Immune and clinical determinants of response to immune checkpoint blockade (ICB) rechallenge after perioperative chemoImmunotherapy in gastroesophageal cancer

Background: The addition of perioperative ICB to chemotherapy improves survival in localized gastroesophageal adenocarcinoma (GEA), but optimal treatment at recurrence remains undefined. A key question is whether prior perioperative ICB influences clinical response or immune sensitivity to subsequent ICB in the metastatic setting. We evaluated clinical outcomes and immune correlatives in patients who recurred after perioperative chemo-immunotherapy and underwent ICB rechallenge. Methods: We retrospectively analyzed patients with localized MSS GEA treated at Memorial Sloan Kettering (2020-2025) with curative intent perioperative chemo-immunotherapy (anti-PD-1 or anti-PD-L1). Patients treated on clinical trials were excluded. Clinical endpoints included RECIST response to ICB rechallenge at recurrence and progression-free survival (PFS) on rechallenge. Correlative studies (ongoing) include immune profiling and TCR clone-tracking from paired baseline and recurrence tumor biopsies and serial PBMCs in a subset of patients. Results: Among 66 patients with localized gastric (n=26) and esophagus/GEJ (n=40) cancer, 33 received neoadjuvant ICB (anti-PD-1 + FLOT, n=17; anti-PD-1 + FOLFOX/CAPEOX followed by surgery and adjuvant chemo/ICB, n=28; or non-operative management, n=5), and 33 received chemotherapy alone followed by surgery and adjuvant ICB only. Eighteen of 66 patients (27%) experienced disease recurrence or progression; of these, 55% (10/18) were rechallenged with ICB plus chemotherapy at recurrence (4 with prior neoadjuvant ICB; 6 with adjuvant-only ICB). Rechallenged patients had a longer interval from completion of perioperative therapy to recurrence compared with those not rechallenged (6.30 vs 1.27 months; p=0.315). Among rechallenged neoadjuvant-exposed patients, all four experienced tumor regression or disease stabilization with chemo-ICB (1 CR, 2 PRs, 1 SD). Among rechallenged patients who received adjuvant-only ICB, disease progression occurred in 50% (3/6), and two had short-lived responses; all ultimately progressed, including two deaths. Overall, median PFS from time of ICB rechallenge was 6 months (95% CI 4.27-NR): NR (0 events) in the neoadjuvant-exposed group versus 5 months (95% CI 4.14-NR) in the adjuvant-only group (log-rank p=0.056). Conclusions: In this perioperative chemo-immunotherapy cohort, prior neoadjuvant ICB exposure did not preclude - and may be associated with improved - response to ICB rechallenge at recurrence. Neoadjuvant-exposed patients showed numerically higher response rates and longer PFS on rechallenge compared with those who received adjuvant-only ICB. Ongoing correlative analyses of tumor and PBMC specimens aim to define immune determinants and TCR-based signatures associated with benefit from ICB rechallenge in MSS GEA.