Reimbursement Review

Trastuzumab Deruxtecan (Enhertu)

Sponsor: AstraZeneca Canada Inc.

Therapeutic area: Gastric or gastroesophageal junction adenocarcinoma

This multi-part report includes:

Clinical Review

Pharmacoeconomic Review

Clinical Review

Abbreviations

Executive Summary

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

Table 1: Background Information on Application Submitted for Review

GEJ = gastroesophageal junction; HER2 = human epidermal growth factor 2; NOC = Notice of Compliance; NOC/c = Notice of Compliance with conditions; TLR = time-limited reimbursement.

Sources: Sponsor’s Summary of Clinical Evidence;¹ draft product monograph;² Drug Reimbursement Review sponsor submission for trastuzumab deruxtecan.³

Introduction

Gastric cancer is the fifth most common cancer and the fifth leading cause of cancer mortality worldwide, with approximately 968,000 incident cases and 659,853 associated deaths in 2022 (equating to 6.8% of all cancer-related deaths).⁴ Gastric adenocarcinoma is the most common histological type of gastric cancer, accounting for more than 95% of gastric cancer cases.⁵ In clinical trials, patients with advanced gastroesophageal junction (GEJ) adenocarcinoma are often included alongside patients with advanced gastric adenocarcinoma because of the similarities in tumour growth and patterns of disease spread between the 2 patient popualitons.^6,7 In fact, gastric and GEJ adenocarcinoma have often been reviewed, investigated, or presented together in literature reviews, clinical trials, and clinical management guidelines.^8-11 The projected incident rate of gastric cancer in Canada is 8.3 per 100,000 adults in 2024, with an estimated 1,400 cases in females and 2,600 cases in males.¹² Signs and symptoms of gastric cancer include abdominal pain, heart burn, loss of appetite, bloating, nausea, vomiting, difficulty swallowing, blood in the stool, anemia, fatigue, ascites, and jaundice.¹³ The overall 5-year survival for all patients with gastric cancer is estimated to be 29%.¹⁴ Patients with distant metastases experience worse outcomes, with an estimated 5-year relative survival rate of 7%.¹⁵ Compared to patients with gastric adenocarcinoma, patients with GEJ adenocarcinoma might have worse disease-specific survival, with an approximately 10% higher cumulative incidence of recurrence.¹⁶ The prognostic role of human epidermal growth factor 2 (HER2) in gastric cancer remains controversial due to conflicting evidence.^17-21 In a population of patients in Canada, an estimated 21% of all gastric and GEJ cancers showed HER2 positivity.²² All patients with advanced or metastatic gastric or GEJ cancer, including patients with both gastric and gastroesophageal adenocarcinomas, should undergo HER2 testing.²³ HER2 testing is typically conducted at the time of diagnosis or at the onset of advanced or metastatic disease.²³ Additionally, HER2 testing may be repeated if there is a need for re-evaluation due to disease progression or metastases.²³ HER2 positivity is confirmed when test results show immunohistochemistry (IHC) 3+ or IHC 2+ followed by in situ hybridization (ISH) positivity.^23,24

According to the clinical experts consulted by the review team, most patients with unresectable locally advanced or metastatic HER2-positive gastric or GEJ cancers are treated with palliative intent; the treatment goals of all therapies in this setting are to prolong overall survival (OS) and improve quality of life. The clinical experts consulted by the review team noted that the cornerstone of treatment for patients with unresectable locally advanced or metastatic HER2-positive gastric or GEJ cancers involves the sequential use of the best available systemic therapies. The clinical experts consulted by the review team noted that, in the first-line treatment setting, the standard of care for patients with locally advanced or metastatic HER2-positive gastric or GEJ cancers with a programmed death-ligand 1 (PD-L1) combined positive score (CPS) of less than 1 includes a fluoropyrimidine-platinum doublet chemotherapy (e.g., folinic acid–fluorouracil-oxaliplatin [FOLFOX], capecitabine-oxaliplatin [CAPOX], or cisplatin-capecitabine) in combination with trastuzumab. In the second-line treatment setting, according to the clinical experts consulted by the review team, the standard of care for locally advanced or metastatic HER2-positive gastric or GEJ cancers is treatment with ramucirumab-paclitaxel or with ramucirumab alone. However, the clinical experts consulted by the review team noted that, as a single drug, ramucirumab is not reimbursed in many jurisdictions across Canada, including Ontario. The clinical experts consulted by the review team also noted that the current second-line treatment of HER2-positive gastric or GEJ cancers is identical to that of HER2-negative gastroesophageal cancers. The sponsor noted that single-drug chemotherapy options, such as irinotecan, paclitaxel, or docetaxel, have been suggested in guidelines for patients who are not eligible for ramucirumab-paclitaxel.^25,26 Further, according to the sponsor, relevant guidelines^25,26 suggest the use a fluoropyrimidine and platinum combination, such as FOLFOX or CAPOX for patients previously treated with folinic acid–fluorouracil-irinotecan (FOLFIRI) in the first-line setting. In the third-line setting, the clinical experts consulted by the review team noted that the treatment options for patients with locally advanced or metastatic HER2-positive gastric or GEJ cancers include trifluridine-tipiracil (i.e., TAS-102), nivolumab, and pembrolizumab.

The objective of this report is to review and critically appraise the evidence submitted by the sponsor on the beneficial and harmful effects of trastuzumab deruxtecan (Enhertu),100 mg, powder for concentrate for solution for IV infusion for the treatment of adult patients with unresectable locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma who have received a prior trastuzumab-based regimen. Trastuzumab deruxtecan has been previously reviewed by the review team for other indications.

Of note, trastuzumab deruxtecan received an NOC/c from Health Canada on January 17, 2025. The sponsor filed for a time-limited reimbursement (TLR) recommendation on an NOC/c basis while awaiting results from the confirmatory, phase III DESTINY-Gastric04 study. More details on TLR recommendation eligibility are provided in the next section. The sponsor also requested a deviation from the Health Canada indication and limited the requested reimbursement criteria for trastuzumab deruxtecan monotherapy to the second-line treatment of adult patients with unresectable locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma who have received a prior anti–HER2-based regimen.”³ The sponsor noted that this request was more aligned with both the DESTINY-Gastric02 study population and the trial design for the ongoing, confirmatory, phase III study, DESTINY-Gastric04. Of note, the proposed Health Canada indication targets patients who have received a prior trastuzumab-based regimen, while the reimbursement request targets those who have received a prior anti–HER2-based regimen (i.e., not necessarily a trastuzumab-based regimen). Trastuzumab is currently the only anti-HER2 drug that has been authorized for the first-line treatment of gastric or GEJ cancer in Canada.

Consideration for a TLR Recommendation

A TLR is a recommendation by the CDA-AMC expert committee to publicly fund a drug or drug regimen for a certain period of time on the condition that the sponsor will conduct 1 or more clinical studies that address uncertainty in the clinical evidence. CDA-AMC subsequently conducts a reassessment of the additional evidence and issues a final reimbursement recommendation within a defined period of time. Based on the preliminary assessment by CDA-AMC (Table 36 in Appendix 1), trastuzumab deruxtecan meets the requirements to be considered by the expert committee for a TLR recommendation.

The following paragraph describes these requirements and provides additional background on the reimbursement request.

Trastuzumab deruxtecan received an NOC/c from Health Canada on January 17, 2025, through Health Canada’s advance consideration process under the NOC/c policy. A phase III clinical trial (DESTINY-Gastric04) was being conducted at the time of the submission to CDA-AMC. The ongoing DESTINY-Gastric04 phase III study evaluates the efficacy and safety of trastuzumab deruxtecan relative to ramucirumab-paclitaxel for up to 3 years of follow-up in approximately 490 patients with HER2-positive gastric or GEJ adenocarcinoma. The DESTINY-Gastric04 study population targets the second-line treatment setting for patients with HER2-positive gastric or GEJ cancer, which aligns with the current reimbursement request proposed by the sponsor. However, the Health Canada indication targets a broader population, including not only patients in the second-line treatment setting, but also patients in the third-line and later settings. The DESTINY-Gastric04 trial population does not completely align with the patients in the third- and later-line settings described by the Health Canada indication. As a result, findings from the DESTINY-Gastric04 trial may not be generalizable to patients in the third and subsequent lines setting. According to the clinical experts consulted by the review team, the selection of ramucirumab-paclitaxel as a comparator in the phase III DESTINY-Gastric04 trial is appropriate because treatment with ramucirumab-paclitaxel is currently among the standard of care in the second-line setting for locally advanced or metastatic HER2-positive gastric or GEJ cancer, and will likely remain the standard of care in the second-line setting when the results of the DESTINY-Gastric04 trial become available. The results of the DESTINY-Gastric04 study are expected to be ready in the fourth quarter of 2025. The sponsor has expressed that it will commit to file a reassessment application with CDA-AMC in accordance with the time frames specified in the procedures for TLR recommendations.

Perspectives of Patients, Clinicians, and Drug Programs

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

Patient Input

One input from My Gut Feeling – Stomach Cancer Foundation of Canada was received for this review. My Gut Feeling – Stomach Cancer Foundation of Canada is a nonprofit organization in Canada, dedicated to providing “support, awareness, education, information, and advocacy to stomach cancer patients, cancer survivors, caregivers, and family members.” The patient group gathered information from 30 respondents (75% patients, 25% caregivers) through an online survey conducted in September 2024.

According to the patient group input, 95% of respondents felt that their cancer diagnosis had a significant impact on their quality of life, and that cancer and its treatment affected their physical health, mental health, ability to eat, work, finances, social life, identity, psychosocial well-being, and self-image. Many respondents reported concerns about finances due to the inability to work because of their cancer diagnosis and/or treatment for cancer. Based on the input, patients and caregivers commented on the time and money spent for cancer treatment appointments, medications, driving and parking costs, and the costs of eating at the hospital as financial stressors.

The important outcomes reported by the respondents included quality of life, treatment side effects, cost of treatment, convenience of treatment, treatment access, duration of treatment, and the survival benefits.

My Gut Feeling – Stomach Cancer Foundation of Canada stated that there is an unmet patient and caregiver need to receive equitable access to therapies that may prolong life, improve symptoms, reduce the risk of recurrence, and improve treatment tolerability. The organization also noted that 4 respondents who had experience with trastuzumab deruxtecan were satisfied because trastuzumab deruxtecan had fewer side effects, was easier to tolerate, improved their quality of life, and better controlled their cancer.

Clinician Input

Input From Clinical Experts Consulted for This Review

According to the clinical experts consulted by the review team, the goals for the treatment of patients with unresectable locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma who have received a prior anti–HER2-based regimen are to prolong OS and improve quality of life. The clinical experts consulted by the review team noted that there was a considerable unmet need for effective anti-HER2 therapies beyond the first-line treatment setting for patients with locally advanced unresectable or metastatic HER2-positive gastric or GEJ adenocarcinoma.

According to the clinical experts consulted by the review team, following disease progression on first-line, HER2-directed therapy, the current standard of care in the second-line setting for patients with HER2-negative gastric or GEJ adenocarcinoma is treatment with ramucirumab in combination with paclitaxel or treatment with ramucirumab alone. The clinical experts noted that trastuzumab deruxtecan would cause a shift in the current treatment paradigm for adult patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma who have received a prior trastuzumab-based regimen, such that all other current second-line treatment regimens would shift to the third and subsequent lines. According to the clinical experts consulted by the review team, in alignment with the eligible participants in the sponsor-submitted DESTINY-Gastric02 trial, the patients best suited for treatment with trastuzumab deruxtecan in the second-line treatment setting would be those who have all of the following criteria, unresectable or metastatic gastric or GEJ cancer with progressive disease on or after first-line therapy with a trastuzumab-containing regimen; HER2-positive gastric or GEJ cancer (defined as IHC 3+, or IHC 2+ and ISH-positive) confirmed by a repeat biopsy; a preserved Eastern Cooperative Oncology Group Performance Status (ECOG PS); and a preserved cardiac ejection.

According to the clinical experts consulted by the review team, key factors to determine response to treatment include patient-reported symptoms, side effects, and cross-sectional imaging (e.g., CT and/or MRI).

According to the clinical experts consulted by the review team, patient-reported symptoms, side effects, and the overall well-being of patients, in conjunction with assessment of treatment response, would be the major determinants for discontinuing treatment. In terms of toxicities, the clinical experts consulted by the review team noted that interstitial lung disease (ILD) is among the most important adverse events (AEs) to be aware of.

According to the clinical experts consulted by the review team, trastuzumab deruxtecan should only be prescribed by or under the supervision of a specialist in medical oncology with expertise in the diagnosis and management of immunotherapy-related side effects, including ILD. The clinical experts consulted by the review team noted that trastuzumab deruxtecan could be safely administered in a hospital or an outpatient clinic.

Clinician Group Input

Canada’s Drug Agency (CDA-AMC) received inputs from 2 clinician groups: the Ontario Health (Cancer Care Ontario) (OH-CCO) Gastrointestinal Cancer Drug Advisory Committee (5 clinicians) and the ad hoc group of physicians who treat adenocarcinoma and the Canadian Gastrointestinal Oncology Evidence Network (CGOEN), with contribution of 15 clinicians.

According to the clinician groups, the goals of treatment include improve symptoms, response rates, quality of life, and OS. Based on both clinician inputs, there is a gap in treatments for patients with HER2 positivity whose disease progresses after first-line standard therapy, and trastuzumab deruxtecan should be considered in the second-line setting. CGOEN added that efficacy outcomes, such as objective response rate (ORR), progression-free survival (PFS), and OS — along with safety and toxicity outcomes and quality of life — are important when assessing response to treatment. OH-CCO believes that response to treatment should be assessed every 2 months to 3 months.

According to the clinician inputs, factors to be considered to discontinue treatment would include disease progression and intolerance. Further, the outpatient setting under the care of a health care provider with training in oncology is appropriate for treatment.

Drug Program Input

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

• relevant comparators

• consideration for initiation of therapy

• consideration for discontinuation of therapy

• consideration for prescribing of therapy

• generalizability

• funding algorithm

• care provision issues

• system and economic issues.

Clinical Evidence

Systematic Review

Description of Studies

One relevant sponsor-conducted pivotal study, DESTINY-Gastric02 (N = 79), was included in the systematic review of this clinical report. The DESTINY-Gastric02 trial was a phase II, single-arm, open-label study investigating the use of trastuzumab deruxtecan as monotherapy for the treatment of patients (aged ≥ 18 years) who have unresectable or metastatic centrally confirmed HER2-positive gastric or GEJ cancer and have experienced disease progression during or after first-line therapy with a trastuzumab-containing regimen. Patients enrolled in the DESTINY-Gastric02 trial were from Europe and North America (no patients in Canada). The primary objective of the DESTINY-Gastric02 trial was to assess the efficacy of trastuzumab deruxtecan based on the confirmed ORR per independent central review (ICR) assessment (primary outcome). OS, PFS, health-related quality of life (HRQoL) outcomes (e.g., Functional Assessment of Cancer Therapy – Gastric [FACT-Ga]), and harms (e.g., ILD) were also assessed.

The median age in the DESTINY-Gastric02 trial population was 60.7 years (range, 20.3 years to 77.8 years), with 58.5% of patients aged younger than 65 years. The trial population was 27.8% female and 72.2% male. The race distribution of the trial population was 0% American Indian or Alaska Native, 5.1% Asian, 1.3% Black or African American, 1.3% Native Hawaiian or other Pacific Islander, and 87.3% white. The majority of patients in the trial population had an ECOG PS of 1 (63.3%), GEJ as the cancer location (65.8%), and a HER2 status of IHC 3+ (86.1%). Almost all the patients (78 out of 79 patients) had a histological subtype of adenocarcinoma.

Efficacy Results

Results submitted by the sponsor were from 2 data cut-off dates: April 9, 2021, and November 8, 2021. The median duration of follow-up was 5.9 months (range, 0.7 months to 15.4 months) as of the data cut-off date of April 9, 2021, and 10.2 months (range, 0.7 months to 22.1 months) as of the data cut-off date of November 8, 2021.

Overall Survival

As of the data cut-off date of November 8, 2021, the proportion of patients in the full analysis set (FAS) who had OS events was 58.2%. The median OS was 12.1 months (95% confidence interval [CI], 9.4 months to 15.4 months). The probability of being alive was 77.8% (95% CI, 66.8% to 85.6%) at 6 months, 50.6% (95% CI, 38.4% to 61.5%) at 12 months, and 35.1% (95% CI, 22.1% to 48.4%) at 18 months.

PFS per ICR Assessment

As of November 8, 2021, the proportion of patients in the FAS who had PFS events as determined by ICR was 64.6%. The median PFS was 5.6 months (95% CI, 4.2 months to 8.3 months). The probability of being progression-free was 70.5% (95% CI, 58.7% to 79.5%) at 3 months, 48.9% (95% CI, 36.6% to 60.2%) at 6 months, 36.3% (95% CI, 24.5% to 48.1%) at 9 months, and 20.0% (95% CI, 9.4% to 33.3%) at 12 months.

Confirmed ORR per ICR Assessment

As of November 8, 2021, the proportion of patients in the FAS who had achieved a confirmed ORR per ICR assessment was 41.8% (95% CI, 30.8% to 53.4%). There were 4 patients (5.1%) who achieved a best overall response of confirmed complete response (CR), and 29 patients (36.7%) who achieved a confirmed partial response (PR). The results of subgroup analyses on ORR were generally consistent with the results in the FAS.

FACT-Ga Total Score

A higher FACT-Ga total score indicates a better outcome. As of the data cut-off date of April 9, 2021, the mean FACT-Ga total score at baseline was █████ █████████ █████████ ████ █ ██████ The mean FACT-Ga total score at the end of treatment was █████ ███ █ ██████ with a mean change of ██████ ███ █ ███████

Harms Results

Treatment-Emergent AEs

The most commonly reported treatment-emergent adverse events (TEAEs) in the DESTINY-Gastric02 trial were nausea (67.1%), followed by fatigue (57.0%), vomiting (44.3%), and anemia (38.0%). The proportion of patients who had any TEAE of grade 3 or higher was 55.7%. The most commonly reported TEAE of grade 3 or higher was anemia (13.9%), followed by neutropenia (12.7%).

Treatment-Emergent Serious AEs

The proportion of patients who had any treatment-emergent serious adverse event (TESAE) was 41.8%. The most commonly reported TESAE was nausea (5.1%), followed by pneumonitis (3.8%) and vomiting (3.8%).

Treatment Discontinuation Due to TEAEs

The proportion of patients who discontinued trastuzumab deruxtecan was 19.0%. Discontinuation due to pneumonitis or ILD occurred in 7.6% and 2.5% of the trial population, respectively.

Mortality

As of the data cut-off date of November 8, 2021, the number of patients who had any TEAE associated with an outcome of death was 11 patients (13.9%); among these, 1 patient (1.3%) died due to ILD and 1 patient (1.3%) died due to pneumonitis.

Notable Harms

As of the data cut-off date of November 8, 2021, the proportion of patients who had ILD was ████%, and 10.5% of patients had a grade 2 left ventricular (LV) dysfunction (defined as the resting left ventricular ejection fraction [LVEF] ranges from 50% to 40%; and there is a 10% to 19% LVEF decrease from baseline). As of the data cut-off date of April 9, 2021, the proportion of patients who had experienced an infusion-related reaction (IRR) was 5.1%. QT prolongation was not reported in the DESTINY-Gastric02 trial.

Critical Appraisal

Overall, the absence of an internal comparison group in the single-arm DESTINY-Gastric02 trial is a key limitation. Moreover, a comparison between the trastuzumab deruxtecan group in the DESTINY-Gastric02 trial and an external control (e.g., a target value or historical study control) was not available. Lacking comparative data prevents the demonstration of the advantage of trastuzumab deruxtecan over therapies currently available in the second-line setting; in addition, inferences about the efficacy and safety of trastuzumab deruxtecan are challenging to make and cannot be established with certainty. The selection of the primary efficacy end point of confirmed ORR — defined as the sum of CR or PR, as determined by ICR based on the Response Evaluation Criteria in Solid Tumours Version 1.1 (RECIST 1.1) — was necessary for the single-arm DESTINY-Gastric02 trial for regulatory approval as a direct measure of a drug antitumour activity that can be assessed in a single-arm study.²⁷ ORR does not always capture the effects of a treatment on patient survival and may not always correlate with symptoms or function.²⁷ The DESTINY-Gastric02 trial addressed this limitation by examining time-to-event outcomes as secondary end points in the trial, including OS, which was considered the most important efficacy outcome for the trial population by the clinical experts consulted by the review team. Although OS was included in the statistical analysis plan and controlled for multiplicity, this outcome can be sensitive to natural history and progression of the disease as well as heterogeneity of patient characteristics; therefore, inference of treatment efficacy based on reported OS results can be prone to bias in the absence of a comparator.^27-29

The DESTINY-Gastric02 trial targeted a second-line treatment setting for patients with HER2-positive gastric or GEJ cancer. This aligns with the treatment setting in the reimbursement request submitted by the sponsor. However, the Health Canada indication targets not only patients in the second-line treatment setting, but also in the third-line and later settings. The DESTINY-Gastric02 trial population does not align with the patients in the third-line and later settings described in the Health Canada indication. As a result, the findings from the DESTINY-Gastric02 trial may not be generalizable to patients in the third-line and subsequent lines setting, and there remains a gap in evidence. According to the clinical experts consulted by the review team, the eligibility criteria for the DESTINY-Gastric02 trial were generally aligned with the selection criteria in the Canadian setting when identifying eligible patients with HER2-positive gastric or GEJ cancer for the second-line use of trastuzumab deruxtecan.

GRADE Summary of Findings and Certainty of the Evidence

For the pivotal studies and randomized controlled trials (RCTs) identified in the sponsor’s systematic review, Grading of Recommendations Assessment, Development, and Evaluation (GRADE) was used to assess the certainty of the evidence for the outcomes considered most relevant to inform the expert committee deliberations; a final certainty rating was determined, as outlined by the GRADE Working Group.^30,31

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

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

Due to lack of comparators, certainty of evidence was summarized narratively for OS, PFS, ORR, FACT-Ga total score, and harms.

The selection of outcomes for the GRADE assessment was based on the sponsor’s Summary of Clinical Evidence, consultation with clinical experts, and input from patient and clinician groups and public drug plans. The following list of outcomes was finalized in consultation with expert committee members:

• OS

• PFS per ICR assessment

• confirmed ORR per ICR assessment

• HRQoL outcomes (FACT-Ga total score)

• harms (ILD).

Results of GRADE Assessments

Table 2 presents the GRADE summary of findings for trastuzumab deruxtecan for the treatment of adult patients with unresectable or metastatic HER2-positive gastric or GEJ cancer who had disease progression during or after first-line therapy with a trastuzumab-containing regimen.

Table 2: Summary of Findings for Trastuzumab Deruxtecan for the Treatment of Adult Patients With Unresectable or Metastatic HER2-Positive Gastric or GEJ Cancer Who Had Disease Progression During or After First-Line Therapy With a Trastuzumab-Containing Regimen

CI = confidence interval; CR = complete response; FACT-Ga = Functional Assessment of Cancer Therapy – Gastric; GEJ = gastroesophageal junction; HER2 = human epidermal growth factor receptor 2; HRQoL = health-related quality of life; ICR = independent central review; ILD = interstitial lung disease; ORR = objective response rate; OS = overall survival; PFS = progression-free survival.

^aIn the absence of a comparator arm, the certainty of evidence started at very low. There were no observed criteria that would warrant rating up.

Source: DESTINY-Gastric02 Clinical Study Report.^32,33

Long-Term Extension Studies

No long-term extension studies were submitted by the sponsor for this review.

Indirect Comparisons

Description of Studies

In the absence of direct evidence comparing trastuzumab deruxtecan to other second-line treatments currently available in Canada (i.e., ramucirumab-paclitaxel, paclitaxel, FOLFIRI, irinotecan, and docetaxel), an indirect treatment comparison (ITC) was submitted by the sponsor to inform this gap. The sponsor-submitted ITC consisted of an unanchored, matching-adjusted indirect comparison (MAIC) and a network meta-analysis (NMA). The unanchored MAIC was used to connect the single-arm pivotal DESTINY-Gastric02 trial into the evidence network of the NMA. The relative treatment effect estimates between trastuzumab deruxtecan and ramucirumab-paclitaxel were generated based on this unanchored MAIC, while the relative treatment effect estimates between trastuzumab deruxtecan and other relevant comparators (including paclitaxel, FOLFIRI, irinotecan, and docetaxel) were generated from the NMA.

Efficacy Results

Overall Survival

Generated from the MAIC, the hazard ratio (HR) for OS was ████ ████ ████████ ████████ ██████ ████ ██ █████ between trastuzumab deruxtecan and ramucirumab-paclitaxel.

In the fixed-effects (FE) model of the NMA, the estimated base-case HRs for OS were ████ ████ ████ ████ ██ █████ between trastuzumab deruxtecan and paclitaxel, ████ ████ ████ ████ ██ █████ between trastuzumab deruxtecan and FOLFIRI, ████ ████ ████ ████ ██ █████ between trastuzumab deruxtecan and irinotecan, and ████ ████ ████ ████ ██ ████) between trastuzumab deruxtecan and docetaxel.

Progression-Free Survival

Generated from the MAIC, the HR for PFS was ████ ████ ████ ████ ██ █████ between trastuzumab deruxtecan and ramucirumab-paclitaxel.

In the FE model of the NMA, the estimated base-case HRs for PFS were ████ ████ ████ ████ ██ █████ between trastuzumab deruxtecan and paclitaxel, ████ ████ ████ ████ ██ █████ between trastuzumab deruxtecan and FOLFIRI, ████ ████ ████ ████ ██ █████ between trastuzumab deruxtecan and irinotecan, and ████ ████ ████ ████ ██ █████ between trastuzumab deruxtecan and docetaxel.

Harms Results

Harms were not addressed in the sponsor-submitted ITC.

Critical Appraisal

Through MAIC, the comparison was established between the cohort of patients treated with trastuzumab deruxtecan in the DESTINY-Gastric02 trial and the cohort of patients treated with ramucirumab-paclitaxel in the RAINBOW trial. There are concerns regarding patient comparability between the DESTINY-Gastric02 trial and the RAINBOW trial. There were differences in some of the important patient characteristics (e.g., HER2 status, time on first treatment) that were not involved in the weighting process due to lack of information or insufficient sample size. Currently, the prognostic role of HER2 in gastric cancer remains controversial due to conflicting evidence.^17-21 With HER2 status being unavailable in the RAINBOW trial, there is increased uncertainty about the treatment effect estimates between trastuzumab deruxtecan and ramucirumab-paclitaxel, but the direction of bias is unclear. Additionally, only 5 out of 16 potential prognostic factors and treatment effect modifiers were involved in the propensity score weighting. Excluding potentially relevant prognostic factors from the analysis could bias the results; however, the magnitude of the residual bias in the relative treatment effect estimates remains uncertain. Furthermore, after reweighting, apparent differences were identified between the DESTINY-Gastric02 trial and RAINBOW trial in some of the patient characteristics, such as time to progressive disease on first-line therapy, histological subtype, and number of metastases sites, suggesting the possible existence of inadequate balance and increasing the uncertainty of the findings. After reweighting, there was also a marked reduction in effective sample size (ESS), from ██ to ████, indicating that the weights might be highly variable due to a lack of population overlap and that the treatment effect estimates yielded through the MAIC approach might be unstable. Other than heterogeneity in patient characteristics, there was significant design and methodological heterogeneity between the DESTINY-Gastric02 trial (a phase II, single-arm study without a hypothesis specified a priori, or a statistical test) and the RAINBOW trial (a phase III, double-blind RCT with formal hypothesis testing). The MAIC approach can correct only for bias that is directly related to differences in baseline patient characteristics; it does not correct heterogeneity caused by between-trial differences in study design or methods.

The limitations of the MAIC analyses also contributed to the uncertainty of the NMA findings because the NMA evidence network was constructed based on the MAIC, which connected the single-arm DESTINY-Gastric02 trial and the RAINBOW trial. On top of the heterogeneity sources in the MAIC analyses, additional sources of heterogeneity might have introduced uncertainty to the NMA estimates. For instance, in the MAIC, the sponsor assumed that geographical region and ethnicity were important prognostic factors, and that patients from Asia had a better prognosis than patients from Western countries. Subsequently, to limit the number of Asian patients in the MAIC, the sponsor selected only patients from Europe, Israel, Australia, and the US from the RAINBOW trial, and compared them with the study population of the DESTINY-Gastric02 trial of which the majority of participants were white (87.3%). However, in the NMA network, no included study reported on the distribution of ethnicity except for the DESTINY-Gastric02 trial and RAINBOW trials. Moreover, the KSCG/ST10-01 study, the Sym et al. (2013) study, and the WJOG 4007 study were conducted in Asia, while the Roy et al. (2013) study was conducted in both Western and Asian countries. Under the assumption made by the sponsor about geographic region and ethnicity being important prognostic factors, the potential heterogeneity regarding differences in geographical regions and ethnicity in the NMA network could not be ignored. However, the degree of uncertainty remains unknown. The rationale for reporting the results of an FE model is justified when the estimation of between-study variance using the random-effects (RE) model is very imprecise and unstable in situations that consider only a few studies.^34,35 However, the FE model does not sufficiently account for heterogeneity between studies, leading to overly precise and narrow CIs.³⁵ Given that various sources of heterogeneity existed in the sponsor-submitted ITC (described previously), the use of the FE model introduced uncertainty in the NMA treatment effect estimates.

Other Evidence

Description of Studies

The DESTINY-Gastric01 trial, conducted in Asia (i.e., Japan and South Korea), enrolled 188 patients with advanced HER2-positive gastric or GEJ adenocarcinoma who had progressed on or after at least 2 prior regimens including a fluoropyrimidine drug, a platinum drug, and a trastuzumab-containing regimen (i.e., in the third-line and later setting). The primary objective of the DESTINY-Gastric01 trial was to compare the efficacy of trastuzumab deruxtecan versus the physician’s choice of treatment (i.e., irinotecan 150 mg/m² intravenously every 2 weeks or paclitaxel 80 mg/m² intravenously every week), as measured by ORR per ICR assessment. Secondary end points included OS, PFS, FACT-Ga, and harms.

Rationale for the Inclusion of the DESTINY-Gastric01 Trial

The DESTINY-Gastric01 trial population is not aligned with the population described in sponsor’s reimbursement request because the DESTINY-Gastric01 trial focused on the third-line and later treatment settings, while the sponsor’s funding request is limited to the second-line treatment setting. Therefore, the DESTINY-Gastric01 trial was considered out of the scope for this Clinical Review Report.

Of note, the DESTINY-Gastric01 trial population (i.e., patients who received ≥ 2 prior regimens, including an anti-HER regimen) would be relevant for a group of patients who are implied in the broader Health Canada indication for trastuzumab deruxtecan, which is for use “as monotherapy in adult patients with unresectable locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma who have received a prior trastuzumab-based regimen.” According to the clinical experts consulted by the review team, this group of patients who have received 2 or more prior regimens is small in number in the real-world setting, and will mainly include those patients who are on currently available second or later lines of therapy and may miss the window of opportunity for being considered eligible for treatment with trastuzumab deruxtecan under the current funding request for the second-line setting. Therefore, the results from the DESTINY-Gastric01 trial were considered supplementary evidence, and are summarized in this section.

Efficacy Results

Overall Survival

As of the data cut-off date of June 3, 2020, the proportion of patients in the intention-to-treat (ITT) population who had OS events in the DESTINY-Gastric01 trial was 67.2% for the trastuzumab deruxtecan group and 79.0% for the physician’s choice group. The median OS was 12.5 months (95% CI, 10.3 months to 15.2 months) in the trastuzumab deruxtecan group and 8.9 months (95% CI, 6.4 months to 10.4 months) in the physician’s choice group. The adjusted HR was 0.60 (95% CI, 0.42 to 0.86).

PFS per ICR Assessment

As of June 3, 2020, the proportion of patients in the ITT population who had PFS events was 65.1% in the trastuzumab deruxtecan group and 58.1% in the physician’s choice group. The median PFS was 5.6 months (95% CI, 4.3 months to 6.9 months) in the trastuzumab deruxtecan group and 3.5 months (95% CI, 2.0 months to 4.3 months) in the physician’s choice group. The adjusted HR was 0.47 (95% CI, 0.31 to 0.71).

Confirmed ORR per ICR Assessment

The confirmed ORRs per ICR assessment were █████ ████ ███ ████ ██ █████ in the trastuzumab deruxtecan group and 11.3% (95% CI, 4.7% to 21.9%) in the physician’s choice group. The proportion of patients who achieved a best overall response of confirmed CR in the trastuzumab deruxtecan group was 7.9%. No patients achieved CR in the physician’s choice group.

FACT-Ga Total Score

As of the data cut-off date of November 8, 2019, the mean FACT-Ga total scores at the end of treatment were █████ ███ █ ██████ for the trastuzumab deruxtecan group and █████ ███ █ ██████ for the physician’s choice group, with mean changes of █████ ███ █ ██████ and █████ ███ █ ███████ respectively.

Harms Results

The cut-off date for the harms data was June 3, 2020.

Treatment-Emergent AEs

All patients in the trastuzumab deruxtecan group and 98.4% of the patients in the physician’s choice group had TEAEs. The most commonly reported TEAE was neutropenia, reported in 64.8% of patients in the trastuzumab deruxtecan group versus 35.5% in the physician’s choice group.

The proportion of patients who had any TEAE of grade 3 or higher was 85.6% in the trastuzumab deruxtecan group, higher than the 56.5% reported in the physician’s choice group. The most commonly reported TEAE of grade 3 or higher was neutropenia (51.2% in the trastuzumab deruxtecan group versus 24.2% in the physician’s choice group), followed by anemia (38.4% in the trastuzumab deruxtecan group versus 22.6% in the physician’s choice group).

Treatment-Emergent Serious AEs

The proportion of patients who had any TESAE was 44.8% in the trastuzumab deruxtecan group, higher than the 25.8% reported in the physician’s choice group. The most commonly reported TESAE was decreased appetite (10.4% in the trastuzumab deruxtecan group versus 1.6% in the physician’s choice group), followed by ILD (5.6% in the trastuzumab deruxtecan group versus 0 in the physician’s choice group), anemia (3.2% in the trastuzumab deruxtecan group versus 3.2% in the physician’s choice group), and dehydration (3.2% in the trastuzumab deruxtecan group versus 0 in the physician’s choice group).

Treatment Discontinuation Due to TEAEs

The proportion of patients who discontinued study treatment was 17.6% in the trastuzumab deruxtecan group and 6.5% in the physician’s choice group. Discontinuation due to ILD occurred in 6.4% of patients in the trastuzumab deruxtecan group versus 0% in the physician’s choice group.

Mortality

The proportion of patients who had any TEAE associated with an outcome of death was 6.4% in the trastuzumab deruxtecan group, higher than the 3.2% reported in the physician’s choice group.

Notable Harms

The proportion of patients who had ILD was 12.8% in the trastuzumab deruxtecan group; of these, 5.6% occurred as TESAEs. No patients in the physician’s choice group had ILD. The proportion of patients who had IRR was 6.4% in the trastuzumab deruxtecan group and 3.2% in the physician’s choice group. The proportion of patients who had grade 2 LV dysfunction (defined as the resting LVEF ranges from 50% to 40%; and there is a 10% to 19% LVEF decrease from baseline) was 9.4% in the trastuzumab deruxtecan group. The proportion of patients who had QT prolongation events was 0.8% in the trastuzumab deruxtecan group and 3.2% in the physician’s choice group.

Critical Appraisal

The DESTINY-Gastric01 trial enrolled 188 patients, with 126 patients and 66 patients being randomized to the trastuzumab deruxtecan group and physician’s choice group (2:1 randomization), respectively. The randomization was done using an interactive web and voice response system and stratified based on region (Japan or South Korea), ECOG PS (0 or 1), and HER2 status (IHC 3+ or IHC 2+ and ISH-positive) to minimize potential imbalances between the study groups that might bias the results. Despite the relatively small sample size, the distribution of patients in baseline characteristics was generally balanced between the trastuzumab deruxtecan group and the physician’s choice group, indicating a low risk of bias in the randomization process. Despite the open-label study design, the review team determined that there is a low risk of detection bias when determining PFS or ORR, but that there is still increased uncertainty with respect to the treatment efficacy in this setting. The results of both the PFS per ICR assessment and the PFS per investigator assessment (data not shown) were generally consistent, as were the findings from unconfirmed and confirmed ORRs. However, there is a notable risk of performance bias for the FACT-Ga, which was associated with the open-label design and the subjective nature of the measure. The DESTINY-Gastric01 trial reported OS, which was considered by the clinical experts consulted by the review team to be the most important outcome for the study population. Multiplicity adjustment was carried out for unconfirmed ORR (i.e., the primary end point of the trial) and for OS to control for type I error; however, all the remaining efficacy end points (e.g., PFS, FACT-Ga) were not adjusted for multiplicity.

There are some concerns regarding whether the patient population in the DESTINY-Gastric01 trial was representative of the corresponding patient population in Canada. According to the clinical experts consulted by the review team, the inclusion and exclusion criteria of the DESTINY-Gastric01 trial were generally appropriate in terms of selecting eligible patients; however, the efficacies observed in the trastuzumab deruxtecan group and physician’s choice group were higher than the experts expected or have encountered in real-world third-line and later settings, in which patients are usually of poor status and efficacy. This suggests potential differences between the trial population and the real-world population in Canada.

There are additional concerns about generalizing the results from the DESTINY-Gastric01 trial population to the DESTINY-Gastric02 trial population due to obvious differences in patient characteristics. For instance, 87.3% of the patients in the DESTINY-Gastric02 trial were white and from North America, whereas all the patients in the DESTINY-Gastric01 trial were Asian and from Japan or South Korea. As noted in the sponsor-submitted ITC, geographical region and ethnicity were important prognostic factors, and Asian patients’ prognoses differed from those of patients in Western countries. Second, in the DESTINY-Gastric02 trial, 34.2% of patients had gastric cancer and 65.8% had GEJ cancer, whereas in the DESTINY-Gastric01 trial, 87.2% of patients had gastric cancer and 12.8% had GEJ cancer. These differences in patient characteristics may introduce treatment heterogeneity that increases the uncertainty of the results and their generalizability to the Canadian context.

The clinical experts consulted by the review team noted that the use of irinotecan or paclitaxel as comparators in the DESTINY-Gastric01 trial is not reflective of current clinical practice in Canada. According to the clinical experts consulted by the review team, when the DESTINY-Gastric01 trial was designed, irinotecan and paclitaxel were commonly used in the third-line and later settings. However, in current clinical practice, these drugs are rarely used — and if so, by a very small group of patients, such as those who experienced serious neuropathy from previous lines of therapy.

Conclusions

DESTINY-Gastric02 (N = 79), a phase II, single-arm trial submitted by the sponsor, assessed the efficacy and safety of trastuzumab deruxtecan for the treatment of adult patients with unresectable or metastatic HER2-positive gastric or GEJ cancer in the second-line treatment setting. The clinical experts consulted by the review team noted that the results of some efficacy end points that were critical to decision-making (e.g., the probability of survival at 6 months or 12 months and the probability of being progression-free at 6 months) were clinically meaningful. However, the absence of a comparator group in the DESTINY-Gastric02 trial is a key limitation in the interpretation of the efficacy findings, resulting in very low certainty of evidence. The clinical experts consulted by the review team noted that the incidence of the key safety end point (ILD) in the DESTINY-Gastric02 trial met their expectations in terms of being consistent with the incidences reported in the literature. According to the experts, trastuzumab deruxtecan has an overall beneficial effect in the second-line treatment setting, warranting a confirmatory phase III clinical trial. The sponsor is currently conducting a phase III trial (the DESTINY-Gastric04 trial) to assess the efficacy and safety of trastuzumab deruxtecan relative to ramucirumab-paclitaxel in patients with HER2-positive gastric or GEJ adenocarcinoma in the second-line treatment setting. The trial results are anticipated to be ready in the fourth quarter of 2025.

In the absence of direct evidence comparing trastuzumab deruxtecan to other second-line treatments currently available in Canada (i.e., ramucirumab-paclitaxel, paclitaxel, FOLFIRI, irinotecan, and docetaxel), sponsor-submitted ITCs using an unanchored MAIC and NMA were reviewed. The ITC treatment effect estimates for OS and PFS favoured trastuzumab deruxtecan over all other comparators; however, several major limitations in the design and methods of the ITC preclude any definitive conclusion about the magnitude of effect. Specifically, missing prognostic factors (e.g., HER2 status), limited factors involved in the weighting process, residual imbalances in prognostic or effect-modifying factors, a significant reduction in ESS — as well as heterogeneity in study design, statistical analyses, geographical regions, and ethnicity distribution across the studies included in the NMA evidence network — can all result in biased estimates and overly precise credible intervals.

Introduction

The objective of this report is to review and critically appraise the evidence submitted by the sponsor on the beneficial and harmful effects of trastuzumab deruxtecan (Enhertu), 100 mg, powder for concentrate for solution for IV infusion for the treatment of adult patients with unresectable locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma who have received a prior trastuzumab-based regimen.

Disease Background

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

Gastric cancer is the fifth most common cancer and the fifth leading cause of cancer mortality worldwide, with approximately 968,000 incident cases and 659,853 associated deaths in 2022 (equating to 6.8% of all cancer-related deaths).⁴ Gastric adenocarcinoma is the most common histological type of gastric cancer, accounting for more than 95% of gastric cancer cases.⁵ Patients with advanced GEJ adenocarcinoma are often considered within the same clinical trial population as those with advanced gastric adenocarcinoma because of similarities in tumour growth and patterns of spread.^6,7 In fact, gastric and GEJ adenocarcinoma have often been reviewed, investigated, or presented together in literature reviews, clinical trials, and clinical management guidelines.^8-11

It is estimated that 1 in 98 people in Canada will have gastric cancer in their lifetime.³⁶ In 2024, the projected incident rate of gastric cancer in Canada was 8.3 per 100,000 adults, with an estimated 1,400 cases in females and 2,600 cases in males.¹² Signs and symptoms of gastric cancer include abdominal pain, heart burn, loss of appetite, bloating, nausea, vomiting, difficulty swallowing, blood in the stool, anemia, fatigue, ascites, and jaundice.¹³ The median survival duration for patients with advanced gastric cancer is low, approximately 10 months to 12 months, with a 5-year OS of 5% to 20%.³⁷ The overall 5-year survival rate for all patients with gastric cancer is estimated to be 29%,¹⁴ and patients with distant metastases experience worse outcomes, with an estimated 5-year relative survival rate of 7%.¹⁵ Compared to patients with gastric adenocarcinoma, patients with GEJ adenocarcinoma may have worse disease-specific survival rates, with an approximately 10% higher cumulative incidence of recurrence.¹⁶

The prognostic role of HER2 in gastric cancer remains controversial due to conflicting evidence.^17-21 Patients with HER2-positive gastric cancer account for 10% to 20.2% of all gastric cancer cases.³⁸ In a population of patients in Canada between 2022 and 2023, an estimated 21% of all gastric and GEJ cancers showed HER2 positivity.²² All patients with advanced or metastatic gastric or GEJ cancer, including patients with both gastric and gastroesophageal adenocarcinomas, should undergo HER2 testing.²³ HER2 testing should also be performed on biopsy or resection specimens.²³ Recommended HER2 testing methods include IHC, which assesses HER2 protein expression levels, and ISH, which evaluates HER2 gene amplification.²³ HER2 testing is typically conducted at the time of diagnosis or at the onset of advanced or metastatic disease.²³ Additionally, HER2 testing may be repeated if there is a need for re-evaluation due to disease progression or metastases.²³ HER2 positivity is confirmed when test results show IHC 3+ or IHC 2+ followed by ISH positivity.^23,24

Standards of Therapy

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

According to the clinical experts consulted by the review team, most patients with unresectable locally advanced or metastatic HER2-positive gastric or GEJ cancers are treated with palliative intent; the treatment goals of all therapies in this setting are to prolong OS and improve quality of life. The clinical experts consulted by the review team noted that the cornerstone of treatment for patients with unresectable locally advanced or metastatic HER2-positive gastric or GEJ cancers involves the sequential use of the best available systemic therapies.

The clinical experts consulted by the review team noted that, in the first-line treatment setting, the standard of care for patients with locally advanced or metastatic HER2-positive gastric or GEJ cancers with a PD-L1 CPS of less than 1 includes a fluoropyrimidine-platinum doublet chemotherapy (e.g., FOLFOX, CAPOX, or cisplatin-capecitabine) in combination with trastuzumab. For patients with locally advanced or metastatic HER2-positive gastric or GEJ cancers who have a PD-L1 CPS greater than or equal to 1, according to the clinical experts consulted by the review team, the addition of pembrolizumab to the backbone of doublet chemotherapy and trastuzumab has been established as the standard of care first-line therapy.

According to the clinical experts consulted by the review team, in the second-line treatment setting, the standard of care for locally advanced or metastatic HER2-positive gastric or GEJ cancers is treatment with ramucirumab-paclitaxel or ramucirumab alone. However, the clinical experts noted that as a single-drug treatment, ramucirumab is not reimbursed in many jurisdictions across Canada, including Ontario. They also noted that the second-line treatment of HER2-positive gastric or GEJ cancers is identical to that of HER2-negative gastric or GEJ cancers at present.

The sponsor noted that single-drug chemotherapy options, such as irinotecan, paclitaxel, or docetaxel, have been suggested in guidelines for patients who are not eligible for ramucirumab-paclitaxel.^25,26 Furthermore, according to the sponsor, relevant guidelines^25,26 also suggest the use a fluoropyrimidine and platinum combination, such as FOLFOX or CAPOX, for patients previously treated with FOLFIRI in the first-line setting. According to the clinical experts consulted by the review team, FOLFIRI is often chosen for patients who have significant residual neuropathy from first-line therapy and for whom the use of paclitaxel would be relatively contraindicated.

The clinical experts consulted by the review team noted that in the third-line setting, treatment options for patients with locally advanced or metastatic HER2-positive gastric or GEJ cancers include trifluridine-tipiracil (i.e., TAS-102), nivolumab, and pembrolizumab.

Drug Under Review

The key characteristics of trastuzumab deruxtecan as monotherapy for the treatment of adult patients with unresectable locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma who have received a prior trastuzumab-based regimen are summarized in Table 3.

The recommended dose of trastuzumab deruxtecan for locally advanced or metastatic gastric and GEJ cancer is 6.4 mg/kg, given as an IV infusion once every 3 weeks (21-day cycle) until disease progression or unacceptable toxicity.

Trastuzumab deruxtecan as a monotherapy is also indicated for:³⁹

• 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 have developed disease recurrence during or within 6 months of completing neoadjuvant or adjuvant therapy

• the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received prior treatment with trastuzumab emtansine (T-DM1)

• the treatment of adult patients with unresectable or metastatic HER2-low (i.e., IHC 1+ or IHC 2+ and ISH-negative) breast cancer who have received at least 1 prior line of chemotherapy in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant chemotherapy.

Trastuzumab deruxtecan has not been previously reviewed for this indication (i.e., gastric or GEJ adenocarcinomas) by CDA-AMC.

Regarding the mechanism of action, trastuzumab deruxtecan is a HER2-targeted antibody-drug conjugate composed of 3 components: a humanized anti-HER2 immunoglobulin G1 monoclonal antibody with the same amino acid sequence as trastuzumab, covalently linked to a topoisomerase I inhibitor (an exatecan derivative) via a tetrapeptide-based cleavable linker. Deruxtecan is composed of the linker and the topoisomerase I inhibitor. Stability studies have demonstrated that less than 5% of the intact antibody-drug conjugate dissociates into the released topoisomerase inhibitor form within 21 days. After binding to HER2 on tumour cells, trastuzumab deruxtecan undergoes internalization and intracellular linker cleavage by lysosomal enzymes that are upregulated in cancer cells. Upon release, the membrane-permeable topoisomerase I inhibitor causes DNA damage and apoptotic cell death.

On January 15, 2021, the FDA approved trastuzumab deruxtecan for adult patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma who have received a prior trastuzumab-based regimen. Trastuzumab deruxtecan has been given “conditional” authorization by the European Medicines Agency. This means that the European Medicines Agency decided that the benefits of trastuzumab deruxtecan are greater than its risks. However, the manufacturer will have to provide additional evidence after authorization.

Trastuzumab deruxtecan received an NOC/c from Health Canada on January 17, 2025. The sponsor requested a TLR recommendation for trastuzumab deruxtecan on an NOC/c basis while awaiting results of the confirmatory phase III DESTINY-Gastric04 study. More details on TLR recommendation eligibility are provided in the next section.

Table 3: Key Characteristics of Trastuzumab Deruxtecan, Ramucirumab-Paclitaxel, Paclitaxel, Docetaxel, and Irinotecan

CYP3A4 = cytochrome P450 3A4; HER2 = human epidermal growth factor 2; p44 and p42 = extracellular signal-regulated kinase 1 and kinase 2; VEGF-A = vascular endothelial growth factor A; VEGF-C = vascular endothelial growth factor C; VEGF-D = vascular endothelial growth factor D; VEGFR-2 = vascular endothelial growth factor receptor 2.

^aIndications approved by Health Canada.

Sources: Draft product monograph for trastuzumab deruxtecan;² product monograph for ramucirumab;⁴⁰ product monograph for docetaxel;⁴¹ product monograph for irinotecan.⁴²

Consideration for a TLR Recommendation

A TLR is a recommendation by the CDA-AMC expert committee to publicly fund a drug or drug regimen for a certain period of time based on the condition that the sponsor will conduct 1 or more clinical studies that address uncertainty with the clinical evidence. CDA-AMC subsequently conducts a reassessment of the additional evidence and issues a final reimbursement recommendation within a defined period of time. Based on the preliminary assessment by CDA-AMC (Table 36 in Appendix 1), trastuzumab deruxtecan meets the criteria to be considered by the expert committee for a TLR recommendation. In accordance with the CDA-AMC Procedures for Reimbursement Reviews, this section of the report provides an assessment of the existing gaps in the evidence and the sponsor’s evidence-generation plans.

Eligibility Criteria for a TLR

Regulatory Status

Trastuzumab deruxtecan received an NOC/c from Health Canada on January 17, 2025.

Commitment to File for Reassessment

The sponsor has expressed a commitment to file a reassessment application with CDA-AMC in accordance with the time frames specified in the procedures for a TLR recommendation. The phase III trial, DESTINY-Gastric04, will be completed within a time frame that will not exceed 3 years from the target expert committee meeting date.

The sponsor has stated that primary completion of the DESTINY-Gastric04 trial is estimated to occur in the fourth quarter of 2025.⁴³ This is within the 3-year period described within the CDA-AMC procedures for TLR recommendations.

Evidence-Generation Plans (Phase III DESTINY-Gastric04 Trial)

The DESTINY-Gastric04 trial (Table 4) meets the eligibility for a TLR recommendation because it is a phase III clinical trial conducted using trastuzumab deruxtecan as monotherapy in the target population for this review. Specifically, the following was noted by CDA-AMC.

• Study design: Phase III trial that will be reported within the time frame specified in the CDA-AMC procedures.

• Intervention: Trastuzumab deruxtecan will be intravenously administered as monotherapy at a dosage of 6.4 mg/kg every 3 weeks, which is the same dosage used in the phase II DESTINY-Gastric02 trial.

• Patient population: Generally, the trial patient population is the same, with acceptable differences, specifically:

  • Tumour type and histology — These are the same for the indication reviewed by CDA-AMC and the pending phase III trial (i.e., HER2-positive gastric or GEJ adenocarcinoma).

  • Disease status — The pending phase III trial is being conducted in patients with unresectable locally advanced or metastatic disease. This is generally aligned with the indication that was initially submitted to CDA-AMC.

  • Line of therapy — The lines of therapy in the pending phase III trial appear to be the same as those in the reimbursement request that is under review by CDA-AMC (i.e., second-line therapy in the metastatic setting).

  • Required prior therapies — The prior therapies required to be eligible for treatment with trastuzumab deruxtecan are aligned between the funding request under review by CDA-AMC and the sponsor’s ongoing phase III trial (DESTINY-Gastric04). However, the patient population covered in the Health Canada indication (i.e., patients who have received a prior trastuzumab-based regimen) appears be broader than that of the phase III trial.

  • Comparator — Patients in the comparator group will receive IV infusion of ramucirumab-paclitaxel.

  • Outcomes — The primary end point is OS. Other end points include PFS, ORR, FACT-Ga, and harms.

Table 4: Pending Phase III Trial (the DESTINY-Gastric04 Trial)

ASCP-CAP = American Society of Clinical Oncology – College of American Pathologists; CNS = central nervous system; DCR = disease control rate; DOR = duration of response; ECHO = echocardiogram; ECOG PS = Eastern Cooperative Oncology Group Performance Status; FACT-Ga = Functional Assessment of Cancer Therapy – Gastric; GEJ = gastroesophageal junction; HER2 = human epidermal growth factor 2; HRQoL = health-related quality of life; IHC = immunohistochemistry; ILD = interstitial lung disease; ISH = in situ hybridization; LVEF = left ventricular ejection fraction; MUGA = multigated acquisition; NR = not reported; NYHA = New York Heart Association; ORR = objective response rate; OS = overall survival; PFS = progression-free survival; TTR = time to response.

Source: Sponsor’s Summary of Clinical Evidence.¹

Assessment of Gaps in the Evidence

Gaps exist in the evidence derived from the pivotal DESTINY-Gastric02 trial currently under review by CDA-AMC. First, the DESTINY-Gastric02 trial was a single-arm study that lacked a comparator to determine the relative efficacy of trastuzumab deruxtecan on OS and evidence of a minimal important difference. Second, the DESTINY-Gastric02 trial was a phase II study designed to determine the efficacy and safety of trastuzumab deruxtecan for a comparatively short follow-up period in a small sample size (N = 79). The basis for the TLR and subsequent reassessment would be the ongoing DESTINY-Gastric04 phase III study that is evaluating efficacy and safety relative to ramucirumab-paclitaxel for up to 3 years of follow-up in approximately 490 patients with HER2-positive gastric or GEJ adenocarcinoma.

The study population of the DESTINY-Gastric04 trial targeted the second-line treatment setting for patients with HER2-positive gastric or GEJ cancer, which aligned with the current reimbursement request submitted by the sponsor. However, the Health Canada indication targets a broader population that includes not only patients in the second-line treatment setting, but also patients in the third-line and later settings. The DESTINY-Gastric04 trial population does not completely align with the patients in third-line and later settings, as described by the Health Canada indication. As a result, findings from the DESTINY-Gastric04 trial may not be generalizable to patients in the third-line and subsequent lines setting.

According to the clinical experts consulted by the review team, the selection of ramucirumab-paclitaxel as the comparator in the phase III, DESTINY-Gastric04 trial is appropriate because treatment with ramucirumab-paclitaxel is currently a standard of care in the second-line setting for locally advanced or metastatic HER2-positive gastric or GEJ cancer, and it will likely remain so in the second-line setting, when the results of the DESTINY-Gastric04 trial become available.

Perspectives of Patients, Clinicians, and Drug Programs

The full patient and clinician group submissions received are available in the consolidated patient and clinician group input document for this review on the project website.

Patient Group Input

This section was prepared by the review team based on the input provided by patient groups.

One input from My Gut Feeling – Stomach Cancer Foundation of Canada was received for this review. My Gut Feeling – Stomach Cancer Foundation of Canada is a nonprofit organization dedicated to providing “support, awareness, education, information and advocacy to stomach cancer patients, cancer survivors, caregivers, and family members.” Its mission is to improve the quality of life for people affected by gastric or GEJ cancers and to make systemic changes to reduce the incidence and mortality of GEJ cancers. The patient group gathered information from 30 respondents (75% patients, 25% caregivers) through an online survey conducted in September 2024. Respondents ranged in age from 20 years to 80 years, with 90% self-reporting as female and 10% as male; 95% were from Canada, and 5% were from the US.

The majority of respondents (90%) had a diagnosis of gastric cancer, and the remainder had GEJ cancer. The most common type of cancer was adenocarcinoma (85%), and most patients (40%) had been diagnosed with stage IV disease. Among the survey respondents,10% reported having HER2-positive disease; 10% had microsatellite instability–high disease; and 20% reported having a PD-L1 CPS score of greater than 5.

According to the patient group input, 95% of respondents felt that their cancer diagnosis had a significant impact on their quality of life, and that cancer and its treatment affected their physical health, mental health, ability to eat, work, finances, social life, identity, psychosocial well-being, and self-image. Many respondents reported concerns about finances due to the inability to work because of their cancer diagnosis and/or treatment. Patients and caregivers commented on the time and money they spent on cancer treatment appointments, medications, driving and parking, and eating at hospitals, describing these as financial stressors.

Based on the input, the most common symptoms reported by the respondents include reflux, abdominal pain, eating difficulties, poor appetite, weight loss, nausea, painful swallowing, and fatigue.

The survey respondents reported experience with a variety of treatment modalities, including chemotherapy, immunotherapy, targeted therapy, surgery, and radiation. Their satisfaction with their current or past treatment was evaluated on a scale of 1 to 10 (where 1 = “not satisfied” and 10 = “very satisfied”); 64% reported satisfaction of 8 or higher. The patient group added that, while current therapies lead to mixed satisfaction from respondents in terms of perceived efficacy and cancer control, these treatments have a variety of side effects that impair quality of life; all respondents identified at least 1 treatment-related side effect, with 88% reporting fatigue. This was followed by weight loss (80%), appetite changes (80%), nausea and/or vomiting (76%), “chemo brain” (64%), diarrhea (60%), taste changes (52%), neuropathy (52%), hair loss (48%), abdominal pain (44%), and insomnia (44%). The patient group reported that, based on the survey results, most of the patients were able to tolerate treatment as prescribed (40%). Another 16% had their systemic therapy dose reduced due to side effects; 16% had to delay or skip a cycle of their systemic therapy; 12% had to stop treatment due to side effects; and 8% were hospitalized due to the severity of an AE.

My Gut Feeling – Stomach Cancer Foundation of Canada noted that important outcomes reported by the respondents included quality of life, treatment side effects, cost of treatment, convenience of treatment, treatment access, duration of treatment, and survival benefits. According to the input, when respondents were asked if they would pay out of pocket for additional therapies, the majority were interested in discussing treatment options not covered by their current health care plans or universal health care; 48% said they would pay for therapies out of pocket. A total of 49% said “maybe” they would pay for these treatments: 16% said maybe they would pay if it improved their survival; 28% might pay depending on cost; and 5% might pay depending on the impact on their quality of life.

The patient group added that, while the survey found that most respondents (85%) did not have to pay directly out of pocket for specific treatments, the remainder (25%) had paid for targeted therapy or adjunct medications, either through private pay or insurance. Also, respondents mentioned that having more treatment options and access to first-line therapies were “extremely important” to them. The respondents noted that barriers to access included institutional and health care system barriers, limited availability of treatments, and speed of accessing treatment.

My Gut Feeling – Stomach Cancer Foundation of Canada noted that 4 respondents, including 3 patients from Canada, had experience with trastuzumab deruxtecan. At the time of the survey, 3 patients had been on trastuzumab deruxtecan for at least 1 month, but 1 patient had discontinued the treatment after disease progression. The patient group explained that these respondents were satisfied because trastuzumab deruxtecan had caused fewer side effects, was easier to tolerate, improved their quality of life, and better controlled their cancer. The most common side effects reported by the respondents included fatigue, nausea, vomiting, loss of appetite, and constipation.

My Gut Feeling – Stomach Cancer Foundation of Canada stated that there is an unmet patient and caregiver need to receive equitable access to therapies that may prolong life, improve symptoms, reduce risk of recurrence, and improve treatment tolerability.

Clinician Input

Input From Clinical Experts Consulted by the Review Team

All CDA-AMC 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 drug’s potential place in therapy). The following input was provided by 2 clinical specialists with expertise in the diagnosis and management of adult patients with unresectable locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma who have received a prior trastuzumab-based regimen.

Unmet Needs

According to the clinical experts consulted by the review team, the goals for the treatment of patients with unresectable locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma who have received a prior trastuzumab-based regimen are to prolong OS and improve quality of life.

The clinical experts consulted by the review team noted that there was a considerable unmet need for an effective anti-HER2 therapy beyond the first-line treatment setting for patients with unresectable locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma.

Place in Therapy

According to the clinical experts consulted by the review team, following disease progression on first-line HER2-directed therapy, the current standard of care in the second-line setting is treatment with either ramucirumab in combination with paclitaxel or ramucirumab alone, similarly to how patients with HER2-negative cancer would be treated. The clinical experts noted that trastuzumab deruxtecan would cause a shift in the current treatment paradigm in adult patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma who have received a prior trastuzumab-based regimen: all other current second-line treatment regimens would shift to the third and subsequent lines.

Patient Population

According to the clinical experts consulted by the review team, in alignment with the eligible participants in the sponsor-submitted DESTINY-Gastric02 trial, the patients best suited for treatment with trastuzumab deruxtecan in the second-line setting would be those who have all the following criteria, unresectable or metastatic gastric or GEJ cancer with progressive disease on or after first-line therapy with a trastuzumab-containing regimen, a HER2-positive gastric or GEJ cancer (defined as IHC 3+ or IHC 2+ and ISH-positive) confirmed by a repeat biopsy, a preserved ECOG PS, and a preserved cardiac ejection.

Assessing the Response to Treatment

According to the clinical experts consulted by the review team, the key factors in determining response to treatment include patient-reported symptoms, side effects, and cross-sectional imaging (e.g., CT scan and/or MRI).

Discontinuing Treatment

According to the clinical experts consulted by the review team, patient-reported symptoms, side effects, and well-being, in conjunction with assessment of treatment response, would be the major determinants for discontinuing treatment. In terms of toxicities, the clinical experts consulted by the review team noted that ILD is among the most important AEs of which to be aware.

Prescribing Considerations

According to the clinical experts consulted by the review team, trastuzumab deruxtecan should be prescribed only by (or under the supervision of) a specialist in medical oncology with expertise in diagnosing and managing immunotherapy-related side effects, including ILD. The clinical experts noted that trastuzumab deruxtecan could be safely administered in a hospital or outpatient clinic.

Clinician Group Input

This section was prepared by the review team based on the input provided by clinician groups.

CDA-AMC received inputs from 2 clinician groups: the OH-CCO Gastrointestinal Cancer Drug Advisory Committee, and the ad hoc group of adenocarcinoma-treating physicians and the CGOEN.

OH-CCO’s Drug Advisory Committees provide timely, evidence-based clinical and health system guidance on drug-related issues in support of OH-CCO’s mandate, including the Provincial Drug Reimbursement Programs and the Systemic Treatment Program. The OH-CCO Gastrointestinal Cancer Drug Advisory Committee gathered information from 5 clinicians through videocall.

The CGOEN is a virtual and inclusive network of gastrointestinal oncology clinicians in Canada who contribute to the knowledge of gastrointestinal cancer and its treatments, including by participating in clinical trials, conducting observational research, and being involved in local, provincial, and/or national clinical guideline development and health technology assessment. A total of 15 clinicians contributed to the CGOEN submission.

According to the clinician groups, treatment is aimed at improving symptoms, response rates, quality of life, and OS. The clinician groups noted that the current treatment includes the anti–HER2-targeted therapy of trastuzumab with standard chemotherapy (mFOLFOX6), and added that the new standard of care involves adding the anti-PD1 drug, pembrolizumab, to the standard of care of trastuzumab and FOLFOX in tumours that have evidence of PD-L1 expression with a CPS of greater than 1.

Based on both clinician inputs, there is a gap in the treatment of patients with HER2-positive metastatic gastric and GEJ cancer whose disease progresses after first-line standard therapy, and trastuzumab deruxtecan should be considered in the second-line setting.

CGOEN clarified that all patients with metastatic HER2-positive gastric or GEJ cancer should be considered for treatment with trastuzumab deruxtecan if their cancer has progressed after first-line treatment with trastuzumab (plus pembrolizumab if CPS > 1) and chemotherapy (FOLFOX). Patients who have had pneumonitis in the past may not be eligible for trastuzumab deruxtecan, given that this was an exclusion criterion for the use of trastuzumab deruxtecan. Furthermore, if a patient’s cardiac ejection fraction is lower than 50%, a cardiologist would need to be involved to ensure safety, given the 3% cardiotoxicity rate and significant drop in ejection fraction associated with trastuzumab deruxtecan. CGOEN added that efficacy outcomes, such as ORR, PFS and OS — along with safety and toxicity outcomes and quality of life — are important when assessing response to treatment. OH-CCO believes that response to treatment should be assessed every 2 months to 3 months.

According to the clinician inputs, factors prompting the consideration of treatment discontinuation would include disease progression and intolerance. CGOEN added toxicities — including severe myelosuppression, liver toxicity, cardiac toxicity (with a significant drop in ejection fraction), and grade 2 or worse pneumonitis — and patient choice to the list.

OH-CCO stated that an outpatient setting in which the patient is under the care of a health care provider with training in oncology is appropriate for treatment. CGOEN’s view was that treatment with trastuzumab deruxtecan should be performed in an outpatient cancer clinic with health care providers who have experience in the delivery of cytotoxic therapy; these include pharmacists, oncology nurses, and medical oncologists who are aware of treatment side effects (i.e., toxicities). Furthermore, CGOEN noted that access to imaging (e.g., CT scans) and cardiac imaging (e.g., multigated acquisition or echocardiogram) is important for monitoring of both efficacy and toxicity.

Drug Program Input

The drug programs provide input on each drug being reviewed through the 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 the review team are summarized in Table 5.

Table 5: Summary of Drug Plan Input and Clinical Expert Response

CDA-AMC = Canada’s Drug Agency; ECOG PS = Eastern Cooperative Oncology Group Performance Status; ESS = effective sample size; FOLFIRI = folinic acid–fluorouracil-irinotecan; GEJ = gastroesophageal junction; HER2 = human epidermal growth factor receptor 2; IHC = immunohistochemistry; ISH = in situ hybridization; ITC = indirect treatment comparison; NMA = network meta-analysis; OS = overall survival; pERC = pan-Canadian Oncology Drug Review Expert Review Committee; PFS = profession-free survival.

Clinical Evidence

The objective of the Clinical Review Report is to review and critically appraise the clinical evidence submitted by the sponsor on the beneficial and harmful effects of trastuzumab deruxtecan, 100 mg, powder for concentrate for solution for IV infusion, for the treatment of adult patients with unresectable locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma who have received a prior trastuzumab-based regimen. The focus will be on comparing trastuzumab deruxtecan to relevant comparators and identifying gaps in the current evidence.

A summary of the clinical evidence included by the sponsor for the review of trastuzumab deruxtecan is presented in 2 sections, with the review team’s critical appraisal of the evidence included at the end of each. The first section, the systematic review, includes pivotal studies and RCTs that were selected according to the sponsor’s systematic review protocol. The review team’s assessment of the certainty of the evidence in this first section, using the GRADE approach, follows the critical appraisal of the evidence. The second section includes indirect evidence from the sponsor.

Included Studies

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

• One phase II, single-arm study identified in the systematic review (i.e., the DESTINY-Gastric02 trial)

• One ITC consisting of an unanchored MAIC and an NMA

• One phase II RCT identified as other evidence (i.e., the DESTINY-Gastric01 trial).

Systematic Review

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

Description of Studies

One study (the DESTINY-Gastric02 trial) was identified as the pivotal study. Characteristics of the DESTINY-Gastric02 study are summarized in Table 6.

The DESTINY-Gastric02 trial was a phase II, single-arm, open-label study investigating the use of trastuzumab deruxtecan as monotherapy for the treatment of patients (aged ≥ 18 years) who have unresectable or metastatic centrally confirmed HER2-positive gastric or GEJ cancer and have experienced disease progression during or after first-line therapy with a trastuzumab-containing regimen. A total of 79 patients from 24 sites across Europe and North America (no sites in Canada) were enrolled. The primary objective of the DESTINY-Gastric02 trial was to assess the efficacy of trastuzumab deruxtecan based on the confirmed ORR by ICR using RECIST 1.1. OS, PFS, HRQoL outcomes, and harms were also investigated in the DESTINY-Gastric02 trial.

The DESTINY-Gastric02 trial has been completed. Results submitted by the sponsor are mainly from 2 data cut-off dates: April 9, 2021, and November 8, 2021. The median duration of follow-up was 5.9 months (range, 0.7 months to 15.4 months) as of the data cut-off date of April 9, 2021, and 10.2 months (range, 0.7 months to 22.1 months) as of the data cut-off date of November 8, 2021.

Table 6: Details of the DESTINY-Gastric02 Trial Included in the Systematic Review

CNS = central nervous system; DCR = disease control rate; DOR = duration of response; ECHO = echocardiogram; ECOG PS = Eastern Cooperative Oncology Group Performance Status; FACT-Ga = Functional Assessment of Cancer Therapy – Gastric; GEJ = gastroesophageal junction; HER2 = human epidermal growth factor 2; HRQoL = health-related quality of life; ICR = independent central review; IHC = immunohistochemistry; ILD = interstitial lung disease; ISH = in situ hybridization; LVEF = left ventricular ejection fraction; MUGA = multigated acquisition; NYHA = New York Heart Association; ORR = objective response rate; OS = overall survival; PFS = progression-free survival; RECIST 1.1 = Response Evaluation Criteria in Solid Tumours Version 1.1; TTR = time to response.

Sources: Sponsor’s Summary of Clinical Evidence;¹ DESTINY-Gastric02 Clinical Study Report;^32,33 DESTINY-Gastric02 Clinical Study Protocol, Version 3.⁴⁷

Populations

Inclusion and Exclusion Criteria

The DESTINY-Gastric02 trial enrolled patients who were aged 18 years and older with an ECOG PS of 0 or 1 and a diagnosis of unresectable or metastatic HER2-positive (defined as IHC 3+ or IHC 2+ and ISH-positive) gastric or GEJ cancer. Patients were considered eligible if their disease had progressed during or after first-line therapy with a trastuzumab-containing regimen. Patients were excluded if they had received anticancer therapy following a first-line treatment regimen containing trastuzumab.

Interventions

In the single-arm DESTINY-Gastric02 trial, all patients received 6.4 mg/kg of trastuzumab deruxtecan through IV on day 1 (± 2 days) of every 21-day treatment cycle (i.e., every 3 weeks) until disease progression, withdrawal by patient, physician decision, or death. Trastuzumab deruxtecan was administered in a hospital setting. The first infusion of trastuzumab deruxtecan took 90 minutes or greater. Subsequent infusions of trastuzumab were administered over 30 minutes or greater if there was no injection-related reaction after the first infusion.

Outcomes

A list of efficacy end points assessed in this Clinical Review Report is provided in Table 7, followed by descriptions of the outcome measures. Summarized end points are based on outcomes included in the sponsor’s Summary of Clinical Evidence as well as on any outcomes identified as important to this review by the clinical experts consulted by the review team, patient and clinician group inputs, and public drug plans. Using the same considerations, the review team selected end points that were considered most relevant to inform the expert committee deliberations and finalized this list of end points in consultation with members of the expert committee. All summarized efficacy end points were assessed using GRADE. Select notable harms outcomes considered important for informing the expert committee deliberations were also assessed using GRADE.

Table 7: Outcomes Summarized From the Studies Included in the Systematic Review

FACT-Ga = Functional Assessment of Cancer Therapy – Gastric; ICR = independent central review; ORR = objective response rate; OS = overall survival; PFS = progression-free survival.

Sources: Sponsor’s Summary of Clinical Evidence;¹ DESTINY-Gastric02 Clinical Study Report.^32,33

Descriptions of the efficacy and safety outcomes presented in the DESTINY-Gastric02 trial^32,33 and appraised in the Clinical Review Report follow.

Efficacy Outcomes

Overall Survival

In the DESTINY-Gastric02 trial, OS was defined as the time from the date of the first dose of study drug to the date of death due to any cause. If the patient was not known to have died by the analysis cut-off date, OS was censored at the date of last contact. The last contact date was defined as the last date on which the patient was known to be alive up to the data cut-off date.

PFS per ICR Assessment

PFS was defined as the time from the date of the first dose of the study drug to the date of radiographic disease progression (as measured by RECIST 1.1) or death due to any cause. The censoring rules are shown in Table 8.

Table 8: Censoring Rules for PFS Per ICR Assessment in the DESTINY-Gastric02 Trial

ICR = independent central review; PFS = progression-free survival.

Source: DESTINY-Gastric02 Statistical Analysis Plan, Version 2.⁴⁸

Confirmed ORR Per ICR Assessment

Confirmed ORR per ICR assessment was defined as the proportion of patients who achieved a best overall response of confirmed CR or confirmed PR, as determined by ICR committee based on RECIST 1.1. The best overall response was defined as the best response (in the order of CR, PR, stable disease, and progressive disease) across all time points from the start of treatment until when patients were withdrawn from the study or started a new anticancer therapy. The best overall response of CR or PR could not be determined unless it was confirmed no earlier than 4 weeks (28 days) from the date on which a response of CR or PR was first acquired.

Health-Related Quality of Life

Patient-reported HRQoL was measured by FACT-Ga in the DESTINY-Gastric02 trial. The summary of measurement properties of FACT-Ga is shown in Table 9.

Table 9: Summary of Outcome Measures and Their Measurement Properties

FACT-Ga = Functional Assessment of Cancer Therapy – Gastric; MID = minimal important difference; QoL = quality of life; SF-36 = Short Form (36) Health Survey.

Harms Outcomes

The harms outcomes assessed in the DESTINY-Gastric02 trial mainly included TEAEs, TESAEs, withdrawal due to TEAEs, deaths, and notable harms (i.e., ILD, LV dysfunction, QT prolongation, and IRR).

A TEAE was defined as an occurring AE that was absent before the first dose of the study drug — or that worsened in severity or seriousness after initiating the study drug — up to 47 days after last dose of the study drug. Serious AEs with an onset or worsening 48 days or more after the last dose of study drug, if considered related to the study treatment, were also considered as TEAEs.

Statistical Analysis

The sample size was determined based on historical data related to the current standard of care, which suggested that Western patients with second-line gastric or GEJ cancer could have an ORR of up to 27%.⁴⁸ Taking dropout into consideration, a sample size of approximately 80 patients would provide 90% power to achieve a lower limit of 95% CI for the ORR that exceeded 27% under a hypothesized alternative ORR of 45%.

Details on the statistical analysis of efficacy end points in the DESTINY-Gastric02 trial are presented in Table 10. The primary end point for the DESTINY-Gastric02 trial was confirmed ORR assessed per ICR assessment per RECIST 1.1. The estimate of ORR (along with the corresponding 95% exact CI) was calculated using the Clopper-Pearson method.⁵¹ For the key secondary end point in the DESTINY-Gastric02 trial (i.e., PFS per ICR assessment), the median event time and corresponding 95% CI were calculated using the Brookmeyer and Crowley method.⁵² OS, a secondary end point in the DESTINY-Gastric02 trial, was estimated using the Kaplan-Meier (KM) method; CIs for the rates at fixed time points were calculated using the delta method and a log-log transformation of the probabilities. KM estimates of survival curves are presented for PFS and OS. No statistical testing or inference was carried out in the DESTINY-Gastric02 trial.

Table 10: Statistical Analysis of Efficacy End Points in the DESTINY-Gastric02 Trial

CI = confidence interval; FACT-Ga = Functional Assessment of Cancer Therapy – Gastric; ICR = independent central review; KM = Kaplan-Meier; NR = not reported; ORR = objective response rate; OS = overall survival; PFS = progression-free survival.

Sources: Sponsor’s Summary of Clinical Evidence;¹ DESTINY-Gastric02 Statistical Analysis Plan, Version 2.⁴⁸

The following subgroups were examined in the DESTINY-Gastric02 trial for the primary end point of confirmed ORR based on ICR and the key secondary end point of PFS per ICR assessment:

• region (North America, Europe)

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

• sex (female, male)

• ECOG PS (0, 1)

• HER2 status (IHC 3+ or IHC 2+ and ISH-positive)

• primary tumour location (gastric, GEJ)

• histological subtype (intestinal, diffuse, others)

• number of metastatic sites (< 2, ≥ 2)

• previous total gastrectomy (yes, no)

• prior adjuvant or neoadjuvant therapy (yes, no)

• prior nivolumab or pembrolizumab treatment (yes, no)

• prior treatment with immune checkpoint inhibitor or other immuno-oncology therapy (yes, no)

• presence of liver metastasis at baseline (yes, no)

• renal function at baseline (normal, mild impairment, moderate impairment)

• renal impairment status determined by baseline creatinine clearance (CrCl) (calculated using the Cockcroft-Gault equation):

• hepatic impairment at baseline (normal, mild)

In each subgroup defined previously, the analysis was conducted using the same type of methodology as described for the corresponding end point. Results of the subgroup analyses were presented using descriptive summaries. Some subcategories were combined if the sample size within categories was too small (e.g., < 10 patients).

Analysis Populations

The analysis populations of the DESTINY-Gastric02 trial are summarized in Table 11.

Table 11: Analysis of Populations in the DESTINY-Gastric02 Trial

FAS = full analysis set; ICR = independent central review; ORR = objective response rate.

Sources: Sponsor’s Summary of Clinical Evidence;¹ DESTINY-Gastric02 Statistical Analysis Plan, Version 2.⁴⁸

Protocol Amendments and Deviations

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Table 12: Major Protocol Deviations in the DESTINY-Gastric02 Trial (FAS, Data Cut-Off Date: April 9, 2021)

FAS = full analysis set.

Source: DESTINY-Gastric02 Clinical Study Report.^32,33

Results

Patient Disposition

Patient disposition in the DESTINY-Gastric02 trial is summarized in Table 13. Of 89 patients screened, 79 were enrolled and treated with at least 1 dose of trastuzumab deruxtecan. As of November 8, 2021, 11 patients (13.9%) had discontinued trastuzumab deruxtecan due to AEs.

Baseline Characteristics

The baseline characteristics outlined in Table 14 are limited to those that are most relevant to this review or that were believed to affect the outcomes or interpretation of the study results. In the DESTINY-Gastric02 trial, the median age of the trial population was 60.7 years (range, 20.3 years to 77.8 years), with 58.5% of the patients being younger than 65 years. The majority of the trial population was male (72.2%), white (87.3%), presented with an ECOG PS of 1 (63.3%), had GEJ as the cancer location (65.8%), and had a HER2 status of IHC 3+ (86.1%). Almost all the patients (78 patients out of 79 patients) had a histological subtype of adenocarcinoma.

Exposure to Study Treatments

Treatment exposure is summarized in Table 15. As of the data cut-off date of November 8, 2021, the median treatment duration for the DESTINY-Gastric02 study was 4.3 months (range, 0.7 months to 22.1 months), and 10 patients (12.7%) were still on treatment with trastuzumab deruxtecan. The median dose intensity was 6.2 mg/kg per 3 weeks (range, 3.9 weeks to 6.7 weeks). The median relative dose intensity (i.e., the ratio of the amount of drug delivered to the planned dose delivered) was 96.6% (range, 60.3% to 104.1%).

Table 13: Summary of Patient Disposition in the DESTINY-Gastric02 Trial (Data Cut-Off Date: November 8, 2021)

AE = adverse event; FAS = full analysis set.

^aPercentage was based on the number of all-screened patients in the all-screened analysis set.

^bDiscontinued based on objective evidence of disease progression.

^cDiscontinued based on clinical manifestations, as judged by the investigator.

^dThis was a drug hold for a treatment-emergent AE (preferred term for COVID-19 pneumonia) that exceeded the protocol-allowed time limit of 49 days from the last infusion date.

Sources: Sponsor’s Summary of Clinical Evidence;¹ DESTINY-Gastric02 Clinical Study Report.^32,33

Table 14: Summary of Baseline Characteristics in the DESTINY-Gastric02 Trial (FAS)

ECOG PS = Eastern Cooperative Oncology Group Performance Status; FAS = full analysis set; HER2 = human epidermal growth factor receptor 2; IHC = immunohistochemistry; ISH = in situ hybridization.

Sources: Sponsor’s Summary of Clinical Evidence;¹ DESTINY-Gastric02 Clinical Study Report.^32,33

Table 15: Summary of Patient Exposure in the DESTINY-Gastric02 Trial (Safety Analysis Set; Data Cut-Off Date: November 8, 2021)

AE = adverse event; NR = not reported.

^aTreatment duration (in months) was calculated as (date of last dose minus date of first dose + 21) divided by (365.25 × 12). For patients who were still on treatment at the data cut-off date, the last available date of dose was used.

^bDose intensity (mg/kg per 3 weeks) = total amount of study drug taken during the treatment period (mg/kg) divided by (treatment duration in weeks divided by 3).

^cRelative dose intensity (%) = dose intensity / planned dose intensity, where the planned dose intensity was 6.4 mg/kg per 3 weeks.

^dDose delay was defined as at least 24 days (3 days later than scheduled) after the previous dose.

Source: DESTINY-Gastric02 Clinical Study Report.^32,33

Prior Cancer Therapy

Details on prior cancer therapy in the DESTINY-Gastric02 trial are presented in Table 16. The majority of trial participants (96.2%) had received 1 prior regimen of cancer therapy.

Table 16: Prior Cancer Therapy in the DESTINY-Gastric02 Trial (FAS; Data Cut-Off Date: April 9, 2021)

FAS = full analysis set.

^aThe percentage for each subcategory was based on the number of patients with the corresponding prior cancer systemic therapy.

Source: DESTINY-Gastric02 Clinical Study Report.^32,33

Concomitant Medications

Information about the use of concomitant medications in the DESTINY-Gastric02 trial is shown in Table 17.

Table 17: Concomitant Treatments Used in the DESTINY-Gastric02 Trial (FAS; Data Cut-Off Date: November 8, 2021)

FAS = full analysis set.

Sources: Sponsor’s Summary of Clinical Evidence;¹ DESTINY-Gastric02 Clinical Study Report.^32,33

Subsequent Treatment

The summary of subsequent treatment in the DESTINY-Gastric02 trial is shown in Table 18. As of the data cut-off date of November 8, 2021, 49.4% patients had received subsequent anticancer treatment after the completion of trastuzumab deruxtecan. Paclitaxel was the most common subsequent treatment and was used by 17.7% of patients.

Table 18: Summary of Subsequent Treatment in the DESTINY-Gastric02 Trial (FAS; Data Cut-Off Date: November 8, 2021)

FAS = full analysis set.

Source: Sponsor’s Summary of Clinical Evidence.¹

Efficacy

Key efficacy results in the DESTINY-Gastric02 FAS are presented in Table 19. The median duration of follow-up was 10.2 months (range, 0.7 months to 22.1 months) as of the data cut-off date of November 8, 2021, and 5.9 months (range, 0.7 months to 15.4 months) as of the data cut-off date of April 9, 2021. The data cut-off date for efficacy results was November 8, 2021, unless otherwise specified.

Table 19: Summary of Key Efficacy Results in the DESTINY-Gastric02 Trial (FAS; Data Cut-Off Date: November 8, 2021)

CI = confidence interval; CR = complete response; FACT-Ga = Functional Assessment of Cancer Therapy – Gastric; FAS = full analysis set; ICR = independent central review; ORR = objective response rate; OS = overall survival; PFS = progression-free survival; PR = partial response; SD = standard deviation.

^aLost to follow-up was defined as the time interval between the last contact date and analysis cut-off date being longer than the protocol-defined 3-month interval of survival follow-up plus 2 weeks.

^bEstimated using Kaplan-Meier.

^cData on FACT-Ga scores were based on the data cut-off date of April 9, 2021.

^dThe n for the change from baseline section was the number of patients who had the patient-reported outcome assessment values at both baseline and the specified visit.

Sources: Sponsor’s Summary of Clinical Evidence;¹ DESTINY-Gastric02 Clinical Study Report;^32,33 Drug Reimbursement Review Sponsor Submission for trastuzumab deruxtecan.³

Overall Survival

As of the data cut-off date of November 8, 2021, the proportion of patients in the FAS who had OS events was 58.2%. The median OS was 12.1 months (95% CI, 9.4 months to 15.4 months). The probability of being alive was 77.8% (95% CI, 66.8% to 85.6%) at 6 months, 50.6% (95% CI, 38.4% to 61.5%) at 12 months, and 35.1% (95% CI, 22.1% to 48.4%) at 18 months. The KM plot for OS is presented in Figure 1.

Figure 1: KM Plot of OS in the DESTINY-Gastric02 Trial (FAS; Data Cut-Off Date: November 8, 2021)

CI = confidence interval; FAS = full analysis set; KM = Kaplan-Meier; OS = overall survival; T-DXd = trastuzumab deruxtecan.

Sources: DESTINY-Gastric02 Clinical Study Report,^32,33 Summary of Clinical Evidence.¹

PFS per ICR Assessment

As of the data cut-off date of November 8, 2021, the proportion of patients in the FAS who had PFS events as determined by ICR was 64.6%. The median PFS was 5.6 months (95% CI, 4.2 months to 8.3 months). The probabilities of being progression-free were 70.5% (95% CI, 58.7% to 79.5%) at 3 months, 48.9% (95% CI, 36.6% to 60.2%) at 6 months, 36.3% (95% CI, 24.5% to 48.1%) at 9 months, and 20.0% (95% CI, 9.4% to 33.3%) at 12 months. The KM plot for PFS per ICR assessment is presented in Figure 2.

Figure 2: KM Plot of PFS per ICR Assessment in the DESTINY-Gastric02 Trial (FAS; Data Cut-Off Date: November 8, 2021)

CI = confidence interval; FAS = full analysis set; ICR = independent central review; KM = Kaplan-Meier; PFS = progression-free survival; T-DXd = trastuzumab deruxtecan.

Sources: DESTINY-Gastric02 Clinical Study Report;^32,33 Summary of Clinical Evidence.¹

Confirmed ORR per ICR Assessment

As of November 8, 2021, the proportion of patients in the FAS who achieved confirmed ORR per ICR assessment was 41.8% (95% CI, 30.8 to 53.4). There were 4 patients (5.1%) who achieved a best overall response of confirmed CR, and 29 patients (36.7%) who achieved confirmed PR. The results of subgroup analyses on ORR were generally consistent with the results in the FAS.

FACT-Ga Total Score

The FACT-Ga total scores were based on the data as of April 9, 2021. A higher FACT-Ga total score indicates a better outcome.

The mean FACT-Ga total score at baseline was █████ ███ █ █████. The mean FACT-Ga total score at the end of treatment was █████ ███ █ █████, with a mean change of ██████ ███ █ ██████.

Harms

Harms data from the DESTINY-Gastric02 trial are shown in Table 20.

Treatment-Emergent AEs

The most commonly reported TEAE in the DESTINY-Gastric02 trial was nausea (67.1%), followed by fatigue (57.0%), vomiting (44.3%), and anemia (38.0%).

The proportion of patients who had any TEAE of grade 3 or higher was 55.7%. The most commonly reported TEAE of grade 3 or higher was anemia (13.9%), followed by neutropenia (12.7%).

Treatment-Emergent SAEs

The proportion of patients who had any TESAE was 41.8%. The most commonly reported TESAE was nausea (5.1%), followed by pneumonitis (3.8%) and vomiting (3.8%).

Treatment Discontinuation Due to TEAEs

The proportion of patients who discontinued trastuzumab deruxtecan was 19.0%. Discontinuation due to pneumonitis or ILD occurred in 7.6% and 2.5% of the trial population, respectively.

Mortality

As of the data cut-off date of November 8, 2021, the number of patients who had any TEAE associated with an outcome of death was 11 patients (13.9%), among whom 1 patient (1.3%) died due to ILD and 1 patient (1.3%) died due to pneumonitis.

Notable Harms

Interstitial Lung Disease

As of the data cut-off date of November 8, 2021, the proportion of patients who had ILD was ████%.

Infusion-Related Reaction

As of the data cut-off date of April 9, 2021, the proportion of patients who had IRR was ███%. No results were reported as of the data cut-off date of November 8, 2021.

LV Dysfunction

As of the data cut-off date of November 8, 2021, 10.5% of patients had a grade 2 LV dysfunction (defined as the resting LVEF ranges from 50% to 40%; and there is a 10% to 19% LVEF decrease from baseline).

QT Prolongation

QT prolongation was not reported in the DESTINY-Gastric02 trial.

Table 20: Summary of Harms Results in the DESTINY-Gastric02 Trial (Safety Analysis Set; Data Cut-Off Date: November 8, 2021)

ILD = interstitial lung disease; IRR = infusion-related reaction; LV = left ventricular; NR = not reported; TEAE = treatment-emergent adverse event; TESAE = treatment-emergent serious adverse event.

^aAs of the data cut-off date of April 9, 2021.

^bThe percentage was calculated using 57 as the denominator. This was the number of patients who had both baseline and postbaseline data.

Sources: Sponsor’s Summary of Clinical Evidence;¹ DESTINY-Gastric02 Clinical Study Report.^32,33

Critical Appraisal

Internal Validity

One phase II, single-arm clinical trial, the DESTINY-Gastric02 trial, was appraised by the CDA-AMC review team as the pivotal evidence to assess the second-line use of trastuzumab deruxtecan in patients who have unresectable or metastatic HER2-positive gastric or GEJ cancer.

Overall, the absence of an internal comparison group in the single-arm DESTINY-Gastric02 trial is a key limitation. Moreover, a comparison between the trastuzumab deruxtecan group in the DESTINY-Gastric02 trial and an external control (e.g., a target value or historical study control) was not available. The lack of comparative data prevents the demonstration of the advantage of trastuzumab deruxtecan over current therapies available in the second-line setting. Inferences about the efficacy and safety of trastuzumab deruxtecan are challenging to make and cannot be established with certainty.

The DESTINY-Gastric02 trial involved a small sample size of 72 patients. The sample size was calculated based on historical data that suggested that patients with gastric or GEJ cancer in Western countries have a best ORR of up to 27% in the second-line setting. According to the clinical experts consulted by the review team, the ORR of up to 27% used to calculate sample size was reasonable.

The selection of the primary efficacy end point, confirmed ORR (defined as the sum of CR or PR, as determined by ICR based on RECIST 1.1), was necessary for the single-arm DESTINY-Gastric02 trial from the regulatory perspective because ORR is considered by some regulatory bodies as a direct measure of a drug’s antitumour activity — an end point that can be assessed in a single-arm study.²⁷ Of note, there was no a priori hypothesis with a target value of treatment effect prespecified for ORR to establish a clinically meaningful superiority threshold in the DESTINY-Gastric02 trial. Therefore, the significance of the findings is nominal; as such, the interpretation of the results is uncertain.

The DESTINY-Gastric02 trial addressed the limitation of relying solely on ORR by examining time-to-event end points, including OS, which was considered the most important efficacy outcome for the trial population by the clinical experts consulted by the review team. Although OS was included in the statistical analysis plan and controlled for multiplicity, this outcome can be sensitive to natural history and disease progression as well as to heterogeneity in patient characteristics; therefore, the inference of treatment efficacy based on the reported OS results in the absence of a comparator can be prone to bias.^27-29

External Validity

The DESTINY-Gastric02 trial used trastuzumab deruxtecan in the second-line treatment setting for patients with HER2-positive gastric or GEJ cancer, which aligns with the treatment setting in the reimbursement request proposed by the sponsor. However, the indication currently under review by Health Canada is for patients with unresectable locally advanced or metastatic HER2-positive gastric GEJ adenocarcinoma who have received a prior trastuzumab-based regimen. The sponsor confirmed that the indication is not limited to patients in the second-line treatment setting but also includes patients in the third-line and later settings. The DESTINY-Gastric02 trial population does not completely align with the patients in the third-line and later settings described by the Health Canada indication. Consequently, results from the DESTINY-Gastric02 trial may not be generalizable to patients in the third-line setting and beyond; there remains a gap in evidence.

According to the clinical experts consulted by the review team, the eligibility criteria of the DESTINY-Gastric02 trial were generally aligned with the selection criteria in the Canadian setting when identifying eligible patients with HER2-positive gastric or GEJ cancer for the second-line use of trastuzumab deruxtecan.

GRADE Summary of Findings and Certainty of the Evidence

Methods for Assessing the Certainty of the Evidence

For the pivotal studies and RCTs identified in the sponsor’s systematic review, GRADE was used to assess the certainty of the evidence for the outcomes considered most relevant to inform the expert committee deliberations, and a final certainty rating was determined as outlined by the GRADE Working Group:^30,31

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

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

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

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

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

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

Due to lack of comparators, certainty of evidence was summarized narratively for OS, PFS, ORR, FACT-Ga total score, and harms.

Results of GRADE Assessments

Table 2 presents the GRADE summary of findings for trastuzumab deruxtecan for the treatment of adult patients with unresectable or metastatic HER2-positive gastric or GEJ cancer who had disease progression during or after first-line therapy with a trastuzumab-containing regimen.

Long-Term Extension Studies

No long-term extension studies were submitted by the sponsor for this review.

Indirect Evidence

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

Objectives for the Summary of Indirect Evidence

The DESTINY-Gastric02 pivotal trial was a single-arm study. The efficacy of trastuzumab deruxtecan relative to other treatments that are currently available in the second-line setting in Canada is unclear. Therefore, an ITC is warranted to address this evidence gap.

Of note, according to the sponsor, although results of the DESTINY-Gastric01 trial were included in the systematic review section as pivotal evidence, it was not appropriate to include the DESTINY-Gastric01 trial in the ITC, given that this trial provided head-to-head comparisons between trastuzumab deruxtecan and physician’s choice of irinotecan or paclitaxel in a patient population that has already progressed through at least 2 lines of therapy (i.e., third-line and later settings).

Description of the ITC

The sponsor-submitted ITC included a Bayesian NMA in which an unanchored MAIC was used to establish a connection between the single-arm DESTINY-Gastric02 pivotal trial and the rest of the evidence network.

Of note, the NMA focused on comparisons between trastuzumab deruxtecan and ramucirumab-paclitaxel, docetaxel, paclitaxel monotherapy, irinotecan, and FOLFIRI. Although there were available studies in the literature investigating best supportive care, ramucirumab plus best supportive care, ramucirumab-FOLFIRI, and irinotecan-cisplatin, these studies were not included in the NMA for this reimbursement request because the sponsor considered these comparators irrelevant in the Canadian landscape. The sponsor also noted an exception for PEP02, which was not considered by the sponsor as a relevant comparator in Canada but was included in the NMA base-case analysis. The sponsor claimed that the inclusion would ensure all available evidence was incorporated within the NMA and enhance the robustness and credibility of the results.

ITC Design

Objectives

The NMA submitted by the sponsor aimed to answer the following review question: what is the comparative effectiveness of trastuzumab deruxtecan versus guideline-recommended, second-line treatments for advanced or metastatic gastric cancer, based on the currently available literature evidence?

Study Selection Methods

The criteria for study selection and methods for the ITC submitted by the sponsor are shown in Table 21. Relevant studies serving as an evidence base for the ITC were identified from 3 major sources, including a sponsor-conducted systematic literature review (SLR) in 2021, a grey literature search in 2022, and a targeted search between September 2021 and April 2024.

The SLR searches, performed initially in May 2020 and updated on September 9, 2021, were conducted in multiple electronic databases (i.e., MEDLINE, MEDLINE In-Process, Embase, and Cochrane Library), conference proceedings, and submissions to health technology assessment regulatory bodies.

To identify relevant single-arm trials, the grey literature search was carried out by searching the reference lists of the 2016 European Society for Medical Oncology (ESMO) and 2022 National Comprehensive Cancer Network (NCCN) guidelines as well as the records of Clinicaltrials.gov (performed in March 2022).

The targeted searches, which aimed to identify relevant long-term studies, subgroup analyses, and phase III studies, were conducted in MEDLINE, MEDLINE In-Process, Embase, and the reference lists of the updated 2022 ESMO and 2024 NCCN guidelines from September 2021 to April 2024.

Study screening and selection from the SLR were conducted by 2 independent reviewers. Potentially eligible studies selected from the SLR and the records retrieved from the grey literature search were further screened by 1 reviewer to determine eligibility for the NMA. Data extraction was carried out by 1 reviewer, with a second independent reviewer responsible for quality checks for the handsearch. The quality of the selected studies was also assessed by 2 independent reviewers using version 2 of the Cochrane risk-of-bias tool. Any disputes between reviewers were resolved by a third independent reviewer.

Table 21: Study Selection Criteria and Methods for the ITC Submitted by the Sponsor

ESMO = European Society for Medical Oncology; FOLFIRI = folinic acid–fluorouracil-irinotecan; GEJ = gastroesophageal junction; HTA = health technology assessment; ITC = indirect treatment comparison; KM = Kaplan-Meier; NCCN = National Comprehensive Cancer Network; NMA = network meta-analysis; OS = overall survival; PFS = progression-free survival; RCT = randomized controlled trial; SLR = systematic literature review.

Sources: Sponsor’s Summary of Clinical Evidence;¹ sponsor-submitted ITC report.⁴³

ITC Analysis Methods

Unanchored MAIC Analysis Methods

The single-arm DESTINY-Gastric02 pivotal trial was the only eligible study containing the intervention of interest for this reimbursement request (trastuzumab deruxtecan). To include trastuzumab deruxtecan in the NMA, the sponsor used an unanchored MAIC to connect the treatment to the network.

The details regarding the analysis methods of the unanchored MAIC are shown in Table 22.

Table 22: Unanchored MAIC Analysis Methods

CI = confidence interval; ESS = effective sample size; HR = hazard ratio; IPD = individual patient data; ITC = indirect treatment comparison; KM = Kaplan-Meier; MAIC = matching-adjusted indirect comparison; NICE DSU TSD = National Institute for Health and Care Excellence Decision Support Unit Technical Support Document; NMA = network meta-analysis; OS = overall survival; PFS = progression-free survival.

Sources: Sponsor’s Summary of Clinical Evidence;¹ sponsor-submitted ITC report.⁴³

NMA Analysis Methods

After the MAIC of DESTINY-Gastroic02 and the RAINBOW trial were completed, a hypothetical population including the RAINBOW trial and the reweighted trastuzumab deruxtecan groups was connected to the existing network of interventions to perform a Bayesian NMA. The details of the NMA analysis methods are shown in Table 23.

Table 23: NMA Analysis Methods

CrI = credible interval; FE = fixed effect; HR = hazard ratio; ITC = indirect treatment comparison; MAIC = matching-adjusted indirect comparison; MCMC = Markov chain Monte Carlo; NICE DSU TSD = National Institute for Health and Care Excellence Decision Support Unit Technical Support Document; NMA = network meta-analysis; OS = overall survival; PFS = progression-free survival; RE = random effect; SD = standard deviation.

Sources: Sponsor’s Summary of Clinical Evidence;¹ sponsor-submitted ITC report.⁴³

In the unanchored MAIC, 5 treatment effect modifiers or prognostic factors, including age, gender, previous surgery, ECOG PS, and primary tumour location, were included as adjustment variables. The list of treatment effect modifiers or prognostic factors adjusted or not adjusted in the unanchored MAIC is presented in Table 24.

Table 24: List of Treatment Effect Modifiers and Prognostic Factors for the Unanchored MAIC

ECOG PS = Eastern Cooperative Oncology Group Performance Status; ESS = effective sample size; GEJ = gastroesophageal junction; HER2 = human epidermal growth factor 2; ITC = indirect treatment comparison; PD-L1 = programmed death-ligand 1.

Source: Sponsor-submitted ITC report.⁴³

The distribution of baseline characteristics before and after weighting adjustment is shown in Table 25. The ESS of the weighted trastuzumab deruxtecan group was ████, reduced from ██ before weighting.

Table 25: Baseline Characteristics Before and After Weighting Adjustment in the Unanchored MAIC

ECOG PS = Eastern Cooperative Oncology Group Performance Status; ESS = effective sample size; FAS = full analysis set; GEJ = gastroesophageal junction; HER2 = human epidermal growth factor 2; ITC = indirect treatment comparison; MAIC = matching-adjusted indirect comparison; NA = not applicable; NR = not reported; PD-L1 = programmed death-ligand 1.

Note: Because of data privacy issues, the FAS population comprising 79 patients in the DESTINY-Gastric02 trial was reduced to 77.

Source: Sponsor-submitted ITC report.⁴³

Results of the ITC

Summary of Studies Included in the NMA

In total, 6 studies were included in the NMA, including the DESTINY-Gastric02 pivotal trial,^32,33 the RAINBOW trial,⁵⁴ the KCSG ST10-01 trial,⁵⁵ the Sym et al. (2013) trial,⁵⁶ the WJOG 4007 trial,⁵⁷ and the Roy et al. (2013) trial.⁵⁸ According to the ITC report submitted by the sponsor, these included trials assessed the second-line use of treatments. These studies investigated trastuzumab deruxtecan, ramucirumab-paclitaxel, docetaxel, paclitaxel monotherapy, irinotecan, and FOLFIRI, which were considered by the sponsor as relevant therapies in Canada. The characteristics of the 6 included studies are presented in Table 26.

Table 26: Characteristics of Studies Included in the Sponsor-Submitted NMA

FOLFIRI = folinic acid–fluorouracil-irinotecan; ITC = indirect treatment comparison; NMA = network meta-analysis; NR = not reported; OS = overall survival; PFS = progression-free survival; RECIST 1.1 = Response Evaluation Criteria in Solid Tumours Version 1.1.

Source: Sponsor-submitted ITC report.⁴³

In terms of risk of bias, the sponsor claimed that the majority of studies included in the NMA were of low risk; this conclusion was determined by using version 2 of the Cochrane risk-of-bias tool for randomized trials.⁶⁵ According to the sponsor, the majority of included studies were at low risk of bias. The Sym et al. (2013) trial failed to meet its primary end point; therefore, risk-of-bias assessment was not performed for this trial.

The assessment of homogeneity in the sponsor-submitted ITC is shown in Table 27.

Table 27: Assessment of Homogeneity in the Sponsor-Submitted ITC

GEJ = gastroesophageal junction; HER2 = human epidermal growth factor receptor 2; ITC = indirect treatment comparison; NMA = network meta-analysis; RCT = randomized controlled trial.

^aUnless specified otherwise, the values reported for patient characteristics were summarized from 12 studies identified in the SLR, including 6 studies analyzed in this sponsor-submitted NMA and 6 studies that were not analyzed in the NMA because the interventions used were considered by the sponsor to be irrelevant to the Canadian setting.

Sources: Sponsor’s Summary of Clinical Evidence;¹ sponsor-submitted ITC report.⁴³

Results

The NMA base-case network diagram is the same for OS and PFS and is presented in Figure 3.

Figure 3: Network Diagram for the Sponsor-Submitted NMA (OS and PFS, Base-Case Analysis)

FOLFIRI = folinic acid–fluorouracil-irinotecan; ITC = indirect treatment comparison; MAIC = matching-adjusted indirect comparison; NMA = network meta-analysis; OS = overall survival; PFS = progression-free survival; Ram = ramucirumab; T-DXd = trastuzumab deruxtecan.

Sources: Sponsor’s Summary of Clinical Evidence;¹ sponsor-submitted ITC report.⁴³

The summary of the results for OS and PFS in the base-case analyses and sensitivity analyses is shown in Table 28. In the base-case analysis, trastuzumab deruxtecan was linked to the NMA network through an unanchored MAIC comparing it to the ramucirumab plus paclitaxel arm of the RAINBOW trial using the November 2021 data cut-off in the DESTINY-Gastric02 pivotal trial. In sensitivity analysis 1, trastuzumab deruxtecan was linked to the NMA network through a MAIC connecting it to the RAINBOW trial using the April 2021 data cut-off in the DESTINY-Gastric02 trial. In sensitivity analysis 2, the PEP02 arm from the Roy et al. (2013) trial was removed from the network.

Of note, according to the sponsor, the reweighted population of the DESTINY-Gastric02 trial via MAIC was considered as a third arm to the competitor’s trial (i.e., the RAINBOW trial) by using the initial HR of the RAINBOW trial (i.e., ramucirumab-paclitaxel versus placebo-paclitaxel) and the HR between trastuzumab deruxtecan and ramucirumab-paclitaxel, which was calculated through the unanchored MAIC.

Overall Survival

Generated from the MAIC, the HR for OS was ████ ████ ████ ████ ██ █████ between trastuzumab deruxtecan and ramucirumab-paclitaxel.

In the FE model of the NMA, the estimated base-case HRs for OS were ████ ████ ████ ████ ██ █████ between trastuzumab deruxtecan and paclitaxel, ████ ████ ████ ████ ██ █████ between trastuzumab deruxtecan and FOLFIRI, ████ ████ ████ ████ ██ █████ between trastuzumab deruxtecan and irinotecan, and ████ ████ ████ ████ ██ █████ between trastuzumab deruxtecan and docetaxel.

In the RE model of the NMA, the estimated HRs for OS were ████ ████ ████ ████ ██ ██████ between trastuzumab deruxtecan and ramucirumab-paclitaxel, ████ ████ ████ ████ ██ ██████ between trastuzumab deruxtecan and paclitaxel, ███ ████ ████ █ ██ ███████ between trastuzumab deruxtecan and FOLFIRI, ████ ████ ████ █ ██ ██████ between trastuzumab deruxtecan and irinotecan, and ████ ████ ████ █ ██ ███████ between trastuzumab deruxtecan and docetaxel.

In both sensitivity analyses, the HR estimates for OS obtained from the FE model were generally consistent with the results from the base-case analysis.

Progression-Free Survival

Generated from the MAIC, the HR for PFS was ████ ████ ████ ████ ██ █████ between trastuzumab deruxtecan and ramucirumab-paclitaxel.

In the FE model of the NMA, the estimated base-case HRs for PFS were ████ ████ ████ ████ ██ █████ between trastuzumab deruxtecan and paclitaxel | ████ ████ ████ ████ ██ █████ between trastuzumab deruxtecan and FOLFIRI, ████ ████ ████ ████ ██ █████ between trastuzumab deruxtecan and irinotecan, and ████ ████ ████ ████ ██ █████ between trastuzumab deruxtecan and docetaxel.

In the RE model of the NMA, the estimated base-case HRs for PFS were ████ ████ ████ ████ ██ ██████ between trastuzumab deruxtecan and ramucirumab-paclitaxel, ████ ████ ████ ████ ██ ██████ between trastuzumab deruxtecan and paclitaxel, ████ ████ ████ ████ ██ ███████ between trastuzumab deruxtecan and FOLFIRI, ████ ████ ████ ████ ██ ██████ between trastuzumab deruxtecan and irinotecan, and ████ ████ ████ ████ ██ ███████ between trastuzumab deruxtecan and docetaxel.

In both sensitivity analyses, the HR estimates for PFS obtained from the FE model were consistent with the results from the base-case analysis for PFS except that the HR between trastuzumab deruxtecan and ramucirumab-paclitaxel was no longer statistically significant.

Table 28: Summary of Results of the Sponsor-Submitted NMA

CrI = credible interval; FE = fixed effect; FOLFIRI = folinic acid–fluorouracil-irinotecan; HR = hazard ratio; ITC = indirect treatment comparison; MAIC = matching-adjusted indirect comparison; NMA = network meta-analysis; NR = not reported; OS = overall survival; PFS = progression-free survival.

Note: In sensitivity analysis 1, trastuzumab deruxtecan was connected to the NMA network through an unanchored MAIC comparing it to the ramucirumab plus paclitaxel arm of the RAINBOW trial using data from the DESTINY-Gastric02 trial as of the April 2021 cut-off. This sensitivity analysis aimed to assess the impact of the data cut-off change. Sensitivity analysis 2 removed the PEP02 arm from the Roy et al. (2013) trial. This sensitivity analysis aimed to assess the impact of PEP02.

Sources: Sponsor’s Summary of Clinical Evidence;¹ sponsor-submitted ITC report.⁴³

Critical Appraisal of Sponsor-Submitted ITC

In the absence of direct evidence comparing trastuzumab deruxtecan to other second-line treatments currently available in Canada (i.e., ramucirumab-paclitaxel, paclitaxel, FOLFIRI, irinotecan, and docetaxel), an ITC was submitted by the sponsor. The clinical experts consulted by the review team noted that the selection of the comparators was appropriate and reflective of clinical practice in Canada. The sponsor-submitted ITC comprised 2 components: an unanchored MAIC and an NMA. The unanchored MAIC was used to connect the single-arm, pivotal DESTINY-Gastric02 trial into the evidence network of the NMA using the RAINBOW trial as a comparator. The relative treatment effect estimates between trastuzumab deruxtecan and ramucirumab-paclitaxel were generated based on this unanchored MAIC.

A typical unanchored MAIC involves an index trial for which the individual patient data are available and a comparator trial for which aggregate-level data are available. In the sponsor-conducted MAIC, the pivotal, single-arm DESTINY-Gastric02 trial served as the index trial, and the RAINBOW trial served as the comparator trial. Through the MAIC, the comparison was established between the cohort of patients treated with trastuzumab deruxtecan in the DESTINY-Gastric02 trial and the cohort of patients treated with ramucirumab-paclitaxel in the RAINBOW trial. To ensure the comparability of these 2 cohorts in terms of patient characteristics considered to be potential treatment effect modifiers or prognostic factors, a propensity score weighting approach adjusted for these patient characteristics.

There are concerns regarding patient comparability between the DESTINY-Gastric02 trial and the RAINBOW trial. First, there were differences in some of the important patient characteristics (e.g., HER2 status, time on first treatment) that were not involved in the weighting process due to lack of information or insufficient sample size. The RAINBOW trial did not report HER2 status, stating only that “up to 9% of the trial population received prior targeted therapies including anti-HER2, antiepidermal growth factor receptor, or other targeted therapies.” Currently, although HER2 positivity seems to be correlated with poor prognosis in gastric cancer, there is conflicting evidence for the prognostic role of HER2 in gastric cancer.^17-21 With HER2 status unavailable in the RAINBOW trial, there is increased uncertainty about the treatment effect estimates between trastuzumab deruxtecan and ramucirumab-paclitaxel, and the direction of bias is unclear. Second, a list containing more than 16 potential prognostic factors and treatment effect modifiers was prespecified by the sponsor. These were considered relevant and comprehensive by the clinical experts consulted by the review team. However, only 5 of these factors were involved in the propensity score weighting. The rationale for not including the remaining factors is reasonable, given that the information was unavailable in either the DESTINY-Gastric02 trial or the RAINBOW trial. However, the exclusion of potentially relevant factors from the analysis could bias the results, with the magnitude of the residual bias in the relative treatment effect estimates remaining uncertain. Third, after reweighting, apparent differences were identified between the DESTINY-Gastric02 trial and the RAINBOW trial in some patient characteristics, such as time to progressive disease on first-line therapy, histological subtype, and number of metastases sites. These differences suggest the possible existence of inadequate balance and increase the uncertainty of the findings.

ESS is heuristically used to reflect the amount of heterogeneity between studies among the variables included in the weighting process. There was a marked reduction from ██ (i.e., the actual number of patients involved in the reweighting process from the DESTINY-Gastric02 trial) to ████ (i.e., the ESS of the DESTINY-Gastric02 trial after reweighting), indicating that the weights might be highly variable due to a lack of population overlap and that the treatment effect estimates yielded using the MAIC approach might be unstable. Moreover, the MAIC excluded time to progressive disease on first-line therapy from the weighting process because it would have made the ESS very small. This suggests post hoc selection of prognostic factors or treatment effect modifiers, which is inappropriate given that prognostic factors and treatment effect modifiers should be selected before analysis. Excluding a relevant factor from the weighting process would increase the risk of producing biased treatment effect estimates.

There was significant design and methodological heterogeneity between the DESTINY-Gastric02 and RAINBOW trials. The DESTINY-Gastric02 trial was a phase II, single-arm, open-label study without a hypothesis specified a priori or a statistical test, whereas the RAINBOW trial was a phase III, double-blind, randomized, active-controlled trial with formal hypothesis testing. The MAIC approach can correct only for bias directly related to differences in baseline patient characteristics, not for heterogeneity caused by between-trial differences in study design or methods. Therefore, uncertainty exists in the MAIC results; the exact impacts remain unclear based on the currently available information submitted by the sponsor. Due to the weighting process, the results of the MAIC are specific to the baseline characteristics of the population of the comparator trial (i.e., the RAINBOW trial). Consequently, there was uncertainty with respect to generalizing the MAIC results to the target population described in the Health Canada indication and reimbursement request. For instance, the indicated population requires eligible patients to be HER2-positive, whereas HER2 status in the population of the RAINBOW trial is unknown. Additionally, the indicated population requires eligible patients to have received a prior trastuzumab-based regimen, while the RAINBOW trial required the study population to have received first-line platinum and fluoropyrimidine doublet with or without anthracycline.

The treatment effect estimates from the MAIC analyses served as the basis for generating the NMA that includes the DESTINY-Gastric02 trial connected to the evidence network of relative treatment effect estimates between trastuzumab deruxtecan and other relevant comparators, including paclitaxel, FOLFIRI, irinotecan, and docetaxel. This means all the potential limitations of the MAIC analyses discussed previously apply to the NMA results. On top of the sources of heterogeneity existing in the MAIC analyses, additional sources of heterogeneity might have introduced uncertainty to the NMA estimates. For instance, in the MAIC, the sponsor assumed that geographical region and ethnicity were important prognostic factors and that Asian patients had better prognoses than patients from Western countries. Subsequently, to limit the number of Asian patients in the MAIC, the sponsor selected only RAINBOW trial patients from Australia, Europe, Israel, and the US (excluding patients from Argentina, Brazil, Chile, Hong Kong, Japan, Mexico, Singapore, South Korea, and Taiwan), and compared them with the study population of the DESTINY-Gastric02 trial, the majority of whom were white (87.3%). However, in the NMA network, all included studies did not report on the distribution of ethnicity except for the DESTINY-Gastric02 and RAINBOW trials. Moreover, the KSCG/ST10-01, Sym et al. (2013), and WJOG 4007 trials were conducted in Asia, while the Roy et al. (2013) trial was conducted in both Western and Asian countries. Under the assumption made by the sponsor about geographic region and ethnicity being important prognostic factors, the potential heterogeneity regarding differences in geographical regions and ethnicity in the NMA network could not be ignored; the degree of uncertainty remains unknown. The rationale for reporting the results of an FE model is justified when estimation of between-study variance using the RE model is very imprecise and unstable in situations that consider only a few studies.^34,35 However, the FE model does not sufficiently account for heterogeneity between studies, leading to overly precise and narrow CIs.³⁵ Given that various sources of heterogeneity existed in the sponsor-submitted ITC (described previously), use of the FE model introduced uncertainty in the NMA treatment effect estimates.

Other Evidence

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

Table 29: Summary of Gaps in the Systematic Review Evidence

CI = confidence interval; FACT-Ga = Functional Assessment of Cancer Therapy – Gastric; GEJ = gastroesophageal junction; HER2 = human epidermal growth factor 2; ICR = independent central review; IHC = immunohistochemistry; ILD = interstitial lung disease; ISH = in situ hybridization; ORR = objective response rate; OS = overall survival; PFS = progression-free survival; TEAE = treatment-emergent adverse event; TESAE = treatment-emergent serious adverse event.

Source: Sponsor’s Summary of Clinical Evidence.⁴³

Description of Studies

The DESTINY-Gastric01 trial was a phase II, multicentre RCT. Evidence generated from the primary cohort of the DESTINY-Gastric01 trial is the focus of this section. The primary cohort of the DESTINY-Gastric01 trial included 188 patients with HER2-positive (i.e., IHC 3+ or IHC 2+ and ISH-positive), advanced gastric or GEJ adenocarcinoma who had progressed on or after at least 2 prior regimens that included a fluoropyrimidine drug, a platinum drug, and a trastuzumab-containing regimen. The primary objective of the DESTINY-Gastric01 trial was to compare the efficacy of trastuzumab deruxtecan versus the physician’s choice of treatment (i.e., irinotecan 150 mg/m² through IV every 2 weeks or paclitaxel 80 mg/m² through IV every week) in the primary cohort, as measured by ORR per ICR assessment using RECIST 1.1. Secondary end points included OS, PFS, FACT-Ga, and harms.

Characteristics of the DESTINY-Gastric01 trial are summarized in Table 30.

Table 30: Details of the DESTINY-Gastric01 Trial

CNS = central nervous system; DCR = disease control rate; DOR = duration of response; ECHO = echocardiogram; ECOG PS = Eastern Cooperative Oncology Group Performance Status; FACT-Ga = Functional Assessment of Cancer Therapy – Gastric; GEJ = gastroesophageal junction; HER2 = human epidermal growth factor 2; HRQoL = health-related quality of life; ICR = independent central review; IHC = immunohistochemistry; ILD = Interstitial lung disease; ISH = in situ hybridization; LVEF = left ventricular ejection fraction; MUGA = multigated acquisition; NYHA = New York Heart Association; ORR = objective response rate; OS = overall survival; PFS = progression-free survival; RECIST 1.1 = Response Evaluation Criteria in Solid Tumours Version 1.1; TTF = time to treatment failure; TTR = time to response.

Sources: Sponsor’s Summary of Clinical Evidence;¹ DESTINY-Gastric01 Clinical Study Report.^66,67

Populations

Patients in the primary cohort of the DESTINY-Gastric01 trial were enrolled across 66 study cites in Japan and South Korea. Eligible patients were adults (aged at least 20 years) who had been diagnosed with locally advanced or metastatic HER2-positive (defined as IHC 3+ or IHC 2+ and ISH-positive) gastric or GEJ adenocarcinoma and who had an ECOG PS of 0 or 1. Eligible patients must have progressed on or after at least 2 prior regimens that included a fluoropyrimidine drug, a platinum drug, and trastuzumab.

Interventions

Trastuzumab deruxtecan was administered intravenously on day 1 of every 21-day treatment cycle (i.e., every 3 weeks) until disease progression, withdrawal by patient, physician decision, or death. The starting dose was 6.4 mg/kg. Trastuzumab deruxtecan was provided as a lyophilized powder in a single-use glass vial to be reconstituted. The first infusion was administered over approximatively 90 minutes. Subsequent infusions were administered over approximatively 30 minutes if there was no injection-related reaction after the first infusion. Trastuzumab deruxtecan was administered in a hospital setting.

Patients who were enrolled in the physician’s choice treatment arm received either irinotecan monotherapy or paclitaxel monotherapy. Irinotecan was administered intravenously biweekly, with a starting dose of 150 mg/m². Paclitaxel was administered through IV on days 1, 8, and 15, then every 4 weeks, with a starting dose of 80 mg/m².

Outcomes

ORR per ICR assessment, the primary efficacy end point of the DESTINY-Gastric01 trial, was defined as the proportion of patients who achieved a best overall response of CR or PR, as determined by ICR committee based on RECIST 1.1.

OS was defined as the time from the date of randomization to the date of death due to any cause. If there was no death reported for a patient before the OS data cut-off time point, OS was censored at the last contact date on which the patient was known to be alive.

PFS assessed by ICR assessment was defined as the time from the date of randomization to the earliest date of the first objective documentation of progressive disease or death due to any cause.

FACT-Ga is a quality-of-life instrument specific to gastric cancer. The details of the FACT-Ga measurement instrument are shown in Table 9.

The harms outcomes assessed in the DESTINY-Gastric01 trial mainly included TEAEs, TESAEs, withdrawal due to TEAEs, deaths, and notable harms (i.e., ILD, LV dysfunction, QT prolongation, and IRRs).

Statistical Analysis

The target sample size for the primary cohort of the DESTINY-Gastric01 trial was approximately 180 patients (120 patients in the trastuzumab deruxtecan group and 60 patients in the physician’s choice group). The trial would have 92.9% power to detect a difference in the primary end point between the 2 groups at a 2-sided significance level of 0.05 under the assumed ORRs of 40% in the trastuzumab deruxtecan group and 15% in the physician’s choice group.

Approximately 133 OS events would be needed to have 80% power to reject a null hypothesis of no difference under an assumed alternative HR of 0.61 (a 64% improvement in median OS, from 5.5 months in the physician’s choice group to 9.0 months in the trastuzumab deruxtecan group) at a 2-sided significance level of 0.05. This is assuming a 10-month enrolment period and a 12-month follow-up period after randomization of the last patient.

To compare ORR per ICR assessment between treatment groups, a Cochran-Mantel-Haenszel test with region as a stratification factor was used. An ORR estimate and its 2-sided 95% exact CI were provided for each group.

OS and PFS was compared between the treatment groups using stratified log-rank tests with region as a stratification factor. To control the family-wise type I error rate for the primary and secondary efficacy end points of ORR and OS, a serial, hierarchically ordered gatekeeping strategy was applied. The tests were performed in the following order: ORR per ICR assessment, followed by OS. The sequence of tests continued until the test did not meet the significance level of the 2-sided alpha of 0.05. The testing procedure followed the steps shown here:

1. Test the primary end point, ORR, at a 2-sided, 5% significance level. If positive, continue to step 2; otherwise, stop.

2. Test OS (interim and final analyses) at an overall 2-sided, 5% significance level.

The first analysis of OS occurred at the time of the primary analyses for ORR (based on ICR) only if the ORR met the significance level of a 2-sided alpha of 0.05. The ORR (based on ICR) analysis and prespecified interim analysis of OS were conducted after all the patients completed tumour assessments at approximately 24 weeks (or discontinued the study); the final analysis of OS was to be performed after approximately 133 OS events had occurred. A Lan-DeMets alpha-spending function with the O’Brien-Fleming stopping boundary was used to determine the significance levels for the OS analyses.^73,74 The HR and 95% CIs were estimated using stratified Cox proportional hazards regression models with region as a stratification factor for the analyses of OS and PFS. KM-estimated survival curves of OS and PFS were presented for each treatment group. The median, with a 2-sided 95% CI, was calculated using the Brookmeyer and Crowley method.⁵²

Results

Patient Disposition

Patient disposition in the DESTINY-Gastric01 trial is summarized in Table 31. In the DESTINY-Gastric01 trial, 561 patients were screened, and a total of 188 patients were enrolled in the primary cohort. The ITT population is defined as the complete enrolled patient population in the primary cohort. The FAS population excluded 1 patient in the ITT population who did not receive the study drug because informed consent was not obtained before study procedures were performed. As of June 3, 2020, 17.6% of patients in the trastuzumab deruxtecan group and 6.5% of patients in the physician’s choice group discontinued their assigned treatments due to AEs.

Table 31: Summary of Patient Disposition in the DESTINY-Gastric01 Trial (Data Cut-Off Date: June 3, 2020)

AE = adverse event; FAS = full analysis set; ITT = intention to treat; NR = not reported.

Sources: Sponsor’s Summary of Clinical Evidence;¹ DESTINY-Gastric01 Clinical Study Report.^66,67

Baseline Characteristics

The baseline characteristics of the patients in the DESTINY-Gastric01 trial are summarized in Table 32. The median age of patients was 66.0 years (range, 28 years to 82 years). All patients were Asian; 79.2% of patients in the trastuzumab deruxtecan group and 80.6% of patients in the physician’s choice group were Japanese. The majority of patients had gastric adenocarcinoma (86.4% in the trastuzumab deruxtecan group and 88.7% in the physician’s choice group).

Table 32: Summary of Patient Baseline Characteristics in the DESTINY-Gastric01 Trial (FAS)

ECOG PS = Eastern Cooperative Oncology Group Performance Status; FAS = full analysis set; HER2 = human epidermal growth factor receptor 2; IHC = immunohistochemistry; ISH = in situ hybridization; NA = not applicable.

Sources: Sponsor’s Summary of Clinical Evidence;¹ DESTINY-Gastric01 Clinical Study Report.^66,67

Exposure to Study Treatments

Treatment exposure in the DESTINY-Gastric01 trial is summarized in Table 33. As of the data cut-off date of June 3, 2020, the treatment duration was 4.6 months (range, 0.7 months to 29.7 months) for the trastuzumab deruxtecan group and 2.76 months (range, 0.5 months to 13.1 months) for the physician’s choice group.

Table 33: Summary of Patient Exposure in the DESTINY-Gastric01 Trial (Safety Analysis Set; Data Cut-Off Date: June 3, 2020)

AE = adverse event; NA = not applicable; NR = not reported.

^aDose intensity: Trastuzumab deruxtecan (mg/kg per 3 weeks) = cumulative dose level divided by duration of treatment (days) divided by 21; irinotecan (mg/m² per 2 weeks) = cumulative dose level divided by the duration of treatment (days) divided by 14; paclitaxel (mg/m² per 4 weeks) = cumulative dose level divided by duration of treatment (days) divided by 28.

^bRelative dose intensity: Trastuzumab deruxtecan = dose intensity divided by 6.4 mg/kg per 3 weeks; irinotecan = dose intensity divided by 150 mg/m² per 2 weeks; paclitaxel = dose intensity divided by 240 mg/m² per 4 weeks.

Sources: Sponsor’s Summary of Clinical Evidence;¹ DESTINY-Gastric01 Clinical Study Report.^66,67

Efficacy

Results of the DESTINY-Gastric01 trial (Table 34) provided by the sponsor were from 2 data cut-off dates: November 8, 2019, and June 3, 2020. Data from the former date were used in the final analysis of PFS and ORR. The latter date, which was also the final data cut-off date, was used in the final OS analysis and harms analysis. Efficacy results were based on the ITT population, which included all patients in the primary cohort. Harms results were based on the safety analysis set, which excluded 1 patient in the ITT population who did not receive the study drug.

Table 34: Summary of Key Efficacy Results from the DESTINY-Gastric01 Trial (ITT Population)

CI = confidence interval; CR = complete response; FACT-Ga = Functional Assessment of Cancer Therapy – Gastric; ICR = independent central review; HR = hazard ratio; ITT = intention to treat; NR = not reported; ORR = objective response rate; OS = overall survival; PFS = progression-free survival; PR = partial response; SD = standard deviation.

^aAs of the data cut-off date of June 3, 2020, the median duration of survival follow-up was 10.4 months (range, 0.3 months to 29.7 months).

^bEstimated using Kaplan-Meier.

^cRegion as a stratification factor.

Sources: Sponsor’s Summary of Clinical Evidence;¹ DESTINY-Gastric01 Clinical Study Report.^66,67

Overall Survival

As of the data cut-off date of June 3, 2020, the proportion of patients in the ITT population who had OS events was 67.2% in the trastuzumab deruxtecan group and 79.0% in the physician’s choice group. The median OS duration was 12.5 months (95% CI, 10.3 months to 15.2 months) in the trastuzumab deruxtecan group and 8.9 months (95% CI, 6.4 months to 10.4 months) in the physician’s choice group. The adjusted HR was 0.60 (95% CI, 0.42 to 0.86). The KM curves for OS are presented in Figure 4.

PFS per ICR Assessment

As of June 3, 2020, the proportion of patients in the ITT population who had PFS events was 65.1% in the trastuzumab deruxtecan group and 58.1% in the physician’s choice group. The median PFS was 5.6 months (95% CI, 4.3 months to 6.9 months) in the trastuzumab deruxtecan group and 3.5 months (95% CI, 2.0 months to 4.3 months) in the physician’s choice group. The estimated HR was 0.47 (95% CI, 0.31 to 0.71). The KM plots for PFS per ICR assessment are presented in Figure 5.

Figure 4: KM Plot of OS in the DESTINY-Gastric01 Trial (ITT; Data Cut-Off Date: June 3, 2020)

DS-8201a = trastuzumab deruxtecan; ITT = intention to treat; KM = Kaplan-Meier; OS = overall survival; Phys. = physician’s.

Source: DESTINY-Gastric01 Clinical Study Report.^66,67

Figure 5: KM Plot of PFS per ICR Assessment in the DESTINY-Gastric01 Trial (ITT; Data Cut-Off Date: June 3, 2020)

DS-8201a = trastuzumab deruxtecan; ITT = intention to treat; ICR = independent central review; KM = Kaplan-Meier; PFS = progression-free survival; Phys. = physician’s.

Source: DESTINY-Gastric01 Clinical Study Report.^66,67

ORR per ICR Assessment

As of June 3, 2020, the unconfirmed ORRs per ICR assessment were █████ ████ ███ ████ ██ █████ in the trastuzumab deruxtecan group and █████ ████ ███ ███ ██ █████ in the physician’s choice group. The proportion of patients who achieved a best overall response of unconfirmed CR in the trastuzumab deruxtecan group was █████ while no patients achieved CR in the physician’s choice group.

Of note, according to the sponsor’s response to Health Canada, in the study protocol of the DESTINY-Gastric01 trial, the primary end point was unconfirmed ORR, and no confirmation of ORR was required because the trial design included a randomized control group. The confirmed ORR was defined, as was a supportive end point, not formally specified as a key secondary end point.

As of June 3, 2020, the confirmed ORRs per ICR assessment were █████ ████ ███ ████ ██ ████) in the trastuzumab deruxtecan group and █████ ████ ███ ███ ██ ████) in the physician’s choice group. The proportion of patients who achieved a best overall response of confirmed CR in the trastuzumab deruxtecan group was 7.9%, while no patients achieved CR in the physician’s choice group.

FACT-Ga Total Score

The FACT-Ga total scores were based on the data available as of November 8, 2019.

The mean FACT-Ga total score at the end of treatment was █████ ███ █ █████) in the trastuzumab deruxtecan group and █████ (██ █ █████) in the physician’s choice group, with a mean change of █████ ███ █ ██████ and █████ ███ █ █████), respectively.

Harms

Harms data from the DESTINY-Gastric01 trial are shown in Table 35. The cut-off date for the harms data was June 3, 2020.

Treatment-Emergent AEs

All the patients in the trastuzumab deruxtecan group and 98.4% of the patients in the physician’s choice group had TEAEs. The most commonly reported TEAE was neutropenia, reported by 64.8% of patients in the trastuzumab deruxtecan group and 35.5% of patients in the physician’s choice group.

The proportion of patients who had any TEAE of grade 3 or higher was 85.6% in the trastuzumab deruxtecan group, which was higher than the 56.5% reported in the physician’s choice group. The most commonly reported TEAE of grade 3 or higher was neutropenia (51.2% in the trastuzumab deruxtecan group versus 24.2% in the physician’s choice group). This was followed by anemia (38.4% in the trastuzumab deruxtecan group versus 22.6% in the physician’s choice group).

Treatment-Emergent Serious AEs

The proportion of patients who had any TESAE in the trastuzumab deruxtecan group was 44.8%, which was higher than the 25.8% in the physician’s choice group. The most commonly reported TESAE was decreased appetite (10.4% in the trastuzumab deruxtecan group versus 1.6% in the physician’s choice group). This was followed by ILD (5.6% in the trastuzumab deruxtecan group versus 0% in the physician’s choice group), anemia (3.2% in the trastuzumab deruxtecan group versus 3.2% in the physician’s choice group), and dehydration (3.2% in the trastuzumab deruxtecan group versus 0% in the physician’s choice group).

Treatment Discontinuation Due to TEAEs

The proportion of patients who discontinued the study treatment was 17.6% in the trastuzumab deruxtecan group and 6.5% in the physician’s choice group. Discontinuation due to ILD occurred in 6.4% of patients in the trastuzumab deruxtecan group versus 0% in the physician’s choice group.

Mortality

The proportion of patients who had any TEAE associated with an outcome of death was 6.4% in the trastuzumab deruxtecan group, which was higher than the 3.2% reported in the physician’s choice group.

Notable Harms

Interstitial Lung Disease

The proportion of patients who had ILD was 12.8% in the trastuzumab deruxtecan group; 5.6% of cases occurred as TESAEs. No patients in the physician’s choice group had ILD.

Infusion-Related Reactions

The proportion of patients who had IRRs was ███% in the trastuzumab deruxtecan group and ███% in the physician’s choice group.

LV Dysfunction

The proportion of patients who had grade 2 LV dysfunction (defined as the resting LVEF ranges from 50% to 40%; and there is a 10% to 19% LVEF decrease from baseline) was 9.4% in the trastuzumab deruxtecan group.

QT Prolongation

The proportion of patients who had QT prolongation events was ███% in the trastuzumab deruxtecan group and ███% in the physician’s choice group.

Table 35: Summary of Harms Results in the DESTINY-Gastric01 Trial (Safety Analysis Set; Data Cut-Off Date: June 3, 2020)

ILD = interstitial lung disease; IRR = infusion-related reaction; LV = left ventricular; NR = not reported; TEAE = treatment-emergent adverse event; TESAE = treatment-emergent serious adverse event.

^aThe percentage was calculated by using 117 as the denominator because that was the number of patients who had both baseline and postbaseline data.

Sources: Sponsor’s Summary of Clinical Evidence;¹ DESTINY-Gastric01 Clinical Study Report.^66,67

Critical Appraisal

Internal Validity

The DESTINY-Gastric01 trial enrolled 188 patients, randomizing 126 patients and 66 patients to the trastuzumab deruxtecan group and physician’s choice group (i.e., 2 to 1 randomization), respectively. The randomization was done using an interactive web and voice response system and stratified based on region (Japan or South Korea), ECOG PS (0 or 1), and HER2 status (IHC 3+ or IHC 2+ and ISH-positive) to minimize potential imbalances between the study groups that might bias the results. Despite the relatively small sample size, the distribution of baseline characteristics among patients was generally balanced between the trastuzumab deruxtecan group and the physician’s choice group, indicating a low risk of bias in the randomization process.

The review team determined that, despite the open-label study design, there was a low risk of detection bias in PFS or ORR, but still increased uncertainty with respect to treatment efficacy in this setting. Results for both PFS per ICR assessment and PFS per investigator assessment (data not shown) were consistent in general, as were the findings for unconfirmed and confirmed ORR. However, there is a notable risk of performance bias for the FACT-Ga. This risk was associated with the open-label design and subjective nature of the measure.

The DESTINY-Gastric01 trial reported OS, which was considered by the clinical experts consulted by the review team as the most important outcome for the study population. Multiplicity adjustment was carried out for unconfirmed ORR (i.e., the primary end point of the trial) and OS to control for type I error; however, the remaining efficacy end points (e.g., PFS and FACT-Ga) were not adjusted for multiplicity.

External Validity

The DESTINY-Gastric01 trial population is not aligned with the population described in the sponsor’s reimbursement request because the DESTINY-Gastric01 trial focused on the third-line and later treatment settings, whereas the reimbursement request involves only the second-line treatment setting. However, the DESTINY-Gastric01 trial population aligns with a group of patients who are implied in the Health Canada indication, the trial included adult patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma who have received greater than or equal to 2 prior treatment regimens, including an anti-HER regimen. According to the clinical experts consulted by the review team, this group of patients is small in number in the real-world setting and mainly includes those who are on their second or later lines of therapy.

There are some concerns regarding whether the patient population in the DESTINY-Gastric01 trial was representative of the corresponding patient population in Canada. According to the clinical experts consulted by the review team, the inclusion and exclusion criteria of the DESTINY-Gastric01 trial were generally appropriate in terms of selecting eligible patients; however, the efficacy observed in the trastuzumab deruxtecan group and physician’s choice group were higher than the experts expected or have encountered in real-world, third-line and later settings, in which patients tend to be of poor status and efficacy, suggesting the potential differences between the trial population and the real-world population in Canada.

In addition to the concern about the difference in lines of treatment, there are concerns about generalizing the results from the DESTINY-Gastric01 trial population to the DESTINY-Gastric02 trial population due to differences in patient characteristics. For instance, 87.3% of the patients in the DESTINY-Gastric02 trial were white and from North America, whereas all the patients in the DESTINY-Gastric01 trial were Asian and from Japan or South Korea. As noted in the sponsor-submitted ITC, geographical region and ethnicity were important prognostic factors, and Asian patients had different prognoses than patients in Western countries. Second, in the DESTINY-Gastric02 trial, 34.2% of patients had gastric cancer and 65.8% had GEJ cancer, whereas in the DESTINY-Gastric01 trial, 87.2% had gastric cancer and 12.8% had GEJ cancer. These differences in patient characteristics may introduce treatment heterogeneity that increases the uncertainty of the results and their generalizability to the Canadian context.

The clinical experts consulted by the review team noted that the use of irinotecan or paclitaxel as comparators in the DESTINY-Gastric01 trial is not well reflective of current clinical practice in Canada. According to the clinical experts consulted by the review team, it is understandable that at the time of designing the DESTINY-Gastric01 trial irinotecan and paclitaxel were commonly used in the third-line and later settings; however, in current clinical practice, irinotecan and paclitaxel are rarely used, and generally only in a very small group of patients, such as those who had serious neuropathy during previous lines of therapy.

Discussion

Summary of Available Evidence

One sponsor-conducted pivotal study, DESTINY-Gastric02, was included in the systematic review of this clinical report. The DESTINY-Gastric02 trial was a phase II, single-arm, open-label study investigating the use of trastuzumab deruxtecan as monotherapy for the treatment of patients (aged ≥ 18 years) who had unresectable or metastatic centrally confirmed HER2-positive gastric or GEJ cancer and who had experienced disease progression during or after first-line therapy with a trastuzumab-containing regimen. The DESTINY-Gastric02 trial enrolled 79 patients from 24 sites across Europe and North America (no sites in Canada). The primary objective of the DESTINY-Gastric02 trial was to assess the efficacy of trastuzumab deruxtecan based on confirmed ORR per ICR assessment. OS, PFS, HRQoL-related outcomes (e.g., FACT-Ga), and harms were also investigated in the DESTINY-Gastric02 trial. The median age of patients in the DESTINY-Gastric02 trial population was 60.7 years (range, 20.3 years to 77.8 years), with 58.5% of patients being younger than 65 years. The trial population was 27.8% female and 72.2% male. The race distribution of the trial population was 0% American Indian or Alaska Native, 5.1% Asian, 1.3% Black or African American, 1.3% Native Hawaiian or other Pacific Islander, and 87.3% white. The majority of patients in the trial population had an ECOG PS of 1 (63.3%), GEJ adenocarcinoma (65.8%), and a HER2 status of IHC 3+ (86.1%).

An ITC consisting of 1 unanchored MAIC and 1 NMA was submitted by the sponsor. The ITC aimed to assess the comparative efficacy of trastuzumab deruxtecan versus currently available treatments that are relevant in Canada (i.e., ramucirumab-paclitaxel, docetaxel, paclitaxel monotherapy, irinotecan, and FOLFIRI) for patients with advanced or metastatic HER2-positive gastric cancer in the second-line treatment setting. Because the DESTINY-Gastric02 trial is a single-arm study, the unanchored MAIC was used to establish a connection between the trial and the rest of the NMA evidence network through the RAINBOW trial. In total, 6 studies were involved in the base-case analysis of the NMA. Efficacy was measured by OR and PFS. Safety was not evaluated.

The sponsor also submitted a phase II RCT (the DESTINY-Gastric01 trial) that enrolled 188 patients with HER2-positive advanced gastric or GEJ adenocarcinoma who had progressed on or after at least 2 prior regimens including a fluoropyrimidine drug, a platinum drug, and a trastuzumab-containing regimen (i.e., in the third-line and later settings). The primary objective of the DESTINY-Gastric01 trial was to compare the efficacy of trastuzumab deruxtecan versus the physician’s choice of treatment (i.e., irinotecan 150 mg/m² intravenously every 2 weeks or paclitaxel 80 mg/m² intravenously every week), as measured by ORR per ICR assessment. Secondary end points included OS, PFS, FACT-Ga, and harms.

Interpretation of Results

Efficacy

Among the many treatment goals, survival benefits and quality of life were highlighted as top priorities by both patients and the clinical experts consulted by the review team. These needs were well-captured by the pivotal DESTINY-Gastric02 trial, which assessed OS, PFS per ICR assessment, confirmed ORR per ICR assessment, and FACT-Ga. Despite the inclusion of these end points in the trial, the review team was unable to draw a definitive conclusion as to the beneficial effect of trastuzumab deruxtecan based on efficacy end points. The primary limitation is that, according to a GRADE framework, the certainty of evidence for these end points is very low due to the lack of either an internal control group or an external control.

According to the clinical experts consulted by the review team, assessing the probability of OS until 6 months or 12 months after treatment and assessing the probability of PFS at 6 months are critical to decision-making. The results from the DESTINY-Gastric02 trial showed that the probabilities of being alive were 77.8% (95% CI, 66.8% to 85.6%) at 6 months and 50.6% (95% CI, 38.4% to 61.5%) at 12 months; the probability of being progression-free at 6 months was 48.9% (95% CI, 36.6% to 60.2%). There were no thresholds identified from the literature, yet the clinical experts consulted by the review team noted that a 20% improvement in OS probability and a 10% improvement in PFS could be adopted to determine a minimal clinical benefit. The clinical experts noted that, in their experience, the observed OS and PFS probabilities may meet these thresholds; however, the experts were cautious in their interpretations due to the lack of a control group in the DESTINY-Gastric02 trial. Consequently, although the results suggest a promising treatment effect of trastuzumab deruxtecan on OS and PFS in the second-line setting, comparative evidence from properly designed and executed clinical trials is required to ascertain the existence and magnitude of such benefits.

Confirmed ORR per ICR assessment was the primary efficacy end point of the DESTINY-Gastric02 trial. The results showed a beneficial effect that 41.8% (95% CI, 30.8% to 53.4%) of the patients had ORR, with 5.1% having CR, suggesting a response to trastuzumab deruxtecan. As discussed previously, ORR might be a key end point of a clinical trial with a single-arm study design for regulatory purposes;²⁷ however, based on input from the clinical experts consulted, ORR is considered less relevant and informative than OS or PFS in the clinical setting.

The results of the DESTINY-Gastric02 trial did not show a within-group improvement from baseline by the end of treatment in FACT-Ga total score (mean change from baseline: ██████ ██ █ █████). This aligned with the experience of the clinical experts consulted by the review team, according to whom the cessation of trastuzumab deruxtecan treatment would usually suggest either progression or intolerable side effects that negatively affect a patient’s quality of life. Furthermore, the clinical experts noted that the relative effect of trastuzumab deruxtecan on FACT-Ga could not be determined due to the lack of a comparator group.

An ITC was submitted by the sponsor to determine the efficacy of trastuzumab deruxtecan relative to other second-line treatments currently available in Canada, including ramucirumab-paclitaxel, paclitaxel, FOLFIRI, irinotecan, and docetaxel. A MAIC was used to connect the single-arm DESTINY-Gastric02 trial to the NMA evidence network and yield estimates of the relative treatment effect estimate between trastuzumab deruxtecan and ramucirumab-paclitaxel and the remaining comparators. Findings from the ITC showed that the treatment effect estimates for OS and PFS favoured trastuzumab deruxtecan over all the comparators included. However, the findings from the ITC should be interpreted with caution because the evidence is uncertain due to several major limitations. In the unanchored MAIC, patient comparability between the DESTINY-Gastric02 trial and the RAINBOW trial might not be adequate, given that information about some important prognostic factors (e.g., HER2 status) was missing; only 5 of 16 factors were involved in the weighting process, and imbalances remained after weighting in certain key factors (e.g., time to progressive disease on first-line therapy). A marked reduction in the MAIC ESS (from ██ to ████) suggests that the weights are highly variable due to a lack of population overlap across trials, and that the treatment effect estimates may be imprecise. Furthermore, other sources of heterogeneity in study design and statistical analyses existed that could not be addressed by the MAIC weighting process. The limitations of the MAIC analyses also contributed to uncertainty in the NMA findings because the NMA evidence network was constructed based on the MAIC, which connected the single-arm DESTINY-Gastric02 trial and the RAINBOW trial. One limitation specific to the NMA that can bias the estimate is the heterogeneity of the geographical regions and ethnicities observed between studies across the NMA evidence network.

Findings from the DESTINY-Gastric01 trial favoured trastuzumab deruxtecan over physician’s choice of irinotecan or paclitaxel in third-line and later settings. Until the results of a well-conducted confirmatory phase III trial are available, the positive findings from the DESTINY-Gastric01 trial should be interpreted with caution. In addition, there are concerns with respect to generalizing the results from the DESTINY-Gastric01 trial population to the patient population observed in third-line and later settings in Canada or to the DESTINY-Gastric02 trial population, due to differences in patient characteristics (e.g., cancer location, race) and/or the representativeness of the comparators (e.g., irinotecan or paclitaxel).

Harms

In the single-arm DESTINY-Gastric02 trial, the proportion of patients who had any TEAE of grade 3 or higher was 55.7%, with anemia (13.9%) being the most commonly reported. The proportion of patients who had any TESAE was 41.8%; 19.0% had at least 1 TEAE leading to the discontinuation of trastuzumab deruxtecan, and 13.9% had any TEAE associated with an outcome of death.

Overall, despite the challenge presented by the lack of a comparator group, most of the AEs reported in the DESTINY-Gastric02 trial, such as nausea, vomiting, anemia, and neutropenia, were not contrary to the expectation of the clinical experts consulted by the review team. According to the clinical experts consulted by the review team, trastuzumab deruxtecan associated lung toxicity – ILD, was a key safety end point upon which they would focus in this setting. Results showed that ████% of patients in the DESTINY-Gastric02 safety analysis set had ILD, with 2 events leading to trastuzumab deruxtecan discontinuation and 1 event leading to death. The clinical experts consulted by the review team noted that the incidence of ILD in the DESTINY-Gastric02 trial was consistent with the incidences reported in existing studies of patients who received trastuzumab deruxtecan to treat breast cancer. The clinical experts consulted by the review team also noted that clinicians are still learning about how to address lung toxicity associated with trastuzumab deruxtecan, given that trastuzumab deruxtecan is a relatively new drug. Nonetheless, the clinical experts consulted by the review team determined that the benefits of trastuzumab deruxtecan still outweighed its harms. Harms were not addressed in the sponsor-submitted ITC.

In the DESTNITY-Gastric01 trial, a higher proportion of patients in the trastuzumab deruxtecan group than in the control group had at least 1 TEAE of grade 3 or higher (85.6% versus 56.5%), at least 1 TESAE (44.8% versus 25.8%), at least 1 TEAE leading to the discontinuation of trastuzumab deruxtecan (17.6% versus 6.5%), and any TEAE associated with an outcome of death (6.4% versus 3.2%). The proportion of patients who had ILD was 12.8% in the trastuzumab deruxtecan group versus 0% in the control group. According to the clinical experts consulted by the review team, the use of trastuzumab deruxtecan requires careful attention, especially to ILD and other effects that can result in changes in a patient’s quality of life (e.g., diarrhea).

Consideration for a TLR Recommendation

A TLR recommendation is a recommendation by the CDA-AMC expert committee to publicly fund a drug or drug regimen for a certain period of time based on the condition that the sponsor will conduct 1 or more clinical studies that address uncertainty with the clinical evidence. CDA-AMC will subsequently conduct a reassessment of the additional evidence and issue a final reimbursement recommendation within a defined period of time. Based on the preliminary assessment by CDA-AMC (Table 36 in Appendix 1), trastuzumab deruxtecan meets the requirements to be considered by the expert committee for a TLR recommendation because:

• Trastuzumab deruxtecan received an NOC/c from Health Canada on January 17, 2025, through Health Canada’s advance consideration process under the NOC/c policy.

• A phase III clinical trial (the DESTINY-Gastric04 trial) is currently being conducted. This ongoing study will evaluate the efficacy and safety of trastuzumab deruxtecan relative to ramucirumab-paclitaxel for up to 3 years of follow-up in approximately 490 patients with HER2-positive gastric or GEJ adenocarcinoma. In terms of study population, the DESTINY-Gastric04 trial targets the second-line treatment setting for patients with HER2-positive gastric or GEJ cancer, in alignment with the current reimbursement request proposed by the sponsor. However, the indication currently under review by Health Canada targets a broader population, which includes not only patients in the second-line treatment setting, but also those in third-line and later settings. Therefore, the DESTINY-Gastric04 trial population does not completely align with the settings described in the Health Canada indication. As a result, the findings from the DESTINY-Gastric04 trial may not be generalizable to patients in the third-line setting and beyond. According to the clinical experts consulted by the review team, the selection of ramucirumab-paclitaxel as a comparator in the DESTINY-Gastric04 trial is appropriate because treatment with ramucirumab-paclitaxel is currently part of the standard of care in the second-line setting for locally advanced or metastatic HER2-positive gastric or GEJ cancer, and will likely remain as the standard of care in the second-line setting, when the results of the DESTINY-Gastric04 trial become available.

• The results of the DESTINY-Gastric04 trial are expected to be ready in the fourth quarter of 2025.

• The sponsor has expressed that it will commit to filing a reassessment application with CDA-AMC in accordance with the time frames specified in the procedures for TLR recommendations.

Conclusion

The DESTINY-Gastric02 trial (N = 79), a phase II, single-arm trial submitted by the sponsor, assessed the efficacy and safety of trastuzumab deruxtecan for the treatment of adult patients with unresectable or metastatic HER2-positive gastric or GEJ cancer in the second-line treatment setting. The clinical experts consulted by the review team noted that the results of some efficacy end points that were critical to decision-making (e.g., the probability of survival at 6 months or 12 months and of being progression-free at 6 months) were clinically meaningful. However, the absence of a comparator group in DESTINY-Gastric02 is a key limitation in the interpretation of the efficacy findings, resulting in very low certainty of evidence. The clinical experts consulted by the review team noted that the incidence of the key safety end point in the trial (i.e., ILD) met their expectations in terms of being consistent with the incidences reported in literature. According to the clinical experts, trastuzumab deruxtecan has an overall beneficial effect in the second-line treatment setting, warranting a confirmatory phase III clinical trial. The sponsor is currently conducting a phase III DESTINY-Gastric04 trial assessing the efficacy and safety of trastuzumab deruxtecan relative to ramucirumab-paclitaxel in patients with HER2-positive gastric or GEJ adenocarcinoma in the second-line treatment setting. The trial results are anticipated to be ready in the fourth quarter of 2025.

In the absence of direct evidence comparing trastuzumab deruxtecan to other second-line treatments currently available in Canada (i.e., ramucirumab-paclitaxel, paclitaxel, FOLFIRI, irinotecan, and docetaxel), sponsor-submitted ITCs using an unanchored MAIC and NMA were reviewed. The ITC treatment effect estimates for OS and PFS favoured trastuzumab deruxtecan over all other comparators; however, several major limitations in the design and methods of the ITC preclude any definitive conclusion about the magnitude of effect. Specifically, missing prognostic factors (e.g., HER2 status), the limited number of factors involved in the weighting process, residual imbalances in prognostic or effect-modifying factors, a significant reduction in ESS — and heterogeneity in study design, statistical analyses, geographical regions, and ethnicities across the NMA evidence network — can all result in biased estimates and overly precise credible intervals.

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