Phase II RAINSPOT: A multicentric open label trial of zolbetuximab-paclitaxel-ramucirumab in second-line setting for CLDN18.2-positive gastro-esophageal adenocarcinoma.

Abstract

TPS4243 Background: Claudin 18.2 (CLDN18.2) is an emerging therapeutic biomarker in gastro-oesophageal adenocarcinoma. Phase III trials (SPOTLIGHT, GLOW) showed significant overall survival (OS) and progression-free survival (PFS) benefit from adding zolbetuximab to first-line chemotherapy. However, access to zolbetuximab remains limited in Belgium due to lack of reimbursement, and globally for patients receiving immunotherapy first line. Aim: RAINSPOT (NCT06962137) evaluates the efficacy and safety of adding zolbetuximab to standard second-line paclitaxel–ramucirumab in CLDN18.2-positive advanced gastro-oesophageal adenocarcinoma. Secondary objectives include assessing CLDN18.2 expression loss after first-line progression and evaluating zolbetuximab efficacy according to maintained versus lost CLDN18.2 expression. Methods: RAINSPOT is a national, multicentre, phase II, open-label study with a prospective single-arm cohort and a matched retrospective cohort across six Belgian centres. The prospective cohort will include 100 patients (≥18 years, ECOG 0–1) with metastatic or locally advanced disease progressing after one prior systemic line. Tumours must be CLDN18.2-positive (≥75% moderate-to-strong membranous staining; Ventana 43-14A assay). A fresh biopsy at progression is obtained when feasible. Treatment consists of zolbetuximab (800 mg/m² loading, then 400 mg/m² q2w), paclitaxel (80 mg/m² weekly ×3 q28d) and ramucirumab (8 mg/kg q2w). Treatment continues until progression or unacceptable toxicity. HRQoL is assessed every 4 weeks (EORTC QLQ-C30, QLQ-OG25). The retrospective cohort includes patients treated with second-line paclitaxel–ramucirumab (2021–2023) with archived tissue reassessed for CLDN18.2; only baseline-positive patients are eligible. Propensity score matching (1:1; SMD ≤0.05) uses age, sex, tumour location, gastrectomy, peritoneal metastases and centre. This study is supported by Astellas. Results: (Trial in Progress) Enrollment began December 2025 and will continue for 24 months, with 24 months’ follow-up. Planned analyses include OS, PFS, objective response rate, toxicity and HRQoL. Conclusion: RAINSPOT is the first study evaluating zolbetuximab plus paclitaxel–ramucirumab in second-line CLDN18.2-positive gastro-oesophageal adenocarcinoma. By integrating a matched real-world comparator, it aims to generate near-randomized evidence on survival, tolerability and quality of life, informing optimal treatment sequencing. Clinical trial information: NCT06962137 .