The FDA has granted an accelerated approval to dostarlimab-gxly (Jemperli) for the treatment of patients with recurrent or advanced endometrial cancer that has progressed on or following prior treatment with a platinum-containing chemotherapy and whose cancers are mismatch repair deficient, as determined by an FDA-approved test.
The FDA has granted an accelerated approval to dostarlimab-gxly (Jemperli) for the treatment of patients with recurrent or advanced endometrial cancer that has progressed on or following prior treatment with a platinum-containing chemotherapy and whose cancers are mismatch repair deficient (dMMR), as determined by an FDA-approved test.1,2
The approval is based on results from the dMMR endometrial cancer cohort of the multicenter, single-arm, multiple parallel-cohort, open-label GARNET study, in which dostarlimab elicited a 42.3% objective response rate (ORR) in 71 patients with dMMR recurrent or advanced endometrial cancer. This included a 12.7% complete response (CR) rate and a 29.6% partial response (PR) rate.
The duration of response (DOR) was at least 6 months for 93.3% of responders, and the median DOR was not reached at a median follow-up of 14.1 months (2.6-22.4+).
"Today's approval of Jemperli is evidence of the FDA's progress in applying precision medicine to expand treatment options for patients with cancer," said Richard Pazdur, MD, director of the FDA's Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the FDA's Center for Drug Evaluation and Research. "This immunotherapy was specifically studied to target dMMR endometrial cancer and leverages scientific knowledge surrounding the mechanism of immunotherapy response in this unmet medical need population."
Dostarlimab, a PD-1 inhibitor, recently showcased clinical activity in patients with dMMR and MMR proficient (MMRp) endometrial cancer, regardless of investigator assessment or blinded independent central review (BICR) and immune-related RECIST (irRECIST) or RECIST v1.1 criteria, in a planned interim analysis of the phase 1 GARNET (NCT02715284) trial. The findings were presented during the 2021 SGO Virtual Annual Meeting on Women’s Cancer.3
Results showed that, according to investigator-assessed irRECIST criteria, the ORR was 45.5% in patients with dMMR endometrial cancer (n = 110) at a median follow-up of 16.5 months, and 13.9% in patients with MMRp endometrial cancer at a median follow-up of 13.7 months (n = 144). When assessed by BICR with RECIST v1.1 criteria, the ORRs were 44.7% (n = 103) and 13.4% (n = 142), respectively.
In GARNET, investigators tested single-agent dostarlimab in expansion cohorts across multiple tumor types. Patients who were eligible for enrollment were treated with dostarlimab at 500 mg of intravenous (IV) every 3 weeks for 4 cycles followed by 1000 mg IV every 6 weeks until disease progression.
The study consists of dose-finding (part 1), fixed-dose safety run-in (part 2A), and expansion cohorts (part 2B). The expansion cohort included 5 groups: dMMR endometrial cancer (A1; n = 129), MMRp endometrial cancer (A2; n = 161), non–small cell lung cancer (E), nonendometrial dMMR/MSI-H cancer (F), and platinum-resistant ovarian cancer (G).
The coprimary end points are ORR and DOR by BICR RECIST v1.1 criteria. Additionally, irRECIST criteria served as a prespecified secondary end point, due to standard RECIST criteria potentially undervaluing the clinical benefit of immunotherapy.
Eligibility criteria in cohorts A1 and A2 included disease progression on or after platinum-doublet therapy, have received 2 or fewer prior lines of therapy for recurrent or advanced disease, and have measurable disease at baseline. Additionally, patients had to have PD-L1–naïve disease and confirmed MMR/MSI disease by MMR immunohistochemistry (IHC) results.
Additional results revealed that the investigator-assessed irRECIST disease control rate (DCR) was 63.6% in the dMMR cohort vs 42.4% in the MMRp cohort. The BICR-assessed DCRs by RECIST v1.1 criteria were 57.3% and 35.2%, respectively.
Moreover, the responses according to irRECIST criteria were durable.
The median DOR has not been reached in the dMMR cohort vs 12.2 months in the MMRp cohort by irRECIST criteria. By RECIST v1.1 criteria by BICR, the median DOR has not been reached in the MMRp cohort.
“The approval of dostarlimab has the potential to change the way we’ve been treating dMMR advanced or recurrent endometrial cancer after standard platinum-based chemotherapy, especially given the overall response rate and durability of response that we saw in the GARNET trial,” said study investigator Jubilee Brown, MD, professor and division director of Gynecologic Oncology at Levine Cancer Institute, Atrium Health.
In the data that led to the approval, GlaxoSmithKline, the developer of dostarlimab, noted that among 104 patients evaluable for safety, the most common (≥20%) adverse events (AEs) included fatigue (48%), nausea (30%), diarrhea (26%), anemia (24%), and constipation (20%).
The most common (≥2%) grade 3/4 AEs included anemia and increase in alanine transaminase levels. Discontinuations of dostarlimab due to AEs occurred in 5 (4.8%) of patients, and no drug-related deaths occurred.
The approval was granted under the FDA’s Real-Time Oncology Review pilot program.
In February 2021, the European Medicines Agency’s Committee for Medicinal Products for Human Use granted a positive opinion to dostarlimab as a treatment for patients with recurrent or advanced microsatellite instability–high/dMMR endometrial cancer who have progressed on or following platinum-based chemotherapy.
“Unfortunately, as many as 60,000 women are diagnosed with endometrial cancer in the US each year and these women currently have limited treatment options if their disease progresses on or after first-line therapy," said Hal Barron, MD, chief scientific officer and president R&D, GlaxoSmithKline. "Today’s approval of dostarlimab by the FDA has the potential to transform the treatment landscape for these women and demonstrates our continued commitment to helping patients with gynecologic cancers.”
Dostarlimab is also being evaluated in combination with carboplatin and paclitaxel in patients with primary advanced or recurrent endometrial cancer in the phase 3 RUBY (NCT03981796) trial.