FDA Approval of Dostarlimab Brings Potential Organ-Sparing Approach in dMMR Locally Advanced Rectal Cancer

The FDA approval of dostarlimab-gxly (Jemperli) offers adult patients with stage II/III microsatellite instability–high (MSI-H) or mismatch repair–deficient (dMMR) locally advanced rectal cancer an opportunity to receive upfront immunotherapy and potentially avoid standard chemotherapy, radiation, and surgery options, according to Andrea Cercek, MD.

On October 19, 2026, the regulatory agency granted accelerated approval to the anti–PD-1 monoclonal antibody for the treatment of adult patients with stage II or III dMMR) or MSI-H locally advanced rectal cancer, as determined by an FDA-authorized test.^1,2 This decision was supported by data from the phase 2 AZUR-1 trial (NCT05723562), which showed that evaluable patients (n = 116), sustained clinical complete response for 12 months (cCR12) was achieved at a rate of47% (95% CI, 37%-56%); notably, 33% of patients in this population experienced cCR but had less than 12 months of follow-up at data cutoff, and 38% of patients had a near Cr. In investigator-evaluable patients (n = 144), 68% (95% CI, 60%-76%) experienced cCR12.

“[Allowing patients to potentially avoid chemotherapy, chemoradiation, and surgery] is honestly the most exciting part right now. That’s where we are for patients, and hopefully beyond just this study as well,” Cercek said in an interview with OncLive^®. “[We’re] thinking about a patient-centric outcome and using our biomarkers—in this case, dMMR—and immunotherapy to be able to eliminate the standard of care and enable them to live their lives as best as possible despite having had this cancer.”

In the interview, Cercek discussed the approval’s clinical significance, the design and findings of AZUR-1, and the implications of preserving organ function. Cercek is section head of colorectal cancer, co-director of the Center for Young Onset Colorectal and Gastrointestinal Cancers, and the Ford Family Chair at Memorial Sloan Kettering Cancer Center in New York, New York.

OncLive: What is the significance of the FDA approval of dostarlimab for patients with stage II/III dMMR locally advanced rectal cancer?

Cercek: The most exciting point and the significance is that all patients [with dMMR] locally advanced rectal cancer can receive up-front immunotherapy with dostarlimab and potentially avoid standard of care, which would include chemotherapy, chemoradiation, and surgery.

What’s been most exciting in terms of having immunotherapy and dostarlimab as an option in dMMR rectal tumors is that, from our [phase 2] study [NCT04165772],³ we now have a sufficient number of years of follow-up where we can say that [some] patients were cured with dostarlimab alone. They not only saw their tumors disappear, [but also] had no toxicity in terms of the bladder, bowel, sexual [function], and fertility [effects] that we normally would see with standard of care. Now the tumors have not come back, so they’ve been cured.

How was the phase 2 AZUR-1 trial designed to evaluate nonoperative management in dMMR rectal cancer?

AZUR-1 was a registrational global study conducted in 10 countries worldwide. It was a single-arm design, exactly like the investigator-initiated [phase 2] study at Memorial Sloan Kettering Cancer Center, with up-front or induction dostarlimab for 6 months in stage II/III dMMR locally advanced rectal cancer, followed by the opportunity for nonoperative management if patients had a cCR.

The question was the durability of this clinical complete response, or what’s called cCR12. We wanted to see that the tumors not only disappeared, the patient had a cCR, but that it was durable for 12 months. This was a big deal in terms of an FDA study and an FDA approval for a single-arm, nonrandomized study in the curative setting with this novel end point of a [durable] cCR. It was exciting that this was able to be conducted in the first place and that it was a positive study. A total of 154 patients were enrolled.

What were the key AZUR-1 efficacy findings supporting dostarlimab’s approval?

The important outcomes were cCR [rate], which was 71%, The cCR12 [rate], which is the primary end point, was 68% [per investigator assessment]. The reason there’s that little drop-off [between cCR rate and cCR12 rate] is because 2 patients who were determined to have a cCR went on to have surgery anyway and had a pathologic CR, confirming that they did have a CR. Because of some of the discomfort initially with this end point, on behalf of the investigators and also the patients, they went on to have surgery. Nearly three-fourths of patients had this significant benefit from dostarlimab alone.

The important point is that this was a global study [conducted] in institutions that were not familiar and that did not practice nonoperative management routinely for rectal cancer. That is very different from several academic centers, including Memorial Sloan Kettering Cancer Center, where there is an interest not just from the medical oncologists, but also from the surgeons and radiation oncologists, to watch, wait, and determine whether a tumor is fully gone before making that decision about the next treatment or operating.

What should clinicians know about the safety of dostarlimab in locally advanced rectal cancer?

It was well tolerated [and] in line with what’s been published with single-agent PD-1 inhibitors. Predominantly, [we saw] fatigue, some rashes, and hypothyroidism, with little grade 3/4 toxicity. Overall, I would say [it was] incredibly well tolerated. The majority of the toxicities were not durable.

References

1. FDA grants accelerated approval to dostarlimab for locally advanced rectal cancer. FDA. October 19, 2026. Accessed October 20, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-dostarlimab-locally-advanced-rectal-cancer
2. Jemperli (dostarlimab-gxly) approved in US as first and only immunotherapy for adults with MSI-H/dMMR locally advanced rectal cancer. News release. GSK. October 19, 2026. Accessed October 20, 2026. https://us.gsk.com/en-us/media/press-releases/jemperli-dostarlimab-gxly-approved-in-us-as-first-and-only-immunotherapy-for-adults-with-msi-hdmmr-locally-advanced-rectal-cancer/
3. Cercek A, Sinopoli JC, Shia J, et al. Durable complete responses to PD-1 blockade alone in mismatch repair deficient locally advanced rectal cancer. J Clin Oncol. 2024;42(suppl 17):LBA3512. doi:10.1200/JCO.2024.42.17_suppl.LBA3512