FDA Approves Dostarlimab Plus Chemo for dMMR/MSI-H Primary Advanced or Recurrent Endometrial Cancer

FDA

The FDA has approved dostarlimab-gxly (Jemperli) in combination with carboplatin and paclitaxel, followed by dostarlimab as a monotherapy, for use in adult patients with primary advanced or recurrent endometrial cancer that is mismatch repair deficient (dMMR), as determined by an FDA-approved test, or microsatellite instability high (MSI-H).¹

The regulatory decision is supported by data from an interim analysis of part 1 of the RUBY/ENGOT-EN6/GOG3031/NSGO phase 3 trial (NCT03981796).² At a median follow-up of 24.8 months (range, 19.2-36.9), the addition of dostarlimab to chemotherapy resulted in a 72% reduction in the risk of disease progression or death vs placebo plus chemotherapy in this population (HR, 0.28; 95% CI, 0.16-0.50; P < .001). The estimated 24-month progression-free survival (PFS) rate with dostarlimab was 61.4% (95% CI, 46.3%-73.4%) vs 15.7% (95% CI, 7.2%-27.0%) with placebo.

Moreover, the 24-month overall survival (OS) rate with the dostarlimab combination was 83.3% (95% CI, 66.8%-92.0%) vs 58.7% (95% CI, 43.4%-71.2%) with placebo/chemotherapy (HR, 0.30; 95% CI, 0.13-0.70).

“As a clinician, I celebrate the practice-changing potential of adding Jemperli to chemotherapy for patients with dMMR/MSI-H primary advanced or recurrent endometrial cancer who have had limited treatment options," Matthew Powell, MD, chief of the Division of Gynecologic Oncology at Washington University School of Medicine, and US principal investigator of the trial stated in a press release.¹ "Based on the results from the RUBY clinical trial, I look forward to the addition of [dostarlimab] to chemotherapy becoming a new standard of care for patients.”

With this approval, the agent is now indicated for use in combination with chemotherapy earlier in the treatment journey for this patient population. Notably, dostarlimab is already approved in the United States as a single agent in adult patients with dMMR recurrent or advanced endometrial cancer that has progressed on or after a previous platinum-containing regimen in any setting and are not candidates for curative surgery or radiation.¹

Patients who were at least 18 years of age and had histologically or cytologically confirmed primary advanced or recurrent endometrial cancer that was not amenable to curative treatment were enrolled to the trial.²

To be eligible for enrollment, patients were required to have stage IIIA, IIIB, or IIIC1 disease that was measurable by RECIST v1.1 criteria; primary advanced stage IIIC1 disease with carcinosarcoma, clear-cell, serous, or mixed histologic characteristics; primary advanced stage IIIC2 or stage IV disease; disease that was in first recurrence and had not received systemic therapy or neoadjuvant or adjuvant systemic therapy and recurred or progressed within 6 months of the completion of treatment.

Study participants were randomly assigned in a 1:1 fashion to receive 500 mg of dostarlimab or placebo paired with chemotherapy in the form of carboplatin at an area under the curve of 5 mg/mL/min and paclitaxel at 175 mg/m² every 3 weeks for the first 6 cycles, followed by single-agent dostarlimab at 1000 mg or placebo every 6 weeks. Patients received treatment for up to 3 years or until disease progression, intolerable toxicity, withdrawal, or death.

The primary end points of the trial were investigator-assessed PFS and RECIST v1.1 criteria in those with dMMR/MSI-H disease and in the overall population, as well as OS in the overall population. Important secondary end points comprised PFS by blinded independent central review, objective response rate, disease control rate, duration of response, time to second progression, safety, and patient-reported outcomes. Investigators are also conducting pharmacokinetic and immunogenicity analyses.

A total of 494 patients were randomized on the trial; 245 received dostarlimab plus chemotherapy and 249 received placebo plus chemotherapy. Of those who underwent randomization, 118 had dMMR/MSI-H disease; 53 of these patients were in the investigative arm and 65 were in the control arm.

No significant between-arm differences were reported in terms of demographic and clinical characteristics of patients in either population. In fact, the demographic characteristics were noted to be “generally representative of patients with primary advanced or recurrent endometrial cancer.”

Additional findings indicated that in the overall population, the dostarlimab combination resulted in a 36% reduction in the risk of disease progression or death compared with chemotherapy alone (HR, 0.64; 95% CI, 0.51-0.80; P < .001). The 24-month PFS rates in the dostarlimab and placebo arms were 36.1% (95% CI, 29.3%-42.9%) and 18.1% (95% CI, 13.0%-23.9%), respectively.

At the time of the first interim analysis of OS in the overall population, there was a median follow-up of 25.4 months, and the hazard ratio for OS was 0.64 (95% CI, 0.46-0.87; P = .0021), favoring the dostarlimab regimen. However, this difference between arms was not determined to be statistically significant. The estimated 24-month OS rates in the dostarlimab and placebo arms were 71.3% (95% CI, 64.5%-77.1%) and 56.0% (95% CI, 48.9%-62.5%), respectively.

Additionally, in those with mismatch repair–proficient/microsatellite stable tumors, the 24-month PFS rates with dostarlimab and placebo were 28.4% (95% CI, 21.2%-36.0%) and 18.8% (95% CI, 12.8%-25.7%), respectively (HR, 0.76; 95% CI, 0.59-0.98). The 24-month OS rates in this group were 67.7% (95% CI, 59.8%-74.4%) and 55.1% (95% CI, 46.8%-62.5%), respectively (HR, 0.73; 95% CI, 0.52-1.02).

All patients on the trial were found to experience toxicities. Grade 3 or higher adverse effects (AEs) were observed in 70.5% of those who received dostarlimab (n = 241) and in 59.8% of those who were given placebo (n = 246). Serious toxicities were reported in 37.8% and 27.6% of patients, respectively.

The most common any-grade AEs that were experienced by more than 20% of patients in the investigative and control arms were fatigue (51.9% vs 54.5%, respectively), alopecia (53.5% vs 50.0%), nausea (53.9% vs 45.9%), peripheral neuropathy (44.0% vs 41.1%), anemia (37.8% vs 42.3%), arthralgia (35.7% vs 35.0%), constipation (34.4% vs 35.8%), diarrhea (31.1% vs 28.9%), myalgia (26.1% vs 27.6%), hypomagnesemia (21.6% vs 28.5%), peripheral sensory neuropathy (21.2% vs 19.1%), reduced appetite (21.6% vs 17.5%), dyspnea (18.3% vs 20.3%), and rash (22.8% vs 13.8%)

Grade 3 or higher AEs observed in the investigative and control arms, respectively, included anemia (14.9% vs 16.3%), neutropenia (9.5% vs 9.3%), decreased neutrophil count (8.3% vs 13.8%), decreased lymphocyte count (5.4% vs 7.3%), decreased white cell count (6.6% vs 5.3%), hypertension (7.1% vs 3.3%), pulmonary embolism (5.0% vs 4.9%), and hypokalemia (5.0% vs 3.7%).

WATCH: Mansoor Raza Mirza, MD, of Copenhagen University Hospital, discusses the significance of the FDA approval of dostarlimab-gxly in combination with chemotherapy in patients with dMMR or MSI-H endometrial cancer.

References

1. Jemperli (dostarlimab) plus chemotherapy approved in the US as the first new frontline treatment option in decades for dMMR/MSI-H primary advanced or recurrent endometrial cancer. News release. GlaxoSmithKline. July 31, 2023. Accessed July 31, 2023. https://www.gsk.com/en-gb/media/press-releases/jemperli-plus-chemotherapy-approved-in-us-for-new-indication/
2. Mirza MR, Chase DM, Slomovitz BM, et al. Dostarlimab for primary advanced or recurrent endometrial cancer. N Engl J Med. Published online March 27, 2023. doi:10.1056/NEJMoa2216334