Addition of Durvalumab to neoadjuvant chemoradiotherapy (CROSS) in esophageal adenocarcinoma – first results from the prospective Phase-II RICE trial

Purpose: Anti-PD-(L)1 is effective in esophageal adenocarcinoma (EGA) and appears synergistic with chemoradiotherapy (CRT). The RICE trial (NCT04159974) aims to evaluate addition of neoadjuvant durvalumab and adjuvant durvalumab±tremelimumab to standard CRT.

Methods: In this open-label, randomized phase-2 trial, pts with locally advanced (≥uT3/Nx or uT2/N+) non-metastatic EGA receive two doses of neoadjuvant durvalumab (1500mg) in addition to CRT (CROSS protocol). Adjuvant therapy was randomized 1:1 to durvalumab monotherapy or durvalumab plus tremelimumab. Here we report results from the neoadjuvant part of the trial including the primary endpoints for feasibility, safety, and efficacy. HLA-I genotyping and immunohistochemistry (CD3, PD-L1, dMMR) of pretreatment biopsies were included as predictive biomarkers.

Results: 95% (53/56) of pts completed neoadjuvant therapy and 93% (52/56) underwent resection, which was not lower than 90.4% as predefined benchmark for feasibility. Regarding safety, benchmarks were defined based on CROSS. The rate of grade 3/4 non-hematologic adverse events during neoadjuvant treatment was 25% (13/56 G3, 1/56 G4), above the threshold of 13%, while the rate of anastomotic leakage was 6% (3/52) and well below the predefined cutoff of 22% (p<0.05). Clinicopathological evaluation of response revealed 54% (30/56) major response (MPR, <10% vital tumor cells) and 23% (13/56) complete response (pCR, ypT0/ypN0/cM0). The primary endpoint for efficacy (35% pCR) was not reached, but the rate of MPR was higher than in non-randomized propensity-matched comparison to FLOT and CROSS. Translational analyses revealed complete HLA-I heterozygosity in all patients with pCR compared to 31% homozygosity in non-pCR patients. T-cell abundance and PD-L1 expression were tendentially higher in responders, but results were less conclusive.

Conclusions: The first analyses of the RICE trial demonstrate safety and feasibility of addition of neoadjuvant immunotherapy with durvalumab to CROSS. Higher MPR in non-randomized comparisons to CROSS and FLOT suggests evaluation of RICE in a randomized controlled trial.

präsentiert in der Sitzung: CAOGI: Herausforderungen und Grenzfälle in der onkologischen Ösophagus- und Magenchirurgie

Donnerstag, 03. Oktober 2024, 14:30 – 16:00, MZF 2

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Artikel online veröffentlicht:
26. September 2024