Dostarlimab Plus Chemo Wins MHRA Approval for dMMR/MSI-H Primary Advanced/Recurrent Endometrial Cancer

The Medicines and Healthcare Products Regulatory Agency (MHRA) has authorized the use of dostarlimab-gxly (Jemperli) in combination with chemotherapy for the treatment of patients with mismatch repair-deficient (dMMR)/microsatellite instability–high (MSI-H) primary advanced or recurrent endometrial cancer.¹ This is the first frontline treatment regimen to be licensed for patients in this population.

The phase 3 RUBY trial (NCT03981796) investigated the combination of dostarlimab plus chemotherapy in 494 patients with primary advanced stage III or IV or first recurrent endometrial cancer.²

Of the patients in RUBY with dMMR/MSI-H disease, the estimated 24-month progression-free survival PFS rate was 61.4% (95% CI, 46.3%-73.4%) with dostarlimab plus chemotherapy vs 15.7% (95% CI, 7.2%-27.0%) with chemotherapy plus placebo (HR, 0.28; 95% CI, 0.16-0.50; P < .001).2 In the overall population, the 24-month PFS rate was 36.1% (95% CI, 29.3%-42.9%) with dostarlimab vs 18.1% (95% CI, 13.0%-23.9%) with placebo (HR, 0.64; 95% CI, 0.51-0.80; P < .001).

In the dMMR/MSI-H population, the 24-month OS rate was 83.3% (95% CI, 66.8%-92.0%) in the dostarlimab arm vs 58.7% (95% CI, 43.4%-71.2%) in the placebo arm (HR, 0.30; 95% CI, 0.13-0.70). The estimated 24-month OS rate in the overall population was 71.3% (95% CI, 64.5%-77.1%) in the dostarlimab arm vs 56.0% (95% CI, 48.9%-62.5%) in the placebo arm (HR, 0.64; 95% CI, 0.46-0.87).

In July 2023, the FDA approved dostarlimab 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 dMMR, as determined by an FDA-approved test, or MSI-H.³

RUBY enrolled female patients at least 18 years of age with histologically or cytologically proven recurrent or advanced endometrial cancer.⁴ Patients needed to have primary stage III or IV disease or first recurrent disease with a low curative potential by radiation therapy or surgery either alone or in combination. Additionally, patients were required to have an ECOG performance status of 0 or 1 and adequate organ function. Patients needed to meet at least 1 of the following criteria:

1. Primary stage IIIA to IIIC1 disease with evaluable or measurable disease per RECIST v1.1 criteria
2. Primary stage IIIC1 disease with at least 10% clear cell, carcinosarcoma, serous, or mixed histology (of which at least 10% is clear cell, carcinosarcoma, or serous histology), regardless of the presence of measurable or evaluable disease on imaging
3. Primary stage IIIC2 or IV disease regardless of the presence of measurable or evaluable disease
4. First recurrent disease that is naïve to systemic anticancer therapy
5. Prior neoadjuvant or adjuvant systemic anticancer therapy followed by disease recurrence or progressive disease at least 6 months after completing treatment (first recurrence only)

Patients were randomly assigned 1:1 to receive either 500 mg of dostarlimab (n = 245) or placebo (n = 249) plus carboplatin at 5mg/mL/min and paclitaxel at 175 mg/m² every 3 weeks for 6 cycles, followed by 100 mg of dostarlimab or placebo every 6 weeks for a maximum of 3 years. Among the patients enrolled, 118 had dMMR/MSI-H disease, 53 in the dostarlimab arm and 65 in the placebo arm.

The coprimary end points of RUBY were PFS per RECIST v1.1 and OS. Key secondary end points included PFS per blinded independent central review, overall response rate, duration of response, disease control rate, patient-reported outcomes, and safety.

The most common adverse effects (AEs) that occurred or worsened during treatment were nausea (dostarlimab, 53.9%; placebo, 45.9%), alopecia (53.5%; 50.0%), and fatigue (51.9%; 54.5%).² Moreover, rash and maculopapular rash were observed more frequently in the dostarlimab arm than in the placebo arm (rash, 22.8% vs 13.8%; maculopapular rash, 14.1% vs 3.7%). Grade 3 or higher AEs occurred or worsened during treatment in 70.5% vs 59.8% of patients in the dostarlimab and placebo arms, respectively. Grade 3 or higher serious AEs occurred or worsened during treatment in 37.8% vs 27.6% of patients in the dostarlimab and placebo arms, respectively.

A press release from the MHRA advised any patients who suspect they are experiencing AEs from dostarlimab to speak to their doctor, pharmacist, or nurse, as well as report their AEs directly to the Yellow Card scheme.¹

References

1. MHRA authorises monoclonal antibody treatment, Jemperli, to be used with chemotherapy for endometrial cancer. News release. Medicines and Healthcare products Regulatory Agency. October 2, 2023. Accessed October 6, 2023. https://www.gov.uk/government/news/mhra-authorises-monoclonal-antibody-treatment-jemperli-to-be-used-with-chemotherapy-for-endometrial-cancer
2. Mirza MR, Chase DM, Slomovitz BM, et al. Dostarlimab for primary advanced or recurrent endometrial cancer. N Engl J Med. 2023; 388(23):2145-2158; doi:10.1056/NEJMoa2216334. https://www.nejm.org/doi/full/10.1056/NEJMoa2216334
3. 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 October 6, 2023. https://www.gsk.com/en-gb/media/press-releases/jemperli-plus-chemotherapy-approved-in-us-for-new-indication/
4. A study to evaluate dostarlimab plus carboplatin-paclitaxel versus placebo plus carboplatin-paclitaxel in participants with recurrent or primary advanced endometrial cancer (RUBY). ClinicalTrials.gov. Updated August 14, 2023. Accessed October 6, 2023. https://clinicaltrials.gov/study/NCT03981796