Rectal Cancer: Who Fits the Dostarlimab Approval

The approval defines a narrow treatment population

The FDA decision, dated October 19, 2026, creates a treatment option before chemotherapy, radiation or surgery for a biomarker-selected group with stage II or III rectal cancer. It does not establish dostarlimab as initial therapy for all rectal cancers.

An adult matches the approved population when the tumor is locally advanced rectal cancer, the disease is stage II or III, no treatment has been given for that cancer, and testing demonstrates high microsatellite instability or deficient mismatch repair. The prescribing information and FDA approval notice remain controlling when determining eligibility, including the required test and any label-specific qualifications.

Each element matters. “Untreated” distinguishes this indication from approvals involving previously treated, recurrent or advanced tumors. “Locally advanced” excludes an automatic extrapolation to stage I disease or metastatic stage IV disease. MSI-H and dMMR identify overlapping biological groups in which loss of DNA mismatch-repair function produces numerous mutations and can increase susceptibility to PD-1 blockade.

Patients with mismatch repair-proficient or microsatellite-stable tumors do not match this biomarker-defined indication. Neither do patients whose biomarker status is unknown. A suggestive family history, young age or inherited-cancer risk cannot substitute for testing of the cancer when treatment eligibility depends on tumor status.

What the early clinical evidence showed

The landmark prospective evidence was a single-group phase 2 study of dostarlimab in patients with untreated stage II or III dMMR rectal adenocarcinoma. Participants received PD-1 blockade first and were assessed repeatedly by endoscopy, digital rectal examination and imaging. The protocol planned chemoradiotherapy and surgery for patients without a complete clinical response; those with a sustained complete response entered nonoperative surveillance.

The initial New England Journal of Medicine report included 12 patients who completed treatment and had at least six months of follow-up. All 12 had a complete clinical response, an observed rate of 100% with a reported 95% confidence interval of 74% to 100%. At the time of that report, none had received chemoradiotherapy or surgery, and no progression or recurrence had been reported during follow-up ranging from 6 to 25 months. Median follow-up was 12 months.

These findings were unusually consistent but preliminary. A complete clinical response is determined through clinical, endoscopic and radiologic assessment; it is not identical to a pathologic complete response confirmed by examination of a resected specimen. Avoiding surgery also means there is no surgical specimen against which the clinical assessment can be checked.

The FDA used the accelerated approval pathway, which permits approval based on an endpoint considered reasonably likely to predict clinical benefit. Continued approval can depend on verification and description of benefit in further evidence. The regulatory decision should therefore be read as an authorization for a defined population, not as proof that every treated patient can permanently avoid radiation, chemotherapy or resection.

Testing belongs near the start of the pathway

For a new rectal cancer diagnosis, MSI or mismatch-repair testing needs to be available before the multidisciplinary team commits the patient to a neoadjuvant strategy. In practice, testing follows histologic confirmation and should run alongside staging rather than waiting until treatment begins.

Mismatch-repair status is commonly evaluated by immunohistochemistry for MLH1, PMS2, MSH2 and MSH6. Loss of expression in one or more proteins supports dMMR. MSI testing uses molecular methods to identify instability in repetitive DNA sequences; an MSI-H result can establish the relevant biomarker phenotype. Discordant, indeterminate or technically inadequate results may require repeat testing, an alternative method or pathology review before a treatment decision is made.

Testing has two distinct consequences. First, it may identify an adult who fits the dostarlimab indication. Second, dMMR can signal Lynch syndrome, making hereditary-cancer evaluation relevant for the patient and potentially for relatives. Tumor testing and germline testing answer different questions: the former guides tumor classification and treatment, while the latter assesses inherited predisposition.

Precise staging remains essential even after a positive biomarker result. Pelvic imaging, assessment for distant disease and multidisciplinary review establish whether the cancer is stage II or III and locally advanced. A positive MSI-H or dMMR result alone does not place a patient within the approved population if the anatomical stage, treatment history or primary tumor site does not match.

How the decision changes treatment planning

Standard management of locally advanced rectal cancer has generally combined systemic chemotherapy, pelvic radiation and surgery in varying sequences. These approaches can provide durable tumor control but may affect bowel, urinary, sexual and reproductive function. The dostarlimab approval introduces a biomarker-directed alternative that may allow some patients who achieve a complete clinical response to enter a nonoperative management pathway.

That possibility requires infrastructure, not merely a prescription. Response assessment must integrate endoscopy, examination, and imaging, with close surveillance that can detect local regrowth or distant recurrence. A team that includes medical oncology, colorectal surgery, radiation oncology, radiology, gastroenterology, and pathology should make decisions about withholding chemoradiotherapy and surgery.

A positive biomarker result should therefore trigger a treatment discussion, not an assumption that organ preservation is guaranteed. Patients who do not achieve a complete clinical response, develop progression, or whose response cannot be reliably assessed may still need established multimodality treatment. The FDA approval does not remove those options.

Important uncertainties remain

The foundational study was nonrandomized, had no standard-treatment comparator and initially reported only 12 evaluable patients. Its confidence interval was wide, reflecting the small sample. The study could demonstrate a high observed response rate, but it could not directly compare overall survival, disease-free survival, late recurrence, quality of life or treatment-related function with chemoradiotherapy and surgery.

Generalizability also needs attention. Trial participants were selected for dMMR disease and managed at centers with specialized staging, response assessment and surveillance. Outcomes may differ where pathology confirmation, high-resolution imaging, endoscopic reassessment or rapid salvage treatment is less consistently available. Longer follow-up and confirmatory evidence are needed to establish how often organ preservation remains durable and whether delayed standard treatment preserves long-term outcomes after incomplete response or regrowth.

Questions clinicians ask

Who should be considered under this approval?

Adults with untreated stage II or III locally advanced rectal cancer may be considered when validated tumor testing confirms MSI-H or dMMR. Patients with stage I, metastatic, previously treated, microsatellite-stable or mismatch repair-proficient disease should not be assumed to fit this specific indication.

When should MSI or mismatch-repair testing be ordered?

Testing should be initiated on diagnostic tumor tissue early enough to inform the first multidisciplinary treatment plan, ideally while local and distant staging are being completed. Waiting until after neoadjuvant therapy begins can eliminate the opportunity to consider the approved biomarker-directed approach as initial treatment.

Does a complete clinical response mean surgery is no longer needed?

Not automatically. A complete clinical response can support nonoperative surveillance in an appropriately monitored pathway, but it is not pathologic confirmation of eradication. Long-term durability, local regrowth and the effectiveness of delayed salvage treatment remain central considerations under accelerated approval.

Does dMMR testing replace hereditary-cancer assessment?

No. Tumor testing determines mismatch-repair phenotype and may establish treatment eligibility, whereas germline evaluation addresses whether an inherited pathogenic variant is present. An abnormal mismatch-repair pattern should prompt interpretation using the specific protein-loss pattern, tumor findings, age and family history.

References

1. FDA Grants Accelerated Approval to Dostarlimab for Locally Advanced Rectal Cancer — US Food and Drug Administration, 2026 2. PD-1 Blockade in Mismatch Repair–Deficient, Locally Advanced Rectal Cancer — The New England Journal of Medicine, 2022 3. Dostarlimab in Untreated Mismatch Repair Deficient Locally Advanced Rectal Cancer — ClinicalTrials.gov, 2019 4. Rectal Cancer Treatment (PDQ®)–Health Professional Version — National Cancer Institute, 2026