Short-course radiotherapy and chemotherapy with or without PD-L1 blockade (envafolimab) for MSS locally advanced rectal cancer: Interim analysis of the randomized phase III PRECAM-R trial.

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Background: Microsatellite stable (MSS) locally advanced rectal cancer (LARC) is refractory to immune checkpoint inhibitors. Our prior Phase II trial demonstrated remarkable efficacy, suggesting short-course radiotherapy (SCRT) plus chemotherapy acts as a potent immunogenic primer for PD-L1 blockade (via subcutaneous envafolimab). We conducted this multicenter, randomized Phase III trial (PRECAM-R) to validate if this patient-centric strategy, combining SCRT, chemotherapy, and immunotherapy, improves outcomes versus standard care. Methods: Patients with resectable, stage II/III (cT3-4a/N+) MSS LARC were randomized (1:1) to the Experimental Group (SCRT 5×5 Gy, then only 2 cycles CAPEOX plus subcutaneous envafolimab) or Control Group (SCRT then CAPEOX). Total mesorectal excision (TME) was performed following neoadjuvant therapy. The primary endpoint was pCR (ypT0N0). Secondary endpoints included tumor regression grade (TRG), Neoadjuvant Rectal (NAR) score, and safety. This pre-specified interim analysis was triggered after 58 patients completed surgery. Results: Fifty-eight eligible eligible patients were randomized (n=29 per arm). Baseline characteristics were well-balanced; 77.6% had Stage III disease. The Experimental Group achieved a pCR rate of 44.8% (13/29), significantly tripling that of the Control Group (13.8% [4/29]; P = 0.0195). Major pathological response (TRG 0-1) rates were 72.4% vs. 51.7% (P = 0.176). The Experimental Group showed superior distribution of tumor downstaging based on NAR scores ( P = 0.036). Notably, early distant metastasis occurred in 13.8% (4/29) of patients in the Control Group (liver/lymph nodes) compared to 0% in the Experimental Group. The addition of envafolimab was well-tolerated, with Grade 3-4 adverse events comparable to the control arm (3.4% vs. 0%, P > 0.99). Crucially, this strategy did not compromise surgical safety, showing no increase in operative complexity or postoperative complications (10.3% vs 13.8%, P > 0.99). Conclusions: This regimen, featuring a patient-centric short-course backbone, shows promise in overcoming resistance to PD-L1 blockade in MSS LARC. This strategy yields high pCR rates and tumor regression with high compliance and a favorable safety profile. The early signal for systemic control positions this convenient regimen as a compelling option for organ preservation. Clinical trial information: NCT05752136 .

Interim efficacy and safety outcomes.