Phase I/II trial of perioperative avelumab in combination with chemoradiation (CRT) in the treatment of stage II/III resectable esophageal and gastroesophageal junction (E/GEJ) cancer.

4034 Background: Neoadjuvant CRT followed by surgery is the standard of care for patients (pts) with stage II/III E/GEJ cancer, yet recurrence rates remain high. Immunotherapy has demonstrated activity in advanced E/GEJ cancer and was recently approved for adjuvant treatment of early stage disease. This trial evaluated the safety and efficacy of avelumab with perioperative CRT in resectable E/GEJ cancer. Methods: This is a two part phase I/II trial. Phase I was a safety run-in of 6 pts. Phase II planned to enroll an additional 18 pts in an expansion cohort. Pts with E/GEJ adenocarcinoma or squamous cell cancer received CRT (41.4 Gy in 23 fractions) with weekly carboplatin and paclitaxel. Three doses of avelumab (10 mg/kg IV, q14 days) were administered starting on day 29 of treatment, to coincide with the last chemotherapy dose. Surgery was performed 8-10 weeks after CRT completion. Pts received 6 doses of avelumab after resection (10 mg/kg IV, q14 days). The primary endpoint of the Phase 1 was safety and tolerability. The primary endpoint of the Phase II was pathologic complete response (pathCR) rate, assessing patients from the safety run in and expansion cohorts. Results: Between 6/2018 and 10/2021, 22 pts (20 males, median age 64) enrolled in the study. Enrollment was stopped after 16 patients in the expansion cohort due to accrual delays and changes in standard treatment. 19/22 patients (86%) had adenocarcinoma; 15/22 (68%) had lymph node positive disease at diagnosis. 19 pts underwent successful resection while on study. 3 pts went off study before resection due to grade 3 avelumab-related infusion reaction (1), patient preference (1), and non-adherence (1). There were no unexpected surgical complications. 4 pts (21%) had R1 resection with 3/4 having positive radial margin and 1/4 positive proximal margin. At resection, 5 pts (26%) had pathCR (3/16 adenocarcinomas, 2/3 squamous cell), 4 ypT1N0 disease, and 14/19 were ypN0. 42% had tumor regression score of 0 or 1. The combination of CRT and avelumab had an acceptable toxicity profile. No grade ≥3 immune-related AEs were observed. Immune-related hypothyroiditis was seen in 2 patients (grade 2). Three patients had grade 2 infusion-related reaction, but were able to continue with treatment. 21/22 pts had reversible grade ≥3 lymphopenia; 13/22 grade ≥ 3 wbc decrease; 6/22 grade 3 neutropenia. As of data cutoff on 2/1/2022, 1 patient remains on study treatment, 15 in follow up, 5 expired, 1 off study. Additional efficacy data is being collected. Correlative studies are ongoing. Conclusions: Perioperative CRT with avelumab is well tolerated with no unexpected toxicities. Neoadjuvant chemoradiation with immunotherapy is a promising approach for patients with E/GEJ tumors. Additional safety, efficacy and correlative analysis from this study will be presented at the meeting. Clinical trial information: NCT03490292.