Dostarlimab Expands Options for dMMR Endometrial Cancer

Patients with mismatch repair–deficient recurrent or advanced endometrial cancer gained an efficacious and safe treatment option with the addition of dostarlimab-gxly. The FDA granted accelerated approval to the agent in April. The novel therapy was approved specifically for adult patients with dMMR recurrent or advanced endometrial cancer that has progressed on or following a prior platinum-containing regimen.¹

Findings from a 71-patient dMMR endometrial cancer cohort of the phase 1 GARNET trial (NCT02715284) supported the decision. Results showed that the confirmed overall response rate (ORR) achieved with dostarlimab was 42.3% (95% CI, 30.6%-54.6%), with 12.7% of patients experiencing a complete response (CR). Notably, the median duration of response (DOR) was not reached (2.622.4+) and 93.3% of patients had DORs of at least 6 months.²

In an interview with OncologyLive^®, Bhavana Pothuri, MD, a professor in the Department of Obstetrics and Gynecology at NYU Grossman School of Medicine and director of Gynecologic Oncology Clinical Trials at NYU Langone Health in New York, New York, spoke to how the accelerated approval of dostarlimab opens the treatment landscape to include personalized options for patients with endometrial cancer as well as some safety concerns observed with the agent.

OncLive^®: Please provide an overview of the design and outcomes of the GARNET trial.

Pothuri: The GARNET trial enrolled patients with recurrent endometrial cancer. They were patients who had progressed on a prior platinum-based chemotherapy. These were patients with recurrent or advanced disease that was measurable. Patients were enrolled to 2 parallel cohorts. Cohort A1 [included patients with] dMMR endometrial cancer. [Cohort] A2 [included patients with] mismatch repair–proficient endometrial cancer.

I recently presented an updated analysis at the Society of Gynecologic Oncology 2021 Virtual Annual Meeting on Women’s Cancer. That included a larger cohort than what was presented to the FDA for approval, but the results are very similar. In the dMMR cohort of 103 patients, [investigators] noted an ORR of 44.7%, and that’s the population that dostarlimab was approved for.³ These data actually represent the largest reported cohort of dMMR endometrial cancer treated with the checkpoint inhibitor, and the efficacy was quite good.

Please describe the mechanism of action of dostarlimab.

Dostarlimab is a humanized anti–PD-1 monoclonal antibody that competitively inhibits the PD-1 receptor and blocks the ligand binding of PD-L1 and PD-L2 and belongs to the class of agents known as checkpoint inhibitors.

In terms of safety, what should clinicians know about dostarlimab?

The data that we presented showed the therapy was well tolerated. However, there are some very significant immune-related adverse effects [AEs] that do occur. It’s important to keep these immune-related AEs in mind, counsel patients prior to the start of therapy, identify them early, and promptly manage these AEs. These immune-mediated reactions can occur in any organ system or tissue.

The most important thing is monitoring closely for these by evaluating blood work, including liver enzymes, creatinine, and thyroid function, as well as querying patients about symptoms such as cough or shortness of breath, which could be a sign of pneumonitis, or diarrhea, which could be a sign of colitis.

It’s important to note that most of these immune-related events occur in less than 5% of patients. The more common AEs are fatigue, nausea, and anemia, which are tolerable AEs.

How does this approval affect the treatment standards for patients with dMMR endometrial cancer?

It’s important in terms of having agents for the treatment of advanced endometrial cancer because [patients with] advanced or recurrent endometrial cancer [represent] a true unmet need; we don’t have many other active therapies.

This is a real win for our patients with endometrial cancer. Additionally, [the approval is] important in terms of understanding that endometrial cancer is the most common gynecologic cancer in the United States. The incidence, as well as the mortality [rates associated with the disease], has been increasing because of a greater proportion of obesity, as well as an increase in the number of patients with high-risk histologic subtypes. Having new additional therapies is very important. This is an exciting advance for gynecologic cancer and especially endometrial cancer.

Another thing that’s important about these checkpoint inhibitors is the DOR. Over 90% of responders had a DOR that was greater than 6 months. Having a new therapy is important, but having one that’s effective, well tolerated, and has a long-lasting DOR is also key.

One final thing that’s important is that traditionally when [patients have] recurrent endometrial cancer, we usually think that it is incurable. With immunotherapy agents, such as dostarlimab, we are seeing some CRs. These responses need longer follow-up, but the fact that the DOR for some patients in the dMMR cohort had not been reached is a sign perhaps we could be curing some of these patients. There were approximately 11% of patients who had CRs with dostarlimab in the dMMR cohort. That’s another exciting and important point which will need longer follow-up to address.

What does the future hold for dostarlimab?

Dostarlimab is being evaluated in the frontline setting, with chemotherapy, paclitaxel, and carboplatin in a large randomized, placebo-controlled phase 3 trial [RUBY; NCT03981796]. That trial will serve as the confirmatory trial for this accelerated approval. We’re all eagerly awaiting that data to see whether we can change the frontline treatment paradigm of endometrial cancer even further.

References

1. FDA grants accelerated approval to dostarlimab-gxly for dMMR endometrial cancer. FDA. April 22, 2021. Accessed July 1, 2021. bit.ly/3e2mInW
2. Jemperli. Prescribing information. GlaxoSmithKline LLC; 2021. Accessed July 1, 2021. bit.ly/3yKhkO6
3. Oaknin A, Gilbert L, Tinker AV, et al. Interim analysis of the immune-related endpoints of the mismatch repair deficient (dMMR) and proficient (MMRp) endometrial cancer cohorts from the GARNET study. Presented at: 2021 Society of Gynecologic Oncology Virtual Annual Meeting on Women’s Cancer; March 19-25, 2021; virtual. Accessed July 7, 2021. bit.ly/2UrrHHW