A phase II/III study of peri-operative nivolumab (nivo) and ipilimumab (ipi) in patients (pts) with locoregional esophageal (E) and gastroesophageal junction (GEJ) adenocarcinoma: Results of the neoadjuvant pathologic complete response (pCR) rate (ECOG-ACRIN EA2174).

4000 Background: E/GEJ adenocarcinoma has a high mortality rate despite curative intent therapy. Although the use of immune checkpoint inhibition (ICI) in combination with chemotherapy in the metastatic setting and as adjuvant monotherapy both confer survival benefits, its role in combination with neoadjuvant chemoradiation or with other ICIs in the adjuvant setting remains unclear. Here we report the impact of nivo on pCR rate in pts with E/GEJ adenocarcinoma receiving neoadjuvant chemoradiation as part of the EA2174 clinical trial. Methods: Pts with a localized T1N1-3M0 or T2-3N0-2M0 E/GEJ adenocarcinoma with an ECOG PS of 0-1 and deemed surgical candidates for an esophagectomy were eligible. In step 1, pts were randomized to neoadjuvant therapy with carboplatin AUC 2 and paclitaxel 50 mg/m2 intravenously (IV) weekly x 5 along with 41.4-50.4 Gy radiation without (Arm A) or with (Arm B) nivo 240 mg IV during weeks 1 and 3 of treatment, followed by esophagectomy. Pts underwent a second randomization (step 2) to 6-12 months of adjuvant nivo with or without 6 months of ipi. Planned accrual for step 1 was 278 pts. The primary neoadjuvant endpoint was pCR rate with H0= 23% vs HA= 38%, 90% power, one-sided α = 0.10. The primary adjuvant endpoint comparing nivo to nivo/ipi is disease free survival and will be reported separately once data are mature. Results: Between May 2019 and Dec 2022, 275 pts were enrolled to step 1 of the study (Arm A, n = 138; Arm B, n = 137). Male = 89.5%; White = 92%, Asian = 2.2%, Black 1.5%; median age 65.5 years; E = 60.4%, GEJ = 39.3%. Only 78.5% of pts proceeded to surgery (Arm A = 76.1%, Arm B 81.0%). The pCR rate in Arm A was 21.0% (95% CI, 14.5-28.8) and in Arm B was 24.8% (95% CI, 17.8-32.9), showing no statistically significant difference (p = 0.27). Surgical complication rates between the two arms were similar (Arm A = 28.7%, Arm B = 25.4%). Grade (G) 3/4 events occurring in at least 5% of pts on Arm A—anemia (n = 7), dysphagia (n = 9), esophagitis (n = 7), decreased lymphocytes (n = 80), decreased neutrophils (n = 7); decreased white blood cells (n = 20). G3/4 events occurring in at least 5% of pts on Arm B—anemia (n = 10), dysphagia (n = 8), nausea (n = 8), decreased lymphocytes (n = 84), decreased neutrophils (n = 20), decreased white blood cells (n = 31). Three treatment related deaths occurred on Arm A and two on Arm B. There were no notable differences in chemotherapy or radiation exposure between the two arms. Conclusions: The addition of nivo to neoadjuvant carboplatin, paclitaxel and radiation does not improve the pCR rate in pts with resected E/GEJ adenocarcinoma. Given the known benefit of the addition of ICI to chemotherapy, a further understanding of the impact of radiation on ICI activity is needed. Clinical trial information: NCT03604991 .