FDA Approves Dostarlimab for MSI-H/dMMR Rectal Cancer. In AZUR-1, 47 Percent Had a Sustained Complete Response Without Surgery.
The Oct. 19 accelerated approval of Jemperli covers stage II or III locally advanced disease and rests on a single-arm trial of 154 patients. Biomarker results on the diagnostic biopsy now decide who is eligible.
Idea in Brief
The Approval
On Oct. 19 the FDA granted accelerated approval to dostarlimab-gxly (Jemperli) as a single agent for adults with MSI-H/dMMR stage II or III locally advanced rectal cancer.
The Evidence
In the single-arm AZUR-1 trial (n=154), 47 percent of 116 evaluable patients had a 12-month sustained clinical complete response by independent review (95% CI, 37 to 56 percent).
The Caveats
There is no control arm, the label says the long-term relapse risk is unknown, and continued approval may depend on a confirmatory trial.
On Oct. 19, the Food and Drug Administration granted accelerated approval to dostarlimab-gxly (Jemperli, GSK) for MSI-H/dMMR stage II or III rectal cancer; in the AZUR-1 trial, 47 percent of evaluable patients had a sustained complete response without surgery.
The indication covers adults with stage II or III locally advanced rectal cancer that is mismatch repair deficient (dMMR) or microsatellite instability-high (MSI-H), as determined by an FDA-authorized test for solid tumors, according to the FDA's approval notice. It is the first immunotherapy approved for this setting, GSK said in its announcement. The FDA approved the application four months ahead of its goal date, after review under its Real-Time Oncology Review program, Project Orbis and the Commissioner's National Priority Voucher pilot.
What did AZUR-1 show?
Nearly half of patients assessed by independent reviewers kept a clinical complete response for at least 12 months. AZUR-1 is a multicenter, single-arm, open-label trial of 154 previously untreated patients who received 500 mg intravenously every three weeks for nine cycles, about six months. Response was assessed by endoscopy, rectal MRI and CT, and patients with a clinical complete response (cCR) entered non-operative management.
By independent central review, the 12-month sustained cCR rate was 47 percent (54 of 116 evaluable patients; 95% CI, 37 to 56 percent), according to the updated prescribing information. Another 38 patients had a cCR but less than 12 months of follow-up. By investigator assessment the rate was 68 percent (98 of 144; 95% CI, 60 to 76 percent). The label's indication rests on the lower, independently reviewed figure.
At a median follow-up of 26 months, 110 of the 154 patients (71 percent) had received no further cancer treatment and had not progressed or relapsed, and 26 (17 percent) had undergone surgery, per the label. Of 15 patients who had surgery after dostarlimab alone, 12 had a pathological complete response. The FDA said no patient with a sustained cCR, cCR or near-complete response had disease progression.
A sustained complete response without surgery is a striking result. It is also a single-arm result in 154 patients, and the label itself says the long-term risk of relapse is unknown.
What are the safety and label limits?
Serious adverse reactions occurred in 20 percent of patients and 3 percent permanently discontinued because of adverse reactions, per the label. The most common reactions were fatigue (32 percent), rash (22 percent), diarrhea (18 percent) and pruritus (17 percent). Rectal stenosis occurred in 3.9 percent, and one patient died of sepsis following treatment for intestinal obstruction. Warnings include immune-mediated adverse reactions, infusion-related reactions, complications of allogeneic stem cell transplantation and embryo-fetal toxicity.
Continued approval may be contingent on verification of clinical benefit in a confirmatory trial. With no control arm, AZUR-1 cannot say how outcomes compare with chemoradiation and surgery. A supporting single-arm study of 50 patients reported a 93 percent sustained cCR rate, per the FDA. Full interim AZUR-1 data are scheduled for presentation at the European Society for Medical Oncology (ESMO) Congress this month, GSK said.
Clinical Pearls
- The approval is accelerated and limited to tumors identified as MSI-H or dMMR by an FDA-authorized test for solid tumors.
- AZUR-1 enrolled 154 previously untreated patients with stage II or III MSI-H/dMMR rectal cancer.
- The independently reviewed 12-month sustained cCR rate was 47 percent (54 of 116; 95% CI, 37 to 56 percent); the investigator-assessed rate was 68 percent (98 of 144).
- Serious adverse reactions occurred in 20 percent of patients and 3 percent discontinued for adverse reactions; rectal stenosis occurred in 3.9 percent.
- The label states the long-term risk of relapse is unknown, with additional follow-up expected.
- Check that MMR or MSI status is on every new rectal adenocarcinoma pathology report.
What should referring physicians do now?
Make sure mismatch repair or microsatellite instability status is known before neoadjuvant planning begins. Michael Sapienza, chief executive of the Colorectal Cancer Alliance, said in GSK's announcement that biomarker testing at diagnosis will be essential to identifying patients who may be eligible. That result on every new rectal adenocarcinoma biopsy now determines whether a non-operative option exists at all.
Gastroenterologists, pathologists and primary care physicians who see these patients early should confirm that the pathology report includes the result and that it reaches the tumor board. Patients treated this way also need a surveillance plan: in AZUR-1, patients managed without surgery were assessed every four months for the first two years and every six months thereafter, The ASCO Post reported. The same testing logic drove this month's dMMR colon cancer approval.
Reported, fact-checked and edited by The Script Pad's editorial staff.
This article is for professional education and does not replace clinical judgment. Treatment decisions should be based on the individual patient and current guidelines.
