PD-1 Inhibitor Effective in MSI-High Locally Advanced Rectal Cancer

In rectal cancer, the standard approach of preoperative chemoradiotherapy followed by surgery and adjuvant chemotherapy is being replaced by total neoadjuvant therapy, with patients who achieve a clinical complete response potentially avoiding surgery. Microsatellite instability (MSI)-high rectal cancers represent a rare subset of rectal cancers that may be highly responsive to immune checkpoint inhibitors.

Investigators now report results of a single institution, investigator-initiated phase 2 trial evaluating the anti–PD-1 agent dostarlimab as primary treatment for locally advanced rectal cancer. Patients with DNA mismatch repair protein–deficient rectal cancer detected by immunohistochemistry received intravenous dostarlimab (500 mg) every 3 weeks for 6 months, with frequent disease reassessment and referral for chemoradiotherapy and surgery only if a clinical complete response was not achieved. Treatment staging and follow-up included digital rectal exam, endoscopy with biopsy, rectal MRI, PET scan, and CT scans.

Of 16 patients enrolled, median age was 54, most were female (62%), and most were T3 (56%) and node positive (94%). Of 14 patients tested, 57% had germline DNA mismatch repair protein deficiency. Median follow-up was 12 months. Of 12 patients who completed therapy and had at least 6 months of follow-up, all (100%) achieved a clinical complete response, and none required chemotherapy, radiation, or surgery. This response rate met the trial's primary efficacy endpoint. At the time of the analysis, four of the 12 patients had had a sustained complete response for more than one year after completion of therapy. No new safety signals were observed. Accrual to a total of 30 patients is planned.