Key Advances in Endometrial Cancer - Episode 6

GARNET Clinical Trial Regimen in Advanced Disease


Kathleen Moore, MD: One of the most exciting developments in the field of therapeutics for endometrial cancer has been immunotherapies. We’ll talk quite a bit about monotherapy immunotherapy in this module, then later we’ll talk about combinations. For women whose tumors harbor mismatch repair deficiency [dMMR], microsatellite instability [MSI], and maybe even tumor mutational burden [TMB]—that’s not a validated biomarker yet, but we’re certainly looking at it—use of monotherapy immunotherapy has been a game changer for women with recurrent disease.

Prior to the pembrolizumab approval, there was nothing FDA approved. Our options for second-line treatment of endometrial cancer was doxorubicin or weekly paclitaxel. We have phase 3 data for both of those agents in that setting with a response rate of 15%. That’s the best our patients could expect. There wasn’t really an option for third-line treatment of endometrial cancer because our patients, unfortunately, weren’t living to third and fourth line. When you think about it, that’s not too long ago. Now we’re in this immunotherapy era. It’s such a different environment for our patients, thankfully, with monotherapy immunotherapy.

Pembrolizumab was the first to get approval based on a very large basket trial, and some patients with MSI-high endometrial cancer were included, which was fantastic. Now we have dostarlimab. The GARNET study was presented in 2019 and published in JAMA Oncology in 2020. This was led by Dr Ana Oaknin from Spain. The GARNET study was a huge phase 1 study looking at the efficacy of dostarlimab, which is an anti–PD-1 monoclonal antibody, in patients with recurrent endometrial cancer. They had a number of molecular cohorts, but the 1 we’re talking about today is those patients who have deficient mismatch repair proteins or microsatellite instability. They also had to have had at least 1 prior line of chemotherapy. This is second line and beyond recurrent disease.

This is a very large study. They accrued over 100 patients into this study, so it’s a very large safety database as well as an efficacy database. The efficacy was what we would expect in this population: fantastic. If you look at the 71 patients who were confirmed deficient mismatch repair, the complete response rate—which I don’t think we’ve ever talked about in this disease setting—was almost 13%, with an additional 30% being a partial response. The overall response rate was about 43% or 44%. An additional 15% to 16% were stable disease, which often can also be a win in this disease setting if it’s long-standing. The duration of response was so long that it wasn’t even reached, so we can’t report that at this time.

The other thing that’s important to note is that because this was such a large study, we have nice data for safety. The safety was what we would expect from this class of agents, with very low rates of immune-related toxicities. Those toxicities are real. As we’ve been using these agents more commonly, we’re all getting more familiar with recognizing them and intervening early to prevent them from becoming severe. The toxicities are uncommon but can be important.

We saw low rates of anemia in this study at about 3%. That’s probably disease related. We saw a very low rate of 2% colitis, which is 1 of the adverse effects we always focus on. And then diarrhea had a rate of only 2%. Those were the grade 3 or higher treatment-related adverse events. That’s a very manageable adverse-effect profile and compelling clinical efficacy. This was 1 of the largest studies done just in women with endometrial cancer, so it gives us a really nice data set, proving what we all suspected: This is an active drug.

We’re hopeful that dostarlimab will gain accelerated approval in this setting and be available for us to use in addition to pembrolizumab. It’s always great to have more than 1 option for our patients. From a cost standpoint, for whatever reason, drugs are slightly different from one another. If 1 is working but not tolerable, another may be tolerable. We don’t have data for that, but we’ve certainly seen that with other classes of drugs—PARP inhibitors, for example. Some people tolerate 1 and not the other. We’ve certainly seen that with tyrosine kinase inhibitors. Having more than 1 similar asset available in a disease space is important for a number of reasons—most important access, so that everyone, if for whatever reason that they may not be able to access 1 drug, can get the other and benefit from durable, tolerable efficacy. This is really exciting. Congratulations to this study team.

Transcript Edited for Clarity