Perioperative durvalumab plus neoadjuvant chemoradiotherapy (CROSS) with and without tremelimumab in esophageal adenocarcinoma: The prospective phase II RICE trial (NCT04159974).

4083 Background: Anti-PD-(L)1 is effective in esophageal adenocarcinoma (EGA). The phase II RICE trial (NCT04159974) evaluated the addition of neoadjuvant and adjuvant durvalumab, with or without tremelimumab, to neoadjuvant chemoradiotherapy (CROSS). Methods: Patients with locally advanced (≥uT3/Nx or uT2/N+) non-metastatic EGA received two doses of neoadjuvant durvalumab in addition to CROSS, followed by surgery. Adjuvant therapy was randomized 1:1 to durvalumab (12 doses) alone (arm A) or durvalumab plus one dose of tremelimumab (arm B). Translational analyses included HLA-I genotyping, immunohistochemistry, whole-exome sequencing and RNA-sequencing. Clinical outcomes were analyzed in patients who received at least one neoadjuvant dose (mITT) and in those who were randomized and received at least one adjuvant dose (R-mITT). Results: In the mITT set (n=56), 95% completed neoadjuvant therapy and 93% underwent resection. The rate of grade ≥3 non-hematologic adverse events during neoadjuvant treatment was 25% (13/56 G3, 1/56 G4). Surgery was feasible with a rate of anastomotic leakage of 6%. Major pathological response (MPR, <10% viable tumor cells) was achieved in 54% (30/56) including a 23% (13/56) pathological complete response rate (pCR, ypT0/ypN0). The rate of MPR was higher than in propensity-based comparisons with FLOT (25%) and CROSS (37%). Two-year overall (OS) and progression-free (PFS) survival of the mITT set were 72.7% and 53.1%, respectively. After completion of Stage I of the trial (safety run in), 38 patients were included in the R-mITT set. 80% in arm A (durvalumab monotherapy, n=20) and 44% in arm B (durvalumab plus tremelimumab, n=18) completed at least 80% of adjuvant immunotherapy. Combined immunotherapy in the R-mITT set was associated with higher grade ≥3 toxicity (22% G3/ 22% G4 in Arm B vs. 15% G3 / 0% G4 in arm A) and did not improve survival (2-year OS/PFS 95.0%/80.0% [arm A] vs. 82.4%/54.2% [arm B]). Tumor mutational burden, heterozygosity of HLA-I, expression of genes related to antigen presentation and T-cell abundance were associated with pathological response. However, discordant cases across all biomarkers underscore the complexity of tumor-immune interactions underlying response to immunotherapy. Conclusions: RICE demonstrates safety and feasibility of adding anti-PD-L1 to neoadjuvant CROSS in EGA and shows promising response rates. While CROSS is no longer considered standard of care, our results support efficacy of durvalumab, consistent with results for FLOT plus durvalumab in the MATTERHORN trial. Addition of tremelimumab to durvalumab is not supported by our study. Clinical trial information: NCT04159974 .