Perioperative immunochemotherapy (mDCF + avelumab) in locally advanced gastro-esophageal adenocarcinoma: A phase II trial.

4055 Background: Perioperative chemotherapy improves cure rate in locally advanced gastro-esophageal adenocarcinoma (GEA). Immune checkpoint inhibitors have activity in GEA. This trial is testing the hypothesis that the addition of avelumab, an anti-PD-L1 antibody, to perioperative mDCF chemotherapy, will increase the pathologic complete response (pCR) rate, a potential surrogate for overall survival, in comparison with a historical pCR rate of 7%. Methods: Single-arm phase II study (NCT03288350) of avelumab + chemotherapy (modified docetaxel/cisplatin/5-FU or mDCF) given every 2 weeks x 4 cycles before and after surgery. Planned sample size of 50 operated patients. The hypothesis cannot be refuted if ≥6 patients show pCR, the primary endpoint. Inclusion criteria: histologically proven GEA, locally advanced disease (cT3-4 and/or N+), adequate organ function, WHO performance status 0-1. Exclusion criteria: other histology, metastatic stage, use of immunosuppressants, serious autoimmune disease, intake >10 mg prednisone/d. Adverse effects prospectively recorded per NCI CTCAE guidelines. Pathological response and tumor regression grade (TRG) determined by CAP criteria: 0=complete;1=near complete; 2=moderate; 3 = poor/no response. Data presented as median (range), KM determined survival. Results: Study accrual completed August 2022: 51 patients enrolled, 45 M/6 F, age 64 (18-79), ECOG 0 (35) and 1 (16). One patient withdrew consent after 2 treatment cycles and is excluded from efficacy analysis. Tumor anatomic site: Esophagus =19(38%)/gastroesophageal junction 21(42%)/subcardia stomach 10(20%). Staging: cT3 (88%), cT4 (6%), N+ (62%). Histology: all adenocarcinoma; dMMR 9/50 in 18%; CPS<1, 1-5, 6-10, >10 in 0%/33%/27%/40% of tumors tested. All 4 pre-operative cycles administered to 48/50 (96%); 36/50 received ≥2 adjuvant treatment cycles and 23/50 (46%) received all 8 cycles. Grade 3-4 toxicity events from neoadjuvant therapy affected: GI tract (diarrhea 4%); respiratory system (pneumonia 4%); endocrine system (adrenal insufficiency 2%). Other common side effects (grades 1-2, incidence > 15%) were: fatigue, diarrhea, skin rash/pruritus. Post-operative mortality at 30 and 90 days was 0/50 (0%) and 1/50 (2%). R0 resection was achieved in 48/50 (96%); a median of 36 (13-78) lymph nodes were resected. Pathological response was TRG 0/1/2/3 in 7/2/16/25 with pCR seen in 7 (14%), meeting the primary endpoint. Major pathologic response (TRG 0 and 1) was seen in 9 (18%), but without correlation with CPS or dMMR biomarker status. At 37.5 (9-71) months follow up, overall survival at 1, 2, and 3 years is 93.6%, 75.7%, and 69.2%. MPR showed a trend to improved survival ( p = 0.06). Conclusions: The neoadjuvant combination of avelumab with chemotherapy (mDCF) shows promising safety and efficacy in gastroesophageal adenocarcinoma, without obvious correlation to known biomarkers. Clinical trial information: NCT03288350 .