A phase II study of perioperative pembrolizumab plus mFOLFOX in patients with potentially resectable esophagus, gastroesophageal junction (GEJ), and stomach adenocarcinoma

Abstract

Background: Perioperative chemotherapy/chemoradiation is standard in esophageal/gastric/gastroesophageal junction (GEJ) adenocarcinoma, immune checkpoint inhibitors (ICI) effect in setting of metastatic and postoperatively. This study is to assess ICI + chemotherapy perioperatively.

Methods: Patients with locally advanced (T1N1-3M0 or T2-3NanyM0) potentially resectable esophageal/gastric/GEJ adenocarcinoma by PET/EUS/CT and staging-laparoscopy, were treated preoperative 4 cycles mFOLFOX6 (Oxaliplatin 85 mg/m² /Leucovorin 400 mg/m² /5-FU bolus 400 mg/m² then infusion 2400 mg/m² for 46 h q2weeks) and 3 cycles pembrolizumab (200 mg q3week). Those without distal disease post-neoadjuvant and eligible for resection underwent surgery. Postoperative treatment was initiated at 4-8 weeks with 4 cycles mFOLFOX and 12 cycles pembrolizumab. The primary objective is pathological response (ypRR with tumor regression score, TRS ≤2). The expression of ICI-related markers PD-L1 (CPS), CD8, and CD20 were analyzed before and after preoperative therapy.

Results: Thirty-seven patients completed the preoperative treatment. Twenty-nine patients had curative R0 resection. 6/29 (21%; 95% CI: 0.08-0.40) achieved ypCR with TRS 0 in resected patients. 26/29 (90%; 95% CI: 0.73-0.98) had ypRR with TRS ≤2. Twenty-six patients finished adjuvant therapy with a median 36.3-month follow-up. Three patients had recurrence/metastatic disease (at 9-, 10-, 22 months enrollment) with one dead at 23 months, and two are still alive at 28 and 36.5 months. The remaining (23/26) are free of disease with 3 years DFS of 88.5% and 3 years OS of 92.3%. There were no unexpected toxicities. Preoperative ICI + chemotherapy enhanced immune responses significantly with increasing expression of PD-L1 (CPS ≥10, p = 0.0078) and CD8 (>5%, p = 0.0059).

Conclusions: The perioperative pembrolizumab and mFOLFOX combination in resectable esophageal/gastric/GEJ adenocarcinoma is very effective with 90% ypRR, 21% ypCR, and impressive long-time survival benefits.

Keywords: CD8; GEJ; PD-L1; adenocarcinoma; esophageal gastric; immune checkpoint inhibitor (ICI); pathological response (ypRR); pembrolizumab; perioperative; tumor regression score (TRS).