A phase II/III study of perioperative nivolumab and ipilimumab in patients (pts) with locoregional esophageal (E) and gastroesophageal junction (GEJ) adenocarcinoma: Results of a safety run-in—A trial of the ECOG-ACRIN Cancer Research Group (EA2174).

Abstract

4064 Background: E/GEJ adenocarcinoma has a high mortality rate despite curative intent therapy. The use of immune checkpoint inhibition is beneficial for treatment of this cancer in the metastatic and adjuvant settings but the role of these agents in the perioperative setting remains unclear. Here we report the results of an initial safety run-in of nivolumab when given in combination with neoadjuvant chemoradiation. Methods: Pts with a localized T1N1-3M0 or T2-3N0-2M0 E/GEJ adenocarcinoma with an ECOG PS of 0-1 and whom were deemed surgical candidates for an esophagectomy by a qualified surgeon 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) nivolumab 240 mg IV during weeks 1 and 3 of treatment, followed by esophagectomy. Pts underwent a second randomization (step 2) to adjuvant nivolumab 240 mg IV every 2 weeks x 12 cycles with or without ipilimumab 1 mg/kg IV every 6 weeks during cycles 1, 4, 7 and 10. For the safety run-in, 30 pts were planned for accrual to allow for 12 evaluable pts per arm. Pts were followed for safety during neoadjuvant therapy through surgery and toxicities monitored per CTCAEv5. Pre-specified early stopping rules were defined to allow halting of the trial if deemed unsafe. Planned study accrual is 278 pts. Neoadjuvant primary endpoint is pathologic complete response rate, adjuvant primary endpoint is disease-free survival. Results: A total of 31 pts were enrolled to the safety run-in element of the study (Arm A, n = 16; Arm B n = 15). Male, 94%; White, 100%; median age, 62; esophageal adenocarcinoma, 52%; GEJ, 48%. Grade (G) 3 events occurring in more than one pt on Arm A—decreased lymphocytes (n = 5). G4 events occurring on Arm A—decreased lymphocytes (n = 1). G3 events occurring in more than one pt on Arm B—decreased lymphocytes (n = 2); anemia (n = 2); leukopenia (n = 4); hypotension (n = 2). G4 events occurring on Arm B—decreased lymphocytes (n = 3); cardiac tamponade and pericardial effusion (n = 1). Cardiac events were thought to be secondary to tumor location, not neoadjuvant treatment. On Arm B, notable G3 events seen in one pt each included colonic obstruction, wound infection and esophageal anastomotic leak. Of pts who have reached the time for surgery, 12/14 pts on Arm A and 13/13 pts on Arm B have proceeded to surgery. Of pts who have completed step 1, 7/14 pts on Arm A and 8/11 pts on Arm B have registered to step 2. Conclusions: The addition of nivolumab to carboplatin, paclitaxel and radiation in the neoadjuvant setting appears to be safe with no disproportionate level of toxicity observed between the two treatment arms. Accrual to the remainder of the trial continues with 43/278 patients accrued. Clinical trial information: NCT03604991.

Risk stratification of postoperative cardiopulmonary toxicity after trimodality therapy for esophageal cancer

“…Patients also require optimized medical management for symptoms, including pre-treatment antiemetics and consideration for proactive prescriptions of analgesics. Finally, in the recent EA2174 phase II/III study, elective nodal radiation was not recommended for patients with node-negative disease ( 40 ). Though omission of elective nodal volumes remains controversial in this setting, it may contribute to reduction of dose to organs at risk and thereby reduce the risk of side effects.…”

Immunotherapy in the neoadjuvant treatment of gastrointestinal tumors: is the time ripe?

“…62 The phase II/III trial ECOG-ACRIN-2174 is ongoing and is investigating pCR rate and DFS of EGC treated with preoperative CRT according to CROSS regimen with or without concomitant nivolumab. 63 After surgery, patients will be further randomized to adjuvant nivolumab with or without ipilimumab. So far, only toxicity data are available and the addition of nivolumab to CRT did not significantly increase the rate of side effects, without any new safety concerns.…”

Perioperative Tailored Treatments for Gastric Cancer: Times Are Changing

“…The primary neoadjuvant endpoint is the pCR rate, and the primary adjuvant endpoint is DFS. The safety run-in phase enrolled 31 patients divided into the two arms with no disproportional difference in safety or number of patients who proceeded to surgery [46].…”