Pd1 antibody sintilimab for dMMR/MSI-H locally advanced rectal cancer: An open-label, phase 2, single-arm study (cohort A).
Authors: Chen Gong , Wang Feng , Xiao Weiwei , Jin Ying , Zhang Rong-Xin , Cai Peiqiang , Liu Min , He LongJun , Xi ShaoYan , Chen Xiaobing , Zhang Huizhong , Pan Zhi-Zhong , Xu Rui-hua 
Published: June 2021

e15602 Background: Immunotherapy has shown satisfactory effect for dMMR/MSI-H colorectal cancer patients. Whether Pd-1 antibody would bring benefit for dMMR/MSI-H locally advanced rectal cancer (LARC) patients in neoadjuvant setting is worthy of investigation. This is a clinical trial with two cohorts according the MMR/MSI status(clinicalTrials.gov, NCT04304209). Methods: LARC patients with dMMR or MSI-H tumor will enter Cohort A and receive neoadjuvant Pd1 antibody sintilimab for four cycles and subsequent surgery or watch and wait, followed by adjuvant four cycles of Pd1 antibody sintilimab with or without chemotherapy. Main inclusion criteria include: cT3-4N0M0 or cTxN+M0 rectal adenocarcinoma, dMMR/MSI-H confirmed by immunohistochemistry (IHC) or gene test, aged 18-75y; ECOG performance 0-1; no previous anti-tumor treatment for rectal adenocarcinoma. Primary outcome is pathologic complete response (pCR) rate. We use a Simon two-stage optimum design to test the null hypothesis of a 15% pCR rate, the historical response rate to standard neoadjuvant chemoradiotherapy (NACRT), against the desired alternative of 30% pCR rate. This had a one-sided type I error of 5% and a power of 80%. In the first stage of this design, 19 patients will be accrued. If 3 or fewer pCR was observed, the study was to be terminated and declared negative. If the trial goes on to the second stage, a total of 55 patients will be studied. The study was deemed to have met its primary endpoint if confirmed pCR were observed in 13 or more patients. Considering 10% dropout rate, a total of 61 patients will be enrolled. Whole exome sequencing, bulk RNA sequencing, single cell RNA sequencing and IHC of the rectal primary tumor are planned. The study started in October, 2019. Results: Eight patients have been enrolled and six have response evaluation results. Four patients achieved clinical complete response (cCR) after 4 cycles of neoadjuvant Pd1 antibody sintilimab treatment and three of them enter watch and wait strategy and finished the adjuvant 4 cycles of Pd1 antibody sintilimab treatment. The 4th patient was diagnosed as lynch syndrome, but molecular test was not feasible for the tumors located at the sigmoid and hepatic flexure because of ileus. He received subtotal colectomy and tumors at the sigmoid and hepatic flexure also achieved pCR. The 5th patient has partial response after 4 and 8 cycles of sintilimab treatment, and then received Dixon surgery and pathology showed major reponse (5% cancer cell left only in the mucosal layer, ypTis). The 6th patient has partial response after 4 and 8 cycles of sintilimab treatment, and sintilimab was still continued concerning intact bladder conservation. No grade 3 toxicity was noted yet. Conclusions: Pd1 antibody sintilimab achieved 4CR (pCR+cCR) in 6 dMMR/MSI-H LARC patients with limited toxicities. Pd1 antibody is quite effective and may be an alternative for these patients. Clinical trial information: NCT04304209.