Durable complete responses to PD-1 blockade alone in mismatch repair deficient locally advanced rectal cancer.

Background: Early results have demonstrated that locally advanced mismatch repair deficient rectal cancers can become undetectable with PD-1 blockade alone and do not require chemotherapy, radiation, or surgery. Yet, the durability of this approach is unknown. Methods: We enrolled 47 mismatch repair deficient rectal cancers to a phase II study of 6-months of dostarlimab, a PD-1blocking monoclonal antibody. Co-primary endpoints were response rate that was previously met and the sustained clinical complete response rate, which has not yet been reported. A sustained clinical complete response was defined as complete pathologic response at surgery or no evidence of tumor by MRI, endoscopy, and digital rectal exam for at least 12 months following completion of therapy. If 13 or more patients achieved a sustained clinical complete response out of the first 30 patients, the study would be deemed successful. Results: All of the 41 patients who completed treatment achieved a clinical complete response. No patients required any additional therapy, and no patients experienced local or distant disease recurrence. Twenty patients achieved a sustained clinical complete response with a median follow-up of 28.9 months (95% CI 22.9 -37.1) from first treatment, which satisfied the second co-primary endpoint. No serious adverse events greater than grade 2 were observed. Ultrasensitive tumor-informed circulating tumor DNA levels and tumor bed biopsies normalized earlier than endoscopy, MRI or PET/CT. Conclusions: PD-1 blockade for 6-months alone yields durable recurrence-free responses in locally advanced mismatch repair deficient rectal cancer without the need for chemotherapy, radiation, or surgery. Clinical trial information: NCT04165772.