Pembrolizumab, Radiotherapy, and Chemotherapy in Neoadjuvant Treatment of Malignant Esophago-Gastric Diseases (PROCEED): Assessment of Pathologic Response in a Prospective, Phase II Single-Arm Trial

A standard treatment paradigm for locally advanced, resectable, non-metastatic esophageal or gastric adenocarcinomas (EGA) is neoadjuvant chemoradiation (CRT) followed by surgical resection. Historical pathologic complete response (pCR) rate after CRT with carboplatin/paclitaxel per the CROSS trial was 23%. The efficacy of immune checkpoint inhibition in the adjuvant setting has since been demonstrated in this patient population. The primary objective of this trial was to investigate whether neoadjuvant CRT combined with pembrolizumab improves pCR compared to the historical control of CRT alone.Single-institution, prospective phase II trial (NCT03064490) evaluating the efficacy and safety of neoadjuvant pembrolizumab combined with CRT followed by adjuvant pembrolizumab in patients with locally advanced operable EGA. CRT (45 Gy in 25 fractions with concurrent, weekly carboplatin [AUC 2] and paclitaxel [50mg/m2 of BSA]) with three cycles of pembrolizumab were administered as neoadjuvant therapy. Patients also received three cycles of adjuvant pembrolizumab after surgical resection. Baseline characteristics were collected. Pathologic response was scored from 0-3 based on tumor regression grading (TRG), with 0 indicating a complete response, 1 indicating marked response (<10% residual disease), 2 indicating partial response, and 3 indicating poor or no response. The percentage of patients with pCR and major pathologic response (MPR, score of 0-1) are described.Accrual of this trial is now complete, with 35 patients with cT2-3N0-2M0 EGA enrolled from 10/10/2017-10/07/2022. 89% of enrolled patients are male, and 94% are white. 97% of patients have an esophageal primary. One patient withdrew from the study prior to completing neoadjuvant therapy due to a severe drug reaction. Two other patients did not undergo surgery, one due to preference and the other due to development of metastatic disease. Of 32 remaining eligible patients, 28 have completed neoadjuvant therapy and surgical resection to date. 100% of patients underwent IMRT/VMAT. 27/28 (97%) patients underwent R0 resection. 10/28 (35.7%: 95% CI: 17%, 53%) patients achieved a pCR, and 14/28 (50%: 95% CI: 31%, 68%) patients achieved an MPR.Patients undergoing neoadjuvant CRT combined with pembrolizumab for EGA experienced a higher rate of pCR/MPR compared to historical controls treated with CRT alone. This phase II trial demonstrates the efficacy of this treatment paradigm, which warrants assessment in future prospective studies.