Dostarlimab Delivers Durable Responses in dMMR/MMRp Endometrial Cancer

Bhavana Pothuri, MD, MS

Dostarlimab demonstrated durable antitumor activity in patients with mismatch repair deficient (dMMR) and MMR proficient (MMRp) endometrial cancer, regardless of investigator assessment or blinded independent central review (BICR) and immune-related RECIST (irRECIST) or RECIST v1.1 criteria, according to findings from a planned interim analysis of the phase 1 GARNET (NCT02715284) trial that were presented during the 2021 SGO Virtual Annual Meeting on Women’s Cancer.¹

At a median follow-up of 16.5 months, the objective response rate (ORR) according to investigator-assessed irRECIST criteria was 45.5% in patients with dMMR endometrial cancer (n = 110) and 13.9% in patients with MMRp endometrial cancer at a median follow-up of 13.7 months (n = 144). When assessed by BICR with RECIST v1.1 criteria, the ORRs were 44.7% (n = 103) and 13.4% (n = 142), respectively.

“The irRECIST data were similar to the results [that were seen with] RECIST 1.1 [criteria]. The ORR by irRECIST in each cohort was within 1 percentage point of the respective ORR by RECIST 1.1 [criteria],” said Bhavana Pothuri, MD, MS, senior study author and professor in the Department of Obstetrics and Gynecology at NYU School of Medicine and director of gynecologic oncology clinical trials at NYU Langone Health’s Perlmutter Cancer Center, during a virtual presentation of the data.

Dostarlimab is an investigational, humanized, anti–PD-1 monoclonal antibody that competitively inhibits the PD-1 receptor and prevents ligand binding to PD-L1 and PD-L2.

The agent is currently under FDA review for the treatment of women with recurrent or advanced endometrial cancer who have progressed on or following platinum-based chemotherapy and whose tumors are dMMR, as well as for the treatment of adult patients with dMMR recurrent or advanced solid tumors.²

GARNET is a single-arm study that is evaluating dostarlimab monotherapy in expansion cohorts across tumor types. Eligible patients will receive 500 mg of intravenous (IV) dostarlimab every 3 weeks for 4 cycles followed by 1000 mg IV every 6 weeks until disease progression.

The study consists of dose-finding (part 1), fixed-dose safety run-in (part 2A), and expansion cohorts (part 2B). The expansion cohort comprises 5 groups: dMMR endometrial cancer (A1; n = 129), MMRp endometrial cancer (A2; n = 161), non–small cell lung cancer (E), nonendometrial dMMR/MSI-H cancer (F), and platinum-resistant ovarian cancer (G).

The co-primary end points are ORR and duration of response (DOR) by BICR RECIST v1.1 criteria. Because standard RECIST criteria can undervalue the clinical benefit of immunotherapy, investigator-assessed efficacy by irRECIST criteria served as a prespecified secondary end point.

To be eligible for enrollment into cohorts A1 and A2, patients had to have progression on or after platinum-doublet therapy, have received 2 or fewer prior lines of therapy for recurrent or advanced disease, and have measurable disease at baseline. Additionally, patients had to have PD-L1–naïve disease and confirmed MMR/MSI disease by MMR immunohistochemistry (IHC) results.

Additional results revealed that the investigator-assessed irRECIST disease control rate (DCR) was 63.6% in the dMMR cohort vs 42.4% in the MMRp cohort. The BICR-assessed DCRs by RECIST v1.1 criteria were 57.3% and 35.2%, respectively.

“The [immune-related] DCR was particularly of interest in the MMRp cohort, a group with a poorer prognosis and limited treatment options. The DCR was driven by greater than 20% of patients with a best response of stable disease,” said Pothuri.

Moreover, the responses according to irRECIST criteria were durable.

“The majority of patients with responses lasting longer than 1 year remain in response as of the data cutoff date [of March 1, 2020],” said Pothuri. “The majority of patients with treatment durations less than 1 year remain in response and on treatment as of the data cutoff date, so there is potential for those [patients] to exceed the 1-year mark.”

The median DOR has not been reached in the dMMR cohort vs 12.2 months in the MMRp cohort by irRECIST criteria. By RECIST v1.1 criteria by BICR, the median DOR has not been reached in the MMRp cohort.

“Dostarlimab demonstrated durable antitumor activity in both dMMR and MMRp advanced/recurrent endometrial cancer,” said Pothuri. “dMMR status by IHC was associated with a higher response rate.”

Dostarlimab is also being evaluated in combination with carboplatin and paclitaxel in patients with primary advanced or recurrent endometrial cancer in the phase 3 RUBY (NCT03981796) trial.

References

1. 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 SGO Virtual Annual Meeting on Women’s Cancer; March 19-25, 2021; virtual.
2. GSK receives CHMP positive opinion recommending approval of dostarlimab for women with recurrent or advanced endometrial cancer. News release. GlaxoSmithKline. February 26, 2021. Accessed March 24, 2021. https://bit.ly/3sxJ7P4