Dostarlimab Fills Unmet Need for Patients with dMMR Advanced Endometrial Cancer

With the February 9, 2023, FDA approval of the PD-1-directed monoclonal antibody dostarlimab-gxly (Jemperli), a new and durable option has been ushered into the treatment landscape for patients with mismatch repair deficient (dMMR) recurrent or advanced endometrial cancer who are not candidates for curative surgery or radiation and have disease progression on or following a prior platinum-containing regimen, according to Lucy Gilbert, MD, MSc.¹

Findings from the phase 1 GARNET trial (NCT02715284), which supported the approval, showed that patients with dMMR endometrial cancer who received dostarlimab (n = 141) achieved an overall response rate (ORR) of 45.4% (95% CI, 37.0%-54.0%), including a 15.6% complete response rate. Notably, the median duration of response was not reached (range, 1.2+ to 52.8+). Responses lasted 1 year or longer for 85.9% of patients and 54.7% experienced responses persisting for 2 years or more.²

“This is something we have been waiting ages for because women with recurrent endometrial cancer, once they’ve failed platinum-based chemotherapy, [we] have next to nothing,” Gilbert said. “This is hugely important for women with recurrent endometrial cancer and for gynecologic oncologists and medical oncologists because it gives us something where we had nothing before.”

In an interview with OncLive^®, Gilbert, the director of Gynecologic Oncology and director of the Women’s Health Research Unit at McGill University and McGill University Health Centre in Montreal, Canada, discussed the favorable safety profile of the agent as well as how it compares with the current standard of care in dMMR advanced endometrial cancer.

What is the mechanism of action of dostarlimab and how does it compare with other PD-1 inhibitors in this space?

When cells replicate, DNA errors are common and we have a system in place called the mismatch repair system that corrects DNA replication errors. [However], some tumors are deficient in this mismatch repair mechanism, these are dMMR tumors. Fortunately for women with endometrial cancer, endometrial cancer is a type of cancer that has one of the highest recorded mismatch repairs, so it gives us a target for these cancers and that’s why we are very happy because this is a space that did not have effective treatments.

In women who had failed the gold-standard treatment for advanced endometrial cancers, which is platinum-based chemotherapy, using second-line chemotherapy achieved responses of less than 10%, progression-free survival was in the region of 3 to 4 months, and most women died within a year.

[Comparatively], dostarlimab achieved remarkable results. Approximately one-third of women with endometrial cancer [are] dMMR, so this is a substantial group of women who it can help.

What were some of the key efficacy findings from GARNET, specifically among patients with dMMR endometrial cancer?

The GARNET trial is the largest trial of patients with endometrial cancer who had failed standard-of-care treatment. The GARNET trial is a single-arm trial, and it was open label. These patients had failed standard-of-care chemotherapy and had to have no other efficacious treatment available.

Patients with dMMR [disease] achieved an astounding [ORR] of 45.4%. Compare this with what second-line chemotherapy would have achieved which is approximately 10%, so this is very important. The responses were [also] durable, and that’s extremely important because with second-line chemotherapy the responses were very short lived [and] it was a low response rate. At the end of a year, approximately 85% of patients were still in response and at the end of 2 years, more than half the patients were still in response. This is immensely gratifying.

What is the safety profile of dostarlimab?

Patients who had [any grade] AEs were quite high, approximately 63% of patients had treatment-related AEs, but most of these were very minor. The important thing is grade 3 or more AEs were very low approximately 13% and the discontinuation rate from AEs were very low. For those who use systemic chemotherapy, this is immensely encouraging and for patients it’s wonderful to have such low toxicity. Some of the important grade 3 or more toxicities were anemia…so its safety profile is very good, and this is a boon to patients.

Are there any patients in whom you would hesitate to use this agent because of the possibility of AEs or serious AEs?

Immune checkpoint inhibitors work by activating the immune system and sometimes the immune system can go berserk and cause severe life-threatening problems. This is much more likely to occur in patients who already have a problem with the immune system. If [patients] have autoimmune diseases that have required treatment, this is a group in whom I’d be quite hesitant to use an immune checkpoint inhibitor, even something like dostarlimab which has a good safety profile. You must weigh what else this patient has [and] what else is at your disposal for these patients. If there’s absolutely nothing else then, very cautiously, I would perhaps be willing to try it, but that's a group of patients I’d be extremely careful about.

How do you see dostarlimab fitting into the endometrial cancer treatment paradigm?

For patients with dMMR [disease], there have been trials of other agents, for example, pembrolizumab [Keytruda] and durvalumab [Imfinzi]. Dostarlimab is being used in the largest group of patients with dMMR disease, so oncologists have the reassurance that this has been tried in a large number of patients and been followed up for quite a long time. That is very encouraging. It’s also the only immune checkpoint inhibitor that has trial evidence of having been used every 6 weeks.

This is good for patients if you take into consideration that these patients have already gone through a lot. They have had surgery, approximately 70% of patients have had radiation, some of them have had repeated surgery, [and] they’ve failed carboplatin and paclitaxel. To then go on to a treatment that after 4 doses can be given every 6 weeks as a 30-minute infusion is remarkable. Patients find this very reassuring, and it makes them able to get on with their lives. To come into a hospital, have an infusion only once in 6 weeks, [and] have very little toxicity is something that is phenomenal.I did not expect to see it in my lifetime so I'm very happy.

References

1. FDA grants regular approval to dostarlimab-gxly for dMMR endometrial cancer. FDA. February 9, 2023. Accessed March 16, 2023 https://www.fda.gov/drugs/resources-information-approved-drugs/oncology-cancer-hematologic-malignancies-approval-notifications
2. Jemperli. Prescribing information. GlaxoSmithKline; 2023. Accessed March 15, 2023. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm