Dostarlimab Receives FDA Approval for Uterine Cancer Regardless of dMMR Status

On August 1, 2024, the FDA (United States Food and Drug Administration) approved the immunotherapy dostarlimab (Jemperli, GSK) with carboplatin and paclitaxel, followed by single-agent dostarlimab, for adults with primary advanced or recurrent endometrial cancer.

Dostarlimab had been approved on July 31, 2023, with carboplatin and paclitaxel followed by single-agent dostarlimab, for advanced or recurrent endometrial cancer with high microsatellite instability (MSI-H) or mismatch repair deficiency (dMMR).

Previously, on June 17, 2024, pembrolizumab (Keytruda) received FDA approval for patients in the same setting. However, that approval was based on progression-free rather than overall survival results.

The Importance of Endometrial Cancer

Endometrial cancer is the most common type of  uterine cancer  and among the most frequent gynecological cancers in women. It begins in the endometrium, the uterus's inner lining, and generally occurs in women after menopause.

Endometrial cancer is one of the few cancers with rising incidence and mortality. Worldwide, it is the third most common cancer among women and the fourth leading cause of cancer-related death .

More than half of patients are diagnosed early because endometrial cancer typically causes noticeable symptoms such as abnormal vaginal bleeding. These symptoms generally prompt women to seek medical help, leading to earlier diagnosis. At diagnosis, however, approximately 25-30% are diagnosed at stage 3 or 4 . Survival in women with advanced or metastatic endometrial cancer has changed little over the past 40 years, reflecting limited advances in systemic treatment.

FDA Approval Based on RUBY

The expanded approval, granted after priority review, was based on the effectiveness and safety demonstrated in the randomized, controlled, multicenter RUBY study. It randomized 494 patients to the dostarlimab regimen or placebo with carboplatin and paclitaxel, followed by placebo.

The Only Treatment Showing Overall Survival Benefit in the Entire Patient Population

Comparing immunotherapy plus chemotherapy with placebo plus chemotherapy in the full patient population, researchers observed a significant improvement in median overall survival : respectively, 44.6 months and 28.2 months (hazard ratio [HR], 0.69).

Median progression-free survival was also significantly better in the treatment group than with placebo: respectively, 11.8 months and 7.9 months (HR, 0.64).

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This is the only immunotherapy-containing regimen to demonstrate an overall survival benefit in the entire population, regardless of dMMR status. It represents a meaningful advance in uterine cancer treatment.

In RUBY, 24% of patients with endometrial cancer were dMMR-positive.

What Are dMMR and pMMR?

dMMR and pMMR concern DNA repair mechanisms in endometrial tumors. MMR stands for “Mismatch Repair,” a DNA repair mechanism correcting mismatched base pairs.

dMMR (Mismatch Repair-deficient)  tumors have lost this mechanism's function and cannot correct mismatched DNA base pairs. This leads to a genetic alteration called high microsatellite instability (MSI-H). Such tumors generally tend to be more aggressive and more susceptible to the immune system, so they may respond better to immunotherapy.

pMMR (Mismatch Repair-proficient)  tumors have a functioning MMR mechanism that can correct mismatched DNA base pairs. They are called microsatellite stable (MSS) and tend to show a lower immune response. Understanding how immunotherapy works in these tumors is therefore important.

Adverse Effects Recorded in RUBY

Adverse reactions occurring in at least 20% of patients receiving dostarlimab included anemia, increased creatinine, peripheral neuropathy, decreased white blood cell counts, fatigue, nausea, alopecia (hair loss), low platelet counts, increased glucose, lymphopenia, neutropenia, abnormal liver function tests, arthralgia, rash, constipation, diarrhea, decreased albumin, abdominal pain, dyspnea, decreased appetite, increased amylase, urinary tract infection, and vomiting. Dostarlimab's immune-mediated adverse reactions were similar to those previously reported.

The dostarlimab dose is 500 mg every 3 weeks for six cycles, given before carboplatin and paclitaxel when administered on the same day, followed by 1000 mg monotherapy every 6 weeks until progression or unacceptable toxicity, or for up to 3 years.