Dostarlimab With Chemo Changes Practice for dMMR Endometrial Cancer

“The dMMR population, which are patients who have deficiency in their mismatch repair proteins, had the most pronounced impact in PFS, and we’re seeing that trend for prolonged periods of time; we may be curing many of these patients,” said Ritu Salani, MD.

The FDA recently expanded the approval of dostarlimab-gxly (Jemperli) in combination with carboplatin/paclitaxel to include patients with primary advanced or recurrent endometrial cancer, and is a regimen with curative potential in select patient subgroups.¹

The approval was based on findings of the phase 3 RUBY trial (NCT03981796), in which the combination increased overall and progression-free survival compared with placebo plus chemotherapy among patients with primary advanced or recurrent endometrial cancer. For example, the median overall survival with dostarlimab was 44.6 months (95% CI, 32.6-not reached) vs 28.2 months (95% CI, 22.1-35.6) with placebo, leading to a 31% reduction in the risk of disease progression or death (HR, 0.69; 95% CI, 0.54-0.89; 1-sided P = .002). The regimen also showed a manageable safety profile.²

CancerNetwork® spoke with Ritu Salani, MD, a board-certified gynecologic oncologist and director of gynecologic oncology at the University of California, Los Angeles Health. She shared details surrounding the efficacy and safety profile of dostarlimab for this indication, implementation of the combination therapy into clinical practice, and other endometrial cancer developments based on tumor biology.

In addition to her expressed enthusiasm for the expanded dostarlimab approval, Salani also highlighted the drug’s benefit in mismatch repair–deficient (dMMR) tumors vs mismatch repair–proficient (pMMR) tumor types, the latter of which did not see a statistically significant survival benefit. The role of checkpoint inhibitor therapy following immunotherapy was discussed, and whether the use of frontline immunotherapy can help optimize patient benefit.

CANCERNETWORK: What is the impact of the FDA approval of dostarlimab in combination with carboplatin and paclitaxel in primary advanced or recurrent endometrial cancer?

Salani: The FDA approval of dostarlimab for advanced or recurrent endometrial cancer is wonderful to see. We know since March 2023, when the data were first presented, that the addition of dostarlimab with chemotherapy followed by maintenance dostarlimab had a significant impact on patients in this setting, particularly in those with the dMMR tumor profile, and we're seeing significant impact on survival benefit without adding a lot of toxicity. It is wonderful to see a relatively short turnaround in having access of this drug for our patients who meet these criteria.

Supporting data for the approval in this indication came from the phase 3 RUBY trial. Please contextualize these findings.

The dMMR population, which [comprises] patients who have deficiency in their mismatch repair proteins, had the most pronounced impact in PFS. We’re seeing that trend for prolonged periods of time; we may be curing many of these patients. The pMMR data from the RUBY trial leave a little bit more to be desired. Although we see a PFS benefit and a clinical trend towards [improved] overall survival, it is not statistically significant. It just reminds us that we need to do better for these patients. There are still some opportunities to capitalize on tumor profiles or other biomarkers that may be more meaningful.

What unanswered questions do this approval help clarify?

It improves the outcomes of patients in the frontline setting or in that first-line chemotherapy setting, but it creates an unmet need. [Immunotherapy] was something we were commonly using in the recurrence setting or second-line beyond [setting]. The challenge that we now have is: what is the role, if any, of checkpoint inhibitor therapy, after [another] checkpoint inhibitor, or different types of immunotherapy strategies? It creates a little bit of a need that we are now identifying. It addresses a need that we had, but it creates an unmet need.

How will this combination therapy best be implemented into clinical practice?

We are going to see a variety of practices influenced from these data. You will see some people who are using it for everybody who meets these criteria. The FDA approved it for stage III and stage IV disease—so primary or recurrent endometrial cancer. You will see some people who use it for everything you know. The thing that is interesting is the study highlighted patients who had residual disease, or patients who had measurable disease present when they receiving this therapy, and that seems to be where it has the most significant impact. There are some data emerging about patients who have complete resection of disease. Perhaps the role of immunotherapy is not quite as clear, although that may be a little ahead of its time or premature.

Seeing more data on the right selection of patients will be important. There are other avenues of treatment for this patient population, particularly the pMMR population, where you might see some other therapies that may have equally a profound impact as immunotherapy, and maybe that will lend itself to leading immunotherapy in the second line, if needed. We need to be thoughtful about how we approach immunotherapy in the front line or as [part of] first-line chemotherapy options for these patients. [We need] to sequence therapy in the most optimal way to give the patients the best survival outcomes as well as the best quality of life.

Do any toxicities associated with this combination therapy stand out to you?

There is not anything that stands out. We have been using immunotherapy and chemotherapy for several years in different disease sites. We have all found that there are always some nuances with it, and it is important to be able to recognize and manage toxicities readily. There are no new safety signals that we are seeing, particularly in the endometrial cancer population, but monitoring for thyroid disease and adrenal insufficiency and then having acuity for other less common toxicities, even like myocarditis or cardiac implications and pneumonitis. Things of that sort are important. We will all find that these therapies are easy to implement and manage with appropriate monitoring.

Most of the side effects have been well characterized, but you still have to have acuity to recognize them, and I do not want to say that these therapies are without any side effects. It is important to monitor, and we have labs built in; patients have symptoms to monitor and paying attention is key.

What other developments in endometrial cancer have the potential to impact clinical practice?

We have a target for a maintenance strategy, particularly for the pMMR p53 wild-type [subgroup], called selinexor [Xpovio], which has had some provocative early data. It is being validated in a study right now. I am excited for that, because that might be a way to strategize which patients get immunotherapy up front and which patients may benefit from this alternative option.

There are other new agents. I was talking about that needs gap—about creating that second-line gap in therapy. There are exciting things on the horizon, including TROP2 antibody-drug conjugates [ADCs] and folate receptor–alpha targets, which are helping to inform how patients may do in these later lines of therapy. We also have HER2 [ADCs], which [have] some provocative or compelling data in small numbers; that's being further evaluated.

We have ongoing trials looking at HER2 expression or amplification in combination with chemotherapy, so trastuzumab (Herceptin) in combination with chemotherapy. The thing that this highlights is treatment is shifting from “you have endometrial cancer” to “you have this tumor profile,” and focusing on a personalized approach for patients. This may optimize outcomes and minimize toxicities from unnecessary or ineffective therapies.

Is there anything else in relation to the RUBY outcomes or the dostarlimab approval that you would like to highlight?

These data are exciting. It has changed the landscape, but it is not enough. We need to continue to evaluate why patients who are [pMMR] may not respond to immunotherapies; [is it] something about their tumor profile or their biology? For the patients with [dMMR tumors] who have profound or exceptional responses [to immunotherapy]: can we exploit the tumors further? It is also important that for those patients who do not respond, we look at those and figure out what the better opportunities. are How can we select the patients who are going to get the most benefit and get them the right treatment earlier on? This is [not] by any means the end of the story.

References

1. FDA expands endometrial cancer indication for dostarlimab-gxly with chemotherapy. News release. FDA. August 1, 2024. Accessed August 1, 2024. https://tinyurl.com/mtr6tpyp
2. Positive RUBY phase III data show potential for Jemperli (dostarlimab) combinations in more patients with primary advanced or recurrent endometrial cancer. News release. GSK. March 16, 2024. Accessed August 1, 2024. https://tinyurl.com/bduurwmp