Total neoadjuvant chemoradiation combined with neoadjuvant PD-1 blockade for patients with pMMR, high-risk, and locally advanced middle to low rectal cancer.

3611 Background: Total neoadjuvant therapy (TNT) with chemotherapy and chemoradiotherapy (CRT) is the standard treatment for locally advanced rectal cancer patients, especially for those with high risk factors. And the effects of immune checkpoint inhibitors (ICIs) on rectal cancer with defect mismatch repair (dMMR) have been demonstrated. However, the efficacy of TNT combined with PD-1 blockage for rectal cancer patients with proficient mismatch repair (pMMR) is unknown. The purpose of this study is to evaluate the clinical safety and efficacy of neoadjuvant PD-1 blockade combined with TNT in locally advanced rectal cancer with pMMR. Methods: We designed a prospective, single-arm, phase II study on stage II and III dMMR rectal cancer with high risk factors. Patients received neoadjuvant POC regimen (PD-1 inhibitor, camrelizumab, also called SHR01210, 200mg d1, Oxaliplatin 130mg/m2 d1 and Capecitabine 1250mg/m2 bid1-14, q3wks) for three cycles, then with long course chemoradiation (IMRT, 1.8Gy/f*25f). If there were no disease progression occurs, patients would be treated with another two cycles of CapeOx. The primary endpoint was pathological complete response rate (pCR rate), and the secondary outcome include adverse events and surgical complication. Biopsies and plasma pre-neoadjuvant therapy were collected and performed with whole-exome sequencing (WES), and ctDNA sequencing, respectively. Results: 27 patients were screened, of whom 25 patients were enrolled. All patients have completed the TNT. After neoadjuvant treatment, 21 patients underwent TME surgery. 7 (33.3%) patients were pCR, 3 (14.3%) achieved clinical complete or near complete response and 7 (33.3%) had a major pathological response. No progressive disease was found. WES and ctDNA sequencing analysis showed that tumor mutation burden (TMB) and level of ctDNA did not differ significantly between responders and non-responders. However, 3 responders with TMB high were found to be defective in other DNA damage repair pathways. Conclusions: Total neoadjuvant chemoradiation combined with neoadjuvant PD-1 blockade can achieve high pathological response rate, demonstrating its antitumor efficacy in pMMR locally advanced rectal cancer patients with high risk factors.