Reimbursement Review

Zolbetuximab for Injection (Vyloy)

Sponsor: Astellas Pharma Canada, Inc.

Therapeutic area: Gastric or gastroesophageal junction adenocarcinoma

This multi-part report includes:

Clinical Review

TPA 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 the Application Submitted for Review

NOC = Notice of Compliance.

Introduction

Disease overview: Gastric cancers originate in the cells lining the stomach and are generally classified into 2 topographical subsites.^1-3 Cardia gastric cancer arises in the upper part of the stomach near the gastroesophageal junction (GEJ), and noncardia gastric cancer arises in the more distal regions of the stomach.¹ GEJ cancers occur in the cells lining the GEJ, the area where the esophagus joins the gastric cardia.^2,3 In 2024, it was estimated that 4,000 people in Canada would be newly diagnosed with stomach cancer.⁴ The risk of developing gastric cancer increases with age and is greatest in people older than 50 years.⁵ Stomach cancer occurs more frequently in men than in women.^5-7 Chronic infection with Helicobacter pylori is a major risk factor for noncardia gastric cancer; it is responsible for nearly 90% of these cancer cases worldwide.^8,9 Early gastric cancers that are surgically curable are typically asymptomatic, and if symptoms are present at the early stage, these are usually nonspecific.^10,11 As such, diagnosis of gastric or GEJ cancer frequently occurs when the disease is at an advanced, unresectable, or metastatic stage and is considered incurable.^10,12,13 Quality of life in patients with gastric cancer is affected by emotional, physical, and social aspects of the disease and its treatment.¹⁴ Individuals may experience anxiety and depression as well as increasing symptom burden in advanced stages.^12,14 In Canada from 2015 to 2017, the 5-year net survival rate for individuals diagnosed with stomach cancer was 29%, reflecting that diagnosis is often made at advanced-stage disease that is associated with poor prognosis.^6,7,12,15 US data indicate that the 5-year relative survival rate for patients with metastatic gastric cancer is 7%.¹⁶ A clinical expert consulted by Canada’s Drug Agency (CDA-AMC) stated that, in clinical practice, the median survival duration for patients with metastatic gastric or GEJ cancer is approximately 1 year.

Greater than 90% of gastric cancers are histologically classified as adenocarcinomas.¹³ Various genetic aberrations can occur during the development of gastric cancer.¹⁷ Human epidermal growth factor receptor 2 (HER2) is overexpressed in approximately 20% of gastric or GEJ adenocarcinomas.¹⁸ Biomarker testing of cancer tissue may be performed to inform treatment decisions, including testing for HER2, programmed death-ligand 1 (PD-L1) combined positive score (CPS), and mismatch repair (MMR).^19,20

Claudin 18.2 (CLDN18.2): CLDN18.2 is a membrane tight junction molecule that is inaccessible in normal gastric epithelial tissue. CLDN18.2 may become exposed on the surface of gastric or GEJ adenocarcinoma cells due to the disruption of cell polarity that occurs during carcinogenesis.^21-23 Screening data from the SPOTLIGHT and GLOW trials suggest that 38% of patients with locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma are CDLN18.2-positive (defined as expression with 2+ or 3+ intensity in ≥ 75% of tumour cells).^24,25

Standard treatments: In patients with HER2-negative disease, the standard first-line treatment is nivolumab in combination with a platinum-fluoropyrimidine doublet, based on the results of the CheckMate-649 trial, which demonstrated that the addition of nivolumab to chemotherapy improved overall survival (OS) and progression-free survival (PFS).^26-28 In addition, the combination of pembrolizumab and platinum-fluoropyrimidine doublet therapy is recommended as a standard first-line treatment for patients with advanced or metastatic HER2-negative GEJ adenocarcinoma and esophageal adenocarcinoma, based on the double-blind, phase III KEYNOTE-590 study.^27,29 Standard first-line platinum-fluoropyrimidine doublet chemotherapy options in Canada include FOLFOX (leucovorin calcium [folinic acid], 5-fluorouracil, and oxaliplatin), CAPOX (capecitabine and oxaliplatin), FP (5-fluorouracil and cisplatin), or capecitabine-cisplatin. CDA-AMC issued a recommendation in September 2024 that pembrolizumab be reimbursed for use in combination with fluoropyrimidine- and platinum-containing chemotherapy for the first-line treatment of adult patients with locally advanced unresectable or metastatic HER2-negative gastric or GEJ adenocarcinoma.

Drug under review: Zolbetuximab is a monoclonal antibody that targets CLDN18.2. Zolbetuximab acts through antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) to deplete CLDN18.2-positive cells. Cytotoxic drugs were shown to increase CLDN18.2 expression on human cancer cells and to improve the ADCC and CDC activities of zolbetuximab.²¹ Zolbetuximab is supplied in single-use vials containing zolbetuximab 100 mg as a lyophilized powder for concentrate for solution for IV infusion.²¹ The product monograph–recommended dosage consists of a single loading dose (800 mg/m² IV) followed by a maintenance dosage of 600 mg/m² IV once every 3 weeks or 400 mg/m² IV once every 2 weeks. To align the administration schedule for zolbetuximab with the concomitant chemotherapy schedule, the product monograph recommends the 400 mg/m² every 2 weeks maintenance dosage when used in combination with leucovorin calcium (folinic acid), fluorouracil, and oxaliplatin (mFOLFOX6) and the 600 mg/m² every 3 weeks maintenance dosage when used in combination with CAPOX.²¹

Purpose of review: The objective of this clinical review report is to review and critically appraise the clinical evidence submitted by the sponsor on the beneficial and harmful effects of zolbetuximab, in combination with fluoropyrimidine- and platinum-containing chemotherapy, for the first-line treatment of patients with locally advanced unresectable or metastatic HER2-negative gastric or GEJ adenocarcinoma whose tumours are CLDN18.2-positive as determined by a validated test.

Perspectives of Patients, Clinicians, and Drug Programs

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

Patient Input

One patient group provided input for this review. My Gut Feeling – Stomach Cancer Foundation of Canada is a nonprofit organization providing support, awareness, education, information, and advocacy to patients with stomach cancer along with survivors and caregivers. My Gut Feeling conducted an international online survey of patients and caregivers affected by gastric, esophageal, and/or gastroesophageal cancer. A total of 35 respondents completed the survey, 14.3% of whom were caregivers and 85.7% of whom were patients; the majority of respondents resided in Canada (71.4%) or the US (25.7%).

Nearly all participants (97.2%) responded that their quality of life was significantly affected by the cancer diagnosis. Specifically, their physical and mental health, ability to eat, work life, finances, social life, identity, and personal image were all impacted. For example, respondents expressed the exhaustion of managing adequate daily nutrition and the toll of experiencing weight loss or weight gain, including its impact on body image. Patients and caregivers (particularly those affected by metastatic disease) communicated that the cancer diagnosis and its treatment had negative impacts on their mental health and caused anxiety surrounding finances (e.g., loss of income due to work absenteeism; additional expenses due to travel for medical care and specialized diet). Patients reported feeling anxiety, depression, and/or anger, and said that experiencing fatigue greatly impacted their daily activities.

Survey participants stated that many factors are considered when weighing treatment options, such as quality of life, survival benefits, side effects, convenience, and duration of therapy, recognizing that treatments have trade-offs that need to be considered on an individual basis. For example, most respondents (82.9%) would choose a treatment that prolongs life despite side effects. Patients also expressed a preference for the convenience of oral chemotherapy taken at home over IV chemotherapy administered in a hospital setting.

My Gut Feeling indicated that gastric and gastroesophageal cancers are rare in Canada, with few treatment options. This group expressed an unmet need for equitable access to therapies that prolong life, improve symptoms, reduce the risk of recurrence, and have improved tolerability. My Gut Feeling strongly supports the use of zolbetuximab in combination with chemotherapy as a first-line treatment for patients with locally advanced unresectable or metastatic HER2-negative gastric or GEJ adenocarcinoma whose tumours are CLDN18.2-positive and expressed that biomarker testing should be accessible at the onset of disease for all patients in Canada. The patient group believed that patients should have a choice of treatment options that are barrier-free and covered under the universal health care system in Canada.

Clinician Input

Input From the Clinical Experts Consulted by CDA-AMC

The clinical experts consulted for the purpose of this review emphasized that locally advanced and metastatic HER2-negative gastric or GEJ cancer is associated with considerable unmet needs. Treatment with nivolumab in combination with chemotherapy is the currently available first-line option for locally advanced metastatic HER2-negative gastric or GEJ cancer; however, OS outcomes remain poor (median OS = 13 months to 15 months). The clinical experts suggested that the addition of zolbetuximab to chemotherapy would represent an alternative to combination therapy with nivolumab plus chemotherapy in the first-line metastatic treatment setting for patients with locally advanced and metastatic HER2-negative gastric or GEJ cancer whose tumours are CLDN18.2-positive. Regulatory approval and reimbursement for nivolumab for patients with gastric or GEJ cancer is not limited based on a patient’s PD-L1 CPS; however, the clinical experts noted that there is some uncertainty in the clinical community regarding the effectiveness of nivolumab plus chemotherapy in patients with a PD-L1 CPS of less than 5. For example, a subgroup analysis from the pivotal CheckMate-649 study suggested a reduced effect of nivolumab in patients with a PD-L1 CPS of less than 5 (hazard ratio [HR] = 0.94; 95% confidence interval [CI], 0.78 to 1.13). As such, the clinical experts noted that zolbetuximab plus chemotherapy could be a preferred option for patients with CLDN18.2-positive tumours and a PD-L1 CPS of less than 5. For patients with both CLDN18.2-positive tumours and a PD-L1 CPS of greater than or equal to 5, it is currently unclear which option could offer the best outcomes.

The clinical experts noted that the following factors should be used to determine response to treatment: patient-reported symptoms and side effects, and response on cross-sectional imaging via CT or MRI scans. The clinical experts suggested that patients should be assessed by a clinician after every 2 to 3 cycles of treatment. Clinician assessment may occur more frequently if patients report the occurrence of bothersome symptoms or side effects. The clinical experts suggested that patients should undergo CT scans every 2 to 3 months. Tumour markers can be used, as per clinical judgment, to supplement a fulsome patient assessment. The clinical experts noted that the clinically meaningful end points across all oncology types are OS and quality of life, and that PFS has limited value in assessing clinical benefit for patients with metastatic disease and a relative short OS duration. The clinical experts suggested that the decision to discontinue treatment with zolbetuximab should be based on patient-reported symptoms, patient preference, side effects, and well-being, in combination with an assessment of treatment response and disease progression, either radiologic or clinical.

Clinician Group Input

Four clinicians from the Ontario Health (Cancer Care Ontario) Gastrointestinal Cancer Drug Advisory Committee (OH-CCO GI DAC) provided a joint clinician group input for this review. These committees provide timely, evidence-based clinical and health system guidance on drug-related issues in support of Cancer Care Ontario’s mandate, including the Provincial Drug Reimbursement programs and the Systemic Treatment Program.

Regarding current treatments for metastatic HER2-negative gastric cancer, the clinician group providing input stated that standard first-line therapy consists of chemotherapy (typically FOLFOX combined with immunotherapy [nivolumab, which is currently funded, or pembrolizumab, which is approved but not funded]). The goals of treatment are to prolong life, delay disease progression, and maintain quality of life. This clinician group expressed that there are currently no approved treatments that specifically target tumours overexpressing CLDN18.2, which represents an unmet need for this population. Clinical experts consulted by CDA-AMC also identified FOLFOX with or without nivolumab as a first-line therapy in this population, with goals of therapy that were aligned with those identified by the clinician group. These experts identified an unmet need for treatments with other biological targets and for new treatments that will increase survival.

The OH-CCO GI DAC remarked that patients best suited for treatment with zolbetuximab are those with HER2-negative, CLDN18.2-positive, advanced gastric or GEJ cancer. This clinician group stated that zolbetuximab would provide an alternative to nivolumab. For patients with CLDN18.2 overexpression and PD-L1-negative or -low disease, the clinician group suspects that zolbetuximab and chemotherapy would be the clear first-line choice of therapy, but acknowledges that the best first-line therapy (nivolumab, pembrolizumab or zolbetuximab) for patients with CLDN18.2 overexpression and a PD-L1 CPS greater than 5% is unclear. For the latter population, the choice of drug to add (i.e., zolbetuximab, nivolumab, or immunotherapy) would be at the physician’s discretion, based on comorbidities and toxicity profile and with consideration for maintaining good quality of life.

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 impact the implementation of a reimbursement recommendation for zolbetuximab (refer to Table 4 for complete details):

• Considerations for initiation of therapy: Drug programs are seeking advice on scenarios that may arise in which a patient’s biomarker status (i.e., HER2 or CLDN18.2) is delayed or uncertain; where a patient may not be eligible for platinum-based chemotherapy; or where a patient has previously been treated with nivolumab in the adjuvant setting.

• Access to CLDN18.2 testing: The test is not widely available and would need to be implemented to evaluate patients for zolbetuximab eligibility.

• Consideration for discontinuation of therapy: Drug programs are seeking advice on the potential continuation of therapy with zolbetuximab after a patient has been required to discontinue chemotherapy.

• Prescribing considerations: Drug programs are seeking advice on considerations for potentially switching from other treatments used in the first-line metastatic setting (e.g., nivolumab plus chemotherapy) to zolbetuximab plus chemotherapy.

• Provision funding algorithm: Drug programs identified the likely need for a provisional funding algorithm to support the implementation of zolbetuximab and other recently approved therapies for gastric or GEJ cancer.

• Care provision issues: Drug programs noted that more health care resources (i.e., chair time, nursing time, and pharmacy time) could be required for zolbetuximab in comparison with nivolumab due to longer infusion times and a more complicated process to prepare the dosage for infusion.

Clinical Evidence

Systematic Review

Description of Studies

The systematic review included 2 multinational, double-blind, placebo-controlled, randomized studies of zolbetuximab in combination with fluoropyrimidine- and platinum-based chemotherapy compared with placebo in combination with fluoropyrimidine- and platinum-based chemotherapy for the first-line treatment of patients with locally advanced unresectable or metastatic HER2-negative gastric or GEJ adenocarcinoma whose tumours are CLDN18.2-positive (SPOTLIGHT trial [N = 565] and GLOW trial [N = 507]). In both trials, patients were randomized in a 1:1 ratio to zolbetuximab or placebo groups, with randomization stratified by region (Asia versus non-Asia), number of organs with metastatic sites (0 to 2 versus ≥ 3), and prior gastrectomy (yes or no). The chemotherapy backbones were mFOLFOX6 in the SPOTLIGHT trial and CAPOX in the GLOW trial.

The primary objective in both the SPOTLIGHT and GLOW trials was to assess the PFS benefit of zolbetuximab plus chemotherapy compared to placebo plus chemotherapy. Key secondary objectives were to evaluate OS and time to confirmed deterioration (TTCD) using the European Organisation for Research and Treatment of Cancer (EORTC) Global Health Status/Quality of Life (GHS/QoL) scale, the EORTC QLQ-C30 Physical Functioning (PF) scale, and the EORTC Quality of Life Questionnaire Oesophago-Gastric 25 (QLQ-OG25) scale on abdominal pain and discomfort. Additional secondary objectives were to evaluate objective response rate (ORR), duration of response (DOR), safety, tolerability, and additional patient-reported outcomes.

Efficacy Results

Table 2 summarizes results for the efficacy end points from the SPOTLIGHT and GLOW trials. The data cut-offs used in the report were from the primary analysis of PFS (September 9, 2022, and October 7, 2022, for the SPOTLIGHT and GLOW trials, respectively) and from the final analysis of OS (September 8, 2023, and January 12, 2024, for the SPOTLIGHT and GLOW trials, respectively).

• OS: In the final analysis of OS in the SPOTLIGHT trial, treatment with zolbetuximab plus mFOLFOX6 demonstrated a statistically significant improvement in OS compared with placebo plus mFOLFOX6 treatment (HR = 0.78; 95% CI, 0.64 to 0.95; P = 0.0075). Median OS was 18.2 months (95% CI, 16.1 months to 20.6 months) in the zolbetuximab plus mFOLFOX6 arm and 15.6 months (95% CI, 13.7 months to 16.9 months) in the placebo plus mFOLFOX6 arm. In the GLOW trial, the final analysis of OS demonstrated that treatment with zolbetuximab plus CAPOX was associated with a statistically significant improvement in OS compared with placebo plus CAPOX (HR = 0.763; 95% CI, 0.622 to 0.936; P = 0.0047).

• PFS: In the SPOTLIGHT trial, treatment with zolbetuximab plus mFOLFOX6 showed a statistically significant improvement in PFS compared with placebo plus mFOLFOX6 (HR = 0.751; 95% CI, 0.598 to 0.942; 1-sided P = 0.0066). The median PFS durations were 10.61 months (95% CI, 8.90 months to 12.48 months) and 8.67 months (95% CI, 8.21 months to 10.28 months) in the zolbetuximab plus mFOLFOX6 and placebo plus mFOLFOX6 groups, respectively. In the GLOW trial, treatment with zolbetuximab plus CAPOX demonstrated a statistically significant improvement in PFS compared with placebo plus CAPOX (HR = 0.687; 95% CI, 0.544 to 0.866; 1-sided P = 0.0007). The median PFS durations were 8.21 months (95% CI, 7.46 months to 8.84 months) and 6.80 months (95% CI, 6.14 months to 8.08 months) in the zolbetuximab plus CAPOX and placebo plus CAPOX groups, respectively.

• ORR: There was no statistically significant difference between the zolbetuximab plus mFOLFOX6 or CAPOX and placebo plus mFOLFOX6 or CAPOX groups in either the SPOTLIGHT or GLOW trials. In the SPOTLIGHT trial, the ORRs were 47.7% (95% CI, 41.76% to 53.70%) in the group receiving zolbetuximab plus mFOLFOX6 and 47.5% (95% CI, 41.56% to 53.52%) in the group receiving placebo plus mFOLFOX6. In the GLOW trial, the ORRs per independent review committee (IRC) were 42.5% (95% CI, 36.36% to 48.85%) in the group receiving zolbetuximab plus CAPOX and 40.3% (95% CI, 34.22% to 46.64%) in the group receiving placebo plus CAPOX.

• Disease control rate (DCR): Similar to ORR, there was no statistically significant difference in DCR between the zolbetuximab plus mFOLFOX6 or CAPOX group and the placebo plus mFOLFOX6 or CAPOX group in either the SPOTLIGHT or GLOW trial.

• DOR: There was no statistically significant difference in DOR between the zolbetuximab plus mFOLFOX6 or CAPOX group and the placebo plus mFOLFOX6 or CAPOX group in either the SPOTLIGHT trial (HR = 0.876; 95% CI, 0.623 to 1.233; P = 0.2218) or the GLOW trial (HR = 0.758; 95% CI, 0.527 to 1.089; P = 0.0673).

• Time to progression (TTP): In the SPOTLIGHT trial, the median TTPs were 17.81 months in the zolbetuximab plus mFOLFOX6 arm and 12.52 months in the placebo plus mFOLFOX6 arm (P = 0.0133). In the GLOW trial, the median TTPs, according to IRC, were 11.99 months (95% CI, 8.84 months to 20.80 months) in the zolbetuximab plus CAPOX arm and 8.31 months (95% CI, 8.11 months to 9.95 months) in the placebo plus CAPOX arm (P = 0.0002).

• Progression-free survival following second-line anticancer treatment (ACT) (PFS2): In the SPOTLIGHT trial, treatment with zolbetuximab plus mFOLFOX6 was associated with reduced risk of a PFS2 event compared with placebo plus mFOLFOX6 treatment (HR = 0.782; 95% CI, 0.637 to 0.961). The median PFS2s were 14.23 months (95% CI, 12.12 months to 16.82 months) in the group receiving zolbetuximab plus mFOLFOX6 and 11.99 months (95% CI, 11.20 months to 13.40 months) in the group receiving placebo plus mFOLFOX6. In the GLOW trial, treatment with zolbetuximab plus CAPOX demonstrated a reduced risk of PFS2 event compared with placebo plus CAPOX (HR = 0.708; 95% CI, 0.575 to 0.871). The median PFS2s were 11.01 months (95% CI, 10.02 months to 13.11 months) in the group receiving zolbetuximab plus CAPOX and 9.03 months (95% CI, 8.28 months to 9.89 months) in the group receiving placebo plus CAPOX.

Harms Results

In the pooled analysis of safety from the SPOTLIGHT and GLOW trials, the AEs that were reported for at least 20% of patients in either group included (for zolbetuximab versus placebo, respectively) nausea (75.8% versus 55.8%), vomiting (66.8% versus 33.4%), decreased appetite (44.3% versus 33.6%), anemia (35.6% versus 37.0%), diarrhea (35.6% versus 39.5%), neutrophil count decrease (31.0% versus 28.5%), peripheral sensory neuropathy (30.4% versus 33.0%), neutropenia (28.5% versus 24.5%), constipation (25.9% versus 31.1%), fatigue (21.0% versus 25.2%), aspartate aminotransferase increase (21.0% versus 22.0%), abdominal pain (20.1% versus 25.8%), asthenia (20.1% versus 18.2%), and platelet count decrease (18.9% versus 20.7%). Serious adverse events (SAEs) were reported in 245 patients (46.0%) in the combined zolbetuximab group and in 245 patients (46.5%) in the combined placebo group. SAEs reported in at least 4% of patients in either group included (zolbetuximab versus placebo, respectively) vomiting (7.1% versus 4.6%), nausea (5.6% versus 3.2%), and malignant neoplasm progression (3.6% versus 4.7%). Adverse events (AEs) leading to permanent discontinuation of zolbetuximab or placebo were reported in 106 patients (19.9%) and 66 patients (12.5%), respectively. The most frequent AEs leading to permanent discontinuation of zolbetuximab or placebo (present in 2% or more of patients in either combined group) were vomiting (3.8% versus 0.6%) and nausea (3.4% versus 0.4%), respectively.

Critical Appraisal

Baseline and demographic characteristics were generally well balanced across the zolbetuximab and placebo groups in both the SPOTLIGHT and GLOW trials. The clinical experts consulted during this review had no concerns regarding the baseline characteristics of the SPOTLIGHT and GLOW trial populations. Both SPOTLIGHT and GLOW were double-blind clinical trials. Patients who received zolbetuximab more commonly reported AEs of nausea and vomiting as well as infusion-site reactions. The clinical experts consulted during this review noted that the AE profile in the trial could potentially allow some patients and investigators to infer the allocated treatment group. The objective end points (e.g., PFS, OS, and ORR) would not be subject to bias in the event that treatment groups could be inferred as a result of AEs; however, health-related quality of life (HRQoL), which requires subjective reporting, could potentially be biased. The primary and secondary end points of the SPOTLIGHT and GLOW trials were aligned with those recommended by regulatory authorities for gastric cancer trials in the metastatic setting. The clinical experts consulted by CDA-AMC noted that PFS is not a particularly useful end point in the context of metastatic disease, in which survival is typically limited to 1 year. However, the final analyses showing an improvement in OS were considered demonstrative of a clinically meaningful benefit compared with chemotherapy alone.

The clinical experts consulted during this review noted that the baseline and demographic characteristics for the SPOTLIGHT and GLOW trials are a reasonable reflection of the target patient population in Canada. There are no other drugs specifically indicated for use in the treatment of patients with CLDN18.2-positive gastric or GEJ cancer in Canada; therefore, the choice of placebo plus mFOLFOX6 or CAPOX was considered appropriate by regulatory authorities. However, the clinical experts consulted during this review noted that the comparator used in the SPOTLIGHT and GLOW trials (i.e., placebo plus mFOLFOX6 or CAPOX) is not reflective of routine practice in Canada, where patients would typically be offered nivolumab plus chemotherapy as the preferred treatment option. The SPOTLIGHT and GLOW trials began in 2018, predating the regulatory approval of nivolumab plus chemotherapy for gastric and GEJ cancer in Canada (in October 2021); however, nivolumab plus chemotherapy remains the most relevant comparator for the current review. In the absence of a direct comparison against nivolumab plus chemotherapy, the sponsor has provided an indirect comparison, which was reviewed by CDA-AMC. In October 2024, pembrolizumab received a recommendation in favour of reimbursement from the pan-Canadian Oncology Drug Review Expert Review Committee (pERC) for use in combination with fluoropyrimidine- and platinum-containing chemotherapy for the first-line treatment of adult patients with locally advanced unresectable or metastatic HER2-negative gastric or GEJ adenocarcinoma.

The SPOTLIGHT and GLOW trials involved the following zolbetuximab dosage regimen (single loading dose of 800 mg/m² IV, followed by 600 mg/m² IV every 3 weeks maintenance dosing). This is likely reflective of how zolbetuximab would be used in Canadian practice for patients receiving it in combination with CAPOX (which is administered every 3 weeks), but not when receiving it in combination with mFOLFOX6 (which is administered every 2 weeks). As such, the product monograph recommends the following regimen when zolbetuximab is used in combination with mFOLFOX6: 800 mg/m² loading dose followed by 400 mg/m² every 2 weeks. This was based on population pharmacokinetic modelling that predicted the 400 mg/m² every 2 weeks maintenance dosage would have similar exposure as the 600 mg/m² every 3 weeks regimen.

Zolbetuximab is the first drug to specifically target CLDN18.2. Routine screening for CLDN18.2 is not currently performed in Canada for patients with gastric or GEJ cancer (or any other cancer). The SPOTLIGHT and GLOW trials enrolled patients who had CLDN18.2-positive tumours, defined as at least 75% of tumour cells demonstrating moderate to strong membranous CLDN18.2 staining based on central immunohistochemistry (IHC) assessment using the companion diagnostic test (i.e., the CLDN18 RxDx Assay). The clinical experts consulted during this review supported the use a 75% threshold for concluding that a patient harbours CLDN18.2-positive tumours. The experts further noted that they would not anticipate any challenges with interpreting the results of the CLDN18 RxDx Assay (e.g., diagnosis would likely be consistent across different centres in Canada).

GRADE Summary of Findings and Certainty of the Evidence

The selection of outcomes for the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) assessment was based on the sponsor’s Summary of Clinical Evidence, consultation with clinical experts, and input received from patient and clinician groups and public drug plans. Table 2 provides the list of outcomes that was finalized in consultation with expert committee members.

Table 2: Summary of Findings for Zolbetuximab Plus Chemotherapy Versus Placebo Plus Chemotherapy

CAPOX = capecitabine plus oxaliplatin; CDA-AMC = Canada’s Drug Agency; CI = confidence interval; EORTC GHS/QoL = European Organisation for Research and Treatment of Cancer Global Health Status/Quality of Life; EORTC QLQ-C30 PF = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - Core Questionnaire Physical Functioning; EORTC QLQ-OG25 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Oesophago-Gastric 25; GRADE = Grading of Recommendations, Assessment, Development, and Evaluations; IRC = independent review committee; IRR = infusion-related reaction; mFOLFOX6 = modified 5-fluorouracil, folinic acid, and oxaliplatin; NA = not available; NE = not estimable; NR = not reported; OS = overall survival; PFS = progression-free survival; RCT = randomized controlled trial; RECIST 1.1 = Response Evaluation Criteria in Solid Tumours Version 1.1.

^aRated down 1 level for serious imprecision. Although the point estimate suggests a clinically important benefit (exceeding the 5% to 10% threshold suggested by the clinical experts consulted on this review), the lower bound of the 95% CI is compatible with little to no difference in clinical benefit.

^bRated down 1 level for serious imprecision because the lower bounds of the 95% CI were compatible with little to no difference in clinical benefit.

^cThe clinical experts consulted on this review indicated a lack of clarity about a threshold of clinical importance; therefore, the null was used. Although the certainty of evidence was not rated down for serious indirectness, there were concerns about the clinical importance of PFS.

^dCertainty of evidence cannot be evaluated because the sponsor did not report the absolute difference between groups and was not able provide this information upon request. In the absence of a reported absolute difference, CDA-AMC was unable to determine an appropriate target for the certainty assessment under the GRADE framework, given that the reported relative effects for these end points were not considered suitable for inferring whether a clinically meaningful difference was observed for these end points. Likewise, the ability to assess the imprecision of any target of the certainty assessment would have been limited if it were based on relative effect estimates alone. Although the certainty for these end points cannot be assessed, the results for these end points were noted to have a potential risk of bias because the sponsor reported that the results of the analyses are not mature enough to derive thresholds for clinically meaningful deterioration.

Long-Term Extension Studies

Not applicable.

Indirect Comparisons

In the absence of direct head-to-head trials evaluating the comparative efficacy of zolbetuximab versus relevant comparators for the first-line treatment of patients with locally advanced unresectable or metastatic HER2-negative gastric or GEJ adenocarcinoma whose tumours are CLDN18.2-positive, a review of indirect evidence was undertaken and submitted by the sponsor. The objective of this section is to summarize and critically appraise the sponsor-submitted indirect treatment comparison (ITC), and to inform the pharmacoeconomic model.

Description of Studies

In the sponsor-conducted systematic review, 174 publications reporting on 92 studies were included. After applying the network meta-analysis (NMA) inclusion and exclusion criteria, 21 randomized controlled trials (RCTs), including the GLOW and SPOTLIGHT trials, were deemed relevant for the sponsor’s NMA; these included 14 unique treatment regimens. After the removal of 1 study that did not include subgroup analysis based on CPS score, 20 studies were included in the analysis. The sponsor reported that the inclusion and exclusion criteria, including disease stage, age, and Eastern Cooperative Oncology Group (ECOG) Performance Status, were generally consistent across trials. The sample size across trials ranged from 38 patients to 1,581 patients, and the median follow-up durations ranged from 7 months to 26.6 months. Half of the included trials were only conducted in Asian countries. The dose schedule for the majority of treatment regimens appears consistent across studies, with some variation for fluorouracil-based regimens and tegafur/gimeracil/oteracil (S-1)–based regimens. OS and PFS were analyzed in the NMA, and the definitions were reported as mainly consistent across the trials.

Efficacy Results

The NMA was constructed using a fixed-effects model, and the sponsor reports that the trace and density plots, Gelman-Rubin plots, and Gelman-Rubin diagnostics showed that convergence of the results was generally achieved. For OS, results from the NMA are consistent with results of the pivotal evidence, in which zolbetuximab combined with CAPOX is superior to CAPOX alone (HR = 0.76; 95% credible interval [CrI], 0.62 to 0.94), and zolbetuximab combined with FOLFOX is superior to FOLFOX alone (HR = 0.78; 95% Crl, 0.64 to 0.95). The HRs for cross-comparisons with CAPOX and FOLFOX are also consistent. However, the wide CrIs may indicate heterogeneity between the studies that used CAPOX versus FOLFOX. CrIs for the comparisons of zolbetuximab plus chemotherapy versus nivolumab or pembrolizumab plus chemotherapy did not favour either comparator in OS; however, the HR was consistently higher with zolbetuximab plus FOLFOX compared to zolbetuximab plus CAPOX. For PFS, results are again consistent with results of the pivotal evidence, in which zolbetuximab combined with CAPOX is superior to CAPOX alone (HR = 0.69; 95% Crl, 0.55 to 0.86) and zolbetuximab combined with FOLFOX is superior to FOLFOX alone (HR = 0.73; 95% Crl, 0.59 to 0.91). The HRs for cross-comparisons with CAPOX and FOLFOX are also consistent; however, the wide CrIs may indicate heterogeneity between the studies that used CAPOX versus FOLFOX. The CrIs for the comparisons of zolbetuximab plus chemotherapy versus nivolumab or pembrolizumab plus chemotherapy did not favour either comparator in OS; however, the HR was consistently higher with zolbetuximab plus FOLFOX compared to zolbetuximab plus CAPOX.

Harms Results

Harms outcomes were not evaluated in the NMA.

Critical Appraisal

The sponsor-submitted NMA was based on studies identified from a systematic literature review of relevant evidence, based on a population, invention, comparator, and outcome (PICO) defined a priori. While the risk of bias of the comparator trials was assessed, it was not reported how many reviewers conducted the quality assessment; nor was the risk of bias assessed per outcome. The sponsor conducted 2 primary analyses: with CAPOX and FOLFOX as separate comparators and then with the 2 regimens combined as a single comparator. This was based on the sponsor’s assumption that CAPOX and FOLFOX were of equivalent efficacy, an assumption that was supported by the clinical experts consulted for this review. However, the results of the primary NMA analysis that keeps the comparators separate do not support combining these comparators because there are wide CrIs in the cross-comparisons between both treatments, indicating systematic heterogeneity between the studies that used CAPOX versus those that used FOLFOX. Therefore, the results of both analyses must be interpreted with caution.

The clinical experts consulted during this review noted that proactive screening for gastrointestinal cancers is more common in some Asian countries and that this tends to contribute to more favourable outcomes for some patients. Thus, the heterogeneity in the trial populations across the network likely introduced bias in the comparisons across the network. The sponsor conducted sensitivity analyses, excluding the Asia-only trials or focusing on Asia-only trials (or Asian subgroups of global trials), and the findings were similar to those of the primary NMA analysis; however, this sensitivity analysis was conducted only in the second primary analysis with CAPOX and FOLFOX combined and in which CDA-AMC has noted greater heterogeneity across studies.

The sponsor reports that differences in median follow-up durations (and, therefore, data maturity) could introduce bias because HRs tend to wane with longer follow-up times; yet the sponsor was unable to account for differences in data maturity in its analysis. With regards to patient baseline characteristics, the sponsor noted variations across trials in the median age, ECOG performance status, tumour location and type, disease stage, number of metastatic sites, mutation status, and prior surgery; however, it noted that it did not adjust for these variations in its analysis. Specifically for tumour location, the clinical experts noted that the trial data do not show benefits for patients with GEJ tumours; therefore, heterogeneity across the network in tumour location could be an important source of bias for these NMAs.

There were variations in the collection and reporting of mutation status across trials; therefore, the sponsor did not adjust for HER2 or CLDN18.2 expression status. The clinical experts consulted for this review noted that, while zolbetuximab plus chemotherapy could be a preferred option for patients with CLDN18.2-positive tumours and a PD-L1 CPS of less than 5, it is unclear which option would be best for patients with CLDN18.2-positive tumours and a PD-L1 CPS of greater than or equal to 5. In this NMA, the sponsor conducted 2 subgroup analyses with CPS greater than or equal 5 and CPS less than 5 in the 5 trials that reported CPS scores; however, these analyses used only CPS-specific HRs from the nivolumab and pembrolizumab trials and did not use the subgroup-specific data from the SPOTLIGHT and GLOW trials. The clinical review team considered this approach to be at risk for severe bias due to the existing evidence that has established CPS testing as a potential effect modifier in this disease area. Therefore, this subgroup analysis has significant limitations, and no definitive conclusions could be drawn for this subpopulation of patients.

NMA results were presented for OS and PFS only; harms outcomes and other outcomes of relevance to patients (e.g., HRQoL) were not reported. The treatment effects measured using HRs of OS or PFS assumed proportional hazards, which were confirmed in 3 trials but not reported in most included studies. The consistency test performed in the primary analysis using CAPOX and FOLFOX as combined treatments suggested evidence of inconsistency in the PFS network.

Studies Addressing Gaps in the Evidence From the Systematic Review

Not applicable.

Conclusions

Two randomized, double-blind, placebo-controlled, phase III trials (the SPOTLIGHT and GLOW trials) demonstrated that treatment with zolbetuximab in combination with fluoropyrimidine- and platinum-based chemotherapy (i.e., mFOLFOX6 or CAPOX) resulted in a clinically important improvement in OS compared with placebo in combination with fluoropyrimidine- and platinum-based chemotherapy for the first-line treatment of patients with locally advanced unresectable or metastatic HER2-negative gastric or GEJ cancer adenocarcinoma whose tumours are CLDN18.2-positive. The SPOTLIGHT and GLOW trials similarly demonstrated that treatment with zolbetuximab in combination with chemotherapy resulted in improvements in PFS compared with placebo in combination with chemotherapy. The results for time to deterioration based on changes in HRQoL scales were inconsistent across the SPOTLIGHT and GLOW trials.

The sponsor-submitted ITC suggested that there was little to no difference in treatment effect on OS and PFS between zolbetuximab and nivolumab in combination with chemotherapy; however, these comparisons were not limited to patients whose tumours were CLDN18.2-positive. However, the indirect evidence is associated with uncertainty due to clinical and methodological heterogeneity between the studies included in the network, with a potential to introduce bias to the ITC results.

Treatment with zolbetuximab in combination with chemotherapy is associated with an increased risk of nausea, vomiting, and infusion-related reactions (IRRs) compared with chemotherapy alone. The product monograph provides recommendations regarding pretreatment with medications to reduce the risk, as well as recommendations for treatment interruption and discontinuation (if required) for those who experience grade 2, 3, or 4 AEs. The clinical experts consulted during this review indicated that these events would be manageable in clinical practice and would not be expected to limit the usage of zolbetuximab. The sponsor’s submitted ITC did not include an evaluation of the comparative safety of zolbetuximab versus nivolumab or pembrolizumab. Acknowledging the absence of comparative evidence, the clinical experts noted that the AE profile for zolbetuximab in combination with chemotherapy is generally comparable to those of the alternative regimens that would be available for patients with metastatic gastric or GEJ cancer.

Introduction

The objective of this clinical review report is to review and critically appraise the clinical evidence submitted by the sponsor on the beneficial and harmful effects of zolbetuximab in combination with fluoropyrimidine- and platinum-containing chemotherapy for the first-line treatment of patients with locally advanced unresectable or metastatic HER2-negative gastric or GEJ adenocarcinoma whose tumours are CLDN18.2-positive as determined by a validated test. The focus will be on comparing zolbetuximab to relevant comparators and identifying gaps in the current evidence.

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 CDA-AMC.

Gastric cancers originate in the cells lining the stomach and are generally classified into 2 topographical subsites.^1-3 Cardia gastric cancer arises in the upper part of the stomach near the GEJ, and noncardia gastric cancer arises in the more distal regions of the stomach.¹ GEJ cancers occur in the cells lining the GEJ, the area where the esophagus joins the gastric cardia.^2,3

In 2024 in Canada, an estimated 4,000 people (2,600 males and 1,400 females) will be newly diagnosed with stomach cancer, and an estimated 2,000 individuals will die from this disease.⁴ The risk of developing gastric cancer increases with age and is greatest in people aged 50 years or older.⁵ Canadian statistics from 2019 showed that the lifetime probability of developing stomach cancer was higher among males (1.3%) than females (0.7%)^5-7 and that the projected, estimated, age-standardized incidence rates for stomach cancer in 2022 were 12 per 100,000 and 5.6 per 100,000 for males and females, respectively.¹ Chronic infection with Helicobacter pylori is a major risk factor for noncardia gastric cancer and is responsible for nearly 90% of these gastric cancer cases worldwide.^8,9 Other risk factors for stomach cancer include smoking, heavy alcohol consumption, being overweight, and high consumption of foods preserved by nitrates and/or nitrites.^30-32

Advanced, unresectable, or metastatic G/ GEJ cancers are considered incurable.¹³ Early gastric cancers that are surgically curable are typically asymptomatic.¹² If symptoms are present at the early stage, these are usually nonspecific (e.g., indigestion, heartburn, bloating, mild nausea).^10,11 Diagnosis of gastric or GEJ cancer frequently occurs when the disease is at an advanced, unresectable, or metastatic stage.^10,12,13 According to data from the US, 36% of stomach cancers are diagnosed at the metastatic stage.¹⁶ Advanced gastric cancers are associated with symptoms such as unexplained weight loss, abdominal pain, early satiety, dysphagia, asthenia, nausea, vomiting, bleeding, anemia, ascites, and jaundice.^{11,12,14,28,33,34} Quality of life in patients with gastric cancer is affected by emotional, physical, and social aspects of the disease and its treatment.¹⁴ Individuals may experience anxiety and depression as well as increasing symptom burden in advanced stages.^12,14 In Canada, from 2015 to 2017, the 5-year net survival rate for individuals diagnosed with stomach cancer was 29%, reflecting that diagnoses are often made at the advanced stages of the disease, a situation associated with poor prognosis.^6,7,12,15 US data indicate that the 5-year relative survival rate for patients with metastatic gastric cancer is 7%.¹⁶ A clinical expert consulted by CDA-AMC stated that the median survival duration for patients with metastatic gastric or GEJ cancer is approximately 1 year.

Greater than 90% of gastric cancers are histologically classified as adenocarcinomas.¹³ Various genetic aberrations can occur during the development of gastric cancer.¹⁷ HER2 is overexpressed in approximately 20% of gastric or GEJ adenocarcinomas.¹⁸ Although the prognostic significance of HER2 status is not well established in gastric cancer, HER2 status can be applied clinically in individualizing treatment for advanced or metastatic gastric disease.¹⁷ Testing for HER2 expression is a routine part of clinical practice in Canada upon diagnosis of advanced gastric or GEJ cancer.³⁵ CLDN18.2 is a membrane tight junction molecule that is inaccessible in normal gastric epithelial tissue. CLDN18.2 may become exposed on the surface of gastric or GEJ adenocarcinoma cells due to the disruption of cell polarity that occurs during carcinogenesis.^21-23 The sponsor reported that, based on screening data from the SPOTLIGHT and GLOW trials, 38% of patients with locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma are CDLN18.2-positive (defined as expression with 2+ or 3+ intensity in ≥ 75% of tumour cells).^24,25

The diagnosis and staging of gastric or GEJ cancer are performed by an oncologist.¹⁹ Procedures include blood tests; imaging with upper gastrointestinal endoscopy; endoscopic ultrasound; CT, PET, and/or MRI scans; and tissue biopsy.^2019,20 Biomarker testing of cancer tissue may also be performed to inform treatment decisions, including testing for HER2, PD-L1 CPS, and MMR.^19,20 A clinical expert consulted by CDA-AMC expressed that upon approval of zolbetuximab, stomach cancers should be reflexively tested for HER2, CPS, MMR, and CLDN18.2 to inform treatment decisions.

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 CDA-AMC.

Drug Under Review

Indication and Requested Reimbursement Criteria

Zolbetuximab is approved for use in combination with fluoropyrimidine- and platinum-containing chemotherapy for the first-line treatment of patients with locally advanced unresectable or metastatic HER2-negative gastric or GEJ adenocarcinoma whose tumours are CLDN18.2-positive as determined by a validated test.²¹ The sponsor has requested reimbursement in accordance with the indication approved by Health Canada. Zolbetuximab has not been reviewed previously by CDA-AMC. Zolbetuximab was approved by the FDA on October 18, 2024.³⁶ On July 25, 2024, the European Medicines Agency (EMA) Committee for Medicinal Products for Human Use recommended that market authorization be granted for zolbetuximab for the treatment of gastric or GEJ adenocarcinoma. The full indication is in alignment with the indication under review by CDA-AMC.³⁷

Mechanism of Action

Zolbetuximab is a monoclonal antibody that targets CLDN18.2, a tight junction molecule that may become exposed on the surface of gastric or GEJ adenocarcinoma cells. Zolbetuximab acts through ADCC and CDC to deplete CLDN18.2-positive cells. Cytotoxic drugs were shown to increase the expression of CLDN18.2 on human cancer cells and to improve ADCC and CDC activities induced by zolbetuximab.²¹

Recommended Dosage

Zolbetuximab is supplied in single-use vials containing zolbetuximab 100 mg as a lyophilized powder for concentrate for solution for IV infusion.²¹ The product monograph–recommended dosage consists of a single loading dose (800 mg/m² through IV) followed by a maintenance dosage of 600 mg/m² through IV once every 3 weeks or 400 mg/m² through IV once every 2 weeks. The recommended dose is administered by IV infusion over a minimum of 2 hours. As outlined in the product monograph, a slower rate is recommended at the start of each infusion to help minimize potential adverse reactions; in the absence of adverse reactions after 30 minutes to 60 minutes, the rate may be increased as tolerated.²¹ To align the administration schedule for zolbetuximab with the concomitant chemotherapy schedule, the product monograph recommends the 400 mg/m² every 2 weeks maintenance dosage when used in combination with mFOLFOX6 and the 600 mg/m² every 3 weeks maintenance dosage when used in combination with CAPOX.²¹

No dose reduction for zolbetuximab is recommended. Infusion rate reduction, interruption, and/or discontinuation is used for management of adverse reactions to zolbetuximab, as detailed in the product monograph.²¹ Patients should be monitored during and after infusion of zolbetuximab for signs and symptoms of hypersensitivity or IRRs.²¹ Premedication with antiemetics before each infusion of zolbetuximab is recommended for the prevention of nausea and vomiting; premedication may also be required for hypersensitivity or IRRs.²¹ Treatment with zolbetuximab should be initiated and supervised by a physician with experience in the use of ACTs.²¹

Proposed Place in Therapy

As shown in Figure 1, the sponsor is proposing that zolbetuximab be a preferred treatment option for the first-line treatment of patients with locally advanced unresectable or metastatic HER2-negative gastric or GEJ adenocarcinoma whose tumours are CLDN18.2-positive.

Figure 1: Sponsor’s Proposed Place in Therapy for Zolbetuximab

HER2 = human epidermal growth factor 2; pCPA = pan-Canadian Pharmaceutical Alliance; pt = platinum.

Note: The asterisk indicates that pembrolizumab is reimbursed only for patients with gastroesophageal junction cancer. (It is also indicated for esophageal cancer, but these patients are not included in this diagram.) It remains under review by Canada’s Drug Agency for the entire population of patients with HER2-negative gastric or gastroesophageal junction adenocarcinoma. Although technically funded, pembrolizumab is not currently used in patients with gastroesophageal junction adenocarcinoma.

Source: Sponsor’s submission.

Characteristics of Drugs for Gastric or GEJ Adenocarcinoma

The key characteristics of zolbetuximab are summarized in Table 3, along with those of other treatments available for gastric or GEJ adenocarcinoma.

Table 3: Key Characteristics of First-Line Treatments for Gastric or GEJ Adenocarcinoma

5-FU = 5-fluorouracil; ADCC = antibody-dependent cellular cytotoxicity; CAPECISP = capecitabine plus cisplatin; CAPOX = capecitabine plus oxaliplatin; CDA-AMC = Canada’s Drug Agency; CDC = complement-dependent cytotoxicity; CLDN18.2 = Claudin 18.2; FOLFOX = leucovorin calcium (folinic acid), fluorouracil, and oxaliplatin; FP = 5-fluorouracil and cisplatin; GEJ = gastroesophageal junction; HER2 = human epidermal growth factor receptor 2; PD-1 = programmed death protein 1; PD-L1 = programmed death-ligand 1; PD-L1 = programmed death-ligand 2; WBC = white blood cell.

^aHealth Canada–approved indication.

Source: Product monographs.

Perspectives of Patients, Clinicians, and Drug Programs

Patient Group Input

This section was prepared by CDA-AMC based on the input provided by patient groups. The full original patient group input received by CDA-AMC is available on the project webpage.

One patient group provided input for this review. My Gut Feeling – Stomach Cancer Foundation of Canada is a nonprofit organization providing support, awareness, education, information, and advocacy to patients with (and survivors of) stomach cancer and their caregivers. Individuals with gastroesophageal and esophageal cancer receive support and are included in service programs. The mission of this organization is to improve the quality of life for people affected by gastroesophageal cancers and to make systemic changes to reduce the incidence and mortality of gastroesophageal cancers.

From June 21 to July 2, 2024, My Gut Feeling – Stomach Cancer Foundation of Canada conducted an international online survey of patients and caregivers affected by gastric, esophageal, and/or gastroesophageal cancer. The survey was shared through the social media platforms and email distribution lists of My Gut Feeling and other organizations (e.g., the Gastrointestinal Society). A total of 35 respondents completed the survey, 14.3% of whom were caregivers and 85.7% of whom were patients. Of the participants, 17.1% were currently receiving treatment and 68.6% had completed treatment; 68.6% and 31.4% of respondents identified as female and male, respectively, and their ages at initial diagnosis ranged from 20 to 80 years. The majority of respondents resided in Canada (71.4%) or the US (25.7%); survey results were presented for the overall population surveyed. Most participants had gastric cancer (88.6%); the remainder had gastroesophageal cancer (11.4%). The stage at diagnosis ranged from I to IV; 71.4% of patients were reported to have adenocarcinoma, while 20% did not know the type of cancer they had. Regarding biomarker testing, 51% of participants confirmed having been tested; 8.6% reported being CLDN18.2-positive, 20% reported being HER2-negative, and 34.3% reported that the results were not shared with them.

Nearly all participants (97.2%) responded that their quality of life was significantly affected by the cancer diagnosis. Specifically, their physical and mental health, ability to eat, work, finances, social life, identity, and personal image were all impacted. For example, respondents expressed the exhaustion of managing adequate daily nutrition and the toll of experiencing weight loss or weight gain, including its impact on body image. Patients and caregivers (particularly those affected by metastatic disease) communicated that the cancer diagnosis and its treatment had negative impacts on their mental health and caused anxiety surrounding finances (e.g., loss of income due to work absenteeism, additional expenses due to travel for medical care and/or specialized diets). Patients reported feeling anxiety, depression, and/or anger, and said that experiencing fatigue greatly impacted their daily activities.

Regarding previously received and current treatments, patients reported receiving fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) (45.7%), chemotherapy consisting of either FOLFOX or leucovorin calcium (folinic acid), fluorouracil, and irinotecan hydrochloride (FOLFIRI) alone (8.6%), or combined chemotherapy and immunotherapy (8.6%). A combination of various treatments (e.g., 5-fluorouracil plus radiation, surgery, capecitabine, pembrolizumab) were received by the remainder of patients. Participants reported experiencing a wide range of side effects during treatment, with fatigue (91.4%) and weight loss (77.1%) being most frequently mentioned. Regarding the effectiveness of controlling cancer and symptoms, 62.9% and 31.5% of respondents felt that their treatment had been very effective or moderately effective, respectively, while the remainder of respondents (5.6%) felt there was little or no efficacy. None of the survey participants had experience with zolbetuximab.

Participants stated that many factors are considered when weighing treatment options (such as quality of life, survival benefits, side effects, convenience, and duration of therapy), recognizing that treatments have trade-offs that need to be considered. For example, most respondents (82.9%) would choose a treatment that prolongs life despite side effects. Patients also expressed a preference for the convenience of oral chemotherapy taken at home over IV chemotherapy administered in a hospital setting.

My Gut Feeling indicated that gastric and gastroesophageal cancers are rare in Canada, with few treatment options. The organization expressed an unmet need for equitable access to therapies that prolong life, improve symptoms, reduce the risk of recurrence, and have improved tolerability. My Gut Feeling strongly supports the use of zolbetuximab in combination with chemotherapy as first-line treatment for patients with locally advanced unresectable or metastatic HER2-negative gastric or GEJ adenocarcinoma whose tumours are CLDN18.2-positive. The organization also expressed the view that biomarker testing should be accessible at the onset of disease for all patients in Canada. This patient group believes that there should be a choice in treatment options that are available barrier-free and covered under the universal health care system in Canada for the benefit of these patients.

Clinician Input

Input From Clinical Experts Consulted by CDA-AMC

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

Unmet Needs

The clinical experts consulted for the purpose of this review emphasized that locally advanced and metastatic HER2-negative gastric or GEJ cancers are associated with considerable unmet needs. Treatment with nivolumab in combination with chemotherapy is the only available first-line option for locally advanced metastatic HER2-negative gastric or GEJ cancer; however, OS outcome remains poor (with a median OS of 13 months to 15 months).

Place in Therapy

The clinical experts suggested that the addition of zolbetuximab to chemotherapy would represent an alternative to combination therapy with nivolumab plus chemotherapy in the first-line metastatic treatment setting for patients with locally advanced and/or metastatic HER2-negative gastric or GEJ cancer whose tumours are CLDN18.2-positive.

Patient Population

Regulatory approval and reimbursement for nivolumab for patients with gastric or GEJ cancer is not limited based on a patient’s PD-L1 CPS; however, the clinical experts noted that there is some uncertainty in the clinical community regarding the effectiveness of nivolumab plus chemotherapy in patients with a PD-L1 CPS of less than 5. As such, the clinical experts noted that zolbetuximab plus chemotherapy could be a preferred option for patients with CLDN18.2-positive tumours and a PD-L1 CPS of less than 5. For patients with CLDN18.2-positive tumours and a PD-L1 CPS of at least 5, it is currently unclear which option could offer the best outcomes.

Assessing the Response Treatment

The clinical experts noted that the clinically meaningful end points across all oncology types are OS and quality of life, and that PFS has limited value when assessing clinical benefit for patients with metastatic disease and a relative short OS duration. The clinical experts noted that the following factors should be used to determine response to treatment: patient-reported symptoms and side effects and response on cross-sectional imaging with CT or MRI. The clinical experts suggested that patients should be assessed by a clinician after every 2 to 3 cycles of treatment. Clinician assessment may occur more frequently if a patient reports the occurrence of bothersome symptoms or side effects. The clinical experts suggested that patients should undergo CT scans every 2 to 3 months. Tumour markers can be used as per clinical judgment to supplement a fulsome patient assessment.

Discontinuing Treatment

The clinical experts suggested that the decision to discontinue treatment with zolbetuximab should be based on patient-reported symptoms, patient preference, side effects, and well-being, in combination with an assessment of treatment response and disease progression, either radiological or clinical.

Prescribing Considerations

The clinical experts suggested that zolbetuximab should be prescribed only by (or under the supervision of) a medical oncologist with expertise in the management of immunotherapy side effects. The clinical experts noted that immunotherapy and chemotherapy are currently delivered as standard of care in all oncology centres. Accordingly, these therapies, with the addition of zolbetuximab, can be safely administered in all centres approved for oncology care.

Clinician Group Input

This section was prepared by CDA-AMC based on the input provided by clinician groups. The full original clinician group input received by CDA-AMC is available on the project webpage.

Four clinicians from the OH-CCO GI DAC provided input for this review. These committees provide timely, evidence-based clinical and health system guidance on drug-related issues in support of Cancer Care Ontario’s mandate, including the Provincial Drug Reimbursement programs and the Systemic Treatment Program.

Regarding currently available treatments for metastatic HER2-negative gastric cancer, the clinician group stated that standard first-line therapy consists of chemotherapy (typically FOLFOX) combined with immunotherapy (nivolumab, which is currently funded, or pembrolizumab, which is approved but not funded). The goals of treatment are to prolong life, delay disease progression, and maintain quality of life. The OH-CCO GI DAC expressed that there are currently no approved treatments that specifically target tumours overexpressing CLDN18.2; therefore, there is an unmet need in this population. Clinical experts consulted by CDA-AMC also identified FOLFOX with or without nivolumab as a first-line therapy in this population, with the goals of therapy including to improve symptoms, delay progression, improve quality of life, and prolong survival. These experts identified an unmet need for treatments with other biological targets and for new treatments that will increase survival.

The OH-CCO GI DAC remarked that the patients best suited for treatment with zolbetuximab are those with HER2-negative, CLDN18.2-positive advanced gastric or GEJ cancer. This clinician group stated that zolbetuximab would provide an alternative to nivolumab, noting that zolbetuximab and nivolumab in the first-line setting have not been compared head-to-head. For patients with CLDN18.2 overexpression and a negative or low PD-L1 CPS, the clinician group suspects that zolbetuximab and chemotherapy would be the clear first-line choice of therapy, but acknowledges that the best first-line therapy (i.e., nivolumab, pembrolizumab or zolbetuximab) for patients with CLDN18.2 overexpression and a PD-L1 CPS of greater than 5 is unclear. For the latter population of patients, the choice of drug to add (i.e., zolbetuximab, nivolumab, or immunotherapy) would be at the physician’s discretion based on comorbidities and toxicity profile and with consideration for maintaining good quality of life. Clinical experts consulted by CDA-AMC also indicated that zolbetuximab would be offered to patients with HER2-negative, CLDN18.2-positive metastatic or locally advanced unresectable gastric or GEJ cancer One expert noted that treatment would be based on clinical decision-making by the treating physician for patients who are both HER2-positive and CLDN18.2-positive; another expert reported that the choice of FOLFOX plus zolbetuximab versus FOLFOX plus nivolumab would be unclear for patients with HER2-negative, CLDN18.2-positive disease and a PD-L1 CPS of 5 or greater.

The clinician group communicated that, upon approval of zolbetuximab, upfront CLDN18.2 testing will be required in all patients (in addition to HER2 and PD-L1 CPS testing, which are already mandated). The group noted that while the testing is inexpensive, assays will need to be developed and standardized.

The clinician group stated that, in clinical practice, CT scans are performed regularly at clinician discretion to determine response to treatment and that the decision to discontinue treatment with zolbetuximab would consider disease response, immune-related toxicities, and overall functional status. Similarly, disease progression and symptoms and adverse effects were identified as considerations for discontinuing treatment by clinical experts consulted by CDA-AMC. Patients treated with zolbetuximab should be under the care of a medical oncologist.

Drug Program Input

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

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

CDA-AMC = Canada’s Drug Agency; CLDN18.2 = Claudin 18.2; ECOG = Eastern Cooperative Oncology Group; GEJ = gastroesophageal junction; HER2 = human epidermal growth factor receptor 2.

Clinical Evidence

The objective of this clinical review report is to review and critically appraise the clinical evidence submitted by the sponsor on the beneficial and harmful effects of zolbetuximab in combination with fluoropyrimidine- and platinum-containing chemotherapy for the first-line treatment of patients with locally advanced unresectable or metastatic HER2-negative gastric or GEJ adenocarcinoma whose tumours are CLDN18.2-positive as determined by a validated test. The focus will be on comparing zolbetuximab to relevant comparators and identifying gaps in the current evidence.

A summary of the clinical evidence included by the sponsor in the review of zolbetuximab is presented in 4 sections, with 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 CDA-AMC 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 sponsor-submitted long-term extension studies (not submitted). The third section includes indirect evidence from the sponsor. The fourth section includes additional studies that were considered by the sponsor to address important gaps in the systematic review evidence (not submitted).

Included Studies

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

• two pivotal studies RCTs identified in systematic review (i.e., the SPOTLIGHT and GLOW trials)

• one ITC.

Systematic Review

Contents within this section are informed by materials submitted by the sponsor. The following have been summarized and validated by CDA-AMC.

Description of Studies

Key characteristics of the SPOTLIGHT and GLOW trials are summarized in Table 5.

The SPOTLIGHT and GLOW trials are both ongoing, multinational, double-blind, placebo-controlled, randomized studies of zolbetuximab in combination with fluoropyrimidine- and platinum-based chemotherapy compared with placebo in combination with fluoropyrimidine- and platinum-based chemotherapy for the first-line treatment of patients with locally advanced unresectable or metastatic HER2-negative gastric or GEJ adenocarcinoma whose tumours are CLDN18.2-positive. In both trials, patients were randomized 1:1 into zolbetuximab or placebo arms, with randomization stratified by region (Asia versus non-Asia), number of organs with metastatic sites (0 to 2 versus ≥ 3), and prior gastrectomy (yes or no). The chemotherapy backbone used in the SPOTLIGHT trial was mFOLFOX6, while the backbone used in the GLOW trial was CAPOX.^24,25 Notably, the SPOTLIGHT trial enrolled more patients from Japan and South Korea, whereas the GLOW trial enrolled more patients from mainland China, whose disease course tends to be more similar to that of patients from western countries, with a lower OS than patients from Japan.^10,39,41

Table 5: Details of Studies Included in the Systematic Review

5-FU = 5-fluorouracil; AE = adverse event; b.i.d. = twice daily; CAPOX = capecitabine and oxaliplatin; CLDN18.2 = Claudin 18.2; CR = complete response; DCR = disease control rate; DOR = duration of response; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EORTC GHS/QoL = European Organisation for Research and Treatment of Cancer Global Health Status/Quality of Life; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; EORTC QLQ-OG25 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Oesophago-Gastric 25; GEJ = gastroesophageal junction; GP = Global Pain; HER2 = human epidermal growth factor receptor 2; HRQoL = health-related quality of life; IHC = immunohistochemistry; IRC = independent review committee; mFOLFOX6 = modified 5-fluorouracil, folinic acid, and oxaliplatin; ORR = objective response rate; OS = overall survival; PD = progressive disease; PFS = progression-free survival; PFS2 = progression-free survival following second-line anticancer treatment; PR = partial response; q.2.w. = every 2 weeks; q.3.w. = every 3 weeks; RCT = randomized controlled trial; RECIST 1.1 = Response Evaluation Criteria in Solid Tumours Version 1.1; SAE = serious adverse event; STO22 = EORTC Quality of Life Questionnaire - Gastric Cancer Module; TTCD = time to confirmed deterioration; TTP = time to progression.

Sources: SPOTLIGHT trial Primary Analysis Clinical Study Report (2023);²⁴ GLOW trial Primary Analysis Clinical Study Report (2023).²⁵

The primary objective in both the SPOTLIGHT and GLOW trials was to assess the PFS benefit of zolbetuximab plus chemotherapy compared to placebo plus chemotherapy. Key secondary objectives were to evaluate OS and TTCD using the EORTC GHS/QoL scale, the EORTC QLQ-OG25 scale, and EORTC QLQ-C30 PF. Additional secondary objectives were to evaluate ORR, DOR, safety, tolerability, and additional patient-reported outcomes.

Each study consisted of the following periods: screening, treatment, safety follow-up, posttreatment follow-up for PFS, long-term follow-up for PFS2, and survival follow-up for OS. During the screening period, formalin-fixed, paraffin-embedded tumour tissue was collected for central testing to determine CLDN18.2 and HER2 status. Confirmation of CLDN18.2 status was to be obtained before patients proceeded to any other screening procedures. If the specimen was insufficient or unavailable, a biopsy may have been performed to obtain a tumour sample. Patients who were screened out could be rescreened 1 time after consultation with the medical monitor. In these cases, a new patient number was assigned, and patients had to reconsent to the study and all screening procedures (with the exception CLDN18.2 and HER2 testing and radiological imaging procedure to confirm eligibility, if the scan was within 28 days before the first dose of study treatment).

Figure 2: SPOTLIGHT Study Schema

5FU = 5-fluorouracil; CLDN18.2 = Claudin 18.2; GEJ = gastroesophageal junction; HER2 = human epidermal growth factor receptor 2; IRC = independent review committee; mFOLFOX6 = modified 5-fluorouracil, folinic acid, and oxaliplatin; PFS = progression-free survival; RECIST 1.1 = Response Evaluation Criteria in Solid Tumours Version 1.1.

Note: Sample size in the figure (n = 550) represents the planned total. In the SPOTLIGHT trial, 565 patients were randomized 1:1 to arm A (n = 283) and arm B (n = 282).

Source: SPOTLIGHT trial Primary Analysis Clinical Study Report (2023).²⁴

The recruitment period for the SPOTLIGHT trial was from October 29, 2018 (first patient randomized) to April 1, 2022 (last patient randomized). The data cut-off for the primary analysis of PFS and interim analysis of OS occurred on September 9, 2022.²⁴ The data cut-off for the final analysis of OS occurred on September 8, 2023.⁴² The recruitment period for the GLOW trial was from January 21, 2019 (first patient randomized), to February 18, 2022 (last patient randomized). The data cut-off for the primary analysis of PFS and interim analysis of OS occurred on October 7, 2022.²⁵ The data cut-off for the final analysis of OS occurred on January 12, 2024.

Figure 3: GLOW Study Schema

CAPOX = capecitabine and oxaliplatin; CLDN18.2 = Claudin 18.2; GEJ = gastroesophageal junction; HER2 = human epidermal growth factor receptor 2; IRC = independent review committee; OS = overall survival; PFS = progression-free survival; PFS2 = progression-free survival following subsequent anticancer treatment; RECIST 1.1 = Response Evaluation Criteria in Solid Tumours Version 1.1.

Note: Sample size in the figure (n = 500) represents the planned total. In the GLOW trial, 507 patients were randomized 1:1 to arm A (n = 254) and arm B (n = 253).

Source: GLOW trial Primary Analysis Clinical Study Report (2023).²⁵

Populations

Inclusion and Exclusion Criteria

Key inclusion criteria were aligned in the SPOTLIGHT and GLOW trials. Eligible patients were aged 18 years or older with CLDN18.2-positive (defined as ≥ 75% of tumour cells showing moderate to strong membranous CLDN18.2 staining, as determined by central IHC using the investigational VENTANA CLDN18 [43-14A] RxDx Assay [Roche Diagnostic Solutions; Tucson, AZ, US]), HER2-negative (based on local or central evaluation), previously untreated, locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma with radiologically evaluable disease (measurable or nonmeasurable) according to Response Evaluation Criteria in Solid Tumours Version 1.1 (RECIST 1.1); patients were also required to have an ECOG Performance Status score of 0 or 1 and adequate organ function.^24,25,39 Differences in the exclusion criteria between the SPOTLIGHT and GLOW trials included treatment with herbal medications that had known antitumour activity less than or equal to 28 days before randomization (excluded in the GLOW trial only), as well as prior severe allergic reaction or intolerance to any component of mFOLFOX6 (SPOTLIGHT trial only) or CAPOX (GLOW trial only).^24,25

Interventions

In the SPOTLIGHT and GLOW trials, 565 patients and 507 patients, respectively, were randomized in a 1:1 ratio to 2 treatment arms, with dosing and administration summarized in Table 6. In real-world practice, zolbetuximab and all chemotherapy components, with the exception of capecitabine, are administered in an outpatient hospital setting or infusion centre. Capecitabine is administered at home or in a community setting. Both of the chemotherapy backbones used in the SPOTLIGHT and GLOW trials (mFOLFOX6 and CAPOX, respectively) are used in Canada as part of routine clinical practice.

Prophylactic Medications Used in the SPOTLIGHT and GLOW Trials

Prophylactic antiemetics were given to patients before administration of the chemotherapy backbones in accordance with institutional standard of care, published guidelines, and the respective product package insert(s):^43,44

• All antiemetic premedications were to be given at minimum 30 minutes before treatment.

• On days when zolbetuximab or placebo and the chemotherapy backbone were administered together, the antiemetic premedication was to be given before zolbetuximab or placebo administration.

• It was recommended that the prophylactic antiemetic regimen include (but not be limited to) neurokinin-1 and 5-hydroxytryptamine type 3 receptor blockers.

Table 6: Treatment Groups and Dosing Regimens in the SPOTLIGHT and GLOW Trials

5-FU = 5-fluorouracil; b.i.d. = twice daily; C1D1 = cycle 1, day 1; CAPOX = capecitabine oxaliplatin; mFOLFOX6 = modified 5-fluorouracil, folinic acid, and oxaliplatin; q.2.w. = once every 2 weeks; q.3.w. = every 3 weeks.

Sources: SPOTLIGHT trial and GLOW trial Clinical Study Reports.^24,25

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

AE = adverse event; DCR = disease control rate; DOR = duration of response; EORTC GHS/QoL = European Organisation for Research and Treatment of Cancer Global Health Status/Quality of Life; EORTC QLQ-C30 PF = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Physical Functioning; EORTC QLQ-OG25 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Oesophago-Gastric 25; EORTC QLQ-STO22 = EORTC Quality of Life Questionnaire - Gastric Cancer Module; HRQoL = health-related quality of life; HRU = health resource utilization; IRC = independent review committee; NA = not applicable; ORR = objective response rate; OS = overall survival; PD = progressive disease; PFS = progression-free survival; PFS2 = second progression-free survival; PF = Physical Functioning; RECIST 1.1 = Response Evaluation in Solid Tumours Version 1.1; TTCD = time to first clinically meaningful deterioration; TTP = time to progression.

^aStatistical testing for these end points was adjusted for multiple comparisons using a gatekeeping testing strategy to address multiplicity.

Sources: SPOTLIGHT trial and GLOW trial Clinical Study Protocols.^43,44

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, according to the clinical experts consulted during this review and input from patient and clinician groups and public drug plans. Using the same considerations, the review team selected end points that were 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.

Progression-Free Survival

PFS was the primary end point of both the SPOTLIGHT and GLOW trials and was assessed by the blind IRC. PFS was defined as the time from randomization until the date of radiological disease progression assessed by IRC, or until death due to any cause, whichever was earlier. If a patient had neither progressed nor died, they were censored at the date of last radiological assessment. Patients who received new anticancer therapy before radiological progression were censored at the date of the last radiological assessment before the new anticancer therapy started. If progression or death occurred after a patient missed 2 or more scheduled radiological assessments, the patient was censored at the date of the last radiological assessment or at the date of randomization, if no postbaseline radiological assessment was available.^43,44

Overall Survival

OS was a key secondary end point in both the SPOTLIGHT and GLOW trials. It was defined as the time from the date of randomization until the documented date of death from any cause. Patients still alive at the time of the analysis were censored at the last date known to be alive.^43,44

Objective Response Rate

Best overall response (BOR) was classified based on RECIST 1.1 criteria. For BOR of stable disease, stable disease had to be documented as present at least once after study entry and at least 8 weeks after the first dose. ORR was defined as the proportion of patients with a BOR of complete or partial response based on IRC per RECIST 1.1.^43,44

Duration of Response

DOR was defined as the time from first complete or partial response (whichever was first recorded) as assessed by IRC to the date of radiological progression or death, whichever was earlier. If a patient had not progressed, the patient was censored at the date of the last radiological assessment or at the date of first complete or partial response if no postbaseline radiological assessment was available. Other censoring used for the PFS analysis applied to DOR as well. The distribution of DOR was estimated for each treatment arm using Kaplan-Meier methodology and compared using the log-rank test stratified by the same factors used for PFS. A stratified Cox proportional hazard model was used to estimate the HR and corresponding 95% CI.^43,44

Time to Confirmed Deterioration

TTCD was defined as the duration of time from the date of randomization to the date of the first deterioration in patient-reported outcome scores of at least 1 threshold unit compared to the baseline score, if the deterioration (of at least 1 threshold unit compared to the baseline score) is also observed at the next consecutive scheduled visit (e.g., after the first deterioration was observed) or if the patient dropped out or died after deterioration, resulting in missing data.^43,45 Given the absence of reliable and well-accepted thresholds for within-patient clinically meaningful change, the clinically meaningful threshold denoting a deterioration was defined based on anchor-based analyses performed on the same trial data.

Health-Related Quality of Life

HRQoL end points were summarized using descriptive statistics with respect to change from baseline for each treatment arm. Completion rate for each questionnaire was summarized by time point.^43,44

Time to Progression

TTP is defined as the time from the date of randomization until the date of progressive disease (PD) (per RECIST 1.1, as determined by IRC). TTP did not include deaths as events. For deaths before the first documented PD by IRC, patients were censored at the time of their last radiological assessment. Kaplan-Meier and log-rank methods were applied to TTP end point.^43,44

Progression-Free Survival Following Second-Line Anticancer Treatment (PFS2)

PFS2 is defined as the time from the date of randomization until the date of PD (per investigator) following subsequent anticancer therapy, death from any cause, or start of any other anticancer therapy, whichever is earliest. In cases where PFS2 could not reliably be determined, discontinuation of subsequent ACT could be used as the event date. Patients who were alive and for whom a PFS2 event date had not been observed were to be censored at the last time known to be alive and without second objective disease progression.^43,44

Disease Control Rate

DCR was defined as the proportion of patients with a BOR of complete response, partial response, or stable disease, based on RECIST 1.1 by IRC.^43,44

Adverse Events

An AE was defined as any untoward medical occurrence. It did not necessarily have to have a causal relationship with the study treatment. SAEs were considered events that the investigator or sponsor concluded resulted in death; life-threatening events; persistent or significant disability or incapacity; substantial disruption of the ability to conduct normal life functions; congenital anomaly; or inpatient hospitalization. AEs of special interest included nausea, vomiting, and hypersensitivity or IRRs.^43,44

Statistical Analysis

Sample size and power calculation: In the SPOTLIGHT trial, the sponsor planned to randomize approximately 550 patients 1:1 to zolbetuximab plus mFOLFOX6 or placebo plus mFOLFOX6. Three hundred PFS events during the study would provide 93.4% power to detect a difference in PFS between the treatment groups, with the assumption of 9 months’ median PFS time for zolbetuximab and 6 months median PFS time for placebo (HR = 0.67) at the 1-sided 0.025 significance level. The planned 396 OS events during the study would provide 81% power to detect a difference in OS between the treatment groups, with the assumption of 14.7 months’ median survival time with zolbetuximab and 11 months’ median survival time (HR = 0.75) with placebo at the 1-sided 0.025 significance level.²⁴

In the GLOW trial, the sponsor planned to randomize approximately 500 patients 1:1 to receive zolbetuximab plus CAPOX or placebo plus CAPOX. Three hundred PFS events during the study would provide 93.4% power to detect a difference in PFS between the treatment groups, with assumptions of 9 months’ and 6 months’ median PFS in the zolbetuximab and placebo groups, respectively (HR = 0.67) at the overall 1-sided 0.025 significance level. The planned 386 OS events during the study would provide 80% power to detect a difference in OS between the treatment groups, with the assumption of 14.7 months’ and 11 months’ median OS in the zolbetuximab and placebo groups, respectively (HR = 0.75) at the overall 1-sided 0.025 significance level.²⁵

Data imputation methods: Missing variable values were not imputed in the SPOTLIGHT and GLOW trials.

Subgroup analyses: For both the SPOTLIGHT and GLOW trials, PFS, ORR, and DOR — based on IRC assessments — and OS were summarized for the following subgroups:^45,46 age group 1 (≤ 65 years versus > 65 years); age group 2 (≤ 75 years versus > 75 years); sex (male versus female); race (white versus Asian); tobacco history (never, current, or former); region (Asia versus non-Asia); number of organs with metastatic sites (0 to 2 versus greater than or equal to 3); prior gastrectomy (no versus yes [total or partial]); histology (tumour type) (diffuse versus intestinal versus mixed or other); tumour location (gastric versus GEJ; gastric proximal versus gastric distal; GEJ proximal versus GEJ distal); country (Japan versus non-Japan; China versus non-China). These subgroup analyses were not controlled for multiplciticity.^45,46

Sensitivity analyses: Sensitivity analyses performed in the SPOTLIGHT and GLOW trials and summarized in Table 8.

Statistical Testing

Primary End Point

The primary analysis of PFS used radiological assessment of PD by the IRC and performed using the full analysis set (FAS). The comparisons of zolbetuximab and placebo were tested at a 1-sided significance level of 0.025.^45,46 The distribution and median of PFS were estimated using Kaplan-Meier methodology. PFS rates at 6 months, 12 months, and 18 months were also presented. In addition, numbers of patients who had PFS events and were censored — and 95% CIs for median PFS and PFS rates — were presented.^45,46 Hypotheses testing for zolbetuximab versus placebo was performed using log-rank test stratified by region (Asia versus non-Asia); number of organs with metastatic sites (0 to 2 versus ≥ 3); and prior gastrectomy (yes versus no).

A stratified Cox proportional hazards model was used to estimate the HR and corresponding 95% CI. Evaluable radiological assessments included all except those assessed by IRC as not evaluable.^45,46

Secondary End Points

To maintain the overall type I error rate at the 0.025 significance level, the hypothesis testing for OS interim and OS final analyses was performed only if the null hypothesis in PFS primary analysis was rejected at the overall 1-sided 0.025 significance level.^45,46

The formal OS interim analysis was planned when the final PFS analysis occurred with the prespecified number of PFS events. A group sequential design using the O’Brien-Fleming–type alpha-spending function was utilized to control the overall 1-sided 0.025 significance level for the OS analysis. In the case of favourable results, the 1-sided significance levels for superiority were 0.0074 for the interim OS analysis and 0.0228 for the final OS analysis. These alpha boundaries were based on an information factor of 70% and were subject to adjustment if the observed information factor deviated from 70%. If the 1-sided P value of the interim analysis was less than 0.0074, the Independent Data Monitoring Committee (IDMC) could recommend terminating the trial for success without the need to conduct the final OS analysis. If the study was not stopped after the interim analysis, the final OS analysis was planned to occur after 100% of the planned number of deaths had been observed.^45,46

The distribution and median of OS, as well as OS rates at 12 months, 18 months, 24 months, 30 months, and 36 months, were estimated for each treatment arm using Kaplan-Meier methodology. The 95% CIs for median OS and milestone OS rates were presented. Zolbetuximab and placebo were compared using the log-rank test stratified by the same stratification factors used for the PFS analysis.^45,46 A stratified Cox proportional hazard model was used to estimate the HR and corresponding 95% CI.^45,46

The median of time on study using reverse Kaplan-Meier approach and range were provided. Patients who were alive up to the cut-off date were considered as events, and deaths of patients on or before the data cut-off date were censored in the reverse Kaplan-Meier approach for the estimation of median of time on study.^45,46

The key secondary TTCD end points of the EORTC QLQ-C30 PF scale, EORTC QLQ-OG25 Pain scale, and EORTC GHS/QoL scale scores were analyzed using the same method as for OS and PFS. To maintain the overall type I error rate at the 0.025 significance level, the hypothesis testing of TTCD end points was to be performed only if the null hypothesis on the OS was rejected at the 1-sided 0.025 significance level.^24,25 If the null hypothesis on the OS was rejected at the overall 1-sided 0.025 significance level, then TTCD would be tested using the gatekeeping procedure, using the following order:

• noninferiority testing for TTCD in EORTC QLQ-C30 PF scale at the 0.025 significance level

• noninferiority testing for TTCD in the EORTC QLQ-OG25 Pain scale at the 0.025 significance level

• noninferiority testing for TTCD in the EORTC GHS/QoL scale at the 0.025 significance level

• superiority testing for TTCD in the EORTC QLQ-C30 PF scale at the 0.025 significance level

• superiority testing for TTCD in the EORTC QLQ-OG25 Pain scale at the 0.025 significance level

• superiority testing for TTCD in the EORTC GHS/QoL scale at the 0.025 significance level.

The secondary HRQoL end points collected through the EORTC QLQ Core 30, EORTC QLQ-OG25, Global Pain, and EQ-5D-5L were analyzed with summary of change from baseline.^24,25

Exploratory End Points

TTP and PFS2 were analyzed in a similar manner to PFS; however, in the TTP analysis, deaths were censored instead of being counted as events. DCR was analyzed similarly to ORR. The health resource utilization variables were summarized by treatment arm.

Multiple Testing Procedure

To address multiplicity, a gatekeeping testing strategy was used for PFS (the primary efficacy end point) and OS (the key secondary end point). PFS was tested once at a 1-sided significance level of 0.025. Only if PFS was significant, hypothesis testing for the OS interim and final analyses was performed. An O’Brien-Fleming–type alpha-spending function was utilized to control the overall 1-sided 0.025 significance level for the OS interim and final analyses.⁴⁷ Other secondary end points’ tests results were not multiplicity adjusted.^45,46

Analysis Populations

Analysis populations, including the FAS, safety analysis set (SAF), pharmacokinetic analysis set, and per-protocol analysis set, were defined the same way in the SPOTLIGHT and GLOW trials, as summarized in Table 9.^24,25

Table 8: Statistical Analysis of Efficacy End Points in the SPOTLIGHT and GLOW Trials

ACT = anticancer treatment; BOR = best overall response; CI = confidence interval; DOR = duration of response; EORTC GHS/QoL = European Organisation for Research and Treatment of Cancer Global Health Status/Quality of Life; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; EORTC QLQ-C30 PF = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 Physical Functioning; EORTC QLQ-OG25 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Oesophago-Gastric 25; GP = Global Pain; HR = hazard ratio; HRQoL = health-related quality of life; HRU = health resource utilization; KM = Kaplan-Meier; NE = not evaluable; ORR = objective response rate; OS = overall survival; PD = progressive disease; PFS = progression-free survival; PFS2 = progression-free survival following second-line anticancer treatment; PRO = patient-reported outcome; SD = stable disease; TTCD = time to first clinically meaningful deterioration; TTP = time to progression; vs. = versus.

Sources: SPOTLIGHT trial and GLOW trial Statistical Analysis Plans.^45,46

Table 9: Analysis Populations in the SPOTLIGHT and GLOW Trials

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

Sources: SPOTLIGHT trial and GLOW trial Primary Analysis Clinical Study Reports.^24,25

Results

Patient Disposition

In the SPOTLIGHT trial, of the 2,767 patients (including rescreened patients), 2,403 unique patients had valid CLDN18.2 IHC results, and 38.4% (n = 922) of screened patients had tumours that were CLDN18.2-positive (defined as ≥ 75% of tumour cells demonstrating moderate to strong membranous CLDN18.2 staining).²⁴ In total, 2,735 patients were screened, and 565 patients were randomized to receive either zolbetuximab plus mFOLFOX6 (n = 283) or placebo plus mFOLFOX6 (n = 282). (Of the 922 patients with a positive CLDN18.2 result, 357 patients failed screening for other reasons, including withdrawal by patient, laboratory findings, HER2-expression status, and ECOG Performance Status).³⁹

In the GLOW trial, of the 2,333 patients screened, 2,104 unique patients had valid CLDN18.2 IHC results, and 38.4% of patients (n = 808) had tumours that were CLDN18.2-positive (defined as ≥ 75% of tumour cells demonstrating moderate to strong membranous CLDN18.2 staining).²⁵ In total, 507 patients were randomized to receive either zolbetuximab plus CAPOX (n = 254) or placebo plus CAPOX (n = 253). The recruitment period was from January 21, 2019 (first patient randomized) to February 18, 2022 (last patient randomized).

Table 10: Summary of Patient Disposition in the SPOTLIGHT and GLOW Trials

CAPOX = capecitabine plus oxaliplatin; CLDN18.2 = Claudin 18.2; FAS = full analysis set; mFOLFOX6 = modified 5-fluorouracil, folinic acid, and oxaliplatin; SAF = safety analysis set.

Source: Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Baseline Characteristics

The baseline characteristics outlined in Table 11 are limited to those that are most relevant to this review or were believed to affect the outcomes or interpretation of the study results.

Table 11: Summary of Baseline Characteristics in the SPOTLIGHT and GLOW Trials

BMI = body mass index; BSA = body surface area; CAPOX = capecitabine plus oxaliplatin; CLDN18.2 = Claudin 18.2; ECOG = Eastern Cooperative Oncology Group; FAS = full analysis set; GEJ = gastroesophageal junction; HER2 = human epidermal growth factor receptor 2; mFOLFOX6 = modified 5-fluorouracil, folinic acid, and oxaliplatin; SD = standard deviation.

Note: Data cut-offs were on September 9, 2022 (SPOTLIGHT trial) and October 7, 2022 (GLOW trial).

^aDistant metastases (M1) and tumour metastatic (Y) may differ depending on date of initial diagnosis.

^bOther metastasis locations (reported in < 5% of patients) were omentum (3.9%), retroperitoneum (2.8%), adrenal gland (2.3%), esophagus (1.2%), mediastinum (1.2%), stomach (1.8%), pleura (1.6%), pancreas (1.1%), chest (0.9%), colon (0.9%), pelvis (0.9%), spleen (0.9%), heart (0.5%), rectum (0.5%), kidney (0.4%), bladder (0.2%), brain (0.2%), breast (0.2%), gallbladder (0.2%), neck (0.2%), pericardium (0.2%), skin (0.2%), and/or other (7.1%).

Sources: SPOTLIGHT trial and GLOW trial Clinical Study Reports.^24,25

Exposure to Study Treatments

In the SPOTLIGHT trial, the mean duration of treatment with zolbetuximab was 260.6 days in the zolbetuximab plus mFOLFOX6 arm (SAF). The majority of patients had cumulative zolbetuximab exposure of more than 6 weeks (239 patients [85.7%]) or more than 12 weeks (206 patients [73.8%]). Exposure to chemotherapy was similar between the 2 arms. All patients received mFOLFOX6. In the SAF, the mean duration of treatment with the components of mFOLFOX6 was similar between the arms.²⁴ In the GLOW trial, the mean duration of treatment with zolbetuximab was 194.8 days. A total of 170 patients (66.9%) had cumulative zolbetuximab exposure of more than 12 weeks. All patients in the SAF received CAPOX. The mean durations of treatment with the components of CAPOX were similar between the treatment groups.²⁵

Patient exposure to study treatment in the SPOTLIGHT and GLOW trials is summarized in Table 12.

Table 12: Summary of Patient Exposure in the SPOTLIGHT and GLOW Trials

CAPOX = capecitabine plus oxaliplatin; mFOLFOX6 = modified 5-fluorouracil, folinic acid, and oxaliplatin; NA = not applicable; SD = standard deviation.

Source: Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Prior Medications

In the SPOTLIGHT trial, 119 patients (21.1%) had received prior chemotherapy. The mean duration of medication was 5.33 months. Prior radiation therapy was received by 41 patients (7.3%). Of the randomized patients, 245 patients (43.4%) had undergone prior procedures for primary cancer.²⁴ In the GLOW trial, 93 patients (18.3%) had received prior chemotherapy. The mean duration of medication was 5.5 months. Prior radiation therapy had been received by 20 patients (3.9%). A total of 182 patients (35.9%) had undergone prior procedures for primary cancer.²⁵

Concomitant Medications

In both the SPOTLIGHT and GLOW trials, the frequency of concomitant medication use was similar across treatment groups (Table 14).^24,25

Table 13: Prior Cancer Therapy (FAS)

CAPOX = capecitabine plus oxaliplatin; FAS = full analysis set; mFOLFOX6 = modified 5-fluorouracil, folinic acid, and oxaliplatin; S1 = oral 5-fluorouracil (5-FU) anticancer agent.

Note: Data cut-offs were September 9, 2022 (SPOTLIGHT trial) and October 7, 2022 (GLOW trial).

Sources: SPOTLIGHT trial Primary Analysis Clinical Study Report;²⁵ GLOW trial Primary Analysis Clinical Study Report.²⁵

Table 14: Concomitant Medications Used by at Least 20% of Patients in Any Group of Either Study (FAS)

5-HT3 = 5-hydroxytryptamine type 3; ATC = anatomical therapeutic chemical; CAPOX = capecitabine plus oxaliplatin; FAS = full analysis set; mFOLFOX6 = modified 5-fluorouracil, folinic acid, and oxaliplatin.

Note: Data cut-offs were on September 9, 2022 (SPOTLIGHT trial) and October 7, 2022 (GLOW trial).

Sources: SPOTLIGHT trial Primary Analysis Clinical Study Report;²⁵ GLOW trial Primary Analysis Clinical Study Report.²⁵

Subsequent Treatment: New ACTs

In the SPOTLIGHT trial, a total of 135 patients (47.7%) in the zolbetuximab plus mFOLFOX6 arm and 148 patients (52.5%) in the placebo plus mFOLFOX6 arm received a new ACT after discontinuation of study treatment. The most frequently received new ACTs (at least 10% of patients) in both arms were (shown by preferred WHO name) paclitaxel (17.0% of patients in the zolbetuximab plus mFOLFOX6 arm and 19.5% of patients in the placebo plus mFOLFOX6 arm) and ramucirumab (12.4% of patients in the zolbetuximab plus mFOLFOX6 arm and 12.1% of patients in the placebo plus mFOLFOX6 arm).²⁴

In the GLOW trial, a total of 118 patients (46.5%) in the zolbetuximab plus CAPOX arm and 140 patients (55.3%) in the placebo plus CAPOX arm received a new systemic anticancer therapy. The most frequently received (i.e., by at least 10% of patients in either arm) new ACTs in both arms were (shown by preferred WHO name) paclitaxel (18.1% of patients in the zolbetuximab plus CAPOX arm and 20.2% of patients in the placebo plus CAPOX arm) and ramucirumab (8.3% of patients in the zolbetuximab plus CAPOX arm and 11.1% of patients in the placebo plus CAPOX arm).²⁵

Efficacy

Table 15 summarizes the efficacy end points from the SPOTLIGHT and GLOW trials.

Overall Survival

In the SPOTLIGHT trial final analysis of OS (September 8, 2023, data cut-off), treatment with zolbetuximab plus mFOLFOX6 demonstrated a statistically significant improvement compared with placebo plus mFOLFOX6 (P = 0.0075). The HR was 0.78 (95% CI, 0.64 to 0.95), and the median OS was 18.2 months (95% CI, 16.1 months to 20.6 months) in the zolbetuximab plus mFOLFOX6 arm and 15.6 months (95% CI, 13.7 months to 16.9 months) in the placebo plus mFOLFOX6 arm. In the GLOW trial, the final analysis of OS (January 12, 2024, data cut-off) demonstrated that treatment with zolbetuximab plus CAPOX was associated with a statistically significant improvement in OS compared with placebo plus CAPOX (P = 0.0047). The HR was 0.763 (95% CI, 0.622 to 0.936).

Kaplan-Meier plots of OS for the SPOTLIGHT and GLOW trials are provided in Figure 4 and Figure 5, respectively.

Table 15: Summary of Key Efficacy Results in the SPOTLIGHT and GLOW Trials

CAPOX = capecitabine plus oxaliplatin; CI = confidence interval; CR = complete response; DCR = disease control rate; DOR = duration of response; EORTC QLQ-C30 PF = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 Physical Functioning; EORTC GHS/QoL = European Organisation for Research and Treatment of Cancer Global Health Status/Quality of Life; EORTC QLQ-OG25 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Oesophago-Gastric 25; HR = hazard ratio; IRC = independent review committee; mFOFLOX6 = modified 5-fluorouracil, folinic acid, and oxaliplatin; NE = not evaluable; NR = not reported; NYR = not yet reached; ORR = objective response rate; OS = overall survival; PD = partial disease; PFS = progression-free survival; PR = partial response; RECIST 1.1 = Response Evaluation Criteria in Solid Tumours Version 1.1; TTCD = time to confirmed deterioration.

^aBased on a Cox proportional hazards model with treatment, region, number of organs with metastatic sites, and prior gastrectomy as the explanatory variables. Assuming proportional hazards, an HR < 1 indicates a reduction in the rate in favour of the treatment arm.

^bBased on Kaplan-Meier estimate.

^cBased on 1-sided log-rank test; P values for the TTCD end points are not suitable to support inference because the test for noninferiority failed for these end points.

^dRate and 95% CI were estimated using the Kaplan-Meier method and Greenwood formula.

^eBased on stratified Cox proportional hazard model with region, number of organs with metastatic sites, and prior gastrectomy as the explanatory variables. Assuming proportional hazards, an HR < 1 indicates a reduction in the hazard rate in favour of the treatment arm.

^fThe definition of best overall response followed RECIST 1.1. When stable disease (or non-CR/non-PD) is believed to be best response, the assessment should be at least 8 weeks after randomization. For calculation of percentages, the denominator includes the total number of patients in each arm.

^gNo postbaseline imaging assessment.

^hBased on a 1-sided Cochran-Mantel-Haenszel test. Stratification factors were region, number of organs with metastatic sites, and prior gastrectomy.

ⁱDCR was defined as the proportion of patients who have a best overall response of CR, PR, stable disease, or non-CR or non-PD (≥ 8 weeks).

^jStratification factors were region, number of organs with metastatic sites, and prior gastrectomy from interactive response technology.

^kP value adjusted for multiplicity.

^lP value not adjusted for multiplicity.

Sources: SPOTLIGHT trial and GLOW trial Primary Analysis Clinical Study Reports;^24,25 final OS analysis for the SPOTLIGHT trial from Shitara et al. (2024);⁴⁰ SPOTLIGHT trial Final Analysis Clinical Study Report;⁴² final OS analysis for the GLOW trial.

Progression-Free Survival

In the SPOTLIGHT trial, treatment with zolbetuximab plus mFOLFOX6 showed a statistically significant improvement in PFS compared with placebo plus mFOLFOX6 (HR = 0.75; 95% CI, 0.598 to 0.942; 1-sided P = 0.0066). In the zolbetuximab plus mFOLFOX6 group, 146 patients (51.6%) had either progressed or died by the cut-off date, with a median PFS of 10.61 months (95% CI, 8.90 months to 12.48 months). In the placebo plus mFOLFOX6 group, 167 patients (59.2%) had disease progression or died, with a median PFS duration of 8.67 months (95% CI, 8.21 months to 10.28 months). The PFS rates at 12 months were 48.9% and 35.0% in the zolbetuximab plus mFOLFOX6 group and placebo plus mFOLFOX6 group, respectively. Median follow-up times were similar, with 12.94 months (95% CI, 11.63 months to 15.28 months) in the zolbetuximab plus mFOLFOX6 arm and 12.65 months (95% CI, 10.71 months to 15.24 months) in the placebo plus mFOLFOX6 arm.²⁴

Figure 4: Kaplan-Meier Plot of OS in the SPOTLIGHT trial (FAS; Final Analysis)

CI = confidence interval; FAS = full analysis set; HR = hazard ratio; OS = overall survival.

Source: SPOTLIGHT trial Clinical Study Report.⁴⁸

In the GLOW trial, treatment with zolbetuximab plus CAPOX demonstrated a statistically significant improvement in PFS compared with placebo plus CAPOX (HR = 0.687; 95% CI, 0.544 to 0.866; 1-sided P = 0.0007). In the zolbetuximab plus CAPOX group, 137 patients (53.9%) had disease progression or died, with a median PFS of 8.21 (95% CI, 7.46 to 8.84) months. In the arm receiving placebo plus CAPOX, 172 patients (68.0%) had either progressed or died, with a median PFS of 6.80 months (95% CI, 6.14 months to 8.08 months). The PFS rates at 12 months were 34.86% (95% CI, 27.75% to 42.05%) and 19.13% (95% CI, 13.50% to 25.51%) in the zolbetuximab and placebo groups, respectively. The median follow-up times were 12.62 months (95% CI, 10.32 months to 15.21 months) in the zolbetuximab plus CAPOX arm and 12.09 months (95% CI, 10.25 months to 15.05 months) in the placebo plus CAPOX arm.²⁵ Kaplan-Meier plots of PFS for the SPOTLIGHT and GLOW trials are provided in Figure 6 and Figure 7, respectively.

Figure 5: Kaplan-Meier Plot of OS in the GLOW trial (FAS; Final Analysis)

CI = confidence interval; FAS = full analysis set; HR = hazard ratio; OS = overall survival.

Source: GLOW trial Clinical Study Report.⁴⁹

Objective Response Rate

In both the SPOTLIGHT and GLOW trials, there was no statistically significant difference between the zolbetuximab plus mFOLFOX6 (or CAPOX) group and the placebo plus mFOLFOX6 (or CAPOX group). In the SPOTLIGHT trial, 135 patients (47.7%) in the zolbetuximab plus mFOLFOX6 group and 134 patients (47.5%) in the placebo plus mFOLFOX6 group had an objective response. In the zolbetuximab plus mFOLFOX6 arm, the ORR per IRC was 47.7% (95% CI, 41.76% to 53.70%), and the DCR was 82.0% (95% CI, 77.00% to 86.28%). In the placebo plus mFOLFOX6 group, the ORR per IRC was 47.5% (95% CI, 41.56% to 53.52%), and the DCR was 86.9% (95% CI, 82.37% to 90.59%).²⁴ In the GLOW trial, the ORRs per IRC were 42.5% (95% CI, 36.36% to 48.85%) in the zolbetuximab plus CAPOX group and 40.3% (95% CI, 34.22% to 46.64%) in the placebo plus CAPOX group. The DCRs were 76.4% (95% CI, 70.67% to 81.46%) in the zolbetuximab plus CAPOX group and 75.9% (95% CI, 70.13% to 81.03%) in the placebo plus CAPOX group.

Figure 6: Kaplan-Meier Plot of PFS by IRC per RECIST 1.1 in the SPOTLIGHT Trial (FAS)

CI = confidence interval; FAS = full analysis set; HR = hazard ratio; IRC = independent review committee; mFOFLOX6 = modified 5-fluorouracil, folinic acid, and oxaliplatin; PFS = progression-free survival; RECIST 1.1 = Response Evaluation Criteria in Solid Tumours Version 1.1.

Source: SPOTLIGHT trial Primary Analysis Clinical Study Report.²⁴

Disease Control Rate

Similarly to ORR, there was no statistically significant difference in DCR between the zolbetuximab plus mFOLFOX6 (or CAPOX) group and the placebo plus mFOLFOX6 (or CAPOX) group in either the SPOTLIGHT trial or the GLOW trial. In the SPOTLIGHT trial, the DCRs were 82.0% (95% CI, 77.00% to 86.28%) in the zolbetuximab plus mFOLFOX6 group and 86.9% (95% CI, 82.37% to 90.59%) in the placebo plus mFOLFOX6 group (P = 0.0569). In the GLOW trial, the DCRs were 76.4% (95% CI, 70.67% to 81.46%) in the zolbetuximab plus CAPOX group and 75.9% (95% CI, 70.13% to 81.03%) in the placebo plus CAPOX group (P = 0.4609).

Duration of Response

There were no statistically significant differences in DOR between the zolbetuximab plus mFOLFOX6 (or CAPOX) group and the placebo plus mFOLFOX6 (or CAPOX) group in either the SPOTLIGHT trial (HR = 0.876; 95% CI, 0.623 to 1.233; P = 0.2218) or the GLOW trial (HR = 0.758; 95% CI, 0.527 to 1.089; P = 0.0673).

Figure 7: Kaplan-Meier Plot of PFS by IRC per RECIST 1.1 in the GLOW Trial (FAS)

CAPOX = capecitabine plus oxaliplatin; CI = confidence interval; FAS = full analysis set; HR = hazard ratio; IRC = independent review committee; PFS = progression-free survival; RECIST 1.1 = Response Evaluation Criteria in Solid Tumours Version 1.1.

Source: GLOW trial Primary Analysis Clinical Study Report.²⁵

Health-Related Quality of Life

TTCD in EORTC QLQ-C30 PF

In the SPOTLIGHT trial, based on a total of 217 deterioration events in EORTC QLQ-C30 PF scale score, the median (95% CI) TTCDs for EORTC QLQ-C30 PF scale score were 10.71 months (6.01 months to NE) for patients who received zolbetuximab plus mFOLFOX6 and 12.32 months (9.26 months to NE) for patients who received placebo plus mFOLFOX6 (HR = 1.309; 95% CI, 1.000 to 1.713).²⁴ In the GLOW trial, based on a total of 208 deterioration events in EORTC QLQ-C30 PF scale score, the median TTCDs for EORTC QLQ-C30 PF scale score were 8.31 months (95% CI, 5.88 months to 19.81 months) for patients who received zolbetuximab plus CAPOX and 7.92 months (95% CI, 6.47 months to 11.10 months) for patients who received placebo plus CAPOX (HR = 0.999; 95% CI, 0.759 to 1.315).²⁵

Figure 8: Forest Plot of PFS Assessed by IRC in the SPOTLIGHT Trial — Subgroup Analysis (FAS)

CI = confidence interval; FAS = full analysis set; GEJ = gastroesophageal junction; HR = hazard ratio; IRC = independent review committee; PFS = progression-free survival.

Source: SPOTLIGHT trial Primary Analysis Clinical Study Report.²⁴

TTCD in EORTC QLQ-OG25 Pain Scale

In the SPOTLIGHT trial, based on a total of 92 deterioration events in the EORTC QLQ-OG25 Pain scale, the median TTCD for pain was not yet reached for patients who received zolbetuximab plus mFOLFOX6 or placebo plus mFOLFOX6 (HR = 0.679; 95% CI, 0.446 to 1.034).²⁴ In the GLOW trial, based on a total of 84 deterioration events in pain score, the median TTCD for pain was not yet reached for patients who received zolbetuximab plus CAPOX; it was 25.82 months (95% CI, not estimable) for patients who received placebo plus CAPOX (HR = 1.066; 95% CI, 0.692 to 1.642).²⁵

Figure 9: Forest Plot of PFS Assessed by IRC in the GLOW Trial — Subgroup Analysis (FAS)

CI = confidence interval; FAS = full analysis set; GEJ = gastroesophageal junction; HR = hazard ratio; IRC = independent review committee; PFS = progression-free survival.

Source: GLOW trial Primary Analysis Clinical Study Report.²⁵

TTCD in Global Health Status/Quality of Life

In the SPOTLIGHT trial, based on a total of 216 deterioration events in EORTC GHS/QoL scale score, the median (95% CI) TTCDs for the EORTC GHS/QoL scale were 15.44 months (95% CI, 6.90 months to 22.83 months) for patients who received zolbetuximab plus mFOLFOX6 and 11.83 months (95% CI, 8.74 months to 15.08 months) for patients who received placebo plus mFOLFOX6 (HR = 1.168; 95% CI, 0.890 to 1.533).²⁴ In the GLOW trial, based on a total of 196 deterioration events in EORTC GHS/QoL scale scores, the median TTCDs for the EORTC GHS/QoL scale were 9.69 months (95% CI, 7.39 months to NE) months for patients who received zolbetuximab plus CAPOX and 7.49 months (95% CI, 6.11 months to 9.86 months) for patients who received placebo plus CAPOX (HR = 0.847; 95% CI, 0.636 to 1.129).²⁵

Time to Progression

In the SPOTLIGHT trial, 87 patients (30.7%) in the zolbetuximab plus mFOLFOX6 arm and 98 patients (34.8%) in the placebo plus mFOLFOX6 arm had progression events. The median TTPs were 17.81 months in the zolbetuximab plus mFOLFOX6 arm and 12.52 months in the placebo plus mFOLFOX6 arm (P = 0.0133). In the GLOW trial, 77 patients (30.3%) in the zolbetuximab plus CAPOX arm and 103 patients (40.7%) in the placebo plus CAPOX arm had progression events. The median TTPs, according to IRC, were 11.99 months (95% CI, 8.84 months to 20.80 months) in the zolbetuximab plus CAPOX arm and 8.31 months (95% CI, 8.11 months to 9.95 months) in the placebo plus CAPOX arm (P = 0.0002).

Table 16: Estimates of TTP Assessed by IRC in the SPOTLIGHT and GLOW Trials (FAS)

CAPOX = capecitabine plus oxaliplatin; CI = confidence interval; FAS = full analysis set; IRC = independent review committee; IRT = interactive response technology; mFOLFOX6 = modified 5-fluorouracil, folinic acid, and oxaliplatin; NR = not reported; TTP = time to progression.

Notes: Data cut-offs were September 9, 2022 (SPOTLIGHT trial) and October 7, 2022 (GLOW trial).

^aBased on Kaplan-Meier estimate.

^bStratification factors were region, number of organs with metastatic sites, and prior gastrectomy from IRT.

^cBased on 1-sided log-rank test; not adjusted for multiple comparisons.

Sources: SPOTLIGHT trial Primary Analysis Clinical Study Report²⁴ and GLOW trial Primary Analysis Clinical Study Report.^2.5

PFS After Subsequent Therapy

In both the SPOTLIGHT and GLOW trials, PFS2 was defined as the time from the date of randomization until the date of radiological or objective PD (per patient’s local physician) following subsequent (second-line) ACT or death from any cause, whichever was earliest. In cases where PFS2 could not be reliably determined, the end date of subsequent (second-line) ACT or the start date of third-line ACT was used as the event date. Otherwise, patients were censored.^24,25

In the SPOTLIGHT trial, based on a total 388 PFS2 events at the data cut-off date, treatment with zolbetuximab plus mFOLFOX6 showed a 22% reduction in the risk of a patient experiencing a PFS2 event compared with placebo plus mFOLFOX6 (HR = 0.782; 95% CI, 0.637 to 0.961). A total of 79 patients (27.9%) in the zolbetuximab plus mFOLFOX6 arm and 71 patients (25.2%) in the placebo plus mFOLFOX6 arm had progressed after starting new ACT. The median PFS2s were 14.23 months (95% CI, 12.12 months to 16.82 months) in the zolbetuximab plus mFOLFOX6 arm and 11.99 months (11.20 months to 13.40 months) in the placebo plus mFOLFOX6 arm.²⁴

In the GLOW trial, based on a total of 376 PFS2 events at the data cut-off date, treatment with zolbetuximab plus CAPOX demonstrated a 29.2% reduction in the risk of a patient experiencing a PFS2 event compared with placebo plus CAPOX (HR = 0.708; 95% CI, 0.575 to 0.871). A total of 44 patients (17.3%) in the zolbetuximab plus CAPOX arm and 64 patients (25.3%) in the placebo plus CAPOX arm had progressed after starting new anticancer therapy. The median PFS2s were 11.01 months (95% CI, 10.02 months to 13.11 months) in the zolbetuximab plus CAPOX arm and 9.03 months (95% CI, 8.28 months to 9.89 months) in the placebo plus CAPOX arm.²⁵

Table 17: Summary of PFS2 by Investigator Assessment in the SPOTLIGHT and GLOW Trials (FAS)

ACT = anticancer therapy; CAPOX = capecitabine and oxaliplatin; CI = confidence interval; FAS = full analysis set; IRT = interactive response technology; mFOLFOX6 = modified 5-fluorouracil, folinic acid, and oxaliplatin; NR = not reported; PFS2 = progression-free survival following second-line anticancer treatment.

^aBased on Kaplan-Meier estimate.

^bStratification factors were region, number of organs with metastatic sites, and prior gastrectomy from IRT.

^cBased on 1-sided log-rank test; P value was not adjusted for multiple comparisons.

^dBased on Cox proportional hazards model with treatment, region, number of organs with metastatic sites, and prior gastrectomy as the explanatory variables. Assuming proportional hazards, a hazard ratio of less than 1 indicates a reduction in the hazard rate in favour of the treatment arm.

Sources: SPOTLIGHT trial Primary Analysis Clinical Study Report²⁴ and GLOW trial Primary Analysis Clinical Study Report.²⁵

Harms

All harms data reported here reflect the integrated SPOTLIGHT and GLOW trials analysis. Refer to Table 18 for harms data.

Adverse Events

Nearly all patients had at least 1 treatment-emergent AE. AEs reported for at least 20% of patients in either group included (zolbetuximab versus placebo, respectively): nausea (75.8% versus 55.8%), vomiting (66.8% versus 33.4%), decreased appetite (44.3% versus 33.6%), anemia (35.6% versus 37.0%), diarrhea (35.6% versus 39.5%), neutrophil count decrease (31.0% versus 28.5%), peripheral sensory neuropathy (30.4% versus 33.0%), neutropenia (28.5% versus 24.5%), constipation (25.9% versus 31.1%), fatigue (21.0% versus 25.2%), aspartate aminotransferase increase (21.0% versus 22.0%), abdominal pain (20.1% versus 25.8%), asthenia (20.1% versus 18.2%), and platelet count decrease (18.9% versus 20.7%). Nausea, vomiting, and decreased appetite were reported with at least a 10% higher incidence in the combined zolbetuximab group than in the combined placebo group.

Serious AEs

SAEs were reported in 245 patients (46.0%) in the combined zolbetuximab group and 245 patients (46.5%) in the combined placebo group.⁴² SAEs reported in at least 4% of patients in either group included (zolbetuximab versus placebo, respectively): vomiting (7.1% versus 4.6%), nausea (5.6% versus 3.2%), and malignant neoplasm progression (3.6% versus 4.7%).⁴²

Withdrawals Due AEs

AEs leading to permanent discontinuation of at least 1 component of any study drug were reported in 199 patients (37.3%) in the combined zolbetuximab group and 169 patients (32.1%) in the combined placebo group.⁴² AEs leading to permanent discontinuation of zolbetuximab or placebo were reported in 106 patients (19.9%) and 66 patients (12.5%), respectively. The most frequent AEs leading to permanent discontinuation of zolbetuximab or placebo (present in ≥ 2% of patients in either combined group) were vomiting (3.8% versus 0.6%) and nausea (3.4% versus 0.4%), respectively.

Notable Harms

Nausea

Nausea (any grade) was reported in 404 patients (75.8%) in the combined zolbetuximab group and 294 patients (55.8%) in the combined phase III control group. In most patients, the first event occurred within the first 21 days after the start of the first infusion in cycle 1 (62.5% and 37.2% in the zolbetuximab and placebo groups, respectively).⁴² Grade 3 events were reported in 12.6% and 4.6% of patients in the zolbetuximab and placebo groups, respectively.⁴²

Vomiting

Vomiting (any grade) was reported in 357 patients (67.0%) in the combined zolbetuximab group and 178 patients (33.8%) in the combined placebo group. In most patients, the first event occurred within the first 21 days after the start of the first infusion in cycle 1 (51.8% and 17.1% of patients in the zolbetuximab and placebo groups, respectively). Grade 3 events were reported for 14.3% and 4.7% of patients, respectively.⁴²

Table 18: Summary of Harms Results in the SPOTLIGHT AND GLOW Trials

AST = aminotransferase; CAPOX = capecitabine plus oxaliplatin; ISS = integrated summary of safety; MedDRA = Medical Dictionary for Regulatory Activities; mFOLFOX6 = modified 5-fluorouracil, folinic acid, and oxaliplatin; PT = preferred term; SAF = safety analysis set; TEAE = treatment-emergent adverse event.

Note: Data cut-offs were September 9, 2022 (SPOTLIGHT trial) and October 7, 2022 (GLOW trial).

Source: Common Technical Document 2.7.4 (contains integrated analysis).⁴²

Infusion-Related Reactions

IRRs (any grade) were reported in 215 patients (40.3%) in the combined zolbetuximab group and 58 patients (11.0%) in the combined placebo group.⁴² Grade 3 events were reported in 6.8% and 0.4% of patients in the zolbetuximab and placebo groups, respectively. A grade 4 investigator-assessed IRR event was reported in 1 patient (0.2%) in the combined zolbetuximab group and in 1 patient (0.2%) in the combined placebo group.⁴²

Critical Appraisal

Internal Validity

Baseline characteristics: Randomization in the SPOTLIGHT and GLOW trials was performed using an appropriate methodology with adequate allocation concealment (i.e., interactive response technology). Randomization was stratified by region (Asia versus non-Asia); number of organs with metastatic sites (0 to 2 versus ≥ 3); and prior gastrectomy (yes or no). The clinical experts consulted during this review noted that the stratification variables were reasonable for the target patient population. It was noted that proactive screening for gastrointestinal cancers is more common in some Asian countries (e.g., Japan and Korea) and that this can translate to an increase in OS for newly diagnosed patients with gastric or GEJ cancer if the disease is identified at an earlier stage compared with western nations that do not screen as aggressively. The clinical experts consulted during this review noted that the proactive screening is commendable and has contributed to more favourable outcomes for some patients, but that this would not limit the generalizability of the trial findings to the target population in Canada (i.e., those with newly diagnosed metastatic disease). Overall, baseline and demographic characteristics were generally well balanced across the zolbetuximab and placebo groups in both the SPOTLIGHT and GLOW trials. Between-group imbalances were noted for the subset of patients with GEJ in the SPOTLIGHT trial for tumour location (e.g., proximal [47.6% versus 36.6%] and distal [30.2% versus 43.7%] for zolbetuximab and placebo, respectively) and tumour type (e.g., diffuse [29.1% versus 42.1% for zolbetuximab and placebo, respectively]). The clinical experts consulted during this review had no concerns regarding the baseline characteristics of the SPOTLIGHT and GLOW trial populations.

Treatment masking: Both the SPOTLIGHT and GLOW trials were double-blind clinical trials. Patients who received zolbetuximab more commonly reported AEs of nausea and vomiting as well as infusion-site reactions. The clinical experts consulted during this review noted that the AE profile in the trial could potentially allow some patients and investigators to infer the allocated treatment group. The objective end points (e.g., PFS, OS, and ORR) would not be subject to bias in the event that treatment allocation could be inferred as a result of AEs; however, HRQoL, which requires subjective reporting, could potentially be biased.

Concomitant supportive therapies: Supportive cancer therapies were generally well balanced across the groups.

Subsequent ACTs: The most frequent postprogression therapies were paclitaxel (17% versus 19.5% and 18.1% versus 20.2% for zolbetuximab versus placebo in the SPOTLIGHT and GLOW trials) and ramucirumab (12.4% versus 12.1% and 8.3% versus 11.1% for zolbetuximab versus placebo in the SPOTLIGHT and GLOW trials). The clinical experts consulted by CDA-AMC felt that the overall proportion of patients who did not receive any subsequent ACT (approximately 50% of patients in both trials) was a reasonable reflection of the target population in Canada, where survival is often limited to 1 year. The experts noted that the distribution of therapies seemed appropriate for the Canadian setting and that the EMA had concluded that OS results did not seem to have been impacted by differences in the use of subsequent (i.e., postprogression) therapies.⁵⁰

Patient disposition: In general, patient disposition in the SPOTLIGHT and GLOW trials highlights the poor prognosis for those in the target patient population (e.g., across all treatment groups, more than 80% of patients discontinued therapy).⁵⁰ Acknowledging that there is little experience with zolbetuximab in Canadian clinical practice, the clinical experts consulted during this review noted that the patient disposition appears to be a reasonable reflection of what would be anticipated in Canadian practice for a regimen that includes the use of cytotoxic chemotherapy.