Dostarlimab/Chemo Approval Changes Treatment Paradigm for dMMR/MSI-H Advanced or Recurrent Endometrial Cancer

The expanded FDA approval of dostarlimab-gxly (Jemperli) in combination with chemotherapy in the first-line treatment of patients with mismatch repair–deficient (dMMR) or microsatellite instability–high (MSI-H) advanced or recurrent endometrial cancer allows for the agent’s use earlier in the treatment course and enhances the efficacy of standard frontline chemotherapy agents, according to Dana Chase, MD, FACOG.

On July 31, 2023, use of this regimen followed by dostarlimab maintenance was approved by the FDA for this patient population. The regulatory decision was supported by interim findings from part 1 of the phase 3 RUBY/ENGOT-EN6/GOG3031/NSGO trial (NCT03981796), which showed that the dostarlimab regimen provided a statistically significant and clinically meaningful survival benefit.¹

Patients in the experimental arm experienced a 71% reduction in the risk of disease progression or death vs the placebo arm (HR, 0.28; 95% CI, 0.16-0.50; P < .001). Progression-free survival (PFS) rates at 24 months were estimated at 61.4% (95% CI, 46.3%-73.4%) with dostarlimab vs 15.7% (95% CI, 7.2%-27.0%) with placebo. Moreover, 24-month overall survival (OS) rates were 83.3% (95% CI, 66.8%-92.0%) and 58.7% (95% CI, 43.4%-71.2%), respectively (HR, 0.30; 95% CI, 0.13-0.70).²

“[Now that] this regimen is approved for use in [patients with] dMMR [and MSI-H disease], we’re going to potentially see them remain in remission for a lot longer or even survive longer,” said Chase, who is an associate professor in the Division of Gynecologic Oncology in the Department of Obstetrics and Gynecology at the David Geffen School of Medicine at the University of California Los Angeles Health.

In an interview with OncLive^®, Chase discussed key efficacy, safety, and quality of life (QOL) data from the RUBY trial supporting the FDA approval of dostarlimab; explained how this approval could help improve the efficacy of current chemotherapy regimens in advanced-stage or recurrent endometrial cancer; and shared how attempts to utilize immunotherapies like dostarlimab earlier in the disease course opens new avenues for future research.

OncLive: What unmet needs exist for patients with dMMR and MSI-H endometrial cancer?

Chase: Most commonly, patients with endometrial cancer are usually diagnosed at an early stage. Thankfully, this cancer has symptoms [that present] at an early stage. Because [of this], many times, patients come into the office early and they can be cured with surgery. However, we seem to be seeing an increasing number of [patients with] advanced endometrial cancer, meaning they [were not diagnosed] early [on in the disease course] for whatever reason. [Reasons could include] access to care, or that they didn’t have symptoms, or that they had a very aggressive [tumor] type that quickly progressed to an advanced stage.

When the patient has an advanced-stage endometrial cancer, traditional chemotherapy, although effective, doesn’t give the patient a long remission period. Frequently, those patients come back with recurrent disease. Once you have recurrent disease, your chances of survival and of a cure go way down.

Trying to find something to add to traditional chemotherapy to make these patients have a longer remission or increase their survival chances has been a large unmet need. In the frontline, meaning the first round of treatment for advanced endometrial cancer, we’ve been looking for some novel agents that will improve outcomes. Patients who recur after either an early-stage endometrial cancer or an advanced endometrial cancer treated with chemotherapy [have been] in dire need of something new to add to chemotherapy to make their remission last longer and/or for them to survive longer.

What was the rationale for investigating the utility of dostarlimab in combination with standard chemotherapy in the advanced-stage or recurrent setting?

Traditionally, we have used cytotoxic chemotherapy agents to treat many cancers originating from multiple different sites. The field of immunotherapy has really grown; [this modality offers] a way to treat cancer that is not a traditional cytotoxic chemotherapy approach. As many of us are aware, immunotherapy helps the body to identify the cancer as foreign, [which] then potentially improves the immune system’s ability to attack and fight the cancer. Dostarlimab falls under that immunotherapy class. [When added] to traditional chemotherapy, [this agent] has demonstrated an improvement in outcomes that we have not seen with traditional chemotherapy alone.

Please briefly discuss the trial design, methodology, and eligibility criteria of the RUBY trial.

The RUBY trial was a phase 3, double-blind, randomized placebo-controlled trial. It included patients who had either stage III/IV primary advanced endometrial cancer, or those with recurrent endometrial cancer that had previously received treatment. These patients were randomly assigned to receive either traditional chemotherapy alone, meaning carboplatin and paclitaxel, or carboplatin, paclitaxel, and dostarlimab. Following the completion of chemotherapy, patients on the experimental arm went on to receive dostarlimab maintenance therapy for up to 3 years vs placebo [in the control arm]. Patients on this trial could have a dMMR tumor type or an MMR-proficient [pMMR] tumor type.

What were some of the key efficacy findings from part 1 of the RUBY trial in patients with dMMR and MSI-high disease?

In the dMMR/MSI-high population, the PFS [rate] at 24 months was 61.4% in the dostarlimab group and 15.7% in the placebo group. The hazard ratio [for PFS was] 0.28, so [there was] more than a [71%] reduction in the risk of progression or death [in the dostarlimab group]. The [fact] that you could potentially improve [patient] outcomes with this regimen was a groundbreaking, practice-changing finding.

Thankfully, the regimen was very well tolerated. It was unlikely for patients to discontinue [treatment due to] toxicities seen in the experimental arm. At 12 months, for example, over 60% of patients in the dostarlimab arm were still without evidence of recurrence vs over 20% in the placebo arm. It looked as though that response was durable, meaning that the curve in the dostarlimab arm flattened out after 12 months. The placebo arm had already dropped prior to 12 months and then had flattened out. It was amazing to see these curves stay separated, despite having stopped chemotherapy, after 6 cycles and [continuing] on dostarlimab maintenance alone.

What should be known about the safety profile of this combination according to data from RUBY? Are there any patients in whom you would hesitate to use this combination?

Immune checkpoint inhibitors [ICIs] can cause various “itises.” They can cause colitis, pneumonitis, thyroiditis, [etc.] Thankfully, most patients who experience these toxicities [associated with] immunotherapy experience grade 1/2 [events]. It’s rare to experience a grade 3/4 adverse effect [AE] from an ICI. That said, patients on the trial in the dostarlimab arm did have a [10.2%] increase in the number of grade 3/4 AEs compared with traditional chemotherapy alone. Most of these toxicities did not lead to a dose discontinuation, meaning patients were able to continue [treatment] on dostarlimab.

If a patient is actively being treated for an autoimmune disease, I would be hesitant to start them on an ICI [like dostarlimab]. It [could counteract] the treatment that you’re giving them for their autoimmune disease. Other than that, I don’t see any other contraindications to putting a patient on this regimen.

What were the findings from the analysis regarding patient-reported outcomes?

The QOL data from the RUBY trial were presented at the 2023 ASCO Annual Meeting. That’s going to be coming soon. That said, we didn’t see significant differences in QOL between the 2 arms. When you’re introducing a new therapy to patients with advanced or recurrent cancer, you always worry that the new, experimental agent is going to potentially cause worsening QOL for a patient. That makes you wonder: Is it worth the risk to put the patient on the regimen if [their] QOL gets worse, and the benefit is not great?

In this study, the benefit [with dostarlimab] is high for [patients with] dMMR [disease]. Thankfully, the QOL didn’t look [substantially] different between the 2 arms, to the point that we consider that benefit [with dostarlimab] to be worth it. We know that recurrent cancer affects QOL. When a patient starts to recur, you see their QOL worsen. [The aim is to be] able to extend the time that the patient lives in remission without worsening QOL due to disease progression. The QOL data [with the dostarlimab regimen] were reassuring.

How will the recent approval of dostarlimab affect treatment expectations for patients with endometrial cancer? What does this approval mean for future immunotherapy research in this space?

It’s very exciting to be able to tell these patients that the chance of extending their remission and potentially surviving longer is [higher]. We’re [looking to move] this regimen into the frontline, either for newly diagnosed patients or for first recurrence, for example. We’re going to be moving immunotherapy [into earlier lines] of therapy, and we all are very excited about that.

The next place our brains go is: What are we going to do when these patients recur after immunotherapy with chemotherapy? We’re hoping some of these patients might even be cured [in the first line]. Ultimately, we realize that many of them will still recur, although that recurrence hopefully is happening later and later. The place my mind jumps to next is: What do I do in the next line [for patients who have] gotten immunotherapy earlier in their disease course? What am I going to do when they recur after that? That’s where I think research is headed.

References

1. Jemperli (dostarlimab) plus chemotherapy approved in the US as the first new frontline treatment option in decades for dMMR/MSI-H primary advanced or recurrent endometrial cancer. News release. GlaxoSmithKline. July 31, 2023. Accessed August 9, 2023. https://www.gsk.com/en-gb/media/press-releases/jemperli-plus-chemotherapy-approved-in-us-for-new-indication/
2. Mirza MR, Chase DM, Slomovitz BM, et al. Dostarlimab for primary advanced or recurrent endometrial cancer. N Engl J Med. Published online March 27, 2023. doi:10.1056/NEJMoa2216334