PKUCH 04 trial: Total neoadjuvant chemoradiation combined with neoadjuvant PD-1 blockade for pMMR/MSS locally advanced middle to low rectal cancer.

3609 Background: Total neoadjuvant therapy (TNT) with induction chemotherapy and chemoradiation is the standard of care for locally advanced rectal cancers. Incorporation of PD-1 blockade in the neoadjuvant setting is promising for mismatch repair deficient (dMMR) patients, yet the efficacy of TNT combined with PD-1 blockage for pMMR/MSS patients is little unknown. The purpose of this study is to evaluate the clinical benefit of neoadjuvant PD-1 blockade combined with TNT in pMMR/MSS locally advanced rectal cancer. Methods: We designed a prospective, single-arm, phase II study on locally advanced dMMR/MSS rectal cancer (PKUCH 04 trial). Patients will receiving neoadjuvant regimen (PD-1 inhibitor, camrelizumab, also called SHR01210, 200mg d1, oxaliplatin 130mg/m2 d1, capecitabine 1250mg/m2 bid1-14, for three cycles, then long course chemoradiation (IMRT, 1.8Gy/f*25f), then another two cycles of CapeOx (oxaliplatin 130mg/m2 d1, capecitabine 1250mg/m2 bid1-14, q3wks) if no disease progression occurs. The primary endpoint was pathologic complete response (pCR) rate, and the secondary outcome include adverse event and surgical complication. Tumor assessment was carried out after induction, chemoradiation, and before the decision of either surgery or watch and wait. Results: A total of 27 patients were screened and finally 25 patients were eligible for further analysis, with median age 58 years (range 31-70). The median distance from the anal verge was 5.3 cm (1.2-10). 76% were male, 76% had N2 disease, 56% positive MRF, 80% positive EMVI. All patients have completed the induction and chemoradiation phases. 21 patients underwent TME surgery, of which 7 had pathological complete response (33.3%). Four achieved clinical complete or near complete response and chose watch and wait. 7 had major pathological remission (over 90% remission). Another 7 had partial pathological remission. No progressive disease was found. 14 had LAR, 7 APR, and. The surgical complication rate was 14.3%, and the mortality rate was 0. The common adverse events included nausea (80%), lymphopenia (80%), paresthesia (76%), reactive cutaneous capillary endothelial proliferation (72%), neutropenia (68%). Grade 3 adverse events include lymphopenia (24%), diarrhea (8%), and thrombocytopenia (4%) and no grade 4 or 5 events were observed. Till January 2022, no recurrence or regrowth was found. Conclusions: Total neoadjuvant chemoradiation combined with neoadjuvant PD-1 blockade is safe and effective which can achieve good regression and sphincter preservation for pMMR/MSS rectal cancer. This suggests a potential new paradigm for treatment of pMMR/MSS locally advanced rectal cancer and necessitates further investigation. Clinical trial information: NCT04340401.