Colon to Rectum
N Engl J Med. 2022;386(25):2363–76
PD-1 blockade in mismatch repair-deficient, locally advanced rectal cancer
Background: Neoadjuvant chemotherapy and radiation followed by surgical resection of the rectum is a standard treatment for locally advanced rectal cancer. A subset of rectal cancer is caused by a deficiency in mismatch repair (MMR). Because MMR-deficient colorectal cancer is responsive to programmed death 1 (PD-1) blockade in the context of metastatic disease, it was hypothesized that checkpoint blockade could be effective in patients with MMR-deficient, locally advanced rectal cancer.
Methods: The authors initiated a prospective phase 2 study in which single-agent dostarlimab, an anti-PD-1 monoclonal antibody, was administered every 3 weeks for 6 months in patients with MMR-deficient stage II or III rectal adenocarcinoma. This treatment was to be followed by standard chemoradiotherapy (CRT) and surgery. Patients who had a clinical complete response after completion of dostarlimab therapy would proceed without CRT and surgery. The primary end points are sustained clinical complete response 12 months after completion of dostarlimab therapy or pathological complete response after completion of dostarlimab therapy with or without CRT and overall response to neoadjuvant dostarlimab therapy with or without CRT.
Results: A total of 12 patients have completed treatment with dostarlimab and have undergone at least 6 months of follow-up. All 12 patients (100%, 95% confidence interval: 74–100) had a clinical complete response, with no evidence of tumor on magnetic resonance imaging, 18F-fluorodeoxyglucose-positron-emission tomography, endoscopic evaluation, digital rectal examination, or biopsy. At the time of this report, no patients had received CRT or undergone surgery, and no cases of progression or recurrence had been reported during follow-up (range, 6–25 months). No adverse events of grade 3 or higher have been reported.
Conclusions: Mismatch repair-deficient, locally advanced rectal cancer was highly sensitive to single-agent programmed death 1 blockade. Longer follow-up is needed to assess the duration of response.