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Dostarlimab Effective in Endometrial Cancer Regardless of MSI Status

Brandon Scalea
Published Online:2:45 PM, Tue May 28, 2019

Ana Oaknin, MD

Dostarlimab (TSR-042), an investigational anti–PD-1 therapy, demonstrated durable responses across subgroups of patients with microsatellite instability–high (MSI-H) and microsatellite stable (MSS) advanced or recurrent endometrial cancer, according to results from the phase I/II GARNET study.

The findings showed that treatment with dostarlimab (TSR-042) led to an overall response rate (ORR) of 29.6% in the general patient population. In the subgroup of patients with MSI-H tumors, the ORR was even higher at 48.8%; in those whose tumors were MSS, it was 20.3%. Furthermore, the disease control rate was 52.8% in the entire study population, 63.4% in those with MSI-H tumors, and 46.8% in patients with MSS tumors.

The median duration of response with the antibody was not reached at a median follow-up of 10 months. Of the overall population, 89% of patients remained on treatment for >6 months, while 49% continued for >1 year.

“Taking into account the amazing results we have observed, there is a phase III trial that will analyze the activity of dostarlimab in patients with frontline advanced or recurrent endometrial cancer,” said Ana Oaknin, MD, the lead author of the study.

In an interview with Targeted Oncology, Oaknin, who is also head of the Gynecologic Tumors Unit, Medical Oncology Department, senior medical oncologist, and attending physician, at Vall d´Hebron University Hospital, provided insight into the implications of the GARNET trial and the promise of dostarlimab in the field.

TARGETED ONCOLOGY:  Could you discuss the GARNET trial and the key takeaways from this research?

Oaknin: The GARNET trial was a very well-conducted phase I/II trial. It's the largest trial analyzing the role of anti–PD-1 therapy in patients with advanced or recurrent endometrial cancer. In this trial, dostarlimab demonstrated clinically meaningful response rates in all the patients, regardless of MSI status. ORR in the overall population was about 30%. When we sort this out in terms of MSI status, we saw a 20% ORR in the MSS population and about 49% in those with MSI-H tumors.

The most important point to mention is the duration of the response. Although we haven't achieved the median duration of response, 89% of the responders have been on treatment for more than 6 months. Almost 50% have been on therapy for over 1 year. This is important for this poor-prognosis population who have advanced or recurrent endometrial cancer. Approximately 50% of the patients enrolled received at least 2 prior lines of chemotherapy; this means they are a heavily pretreated patient population.

TARGETED ONCOLOGY:  Could you expand on the rationale for this study?

In endometrial cancer, we have patients with both MSS and MSI-H tumors. This is very important, and this is the key difference from pembrolizumab (Keytruda). The anti–PD-1 therapy pembrolizumab is FDA approved under the umbrella of MSI-H solid tumors. However, pembrolizumab was not exclusively addressing endometrial cancer; it was addressing all solid tumors. We are looking to see [what the effectiveness of] anti–PD-1 [agents specifically, looks like] in endometrial cancer.

TARGETED ONCOLOGY:  Why home in on the MSS population specifically?

We have previous data suggesting that patients with both MSS and MSI-H respond to anti–PD-1 therapy. For example, the first trial with pembrolizumab, KEYNOTE-028, enrolled patients with MSS and MSI-H tumors. Another study in endometrial cancer combined pembrolizumab with lenvatinib (Lenvima). We saw responses in both of these patient populations, regardless of MSI status. To say that we have never seen immunotherapy response in the MSS population is not completely true.

TARGETED ONCOLOGY:  Could you speak to the toxicity profile of dostarlimab?

Dostarlimab has a wonderful safety profile. In 70% of patients [in the GARNET trial], we observed some sort of treatment-related adverse events (AEs). However, in terms of immune-related AEs, less than 6% of patients developed grade 3 or 4 events. Remarkably, there were no deaths associated with the drug.

TARGETED ONCOLOGY:  What is the agent’s mechanism of action?

Dostarlimab is an investigational, humanized antibody that prevents the interaction between PD-1 and PD-L1. It also stimulates the immune system so that it will fight the tumor cells.
 
 
Reference:
Oaknin A, Duska LR, Sullivan RJ, et al. Preliminary safety, efficacy, and pharmacokinetic/pharmacodynamic characterization from GARNET, a phase I/II clinical trial of the anti–PD-1 monoclonal antibody, TSR-042, in patients with recurrent or advanced MSI-H and MSS endometrial cancer. Presented at: 2019 SGO Annual Meeting; March 16-19, 2019; Honolulu, HI. Abstract 33.


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