Dostarlimab Monotherapy Elicits Durable cCRs in dMMR/MSI-H Locally Advanced Rectal Cancer

Dostarlimab-gxly (Jemperli) monotherapy produced durable clinical complete responses (cCRs), with no recurrences among those who achieved a cCR, in patients with mismatch repair–deficient (dMMR)/microsatellite instability–high (MSI-H) locally advanced rectal cancer, according to first results from the phase 2 AZUR-1 trial (NCT05723562) presented at the 2026 ESMO Congress.¹

Findings showed at a median follow-up of 26.3 months (range, 2-36), the rate of cCR sustained for at least 12 months (cCR12) by independent central review (ICR) was 47% among ICR-evaluable patients (n = 116), with ICR data 75% mature. The cCR12 rate by investigator assessment was 68% among evaluable patients (n = 144), with data 94% mature. Overall, 71% of the full analysis set (n = 154) achieved a cCR and entered nonoperative management. Among patients with a cCR and at least 12 months of follow-up (n = 100), none experienced a recurrence; 98% maintained their cCR without further treatment, and the remaining 2 patients elected surgery and had a pathologic complete response (pCR).

"What's most important to note here is that [these patients received] dostarlimab monotherapy, which is very well tolerated [with] minimal to no sequelae long term, [including] no pelvic dysfunction, bladder dysfunction, sexual dysfunction, etc., which would have happened had these patients received the standard of care [chemoradiation and surgery]," lead study author Andrea Cercek, MD, of Memorial Sloan Kettering Cancer Center in New York, New York, said in an exclusive interview with OncLive®. "[These data go[ beyond the efficacy; it's the fact that [dostarlimab] was able to really replace all the standard of care that, yes, would have been curative, but at the cost of quality of life and significant morbidity."

On October 19, 2026, the FDA granted accelerated approval to dostarlimab 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, based on data from AZUR-1.²

How was AZUR-1 designed?

The global, single-arm trial enrolled patients with previously untreated stage II or III (T3-T4, N0, or any T, N+) dMMR/MSI-H rectal cancer without tumor-caused symptomatic bowel obstruction.¹

Patients received dostarlimab at 500 mg intravenously every 3 weeks for 9 cycles, followed by endoscopy and MRI/CT 21 days (+7 days) after the last dose.

Patients with a cCR entered nonoperative surveillance. Those with a near-complete or incomplete response could be reevaluated 4 to 8 weeks later, and patients with less than a cCR could receive standard-of-care chemotherapy, radiation, and/or surgery at investigator discretion. A cCR required a normal digital rectal examination, no visible tumor on endoscopy, no residual diffusion restriction on rectal MRI, and target lymph nodes smaller than 5 mm in short-axis diameter.

The primary end point was cCR12 rate per ICR assessment, and investigator-assessed cCR12 rate was a secondary end point; cCR12 rate by investigator plus pCR rate was exploratory.

The median age in the full analysis set was 61.5 years (range, 23-92), 86% of patients had stage III disease, 91% had T3 or T4 tumors, and 84% had middle or low rectal tumors. Fifteen percent of tumors were mucinous, which Cercek noted complicates MRI response assessment.

What did additional efficacy analyses show?

Eight patients converted from a near-complete or partial response to a cCR on reevaluation. Adding patients with a pCR after dostarlimab alone (n = 12) to those with a cCR12 produced a composite rate of 76%.

Among the 40 patients with less than a cCR, 13 underwent surgery (10 pCRs), 7 received chemotherapy/chemoradiation plus surgery (5 pCRs), and 4 received radiation plus surgery (2 pCRs); 3 patients refused further treatment. Overall, 93% of patients remained on study without evidence of progression after dostarlimab with or without standard-of-care therapy.

"Even the patients that were felt by the investigator not to have reached a cCR…and were managed with standard of care did very, very well," Cercek said. "There's definitely a learning curve in terms of seeing that the tumors are responding and perhaps giving them more time, [and] dealing with mucinous tumors…that make radiographic evaluations really challenging."

Cercek attributed the lower ICR rate to central reviewers' reliance on endoscopy and MRI images without the patient present, which delayed cCR determinations; some patients classified as non-cCR by ICR have maintained durable responses. She described cCR as a patient-centric end point that requires the patient and a multidisciplinary tumor board, as well as better assessment tools.

What did the safety analysis show?

Patients received a median of 9 cycles (range, 2-9). Dostarlimab-related adverse effects (AEs) occurred at grade 1 or 2 in 64% of patients and at grade 3 or higher in 10%. The most common related AEs were pruritus (grade 1/2, 14%), hypothyroidism (grade 1/2, 12%), and fatigue (grade 1/2, 10%; grade ≥3, <1%). Immune-mediated AEs occurred at grade 1/2 in 21% of patients and at grade 3 or higher in 3%.

Treatment-emergent serious AEs occurred in 20% of patients, with 5% considered related to dostarlimab. Three patients (2%) discontinued treatment because of related AEs, and no fatal AEs were reported.

References

1. Cercek A, Bachet JB, Folprecht G, et al. Clinical complete response with dostarlimab monotherapy in dMMR/MSI-H locally advanced rectal cancer: first results from the global registrational AZUR-1 trial. Presented at: 2026 ESMO Congress; October 23-27, 2026; Madrid, Spain. Abstract LBA87.
2. FDA grants accelerated approval to dostarlimab for locally advanced rectal cancer. FDA. October 19, 2026. Accessed October 30, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-dostarlimab-locally-advanced-rectal-cancer