Philip Paty

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. Because mismatch repair-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 mismatch repair-deficient, locally advanced rectal cancer. METHODS: We 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 mismatch repair-deficient stage II or III rectal adenocarcinoma. This treatment was to be followed by standard chemoradiotherapy and surgery. Patients who had a clinical complete response after completion of dostarlimab therapy would proceed without chemoradiotherapy 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 chemoradiotherapy and overall response to neoadjuvant dostarlimab therapy with or without chemoradiotherapy. RESULTS: F-fluorodeoxyglucose-positron-emission tomography, endoscopic evaluation, digital rectal examination, or biopsy. At the time of this report, no patients had received chemoradiotherapy or undergone surgery, and no cases of progression or recurrence had been reported during follow-up (range, 6 to 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 PD-1 blockade. Longer follow-up is needed to assess the duration of response. (Funded by the Simon and Eve Colin Foundation and others; ClinicalTrials.gov number, NCT04165772.).

LBA3512 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 .