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 responds to programmed cell death 1 (PD-1) blockade in the context of metastatic disease, we hypothesized that checkpoint blockade might be effective in patients with locally advanced and error repair deficient 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 stage II or III rectal adenocarcinoma with error repair deficiency. pairing.
This treatment was to be followed by standard chemoradiotherapy and surgery. Patients who had a complete clinical response after completing dostarlimab therapy would continue without chemoradiotherapy or surgery .
The primary endpoints are sustained complete clinical response 12 months after completing dostarlimab therapy or pathologic complete response after completing dostarlimab therapy with or without chemoradiotherapy and overall response to neoadjuvant dostarlimab therapy with or without chemoradiotherapy.
Results
A total of 12 patients have completed treatment with dostarlimab and have had at least 6 months of follow-up. All 12 patients ( 100% ; 95% confidence interval, 74 to 100) had a complete clinical response, with no evidence of tumor on magnetic resonance imaging, 18F-fluorodeoxyglucose-positron emission tomography, endoscopic evaluation, digital rectal or biopsy.
At the time of this report, no patients had received chemoradiotherapy or surgery, and no cases of progression or recurrence had been reported during follow-up (range, 6 to 25 months).
No grade 3 or higher adverse events have been reported.
Conclusions
Locally advanced rectal cancer, deficient in mismatch repair, was highly sensitive to single-agent PD-1 blockade. Longer follow-up is needed to evaluate the duration of the response.
In our study, single-agent dostarlimab was remarkably effective in locally advanced and mismatch repair-deficient rectal cancer, providing a complete clinical response in all 12 patients who completed treatment to date.
The study also provides a framework for the evaluation of highly active anticancer therapies in the neoadjuvant setting, in which patients could avoid chemoradiotherapy and surgery while their tumor is treated when it is most likely to respond, that is, before exposure to other agents that could select for cells with a resistant phenotype.
(Funded by the Simon and Eve Colin Foundation and others; ClinicalTrials.gov number, NCT04165772. opens in new tab.)
Deficiency Mismatch Repair (dMMR) Describes cells that have mutations (changes) in certain genes that are involved in correcting errors made when DNA is copied in a cell. Mismatch repair (MMR)-deficient cells usually have many mutations in their DNA, which can lead to cancer. MMR deficiency is most common in colorectal cancer , other types of gastrointestinal cancer, and endometrial cancer, but can also be found in breast, prostate, bladder, and thyroid cancers. MMR deficiency can also be found in an inherited disorder called Lynch syndrome. Knowing if a tumor is deficient in MMR can help plan treatment or predict how well the tumor will respond to treatment. |
