Immunotherapy received FDA approval for uterine cancer based on a specific tumor marker

The approval is for recurrent or advanced endometrial (uterine) cancer with a genetic abnormality known as "DNA mismatch repair deficiency" (dMMR).

On April 22, 2021, FDA (the US Food and Drug Administration) granted accelerated approval for people whose previous treatment with platinum-containing chemotherapy was associated with progression during or after treatment, whose cancers have a specific genetic characteristic known as dMMR, and who have recurrent or advanced endometrial cancer, to receive dostarlimab (Jemperli, manufactured by GSK), an immunotherapy.

What is dMMR?

dMMR (mismatch repair deficient) is an abnormality that affects the proper repair of DNA within cells and is identified in tumor tissue using genetic tests for this purpose.

What is dostarlimab?

Dostarlimab (Jemperli) is a new-generation immunotherapy that binds to PD-1, blocking its interaction with PD-L1 and PD-L2, and belongs to the immune checkpoint inhibitor class.

PD-1is found on the surface of immune system cells, while PD-L1 and PD-L2 are found on immune cells and some cancer cells.

Blocking the interaction of PD-1 and PD-L1-L2 on cell surfaces helps the body’s immune system fight cancer cells. This immunotherapy was specifically designed to target dMMR endometrial cancer.

Endometrial (uterine) cancer is the most common gynecological (female-specific) cancer in Turkey and many Western countries, and its incidence is increasing. 2020 Turkey Cancer Statistics reported that 5918 women in Turkey had been diagnosed with uterine cancer.

Approximately 75% of uterine cancers are diagnosed at an early stage and can typically be treated with surgery. However, women with advanced and recurrent uterine cancer have limited treatment options after standard first-line treatment with a platinum-containing chemotherapy regimen.

Approximately 25% to 30% of patients with advanced uterine cancer have dMMR tumors.

FDA approval based on the GARNET study

The safety and efficacy of dostarlimab in the single-arm, multi-cohort GARNET clinical trial were examined.

• Among 71 patients with dMMR-positive recurrent or advanced endometrial cancer who received dostarlimab in the trial, 42.3% had a complete response (disappearance of the tumor) or partial response (shrinkage of the tumor) to dostarlimab treatment. The complete response rate was 12.7%, while the partial response rate was 29.6%.
• For 93% of responders, the response lasted six months or longer.

Common dostarlimab side effects include fatigue, nausea, diarrhea, anemia and constipation. Dostarlimab can cause serious conditions known as immune-mediated side effects, including inflammation of healthy organs such as the lungs (pneumonia), colon (colitis), liver (hepatitis), endocrine glands (endocrinopathies) and kidneys (nephritis).

The recommended dostarlimab dose and schedule are 500 mg every 3 weeks (doses 1 through 4). Subsequent dosing, starting 3 weeks after the 4th dose, is 1,000 mg every 6 weeks until disease progression or unacceptable toxicity. Dostarlimab should be administered as an intravenous infusion over 30 minutes.

The latest developments in treating advanced endometrial cancer

With the approval of dostarlimab, we have witnessed 2 very important developments in the treatment of advanced endometrial cancer in the past 2 years. In September 2019, pembrolizumab plus lenvatinib received FDA approval for advanced endometrial cancer that had progressed after previous systemic treatment (see the related approval). Under that approval, an endometrial tumor was not to have microsatellite instability-high (MSI-H) status, or mismatch repair deficiency (dMMR). This is precisely where dostarlimab filled an important gap, because its approval covered dMMR-positive tumors.

In advanced endometrial cancers that were negative for dMMR and MSI, Study 111 / KEYNOTE-146 showed the following results for pembrolizumab plus lenvatinib: an objective treatment response of 38.3% (10.6% complete and 27.7% partial response). The objective response rate in the GARNET study was similar (42.3%).

As emphasized above, approximately 25-30% of advanced endometrial tumors are dMMR-positive. Research also shows that endometrial cancers have the highest dMMR positivity among all solid (organ) tumors.