Dostarlimab Yields Promising Responses in dMMR/MSI-H Advanced/Recurrent Endometrial Cancer

Treatment with dostarlimab-gxly (Jemperli) resulted in a promising overall response rate (ORR) in patients with mismatch repair deficient (dMMR), microsatellite instability–high (MSI-H) advanced/recurrent endometrial cancer, according to a post-hoc analysis from cohort A1 of the phase 1 GARNET trial (NCT02715284) that was presented during the 2022 Annual Global Meeting of the International Gynecologic Cancer Society (IGCS).

The ORR in cohort A1 was 45.5% (95% CI, 37.1%-54.0%), and the median duration of response (DOR) was not reached (NR; 95% CI, 38.9-NR). In patients with MLH1/PMS2 dimer loss, the ORR was 48.9% (95% CI, 38.5%-59.5%), and among those with MSH2/6 dimer loss, the ORR was 56.3% (95% CI, 29.9%-80.2%). The DOR in both groups was not reached (NR). Those with another type of MMR protein staining pattern had an ORR of 30.3% (95% CI, 15.6%-48.7%) with a DOR that wasn’t reached (13.7%-NR).

“When we looked at objective response and DOR in those who had MLH1 loss, what we saw was among the cohort of 143 patients, 101 had available mutation data,” according to lead author Anna Tinker, MD, FRCPC, a clinical assistant professor and medical oncologist of the Division of Medical Oncology at the University of British Columbia, Canada, in a presentation on the findings. “Of those, 78 had MLH1 loss by [immunohistochemistry] IHC. When sequencing for mutations, 71 of the 78 did not have a mutation in either of the dimers, so not in the MLH1 gene or the PMS2 gene. Ninety-one percent did not have a mutation and 9% did in 1 of those 2 genes. What you see is that the ORR was similar in these molecular groups and the DOR has not been reached for those who responded to therapy.”

She went on to explain that it could be inferred that patients who don’t harbor a mutation and experience MLH1 loss by IHC testing, the effect is likely due to promoter methylation. This could mean that direct methylation testing may be the most accurate way to identify this group.

The goal of the post-hoc analysis was to assess ORR with dostarlimab in certain patient subgroups, including those with an MMR heterodimer loss pattern or a mutation of the MLH1 gene. The open-label, multi-center, single-arm study treated patients with 500 mg of intravenous dostarlimab every 3 weeks for 4 cycles followed by 1000 mg every 6 weeks until disease progression, discontinuation, or patient withdrawal. MMR protein status was assessed via local or central IHC testing, and MMR mutational status was determined via central Foundation One testing.

The median patient age was 65.0 years, and most patients had FIGO stage III or IV disease (56.6%). Moreover, most patients had grade 1/2 endometrioid histology (64.3%). All patients had previously received anti-cancer treatment, with 62.9% receiving 1 prior line of therapy, 24.5% receiving 2 prior lines, and 12.6% receiving 3 lines or more. Most patients underwent prior radiation therapy (70.6%).

“This is the largest dataset to date examining these relationships between dMMR and response to therapy. We do view these data as hypothesis generating [given] that the GARNET trial was not powered to study the effect of MMR protein pattern or mutation status on response to dostarlimab. Therefore, these data suggest that the route to dMMR does not influence response to dostarlimab treatment,” Tinker concluded.

Reference

Tinker AV, Sabatier R, Gravina A, et al. Post-hoc analysis of objective response rate by mismatch repair protein dimer loss/mutation status in patients with mismatch repair deficient endometrial cancer treated with dostarlimab. Presented at: 2022 Annual Global Meeting of the International Gynecologic Cancer Society; New York, NY; September 29-October 1, 2022. Abstract O007. Accessed September 30, 2022.