2023 Yields Several Promising Trial Updates in dMMR/pMMR Endometrial Cancer

The phase 3 DUO-E/GOG-3041/ENGOT-EN10 trial (NCT04269200) is among various other phase 3 trials—such as the NRG-GY018 (NCT03914612), RUBY (NCT03981796), and AtTEnd (NCT03603184) studies—that have had positive data readout over the course of 2023, impacting how patients with advanced or recurrent endometrial cancer who present with mismatch repair–deficient (dMMR) and mismatch repair–proficient (pMMR) disease may be treated, according to Eirwen M. Miller, MD.

Notably, Miller shared that the DUO-E study results presented at the European Society for Medical Oncology (ESMO) Congress 2023 showed that the addition of durvalumab (Imfinzi) to first-line chemotherapy followed by maintenance therapy with or without olaparib (Lynparza) plus the anti–PD-L1 antibody improved progression-free survival (PFS) vs the control arm, with the dMMR subgroup experiencing the greatest benefit. In the dMMR cohort, those treated with the combination (n = 48) and monotherapy (n = 46) achieved a median PFS of 31.8 months (95% CI, 12.4-not reached [NR]) and NR (95% CI, NR-NR) vs 7.0 months (95% CI, 6.7-14.8) in the control arm (n = 49). HRs vs the control arm were 0.41 (95% CI, 0.21-0.75) with the combination and 0.42 (95% CI, 0.22-0.80) with the monotherapy.

“[These are] huge practice-changing studies in advanced endometrial cancer, and I am hopeful for some more FDA indications in that space,” Miller said in an interview with OncLive following a State of the Science Summit™ (SOSS) on gynecological cancers, which she chaired.

In the interview, Miller, who is a gynecologic oncologist at Allegheny Health Network West Penn Hospital in Pittsburgh, Pennsylvania, detailed her presentation from the SOSS event, delving into an endometrial cancer case study that she presented with colleague Christopher B. Morse, MD. She also highlighted data that have impacted the treatment armamentarium for patients with dMMR disease throughout the course of 2023.

OncLive: What were the key takeaways from your discussion on immunotherapies for advanced endometrial cancer?

Miller: In the past 12 months, we’ve seen practice-changing data in the advanced endometrial cancer space. Starting at the 2023 Society of Gynecologic Oncology Annual Meeting [on Women’s Cancer] in the spring and continuing through the ESMO Congress 2023 this fall, [we] had 3 or 4 randomized phase 3 trials presented evaluating the role of immunotherapy in combination with chemotherapy followed by immunotherapy monotherapy for patients with advanced endometrial cancer. In each of those trials—NRG-GY018, RUBY, AtTEnd, and DUO-E—we saw a statistically significant and incredibly clinically meaningful survival benefit when adding immunotherapy to standard chemotherapy. This [occurred] particularly in the dMMR cohorts.

Some of these trials were powered to also assess the pMMR cohort, [whereas] others were powered to assess the intention-to-treat group. However, in most of these trials, the intention-to-treat or pMMR subgroups also met a statistically significant end point, though the clinical benefit is a bit more modest. The addition of immunotherapy to chemotherapy is certainly going to change the standard of care for patients with dMMR tumors. It’s fair to argue that we should add it to [treatment for] patients with pMMR disease, understanding [it provides] a more modest benefit and is still a place for ongoing clinical investigation.

Please expand on the DUO-E trial subgroup data.

I was interested in the DUO-E data that were presented by Shannon N. Westin, MD, MPH, FACOG, of The University of Texas MD Anderson Cancer Center in Houston, at the ESMO Congress 2023, evaluating the combination of a PARP [inhibitor] with immunotherapy in a maintenance strategy, particularly in the pMMR cohorts where we see a more modest benefit from immunotherapy alone. How the addition of PARP inhibitors may add to the [current] survival benefit [patients experience with immunotherapy is under investigation].

It’ll be interesting as the investigators from that study continue to dig down into the subgroups to understand at a molecular and subgroup level which patients are going to benefit from the addition of a PARP inhibitor. [Overall], we’re likely to see PARP inhibitors become part of our treatment algorithms in that space, certainly with more investigation to narrow down who’s going to benefit the most.

What would you like your colleagues to take away from your case presentation?

The case presentation with Dr Morse was meant to highlight how our practice patterns have changed from the phase 3 GOG 209 [trial (NCT00063999)] era, [when] we weren’t using any maintenance strategies in endometrial cancer. Now, we’re seeing for particularly high-risk patients—those with type 2 histology who have residual disease after surgery, metastatic disease, [or] recurrence after prior platinum therapy—that we’re entering a maintenance phase with a multitude of targeted therapy options.

Looking at the options of trastuzumab [Herceptin], bevacizumab [Avastin], immunotherapy, or immunotherapy with PARP [inhibitors, these are all areas of interest]. We’re going to need to continue to investigate how to sequence these options; it’s probably not a one-size-fits-all. We’re approaching a personalized medicine era where we’re selecting agents by their molecular profiles and tumor characteristics. The case presentation highlighted [these takeaways] and made for some interesting discussion about how we’re going to be selecting those maintenance options and how we’re probably going to struggle to sequence them through the course of a patient’s care.

Reference

Westin SN, Moore KN, Chon HS, et al. Durvalumab (durva) plus carboplatin/paclitaxel (CP) followed by maintenance (mtx) durva ± olaparib (ola) as a first-line (1L) treatment for newly diagnosed advanced or recurrent endometrial cancer (EC): results from the phase III DUO-E/GOG-3041/ENGOT-EN10 trial. Ann Oncol. 2023;34(suppl 2):S1282-S1283. doi:10.1016/j.annonc.2023.10.035