a functional scale represents a low and/or unhealthy level of functioning; a high score for a symptom scale or item represents a high level of symptomatology or problems.

Source: DESTINY-Breast03 Clinical Study Report.¹³

Table 20: EQ-5D-5L Scores in the DESTINY-Breast03 Study (FAS)

EQ-5D-5L = 5-Levels EQ-5D; FAS = full analysis set; SD = standard deviation; VAS = visual analogue scale.

Note: A linear transformation was applied to the health scale, which is measured according to a 0 mm to 100 mm VAS. A high VAS score represents worse overall self-rated health status.

Source: DESTINY-Breast03 Clinical Study Report.¹³

Table 21: EORTC QLQ-BR45 Breast Symptoms Scale Scores in the DESTINY-Breast03 Study (FAS)

EORTC QLQ-BR45 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Breast Cancer 45; FAS = full analysis set; SD = standard deviation.

Note: Linear transformations were applied to all subscales of the EORTC QLQ-BR45. A high score for a functional scale represents a low and/or unhealthy level of functioning; a high score for a symptom scale or item represents a high level of symptomatology or problems.

Source: DESTINY-Breast03 Clinical Study Report.¹³

Objective Response Rate per Blinded Independent Central Review and Investigator Assessment

Analysis of the secondary outcomes of ORR per BICR and per IA in the DESTINY-Breast03 study is summarized in Table 22. Note that this analysis was not part of the statistical hierarchy and not adjusted for multiplicity. The ORR per BICR was 79.7% (95% CI, 74.3% to 84.4%) in the trastuzumab deruxtecan arm and 34.2% (95% CI, 28.5% to 40.3%) in the trastuzumab emtansine arm. The ORR per IA was 77.0% (95% CI, 71.4% to 82.0%) in the trastuzumab deruxtecan arm and 36.9% (95% CI, 31.0% to 43.0%) in the trastuzumab emtansine arm. The difference in ORR per BICR was 45.5% (95% CI, 37.6% to 53.4%) in favour of trastuzumab deruxtecan.

Table 22: ORR per BICR and IA in the DESTINY-Breast03 Study (FAS)

BOR = best overall response; BICR = blinded independent central review; CI = confidence interval; CMH = Cochran-Mantel-Haenszel; FAS = full analysis set; IA = investigator assessment; NE = not estimable; ORR = objective response rate.

^aResult per BICR. This test was outside of the statistical hierarchy and the P value was not adjusted for multiplicity.

^bResult per IA. This test was outside of the statistical hierarchy and the P value was not adjusted for multiplicity.

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

^dBased on the CMH test adjusted for hormone receptor status, prior treatment with pertuzumab, and history of visceral disease stratification factors.

Source: DESTINY-Breast03 Clinical Study Report.¹³

Duration of Response per Blinded Independent Central Review and Investigator Assessment

An analysis of the secondary outcomes of DOR per BICR and per IA in the DESTINY-Breast03 study is summarized in Table 23. Note that this analysis was not part of the statistical hierarchy and not adjusted for multiplicity. Among patients who achieved objective responses to treatment, median DOR per BICR was not yet reached in either treatment arm (trastuzumab deruxtecan 95% CI, 20.3 months to not estimable; trastuzumab emtansine 95% CI, 12.6 months to not estimable). Among patients who achieved objective responses to treatment, median DOR per IA was not yet reached in either treatment arm (trastuzumab deruxtecan 95% CI, 20.8 months to not estimable; trastuzumab emtansine 95% CI, 14.1 months to not estimable).

Table 23: DOR per BICR and IA in the DESTINY-Breast03 Study (FAS)

BICR = blinded independent central review; CI = confidence interval; CR = complete response DOR = duration of response; FAS = full analysis set; IA = investigator assessment; NE = not estimable; partial response.

^aResult per BICR.

^bResult per IA.

^cPercentage was calculated using the number of patients with CR and PR.

^dFrom Kaplan-Meier estimate.

Source: DESTINY-Breast03 Clinical Study Report.¹³

Harms

Only those harms identified in the review protocol are reported in the following. Refer to Table 24 for detailed harms data.

Adverse Events

Almost all patients treated with trastuzumab deruxtecan (99.6%) and trastuzumab emtansine (95.4%) experienced at least 1 AE. Common AEs that occurred more frequently in patients receiving trastuzumab deruxtecan than in those receiving trastuzumab emtansine included nausea (75.9% versus 30.3%), fatigue (49.0% versus 34.5%), vomiting (49.0% versus 10.0%), neutropenia (42.8% versus 11.9%), alopecia (37.0% versus 3.1%), constipation (34.2% versus 19.5%), anemia (32.7% versus 17.2%), leukopenia (30.4% versus 8.4%), decreased appetite (29.2% versus 16.9%), diarrhea (29.2% versus 6.9%), abdominal pain (|||||||| versus ||||||||), stomatitis (|||||||| versus ||||||||), and weight loss (|||||||| versus ||||||||). Common AEs that occurred less frequently in patients receiving trastuzumab deruxtecan than in those receiving trastuzumab emtansine included increased aspartate transaminase (25.7% versus 40.2%) and thrombocytopenia (25.7% versus 53.3%).

Serious Adverse Events

SAEs occurred overall at similar rates in patients treated with trastuzumab deruxtecan (19.1%) and trastuzumab emtansine (18.0%). SAEs that occurred more frequently in patients receiving trastuzumab deruxtecan compared with trastuzumab emtansine included ILD (|||||||| versus ||||||||), vomiting (|||||||| versus ||||||||), and pyrexia (|||||||| versus ||||||||).

Withdrawals Due to Adverse Events

WDAEs occurred in 13.6% of patients treated with trastuzumab deruxtecan and 7.3% of patients treated with trastuzumab emtansine. The most common WDAE in patients receiving trastuzumab deruxtecan was ILD (8.2%).

AEs Leading to Dose Modification

AEs leading to study drug interruption occurred in 44.0% of patients treated with trastuzumab deruxtecan and 23.4% of patients receiving trastuzumab emtansine. The most common AEs leading to study drug interruption in patients receiving trastuzumab deruxtecan were neutropenia (||||||||) and leukopenia (||||||||). AEs leading to dose reduction occurred in 21.4% of patients treated with trastuzumab deruxtecan and 12.6% of patients receiving trastuzumab emtansine. The most common AE leading to dose reduction in patients receiving trastuzumab deruxtecan was nausea (||||||||).

Mortality

Five patients (1.9%) in each of the treatment groups had AEs associated with an outcome of death. In both treatment groups, the most common AEs associated with an outcome of death were disease progression (||||||||) and COVID-19 (||||||||).

Notable Harms

The study protocol-defined AESIs of ILD, decreased left ventricular ejection fraction, and LV dysfunction occurred more frequently in patients receiving trastuzumab deruxtecan (10.9%, 2.3%, and 0.4%, respectively) than in patients receiving trastuzumab emtansine (1.9%, 0.4%, and 0%, respectively). Among other notable harms specified in the CADTH review protocol, neutropenia and febrile neutropenia occurred more frequently in patients receiving trastuzumab deruxtecan (42.8% and 0.8%, respectively) than in patients receiving trastuzumab emtansine (11.9% and 0%, respectively).

Table 24: Summary of Harms in the Destiny-Breast03 Study (Safety Set)

AE = adverse event; AESI = adverse event of special interest; ALT = alanine aminotransferase; AST = asparagine aminotransferase; CTCAE = Common Terminology Criteria for Adverse Events; ILD = interstitial lung disease; LV = left ventricular; LVEF = left ventricular ejection fraction; MedDRA = Medical Dictionary for Regulatory Activities; SAE = serious adverse event; WDAE = withdrawal due to adverse event.

Note: AEs were defined and graded using MedDRA version 23.0 and CTCAE version 5.0. All events are within 47 days of the last dose of the study drug unless otherwise indicated.

^aAEs with frequency > 15% in either treatment arm are shown.

^bIncludes the preferred terms fatigue, asthenia, and malaise.

^cIncludes the preferred terms decreased neutrophil count and neutropenia.

^dIncludes the preferred terms hemoglobin decreased, decreased red blood cell count, anemia, and decreased hematocrit.

^eIncludes the preferred terms decreased white blood cell count and leukopenia.

fIncludes the preferred terms decreased platelet count and thrombocytopenia.

^gIncludes the preferred terms migraine, headache, and sinus headache.

^hIncludes the preferred terms abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, and gastrointestinal pain.

ⁱIncludes the preferred terms stomatitis, aphthous ulcer, mouth ulceration, oral mucosa erosion, and oral mucosal blistering.

^jSAEs occurring in 4 or more patients in either treatment arm are shown.

^kWDAEs occurring in more than 1 patient in either treatment arm are shown.

^lAEs leading to treatment interruption with frequency > 5% in either treatment arm are shown.

^mAEs leading to dose reduction with frequency > 5% in either treatment arm are shown.

ⁿAEs associated with an outcome of death occurring in more than 1 patient in either treatment arm or in exactly 1 patient in both treatment arms are shown.

Source: DESTINY-Breast03 Clinical Study Report.¹³

Critical Appraisal

Internal Validity

DESTINY-Breast03 was a large, phase III, randomized, OL, multicentre study comparing the efficacy and safety of trastuzumab deruxtecan and trastuzumab emtansine in patients with HER2-positive MBC who had been previously treated with taxane chemotherapy plus trastuzumab (N = 524).¹² In the study, randomization did not appear to adequately balance baseline demographic and disease characteristics between the trastuzumab deruxtecan and trastuzumab emtansine arms. No imbalances between the study arms of potential prognostic relevance were identified by the clinical experts consulted by CADTH for this review, although a slightly lower proportion of patients in the trastuzumab deruxtecan arm had an ECOG PS of 0 when compared with the trastuzumab emtansine arm (59.0% versus66.5%).

Many of the outcomes used in the DESTINY-Breast03 study (e.g., PFS, OS, ORR, DOR) are standard in oncology trials and tumour responses were objectively evaluated using mRECIST 1.1 per BICR. Neither the key secondary analysis of OS nor the primary analysis of PFS per BICR was censored for patients who initiated other anticancer therapies following the study’s protocol therapy discontinuation. As of the May 21, 2021, data cut-off date, 29.9% and 62.4% of patients in the trastuzumab deruxtecan and trastuzumab emtansine arms, respectively, had initiated a new systemic anticancer therapy. Subsequent therapies received were imbalanced between the study arms and included crossover to trastuzumab emtansine (16.5% of the trastuzumab deruxtecan arm), crossover to trastuzumab deruxtecan (11.4% of the trastuzumab emtansine arm), re-treatment with trastuzumab emtansine (6.5% of the trastuzumab emtansine arm), trastuzumab (8.8% of the trastuzumab deruxtecan arm and 25.1% of the trastuzumab emtansine arm), anti-HER2 tyrosine kinase inhibitors (5.0% of the trastuzumab deruxtecan arm and 25.1% of the trastuzumab emtansine arm), and other systemic therapies (15.3% of the trastuzumab deruxtecan arm and 47.9% of the trastuzumab emtansine arm). The clinical experts consulted by CADTH for this review agreed that imbalances in subsequent therapies, including crossover, may impact the OS analysis and were largely explained by the higher proportion of patients in the trastuzumab emtansine arm who experienced disease progression. Analytical approaches to analyze OS in the presence of treatment switching or crossover that can minimize potential biases (e.g., inverse probability of censoring weighting or the rank-preserving structural failure time model) were not conducted. A sensitivity analysis of PFS per BICR was conducted with censoring at the time of initiating new anticancer therapy and showed a similar result to the primary PFS analysis. Only |||||| patients (|||||| in the trastuzumab deruxtecan arm and |||||| in the trastuzumab emtansine arm) had PFS censored due to initiation of a new anticancer therapy before progression per BICR.

The OL design of the DESTINY-Breast03 study had the potential to introduce bias in several forms, especially in the assessment of subjective outcomes, although the impacts of these biases were most likely minor, affecting small numbers of patients that were generally similar between arms. Rates of patient discontinuation from study therapy for reasons other than disease progression or toxicity were relatively low (patient withdrawal was |||||| and |||||| of the trastuzumab deruxtecan and trastuzumab emtansine arms, respectively; clinical progression per IA was |||||| and |||||| of the trastuzumab deruxtecan and trastuzumab emtansine arms, respectively; physician decision was |||||| and |||||| of the trastuzumab deruxtecan and trastuzumab emtansine arms, respectively), although the proportions of patients assessed with clinical progression per IA and those withdrawn from therapy due to physician decision were slightly higher in the trastuzumab emtansine arm. Likewise, similar proportions of patients in each arm were lost to follow-up in the OS analysis (|||||| and |||||| of the trastuzumab deruxtecan and trastuzumab emtansine arms, respectively), and similar proportions were censored from PFS analyses due to missing tumour assessments (PFS per BICR was 10.3% and 11.8% of the trastuzumab deruxtecan and trastuzumab emtansine arms, respectively; PFS per IA was |||||| and |||||| of the trastuzumab deruxtecan and trastuzumab emtansine arms, respectively). According to the clinical experts consulted by CADTH for this review, the impacts of any attrition biases and associated missing data were unlikely to be directional or to limit interpretation of the study results. Although the assessment of progression in the primary PFS analysis was per BICR, decisions to discontinue protocol therapy were made by investigators based on local imaging scans and clinical assessment, and bias for or against either study drug could have impacted these decisions. A higher proportion of patients in the trastuzumab deruxtecan arm were assessed as having disease progression per BICR (n = ||||||) compared with IA (n = ||||||), while a lower proportion of patients in the trastuzumab emtansine arm were assessed as having disease progression per BICR (n = ||||||) compared with IA (n = ||||||). Thus, a subset of patients may have been selectively continued on trastuzumab deruxtecan post progression per BICR and a subset of patients may have been discontinued from trastuzumab emtansine inappropriately due to an incorrect assignment of progressive disease per IA. This bias would be directional and in favour of trastuzumab deruxtecan, but given the relatively small discordance between the BICR and IA assessments, this potential source of bias would be unlikely to have major impacts on the PFS analyses. Several statistical issues should be considered when interpreting the results of the DESTINY-Breast03 study. First, the OS data are still immature, and although numerically in favour of trastuzumab deruxtecan, the stratified log-rank P value of 0.007172 did not cross the prespecified boundary for the interim analysis (P < 0.000265) calculated based on 86 OS events. Thus, no conclusions regarding OS differences between the trastuzumab deruxtecan and trastuzumab emtansine arms can yet be reached. Statistical tests were overall appropriate, and a hierarchical strategy was applied for multiplicity control of the primary PFS analysis and the key secondary OS analysis, as well as between interim and final analyses. However, analyses of ORR and DOR were not controlled for multiplicity. The primary PFS analysis was robust to an array of sensitivity analyses. Some subgroup analyses of interest to this review were specified a priori (i.e., hormone receptor status, estrogen receptors, progesterone receptors, prior treatment with pertuzumab, lines of prior systemic therapy not including hormone therapy, baseline visceral disease, baseline CNS metastases, history of CNS metastases), 2 of which were based on randomization stratification factors (i.e., hormone receptor status, prior treatment with pertuzumab, history of visceral disease). The study was not specifically powered to evaluate strata among subgroups, there were no tests for differences among subgroups, and subgroup analyses were not controlled for multiplicity.

Patient-reported HRQoL was analyzed as a HEOR outcome in the DESTINY-Breast03 study. The absence of multiplicity control in formal statistical comparisons and missing HRQoL data at later time points post baseline (due to variable completion rates as well as expected attrition of the study population) limited interpretation of potentially important changes in HRQoL outcomes, which were considered highly important by patients and clinical experts. Attrition in this population of patients with HER2-positive MBC was a major contributing factor to missing post-baseline HRQoL data, as all patient-reported HRQoL instruments had completion rates of 82% or higher among patients still receiving protocol therapy in both treatment arms from cycles 3 to 27 (weeks 9 to 81), while the median treatment duration was 14.3 months in the trastuzumab deruxtecan arm and 6.9 months in the trastuzumab emtansine arm. In addition, 51.4% of patients in the trastuzumab deruxtecan arm and 18.0% of patients in the trastuzumab emtansine arm were still receiving treatment at the data cut-off date, thus end-of-treatment HRQoL data have yet to be collected. Furthermore, measurement of patient-reported HRQoL outcomes may have been influenced to some degree by knowledge of treatment allocation. Moreover, although the measurement properties of instruments used (i.e., EQ-5D-5L, EORTC QLQ-C30, EORTC QLQ-BR45) have been studied in patients with MBC, MIDs specific to HER2-positive MBC were not available and MIDs for MBC were only identified for the EORTC QLQ-C30.

External Validity

According to the clinical experts consulted by CADTH for this review, the demographic and disease characteristics of the DESTINY-Breast03 study population were broadly reflective of the population of patients in Canada with HER2-positive MBC who would be candidates for trastuzumab deruxtecan. The clinical experts also felt that the eligibility criteria for the study would be expected to recruit a population of patients with characteristics similar to patients in Canada with HER2-positive MBC they treat in their practice. Although reasons for screen failure were not provided, the clinical experts felt that the final enrolled population generally reflected the patient population that they treat in their clinical practice. However, they emphasized that, as with most oncology trials, the eligibility criteria for the DESTINY-Breast03 study likely selected for a healthier cross section of the overall patient population with HER2-positive MBC who were more likely to tolerate and respond to therapy than the general patient population, as evidenced by the majority of enrolled patients (59% to 67%) having an ECOG PS of 0 at baseline (the inclusion criteria specified an ECOG PS of 0 or 1 only). Nevertheless, the clinical experts expected that in practice, some patients with an ECOG PS of 2 would receive trastuzumab deruxtecan and felt that the study results could be generalized to these patients. The clinical experts commented that relatively few patients in the study were from North America (6.5%) and 59.9% of patients were Asian, which is not reflective of the population of patients in Canada with HER2-positive MBC; moreover, only 2 patients were male. Despite these factors, the clinical experts felt that the results of the study would be generalizable to all patients in Canada with HER2-positive MBC, including small subgroups.

The DESTINY-Breast03 study population included patients with a variety of treatment histories for HER2-positive MBC. Many patients were heavily pretreated (e.g., 52.6% of patients had received 2 or more lines of prior therapy in the metastatic setting, not including hormone therapy; 29.5% of patients had received 3 or more lines of prior therapy in the metastatic setting, not including hormone therapy) and received the study drug well beyond the second line in the metastatic setting; thus, the clinical experts consulted by CADTH for this review noted that the magnitudes of treatment effects would not be expected to directly translate to the intended second-line treatment setting for MBC. The clinical experts also noted that although the DESTINY-Breast03 study was not designed to focus solely on the second-line setting, therapies for HER2-positive MBC are generally expected to be more effective when used in earlier lines.

The eligibility criteria for the DESTINY-Breast03 study precluded prior treatment with an anti-HER2 antibody drug conjugate in the metastatic setting, but allowed for prior use of anti-HER2 antibody drug conjugates in the adjuvant or neoadjuvant setting if disease progression had not occurred within 12 months of end of adjuvant therapy. However, no patients in the study had received anti-HER2 antibody drug conjugates such as trastuzumab emtansine in the neoadjuvant or adjuvant setting. Thus, the generalizability of the study results to patients who have previously been exposed to trastuzumab emtansine (or to trastuzumab deruxtecan) in an earlier line of treatment was uncertain.

As of the May 21, 2021, data cut-off, 51.4% of patients in the trastuzumab deruxtecan arm and 18.0% of patients in the trastuzumab emtansine arm were still receiving protocol-assigned therapies. Discontinuations due to AEs were more frequent in the trastuzumab deruxtecan arm than in the trastuzumab emtansine arm (13.6% and 6.5%, respectively). According to the clinical experts consulted by CADTH for this review, discontinuations due to AEs may be expected to occur more frequently in the general population of patients with HER2-positive MBC compared with a trial population enriched for patients in better health and with better PS. The clinical experts commented that if discontinuations occurred more frequently in real-world practice, this could potentially limit the generalizability of the study results to the subset of patients who are likely to tolerate treatment, who could be identified by medical oncologists based on clinical evaluation.

The doses of trastuzumab deruxtecan and trastuzumab emtansine used in the DESTINY-Breast03 study were aligned with Health Canada–approved dosing and with clinical practice. However, the clinical experts consulted by CADTH for this review noted that many of the subsequent therapies received by patients in the study following progression are not generally available to patients with HER2-positive MBC in Canada after the second-line treatment setting in which trastuzumab deruxtecan would be used. The clinical experts felt that although use of these subsequent therapies may impact OS findings to some extent, the impacts would likely be minor as there are no well-defined guidelines beyond third-line treatment with tucatinib plus capecitabine and trastuzumab, and progression generally occurs rapidly. The clinical experts did not feel that uptake of subsequent therapies that are unavailable to patients in Canada with HER2-positive MBC would be an impediment to generalizing the study findings.

Several of the outcomes assessed in the DESTINY-Breast03 study, including OS, PFS, and HRQoL, were identified as clinically important by both patients and clinical experts. At the time this report was prepared, the duration of follow-up was adequate for assessing the primary efficacy end point of PFS per BICR, but inadequate for assessing OS. Although patients and clinical experts agreed that prolonging survival and delaying progression were the most important goals of treatment, maintaining HRQoL and controlling the symptoms of metastatic disease were also critical considerations. According to the clinical experts consulted by CADTH for this review, the HRQoL instruments used in the DESTINY-Breast03 study are important research tools but are not typically used in clinical practice. Thus, they were uncertain whether the patient-reported HRQoL and cancer symptom data from the study could be generalized to a broader context.

Indirect Evidence

No indirect evidence was identified for this review. No literature search for network meta-analyses was conducted because of the identification of a direct head-to-head comparison between trastuzumab deruxtecan and the only relevant comparator, trastuzumab emtansine, in the systematic review.

Other Relevant Evidence

No other relevant evidence was identified for this review.

Discussion

Summary of Available Evidence

One phase III, randomized, OL, multicentre study (DESTINY-Breast03, N = 524) contributed evidence to this report. The study was a head-to-head comparison of trastuzumab deruxtecan and trastuzumab emtansine in adult patients with HER2-positive MBC (with an ECOG PS of 0 or 1,and without symptomatic clinically active CNS metastases) previously treated with taxane chemotherapy plus trastuzumab in the metastatic setting or those who had progressed within 6 months after neoadjuvant or adjuvant treatment involving a regimen including trastuzumab and taxane. Patients were randomized 1:1 to receive OL trastuzumab deruxtecan (5.4 mg/kg by IV infusion every 21 days) or OL trastuzumab emtansine (3.6 mg/kg by IV infusion every 21 days) until disease progression or unacceptable toxicity, then followed for survival every 3 months until death. The primary outcome of the study was PFS per BICR and the key secondary objective (hierarchically tested) was OS. Other secondary objectives included comparison of PFS per IA, ORR per BICR and IA, and DOR per BICR and IA, while changes in patient-reported HRQoL were evaluated as a HEOR analysis.

According to clinical experts consulted by CADTH for this review, apart from a few important parameters (e.g., only 6.5% of patients were from North America and 59.9% of patients were Asian, which is not reflective of the population of patients in Canada with HER2-positive MBC), the baseline characteristics of the DESTINY-Breast03 study population were broadly representative of patients in Canada with HER2-positive MBC who would be candidates for trastuzumab deruxtecan. The mean age at study entry was 54.4 years, approximately 60% of patients were Asian, and only 2 patients were male. Approximately 73% of patients had visceral metastases at baseline and approximately 22% had a reported a history of CNS metastases. Approximately 60% of patients had received prior pertuzumab. Approximately 72% of patients had received fewer than 3 lines or fewer of prior systemic therapy, excluding hormone therapies, while approximately 28% had received 3 lines or more of systemic therapy, excluding hormone therapies. The primary limitations of the study were its short follow-up as of the May 21, 2021, data cut-off and immaturity of the OS data, its OL design and potential biases in outcome assessment (including decisions to discontinue treatment) due to knowledge of treatment allocation, and assessment of HRQoL and cancer symptoms (evaluated as a HEOR analysis) outside of the formal statistical hierarchy. In addition, the study excluded patients with clinically active symptomatic CNS metastases, so the efficacy and safety of the drug in these patients was not evaluated.

Interpretation of Results

Efficacy

Administration of trastuzumab deruxtecan in the DESTINY-Breast03 study resulted in an HR for PFS per BICR of 0.28 (95% CI, 0.22 to 0.37) compared with trastuzumab emtansine. The median PFS per BICR in the trastuzumab deruxtecan arm had not been reached at the time of the analysis; however, the lower limit of the 95% CI was estimated at 18.5 months. The clinical experts consulted by CADTH considered this to be a clinically meaningful result compared with the median PFS per BICR of 6.8 months (95% CI, 5.6 to 8.2 months) in the trastuzumab emtansine arm, despite the preliminary nature of the data. Analysis of the secondary outcome of PFS per IA was consistent with the primary analysis of PFS per BICR in favour of trastuzumab deruxtecan (HR = 0.2649; 95% CI, 0.2011 to 0.3489). OS data were immature as of the May 21, 2021, data cut-off; although the interim analysis numerically favoured trastuzumab deruxtecan (HR = 0.5546; 95% CI, 0.3587 to 0.8576), the stratified log-rank P value of 0.007172 did not cross the prespecified boundary for the interim analysis (P < 0.000265) calculated based on 86 OS events. In addition, analysis of OS did not consider treatment switching and crossover, which were imbalanced between arms and may have important impacts on the results. Thus, definitive conclusions regarding the treatment effect of trastuzumab deruxtecan versus trastuzumab emtansine on OS are not possible. Multiple studies have suggested the PFS is a significant predictor and useful surrogate end point for OS in MBC, including HER2-positive MBC,^26-28 although the same studies also acknowledge that correlations between PFS and OS are imperfect (coefficient of determination ranging from 0.31 to 0.67) and that OS should be independently examined if possible.

Analyses of ORR per BICR (trastuzumab deruxtecan = 79.7%; 95% CI, 74.3% to 84.4%; trastuzumab emtansine = 34.2%, 95% CI, 28.5% to 40.3%), and analyses of ORR per IA (trastuzumab deruxtecan = 77.0%; 95% CI, 71.4% to 82.0%; trastuzumab emtansine = 36.9%; 95% CI, 31.0% to 43.0%) were outside the statistical hierarchy and not adjusted for multiplicity, but were supportive of the primary analysis of PFS per BICR. The clinical experts commented that the descriptive difference in ORR per BICR (45.5%; 95% CI, 37.6% to 53.4%) in favour of trastuzumab deruxtecan was clinically meaningful in second- and subsequent-line treatment of HER2-positive MBC, where response rates are generally low. Among patients who achieved objective responses to treatment, median DOR per BICR and per IA was not yet reached in either treatment arm.

Changes in EORTC QLQ-C30, EQ-5D-5L, and EORTC QLQ-BR45 scores from baseline to the end of treatment were evaluated as an HEOR analysis. Interpretation of changes in patient-reported HRQoL and cancer symptoms was limited by high rates of missing data at later times post baseline and absence of multiplicity control.

Harms

The safety profile of trastuzumab deruxtecan in the DESTINY-Breast03 study was as expected by the clinical experts consulted by CADTH for this review based on prior experience with the drug. The AEs associated with trastuzumab deruxtecan treatment were not clinically insignificant but were considered by the clinical experts to be manageable with appropriate supportive care. WDAEs (13.6% versus 7.3%), AEs leading to dose interruption (44.0% versus 23.4%), AEs leading to dose reduction (21.4% versus 12.6%), ILD (10.9% versus 1.9%), decreased left ventricular ejection fraction (2.3% versus 0.4%), and LV dysfunction (0.4% versus 0%) occurred more commonly in patients receiving trastuzumab deruxtecan than in those receiving trastuzumab emtansine. Although the potential for ILD is a serious concern, the clinical experts consulted by CADTH for this review emphasized that most oncologists have extensive experience with managing patients who are receiving other drugs (such as immunotherapies and chemotherapies) that are also associated with a risk of ILD. As of the May 21, 2021, data cut-off date, 51.4% of patients in the trastuzumab deruxtecan arm and 18.0% of patients in the trastuzumab emtansine arm were still receiving their assigned protocol therapy; as the data mature, the relative rates of treatment discontinuation for toxicity between the 2 arms may become clearer, and may inform the group of patients most likely to benefit from treatment with trastuzumab deruxtecan.

Conclusions

Evidence from the DESTINY-Breast03 study suggested that, compared with trastuzumab emtansine, administration of trastuzumab deruxtecan improved PFS per BICR among patients with HER2-positive MBC who had previously received taxane chemotherapy plus trastuzumab. Definitive conclusions could not be reached for OS due to immaturity of the data and non-statistically significant OS differences at a prespecified boundary for the interim analysis. Analyses of PFS per IA, ORR, and DOR also numerically favoured trastuzumab deruxtecan, although they were not part of the statistical hierarchy and were supportive of the primary analysis of PFS per BICR. Results for patient-reported HRQoL and symptom scores (i.e., EQ-5D-5L, EORTC QLQ-C30, EORTC QLQ-BR45) could not be interpreted due to an absence of multiplicity control in formal statistical testing, potential for bias in an OL trial, and high rates of missing data at later time points post baseline. Dose interruption, dose reduction, treatment discontinuation, and ILD occurred more commonly in patients receiving trastuzumab deruxtecan than in those receiving trastuzumab emtansine. The observed PFS benefits, consistent numeric improvements in other efficacy outcomes, and toxicity profile considered manageable by clinical experts were aligned with outcomes identified as important to patients with HER2-positive MBC who are seeking additional treatment options to delay progression and prolong survival with an acceptable HRQoL.

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Appendix 1: Literature Search Strategy

Note that this appendix has not been copy-edited.

Clinical Literature Search

Overview

Interface: Ovid

Databases:

• MEDLINE All (1946-present)

• Embase (1974-present)

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

Date of search: April 14, 2022

Alerts: Bi-weekly search updates until project completion

Search filters applied: No filters were applied to limit the retrieval by study type

Limits: Conference abstracts: excluded

Table 25: Syntax Guide

Multi-Database Strategy

1. (trastuzumab deruxtecan* or famtrastuzumab deruxtecan* or Enhertu* or WHO10516 or WHO 10516 or T-DXd or DS8201* or DS-8201* or 5384HK7574).ti,ab,ot,kf,hw,nm,rn.

2. 1 use medall

3. *trastuzumab deruxtecan/

4. (trastuzumab deruxtecan* or famtrastuzumab deruxtecan* or Enhertu* or WHO10516 or WHO 10516 or T-DXd or DS8201* or DS-8201*).ti,ab,kf,dq.

5. 3 or 4

6. 5 use oemezd

7. 6 not (conference abstract or conference review).pt.

8. 2 or 7

9. remove duplicates from 8

Clinical Trials Registries

ClinicalTrials.gov

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

Search -- Studies found for: deruxtecan | “Breast Neoplasms”

WHO ICTRP

International Clinical Trials Registry Platform, produced by the World Health Organization. Targeted search used to capture registered clinical trials.

Search terms – deruxtecan AND breast

Health Canada’s Clinical Trials Database

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

Search terms – deruxtecan AND breast

EU Clinical Trials Register

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

Search terms – trastuzumab deruxtecan AND breast

Grey Literature

Search dates: April 7-14, 2022

Keywords: Enhertu, trastuzumab deruxtecan, breast cancer, breast neoplasms, HER positive

Limits: None

Updated: Search updated prior to the completion of stakeholder feedback period

Relevant websites from the following sections of the CADTH grey literature checklist Grey Matters: A Practical Tool for Searching Health-Related Grey Literature were searched:

• Health Technology Assessment Agencies

• Health Economics

• Clinical Practice Guidelines

• Drug and Device Regulatory Approvals

• Advisories and Warnings

• Drug Class Reviews

• Clinical Trials Registries

• Databases (free)

Appendix 2: Detailed Outcome Data

Note that this appendix has not been copy-edited.

Table 26: Guidelines for Trastuzumab Deruxtecan Dose Modifications in the DESTINY-Breast03 Study

AE = adverse event; ALT = alanine aminotransferase; AST = asparagine aminotransferase; CBC = complete blood count; CT = computed tomography; ECG = electrocardiogram; Hb = hemoglobin; ILD = interstitial lung disease; IV = intravenous; LVEF = left ventricular ejection fraction; NCI-CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events; NSAID = non-steroidal anti-inflammatory drug; PK = pharmacokinetics; QTc = corrected QT interval; SpO₂ = oxygen saturation; ULN = upper limit of normal; WBC = white blood cell.

^aGraded using NCI-CTCAE v. 5.0 unless otherwise specified.

^bDose levels were 3.6 mg/kg (starting dose), 3.0 mg/kg (dose reduction level 1), and 2.4 mg/kg (dose reduction level 2).

Source: DESTINY-Breast03 Clinical Study Report.¹³

Table 27: Sensitivity Analyses of PFS per BICR in the DESTINY-Breast03 Study

BICR = blinded independent central review; CI = confidence interval; FAS = full analysis set; HR = hazard ratio; NA = not applicable; NE = not estimable; PFS = progression-free survival; PP = per protocol.

aFor patients who received new anticancer therapy, the censoring data was the date of the last evaluable tumour assessment prior to start of anticancer therapy.

^bPFS event time was backdated in the case that PFS events occurred after the patient missed one or more tumour assessment. In such cases, the PFS event dat was considered to be 6 weeks after the last evaluable tumour assessment that occurred prior to progression/death.

^cP-values are not adjusted for multiplicity and are descriptive only.

Note: see Table 11 for descriptions of sensitivity analyses.

Source: DESTINY-Breast03 Clinical Study Report.¹³

Table 28: Subgroup Analyses of PFS per BICR in the DESTINY-Breast05 Study (FAS)