Dataset Information

Zolbetuximab plus CAPOX in CLDN18.2-positive gastric or gastroesophageal junction adenocarcinoma: the randomized, phase 3 GLOW trial.

ABSTRACT: There is an urgent need for first-line treatment options for patients with human epidermal growth factor receptor 2 (HER2)-negative, locally advanced unresectable or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma. Claudin-18 isoform 2 (CLDN18.2) is expressed in normal gastric cells and maintained in malignant G/GEJ adenocarcinoma cells. GLOW (closed enrollment), a global, double-blind, phase 3 study, examined zolbetuximab, a monoclonal antibody that targets CLDN18.2, plus capecitabine and oxaliplatin (CAPOX) as first-line treatment for CLDN18.2-positive, HER2-negative, locally advanced unresectable or mG/GEJ adenocarcinoma. Patients (n = 507) were randomized 1:1 (block sizes of two) to zolbetuximab plus CAPOX or placebo plus CAPOX. GLOW met the primary endpoint of progression-free survival (median, 8.21 months versus 6.80 months with zolbetuximab versus placebo; hazard ratio (HR) = 0.687; 95% confidence interval (CI), 0.544-0.866; P = 0.0007) and key secondary endpoint of overall survival (median, 14.39 months versus 12.16 months; HR = 0.771; 95% CI, 0.615-0.965; P = 0.0118). Grade ≥3 treatment-emergent adverse events were similar with zolbetuximab (72.8%) and placebo (69.9%). Zolbetuximab plus CAPOX represents a potential new first-line therapy for patients with CLDN18.2-positive, HER2-negative, locally advanced unresectable or mG/GEJ adenocarcinoma. ClinicalTrials.gov identifier: NCT03653507 .

SUBMITTER: Shah MA

PROVIDER: S-EPMC10427418 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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Zolbetuximab plus CAPOX in CLDN18.2-positive gastric or gastroesophageal junction adenocarcinoma: the randomized, phase 3 GLOW trial.

Shah Manish A MA Shitara Kohei K Ajani Jaffer A JA Bang Yung-Jue YJ Enzinger Peter P Ilson David D Lordick Florian F Van Cutsem Eric E Gallego Plazas Javier J Huang Jing J Shen Lin L Oh Sang Cheul SC Sunpaweravong Patrapim P Soo Hoo Hwoei Fen HF Turk Haci Mehmet HM Oh Mok M Park Jung Wook JW Moran Diarmuid D Bhattacharya Pranob P Arozullah Ahsan A Xu Rui-Hua RH

Nature medicine 20230731 8

There is an urgent need for first-line treatment options for patients with human epidermal growth factor receptor 2 (HER2)-negative, locally advanced unresectable or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma. Claudin-18 isoform 2 (CLDN18.2) is expressed in normal gastric cells and maintained in malignant G/GEJ adenocarcinoma cells. GLOW (closed enrollment), a global, double-blind, phase 3 study, examined zolbetuximab, a monoclonal antibody that targets CLDN18.2, plu ...[more]

PMID: 37524953

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Project description:BackgroundPatients with HER2-negative locally advanced or unresectable metastatic gastric cancer and gastroesophageal junction (G/GEJ) adenocarcinoma have limited first-line treatment options and a poor prognosis. The GLOW clinical trial showed that zolbetuximab plus capecitabine plus oxaliplatin (CAPOX) significantly prolonged these patients' overall survival (OS) and progression-free survival (PFS).ObjectivesThis study evaluated the cost-effectiveness of zolbetuximab plus CAPOX as a first-line treatment for HER2-negative locally advanced or unresectable metastatic G/GEJ adenocarcinoma in the United States and China.DesignThe cost-effective analysis.MethodsBased on the GLOW clinical trial data (NCT03653507), we constructed a 10-year Markov model to assess the cost-effectiveness of the zolbetuximab or placebo plus CAPOX treatment regimen. Only direct medical costs were considered. The primary outcomes of the model were quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratios (ICERs). One-way and probabilistic sensitivity analyses were employed to assess the robustness of the model.ResultsIn the United States, zolbetuximab plus CAPOX added 0.24 QALYs and resulted in an incremental cost of $196,791.11 compared with placebo plus CAPOX, which had an ICER of $821,515.65 per QALY gained. For China, the zolbetuximab group gained 0.23 QALYs at an incremental cost of $62,822.69, resulting in an ICER of $273,568.01/QALY. One-way sensitivity analysis revealed that the results were most sensitive to the price of zolbetuximab. Zolbetuximab plus CAPOX had 0% cost-effectiveness at the willingness-to-pay thresholds of $150,000/QALY in the United States and $38,188/QALY in China.ConclusionZolbetuximab plus CAPOX may be a cost-effective option for patients with locally advanced, unresectable, or metastatic G/GEJ adenocarcinoma when the price of zolbetuximab reduced by 83.37% ($367.7/100 mg) in the United States and 82.25% ($110.8/100 mg) in China.

Project description:BackgroundFirst-line zolbetuximab plus chemotherapy (SPOTLIGHT, mFOLFOX6; GLOW, CAPOX) significantly improved progression-free survival (PFS) and overall survival (OS) versus placebo plus chemotherapy in patients with human epidermal growth factor receptor 2-negative, locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma whose tumors were claudin 18 isoform 2-positive in the phase III SPOTLIGHT (NCT03504397) and GLOW (NCT03653507) studies. We present patient-reported outcomes (PROs) from these studies.Materials and methodsHealth-related quality of life (HRQoL) was measured in the full analysis sets using the European Organisation for Research and Treatment of Cancer Quality of Life of Cancer Patients Core Questionnaire (QLQ-C30) and Oesophago-Gastric Module (QLQ-OG25), Global Pain, and 5-level EQ-5D (EQ-5D-5L) questionnaires. Analyses focused on key PRO domains: global health status (GHS)/QoL, physical functioning, abdominal pain and discomfort, and nausea/vomiting. Least squares mean (LSM) changes from baseline and time to first definitive deterioration (TTDD) were evaluated combined across SPOTLIGHT and GLOW and for individual studies. Time to confirmed deterioration (TTCD) was evaluated independently for SPOTLIGHT and GLOW.ResultsThe combined analysis set included 1072 patients (zolbetuximab plus chemotherapy, 537; placebo plus chemotherapy, 535). Compliance rates were similar between treatment arms. Similar trends were observed in the zolbetuximab versus placebo arms for LSM changes from baseline in key PRO domains, with no clinically meaningful deterioration. Nausea/vomiting worsened during the first few zolbetuximab cycles but later returned to baseline levels. Overall TTCD and TTDD results were similar between arms in both studies.ConclusionsPatients in SPOTLIGHT and GLOW maintained measured HRQoL relative to baseline when treated with first-line zolbetuximab added to chemotherapy. Zolbetuximab plus chemotherapy improved PFS and OS without negatively affecting HRQoL in key PRO domains compared with placebo plus chemotherapy.

Project description:Gastric and gastroesophageal junction (G/GEJ) cancers carry a poor prognosis, and despite recent advancements, most patients die of their disease. Although immune checkpoint blockade became part of the standard-of-care for patients with metastatic G/GEJ cancers, its efficacy and impact on the tumor microenvironment (TME) in early disease remain largely unknown. We hypothesized higher efficacy of neoadjuvant immunotherapy plus chemotherapy in patients with nonmetastatic G/GEJ cancer. In the phase 2 PANDA trial, patients with previously untreated resectable G/GEJ tumors (n = 21) received neoadjuvant treatment with one cycle of atezolizumab monotherapy followed by four cycles of atezolizumab plus docetaxel, oxaliplatin and capecitabine. Treatment was well tolerated. There were grade 3 immune-related adverse events in two of 20 patients (10%) but no grade 4 or 5 immune-related adverse events, and all patients underwent resection without treatment-related delays, meeting the primary endpoint of safety and feasibility. Tissue was obtained at multiple time points, allowing analysis of the effects of single-agent anti-programmed cell death ligand 1 (PD-L1) and the subsequent combination with chemotherapy on the TME. Twenty of 21 patients underwent surgery and were evaluable for secondary pathologic response and survival endpoints, and 19 were evaluable for exploratory translational analyses. A major pathologic response (≤10% residual viable tumor) was observed in 14 of 20 (70%, 95% confidence interval 46-88%) patients, including 9 (45%, 95% confidence interval 23-68%) pathologic complete responses. At a median follow-up of 47 months, 13 of 14 responders were alive and disease-free, and five of six nonresponders had died as a result of recurrence. Notably, baseline anti-programmed cell death protein 1 (PD-1)+CD8+ T cell infiltration was significantly higher in responders versus nonresponders, and comparison of TME alterations following anti-PD-L1 monotherapy versus the subsequent combination with chemotherapy showed an increased immune activation on single-agent PD-1/L1 axis blockade. On the basis of these data, monotherapy anti-PD-L1 before its combination with chemotherapy warrants further exploration and validation in a larger cohort of patients with nonmetastatic G/GEJ cancer. ClinicalTrials.gov registration: NCT03448835 .

Dataset Information

Zolbetuximab plus CAPOX in CLDN18.2-positive gastric or gastroesophageal junction adenocarcinoma: the randomized, phase 3 GLOW trial.

Publications

Zolbetuximab plus CAPOX in CLDN18.2-positive gastric or gastroesophageal junction adenocarcinoma: the randomized, phase 3 GLOW trial.

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