Dostarlimab Gains Accelerated Approval in Rectal Cancer

Who falls within the new indication

The indication is defined by four elements: adulthood, a rectal primary, stage II or III locally advanced disease, and a qualifying tumor biomarker. The tumor must be microsatellite instability-high (MSI-H) or mismatch-repair deficient (dMMR), with status established by an FDA-authorized test.

Each element matters. The indication does not automatically extend to stage I rectal cancer, metastatic stage IV disease, colon cancer, pediatric disease, or tumors with proficient mismatch repair or microsatellite stability. Nor is locally advanced disease synonymous with unresectable disease; stage II and III rectal cancers can be technically resectable while still carrying substantial risks of local or distant recurrence.

MSI-H and dMMR describe related consequences of impaired DNA mismatch repair. Deficiency can be identified through loss of mismatch-repair protein expression, while high microsatellite instability reflects the resulting genomic phenotype. The two findings overlap substantially, but they arise from different testing approaches and should be documented using the terminology and specimen requirements of the authorized assay.

The distinction is clinically important because most rectal cancers are not dMMR or MSI-H. Stage alone therefore cannot establish eligibility. A patient with stage III disease but no qualifying biomarker result does not meet the indication simply because the cancer is locally advanced.

Evidence behind organ-preserving treatment

The FDA used the accelerated approval pathway, under which a drug may be cleared on an endpoint considered reasonably likely to predict clinical benefit. For this setting, clinical complete response and its durability can support an earlier regulatory decision, but they are not identical to longer-term outcomes such as disease-free survival, overall survival, avoidance of distant metastasis, or permanent preservation of rectal function.

The foundational published evidence came from a prospective, single-group phase 2 study of dostarlimab in previously untreated stage II or III dMMR rectal adenocarcinoma. Participants were to receive dostarlimab before standard chemoradiotherapy and surgery. Those with a clinical complete response could instead enter close surveillance without immediately proceeding to those treatments.

In the initial peer-reviewed report, all 12 patients who completed treatment had a clinical complete response, a response rate of 100% (95% CI, 74% to 100%). No patient had received chemoradiotherapy or undergone surgery at publication, and no progression or recurrence had been reported during follow-up ranging from 6 to 25 months.

No comparative effect estimate or p-value was available because the study had no control group. The FDA’s later regulatory assessment is the controlling source for the approved population and the evidence supporting accelerated approval; the initial publication provides context for the treatment strategy but should not be mistaken for the complete regulatory dataset.

Clinical complete response also requires more than improvement on a single scan. In the phase 2 program, assessment incorporated clinical examination, endoscopy and imaging. That intensive evaluation is central to a nonoperative strategy because residual or regrowing disease must be identified while salvage treatment may remain feasible.

Why the authorized-test requirement matters

The biomarker language is not an optional refinement. It is part of the labeled population. An FDA-authorized test has undergone agency review for a defined intended use, including its analytical performance, specimen types, interpretation and limitations. Check the applicable authorization and current labeling because not every assay that reports MSI or mismatch-repair status is necessarily authorized for selecting patients under this indication.

In practice, pathology reports may describe immunohistochemical loss of MLH1, PMS2, MSH2 or MSH6, an MSI result from polymerase chain reaction testing, or an MSI call generated by next-generation sequencing. These methods are related but not interchangeable, depending on their validated use. A report should identify the method, result and laboratory clearly enough for the oncology team to determine whether it satisfies the label.

An indeterminate, technically inadequate or missing result is not the same as a negative result, but neither establishes eligibility. Discordance can also occur—for example, between mismatch-repair immunohistochemistry and an MSI assay. Such cases may warrant pathology review and repeat or orthogonal testing rather than assuming that either result is correct.

Testing has implications beyond drug selection. dMMR or MSI-H rectal cancer can raise the possibility of Lynch syndrome, although tumor biomarker positivity does not itself diagnose an inherited condition. Germline risk assessment remains a separate process guided by the tumor pattern, personal history, family history and applicable clinical criteria.

What accelerated approval does—and does not—establish

The decision creates a federal indication for a biomarker-defined group that has historically received combinations of chemotherapy, radiation and surgery. Avoiding or deferring those treatments could reduce permanent colostomy, bowel dysfunction, infertility, sexual dysfunction and other treatment burdens. The evidence supports that possibility in carefully assessed responders; it does not prove that every eligible patient will avoid standard local therapy indefinitely.

Accelerated approval is conditional on further evidence that verifies clinical benefit. Longer follow-up must establish whether responses remain durable and whether omission of chemoradiotherapy and surgery preserves control without increasing late local regrowth or distant metastasis. Surveillance resources also matter. The phase 2 approach depended on repeated examinations, endoscopy, and imaging, so outcomes from specialized centers may not transfer directly to settings where that follow-up cannot be delivered consistently.

Coverage and operational access may also turn on documentation. Stage, rectal origin, biomarker result, assay identity, and alignment with the current FDA label may all matter for prior authorization. FDA approval does not by itself determine an individual payer’s coverage policy or eliminate the need for multidisciplinary review.

Important uncertainties

The supporting program is nonrandomized and initially small, with no direct comparator receiving contemporary total neoadjuvant therapy, chemoradiotherapy, or surgery. A 100% response rate in 12 patients has a wide confidence interval, and short follow-up cannot establish cure. Selection at expert centers, intensive response assessment, and surveillance may limit generalizability.

Clinical complete response is also a surrogate outcome. It is meaningful because it permits consideration of organ preservation, but comparative long-term data are needed for survival, recurrence, function, and quality of life. Rare immune-mediated harms and outcomes in patients with major autoimmune disease, organ transplants, or other characteristics underrepresented in trials remain additional areas of uncertainty.

Questions clinicians ask

Does stage II or III disease alone make an adult eligible?

No. The indication requires locally advanced rectal cancer at stage II or III plus MSI-H or dMMR status established with an FDA-authorized test. A biomarker-negative, indeterminate, or untested tumor does not meet the biomarker-defined indication based on stage alone.

Can any local MSI or mismatch-repair assay be used?

The label’s authorized-test requirement makes the assay’s regulatory status and intended use relevant. A local result may help with clinical evaluation, but the team should verify the test name, method, specimen requirements and FDA-authorized use rather than assuming that every laboratory-developed or tumor-profiling assay satisfies the indication.

Does approval mean chemoradiotherapy and surgery can always be omitted?

No. The evidence supports surveillance without immediate chemoradiotherapy or surgery for patients who achieve a rigorously documented clinical complete response within the studied strategy. It does not establish organ preservation for patients with residual disease, uncertain response or inadequate access to the intensive follow-up used in the trial.

Why is the approval accelerated rather than traditional?

Accelerated approval permits access based on a response endpoint and its durability when those findings are considered reasonably likely to predict benefit. Continued approval can depend on confirmatory evidence, including longer-term assessment of recurrence, distant metastasis, survival and sustained avoidance of chemoradiotherapy or surgery.

References

1. FDA Grants Accelerated Approval to Dostarlimab for Locally Advanced Rectal Cancer — U.S. 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 Mismatch Repair Deficient Rectal Cancer — ClinicalTrials.gov, U.S. National Library of Medicine, 2019