Dostarlimab Opens Treatment-Only Path in Rectal Cancer

What the FDA decision changes

The decision establishes a treatment-only pathway for a narrowly defined molecular subgroup of rectal cancer. It does not make dostarlimab a replacement for standard multimodality care across all locally advanced disease, nor does receiving the drug alone guarantee that chemotherapy, radiation or surgery will be avoided.

The indication applies to adults with locally advanced rectal cancer that is microsatellite instability-high, or MSI-H, or mismatch repair-deficient, or dMMR, who have not previously received treatment for the cancer. Eligibility therefore depends on both treatment history and a validated tumor biomarker result. Patients with microsatellite-stable or mismatch repair-proficient tumors are not eligible.

Dostarlimab is a programmed death receptor-1 blocking antibody. In this setting, the therapeutic strategy is to induce a complete clinical response before exposing a patient to treatments that can produce permanent bowel, urinary, sexual and reproductive effects. Patients whose tumors respond completely may enter intensive surveillance, while those with an incomplete response, tumor regrowth or progression may still require chemoradiation, surgery or other established treatment.

The word “may” matters. Avoiding conventional therapy depends on response and follow-up, not on treatment initiation.

Evidence behind the treatment-only approach

The evidence comes from a prospective, single-group phase 2 study of dostarlimab in untreated, locally advanced dMMR rectal cancer. There was no randomized comparator. Participants received dostarlimab and underwent repeated clinical, endoscopic and radiologic assessments; patients with a complete clinical response could omit planned chemoradiation and surgery and proceed to surveillance.

In the initial peer-reviewed report, all 12 patients who completed treatment and had at least six months of follow-up achieved a complete clinical response. No patient in that early group had received chemoradiation or undergone surgery, and no progression or recurrence was reported during follow-up ranging from six to 25 months. The median follow-up was 12 months. Because the cohort was small and lacked a control group, those findings demonstrated feasibility and a striking response signal rather than comparative superiority or durable cure.

The FDA subsequently evaluated an expanded experience for the accelerated approval. Its regulatory notice identifies complete clinical response and the durability of that response as the central efficacy evidence. These endpoints can support earlier access to a therapy when they are considered reasonably likely to predict clinical benefit, but accelerated approval requires further evidence to verify benefit.

A clinical complete response is not synonymous with pathologic complete response. The former is determined without removing the rectum, using a combination of digital rectal examination, endoscopy, pelvic magnetic resonance imaging and other assessments specified by the protocol or clinical plan. A pathologic complete response can be confirmed only by examining resected tissue. Nonoperative management therefore accepts residual uncertainty in exchange for the possibility of organ preservation.

Who falls within the approval

The pathway begins with accurate molecular classification. dMMR may be established through loss of mismatch repair protein expression, while MSI-H status is generally identified through a validated molecular assay. Discordant, equivocal or technically inadequate findings warrant clarification before treatment decisions are based on the result. The FDA indication and current prescribing information should guide the required testing framework.

“Previously untreated” should also be read literally in relation to the locally advanced rectal cancer. The approval is not evidence that dostarlimab monotherapy can routinely replace salvage treatment after chemotherapy, pelvic radiation or surgery. Patients treated in the supporting study entered before standard neoadjuvant therapy and were managed under a structured response-assessment protocol.

The evidence is most directly applicable to adults resembling the study population: patients with localized, locally advanced rectal adenocarcinoma; confirmed MSI-H or dMMR status; no previous rectal cancer therapy; and the ability to complete immunotherapy and comply with close surveillance. Extrapolation to early-stage disease, metastatic disease, recurrent tumors, other histologies or medically fragile populations is not established by this approval.

Hereditary risk should remain a separate consideration. dMMR or MSI-H rectal cancer can be associated with Lynch syndrome, although the tumor phenotype does not by itself establish an inherited diagnosis. Appropriate genetic evaluation can affect counseling, surveillance for other cancers and testing of relatives, but it does not replace confirmation of eligibility for dostarlimab.

Framing the option in clinical practice

Discussions should distinguish three decisions: whether the patient meets the labeled molecular and treatment-history criteria, whether dostarlimab is an appropriate initial therapy, and whether the observed response is sufficiently complete and durable to continue without chemoradiation or surgery. These decisions occur at different times and require multidisciplinary review.

The practical attraction is substantial. Standard treatment for locally advanced rectal cancer commonly combines systemic chemotherapy, pelvic radiation and total mesorectal excision, with sequencing determined by the clinical context. Although these approaches can be curative, they may cause neuropathy, bowel dysfunction, infertility, sexual dysfunction, urinary effects or a permanent ostomy. A nonoperative pathway can avoid those burdens for patients who maintain a complete response.

Clinicians should present conventional therapy as deferred rather than erased. The treatment plan needs predefined assessments, a surveillance schedule and a clear route to salvage treatment if residual disease, regrowth or metastasis appears. Patients must understand that surveillance is an active component of care requiring repeated examinations, endoscopy and imaging. Missing follow-up could compromise the opportunity for timely salvage.

Immune-related toxicity also remains relevant even when chemotherapy and radiation are avoided. PD-1 blockade can cause inflammatory adverse reactions affecting organs including the thyroid, pituitary, lungs, liver, bowel, kidneys, skin and nervous system. Some toxicities require corticosteroids or other immunosuppression and may be prolonged or irreversible. Counseling should compare the different burdens of treatment rather than describe immunotherapy as toxicity-free.

Uncertainties that remain

The principal limitation is the nonrandomized design. Without a concurrent standard-care group, the study cannot directly establish that dostarlimab provides equivalent or better overall survival, disease-free survival, quality of life or salvageability. A 100% response proportion in an early, selected cohort is clinically notable, but it does not remove uncertainty about rare failures or outcomes over many years.

Generalizability is also constrained by the rarity of dMMR rectal cancer and the specialized assessments used in an organ-preservation program. Response classification and surveillance quality may differ outside experienced multidisciplinary centers. Longer follow-up is needed to define the frequency and timing of local regrowth, distant metastasis, late immune toxicity and successful salvage.

Accelerated approval explicitly reflects this uncertainty. Continued authorization can depend on confirmatory evidence showing that the response-based endpoint translates into durable clinical benefit. Clinicians and health systems should therefore track outcomes carefully and revisit the evidence as follow-up matures.

Questions clinicians ask

Does every untreated patient with dMMR rectal cancer qualify?

No. The approval concerns adults with previously untreated, locally advanced rectal cancer and confirmed MSI-H or dMMR status. Clinical stage, pathology, biomarker validity, comorbidities and ability to undergo intensive follow-up still require review; the indication should not be extrapolated automatically to earlier-stage, recurrent or metastatic disease.

Can surgery be ruled out before dostarlimab begins?

No. The evidence supports deferring chemoradiation and surgery when a complete clinical response is documented and maintained. Patients should know from the outset that incomplete response, progression or later regrowth may trigger standard treatment, including surgery, if it remains clinically appropriate.

How is complete response established without resection?

Assessment relies on concordant clinical, endoscopic and imaging findings rather than one negative test. Digital rectal examination, endoscopy and pelvic MRI are central to the studied strategy, with repeated evaluations needed because clinical complete response cannot provide the same tissue confirmation as pathologic examination after surgery.

Why is the approval accelerated rather than traditional?

The FDA relied on complete clinical response and its durability as endpoints reasonably likely to predict meaningful benefit. Those findings allow earlier access, but they leave uncertainty about long-term recurrence, survival and successful salvage; confirmatory evidence is required to verify the anticipated clinical benefit.

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. Study of Dostarlimab in Untreated Mismatch Repair Deficient Locally Advanced Rectal Cancer — ClinicalTrials.gov, 2019