SWOG S2303: Randomized phase II/III trial of 2nd line nivolumab + paclitaxel + ramucirumab versus paclitaxel + ramucirumab in patients with PD-L1 CPS ≥ 1 advanced gastric and esophageal adenocarcinoma (PARAMUNE).
Authors: Saeed Anwaar , Colby Sarah , Oberstein Paul Eliezer , Duda Dan G. , Agarwal Rajiv , Figueroa-Moseley Colmar , Vaidya Riha , Unger Joseph M. , Guthrie Katherine A. , Rocha Flavio G , Senthil Maheswari , Safyan Rachael A , Wainberg Zev A. , Iqbal Syma , Chiorean E. Gabriela , Philip Philip A. 
Published: January 2024

TPS430 Background: Anti-VEGFR2 antibody (ramucirumab) has efficacy in gastric cancer (GC), both as monotherapy & in combination with paclitaxel based on the REGARD & RAINBOW trials that led to its FDA approvals in the 2nd line setting. Preclinical data demonstrate significant tumor immune microenvironment modulatory effects from antiangiogenic agents, supporting the clinical study of dual VEGFR with immune checkpoint blockade. This has resulted in at least 7 FDA-approved combinations of anti-VEGF/VEGFR with anti-PD-1/PD-L1 agents in lung, renal, endometrial & liver cancers. Recent data showed encouraging activity with ramucirumab plus nivolumab & other trials with pembrolizumab and durvalumab in GC & esophageal adenocarcinoma. Notably, the addition of nivolumab to 2nd line ramucirumab plus paclitaxel was evaluated in a multi-center phase I/II trial. Study population consisted of 60% (26/43) harboring tumors positive for PD-L1 CPS ≥ 1. Results revealed encouraging efficacy (ORR 37.2%, 6-month PFS 46.5%) in the overall population. Median PFS and OS were found to be numerically higher in PD-L1 CPS ≥ 1 (6.4 months & 13.8 months respectively) compared to CPS-negative participants (5.1 months & 8.0 months), suggesting a predictive impact of PD-L1 CPS in this treatment setting. Methods: SWOG2303 is a national, randomized, open label, phase II/III trial to assess the efficacy and safety of nivolumab + paclitaxel + ramucirumab versus paclitaxel + ramucirumab in adult patients with advanced stage MSS/pMMR PD-L1 CPS ≥ 1 gastric and esophageal adenocarcinoma. Patients must have documented MSI and PD-L1 CPS status by standard of care tissue-based analysis, evaluable disease on imaging, and Zubrod performance status (PS) 0-1. They should also have clinical or radiographic progression or intolerance to frontline standard of care systemic therapy with PD-1 inhibitor containing fluoropyrimidine based chemotherapy regimen. Patients with HER2 positive disease are excluded as well as patients with prior significant immunotherapy related adverse events (iRAEs) that prompted permanent discontinuation of the PD-1 agent. Planned enrollment is 224. Participants will be randomized using a dynamic balancing algorithm with stratification based on Zubrod PS (0 vs 1), tumor location (gastric vs GEJ or esophageal) and PD-L1 CPS (≥5 vs <5). Primary endpoints are PFS for phase II and OS for phase III. Secondary endpoints include overall response rate, disease control rate, & safety. Baseline and pharmacodynamic changes in cellular and plasma angiogenic, inflammatory, and immune biomarkers will be explored & correlated with the efficacy. Other endpoints include health quality of life measured using the Functional Assessment of Cancer Therapy-Gastric (FACT-Ga). Enrollment is ongoing.