PD-1 blockade boosted chemo-target therapy in cT4NxM0 pMMR/MSS colorectal cancer.

Abstract

e15606 Background: Immune checkpoint inhibitors (anti-PD-1 antibodies) have been testified good response in DNA mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) colorectal cancers (CRC), while DNA mismatch repair-proficient/microsatellite stable(pMMR/MSS) CRCs, accounting for 85% of all CRCs, display poor response. Effective combined therapies for pMMR/MSS are needed for patients with local advanced colorectal cancers. Methods: In this pilot study, we administered 6 preoperative doses of anti-PD-1 antibody Sintilimab and Oxaliplatin and 5-FU/CF (mFOLFOX6) combined with Bevacizumab (only 5 doses in order not to delay surgery) in patients with cT4NxM0 colon or upper rectal cancers. Sintilimab (at a fixed dose of 200mg) was administered intravenously every 2 weeks, with surgery planned approximately 12 weeks after the first dose. The primary end point was pathological complete response(pCR). We also evaluated the major pathological response, radiological and pathological regression, safety, tumor mutation burden and tumor microenvironment (TME) molecules. Results: As of data cutoff (Dec 31,2021), median follow-up was 4.5 months (IQR 1.5-9.4). All patients underwent R0 surgical resection without treatment-related surgical delays. Of the 18 tumors that were removed, 18 were completely resected. A pCR occurred in 10 of 18 resected tumors (56%) and a major pathological response (MPR, ≤10% residual viable tumor) in 14/18(78%). At data cutoff, 18 were alive and 17 were free of recurrence. Treatment-related adverse events of grade 3 or higher occurred in 10% of the patients. Among the pCR tumors, two were found to harbored POLE mutation. The degree of pathological regression was deeper than radiological tumor shrinkage. The expression of CD3+ or/and CD3+/CD4+ stroma around tumor in pretreated tissue was significantly lower when comparing pCR and non-pCR (both p= 0.024). Conclusions: Neoadjuvant Sintilimab combined with Bevacizumab and mFOLFOX6 was associated with few side effects, did not delay surgery and lead to a striking 56% and 78% complete and major pathological response. Stroma down-regulation of CD3 or CD3/CD4 expression was related to pCR.