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Commentary: Expert Insight on Key Data From SGO 2023 Informing Treatment for Endometrial, Cervical, and Ovarian Cancers
Expert Commentary and Insight on Key Data From SGO 2023 Informing Treatment for Endometrial, Cervical, and Ovarian Cancers

Released: May 16, 2023

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Key Takeaways
  • Combination of immunotherapy with platinum-based doublet is likely to become the new standard of care in previously untreated advanced endometrial cancer with dMMR/MSI-H status.
  • Immunotherapy sequencing before/after chemoradiation is safe and does not appear to have a detrimental impact on outcomes. Priming with immunotherapy appears to elicit early systemic expansion of tumor-associated T-cell clones.
  • Combining letrozole and ribociclib in low-grade serous ovarian cancer is feasible and yields encouraging survival outcomes when compared with other available treatment options.

In this commentary, adapted from a discussion between David Scott Miller, MD, FACOG, FACS, and Linda Duska, MD, MPH, FACOG, FACS, FASCO, the experts address important clinical questions about how to integrate new data on novel treatments and combinations into the treatment landscape for patients with endometrial, cervical, and ovarian cancers.

Endometrial Cancer

Linda Duska, MD, MPH, FACOG, FACS, FASCO:
Dr. Miller, I have a couple of questions for you about some of the practice-changing results presented at the Society of Gynecologic Oncology (SGO) 2023 annual meeting. Do you think we should be changing our practice based on the results presented for ENGOT-EN6/GOG-3031/RUBY trial and the NRG GY018 trial at SGO 2023?

David Scott Miller, MD, FACOG, FACS:
The randomized phase III ENGOT-EN6/GOG-3031/RUBY trial evaluated carboplatin and paclitaxel with or without dostarlimab followed by dostarlimab or placebo maintenance for 3 years in patients with primary advanced or recurrent endometrial cancer. The coprimary endpoints of the study are progression-free survival (PFS) by investigator and overall survival. Data presented at SGO showed the primary endpoint of PFS was met with a clinically significant 2-year PFS improvement for the dostarlimab arm vs the chemotherapy-alone arm in the overall population (36% vs 18%; HR: 0.64; P <.001), deficient mismatch repair (dMMR)/microsatellite instability high (MSI-H; HR: 0.28; range: 0.16-0.50; P <.001), and proficient mismatch repair (pMMR)/microsatellite stable (MSS) population (HR: 0.76; range: 0.59-0.98).

The NRG GY018 trial also was a randomized phase III study of carboplatin and paclitaxel with or without pembrolizumab followed by pembrolizumab or placebo maintenance for 2 years in patients with measurable stage III/IVA, stage IVB, or recurrent endometrial cancer. Similar to the RUBY trial, the primary endpoint of PFS per RECIST v1.1 by investigator in the pMMR and dMMR population was met. Data presented at SGO 2023 showed a clinically significant improvement in median PFS for the pembrolizumab-containing arm vs chemotherapy-alone arm for the dMMR cohort (not reached vs 7.6 months; HR: 0.30; P <.001) and pMMR cohort (13.1 vs 8.7 months; HR: 0.54; P <.001).

One of the main differences between the RUBY trial and the NRG GY018 trial was the inclusion of patients with carcinosarcoma, which even then only accounted for approximately 10% of patients. Patients with serous and clear cell disease were included in both. But overall, both studies were positive and met their primary endpoints and I believe they are practice changing.

Linda Duska, MD, MPH, FACOG, FACS, FASCO:
I agree with you, Dr. Miller. I have a follow-up question for you based on the results from both of these positive studies: Should we now be changing our practice for patients with pMMR status?

David Scott Miller, MD, FACOG, FACS:
Well, that is the big question, and we are already trying to address this in my own group.  If you have patients who are receiving frontline carboplatin and paclitaxel for advanced endometrial cancer, do you add pembrolizumab? I can tell you that our main impetus to do that is if we have a patient who is not responding to that initial therapy or has a stable disease. In that scenario, we have been adding pembrolizumab. But I think that with the strength of these new data and publications, we will be able to offer this to more of our patients who qualify for it. This approach does leave us with a couple of unanswered questions, such as what are we going to do in that smaller group of patients who experience disease progression? I don’t think we have an answer for that yet.

Linda Duska, MD, MPH, FACOG, FACS, FASCO:
You anticipated my second question. Our second-line therapy for relapsed patients is a single-agent immune checkpoint inhibitor (dostarlimab or pembrolizumab) for those whose disease has dMMR/MSI-H status and pembrolizumab plus lenvatinib in pMMR/MSS. I am curious if we move checkpoint inhibitors into the frontline setting, what are we going to offer in the second line? Do you have any thoughts on that?

David Scott Miller, MD, FACOG, FACS:
One thing we thought about is that we could use dostarlimab in our first-line therapy, and then if the patient does experience progression, and we want to return to an immune checkpoint inhibitor, we can use a different one, for example, pembrolizumab with or without lenvatinib, depending on the mismatch repair status. But I agree with you. We currently have no data for the use of immune checkpoint therapy in the second line after immune checkpoint therapy in the frontline. In other words, we don’t know if immune checkpoint therapy will be an effective therapy a second time.

Linda Duska, MD, MPH, FACOG, FACS, FASCO:
Another important point is, in a patient with dMMR/MSI-H status, how would you choose between the RUBY regimen with dostarlimab and the NRG GY018 with pembrolizumab?

David Scott Miller, MD, FACOG, FACS:
When dostarlimab was first approved, it was priced higher than pembrolizumab, so it did not get much traction with our pharmacy trying to get it on formulary. Now that there is new data in the frontline setting for dMMR/MSI-H, I think we will be able to make some progress and offer this agent.

As stated before, I would be inclined to start with dostarlimab in anticipation of what might be happening with second-line therapy because we do not have a pembrolizumab plus lenvatinib equivalent with dostarlimab in the second line.

Linda Duska, MD, MPH, FACOG, FACS, FASCO:
Would it be fair to say in the upfront setting, we don’t yet have data to indicate that one is any different or better than the other?

David Scott Miller, MD, FACOG, FACS:
I agree.

Locally Advanced Cervical Cancer

Linda Duska, MD, MPH, FACOG, FACS, FASCO:
As in endometrial cancer, there is much interest in evaluating immunotherapy earlier during the course of treatment for locally advanced cervical cancer.  Of importance, there continues to be an unmet need in this area.  We are certainly doing better with the addition of cisplatin to chemoradiotherapy, but we are just not quite there.  I think the prevention of cervical cancer is key.

Two of the abstracts presented at SGO for cervical cancer examined the question of sequencing of immunotherapy with chemoradiation in the upfront setting for locally advanced cervical cancer. We know that in the CALLA trial, the combination of the PD-L1 inhibitor durvalumab concurrent with chemoradiation, followed by durvalumab maintenance failed to meet the prespecified PFS endpoint. It remains unclear to me why that happened. One hypothesis was that maybe adding immunotherapy to the chemoradiation therapy might adversely affect the overall outcome.

The first study, presented by Dr. Zamarin from Memorial Sloan Kettering Cancer Center, was the phase I NRG GY017 trial evaluating atezolizumab before and concurrent or only concurrent with chemoradiotherapy in patients with high-risk locally advanced cervical cancer (n = 36). In that study, patients received atezolizumab administered in 3 doses with no maintenance.  In arm A, a priming dose was used with 2 subsequent doses together with chemoradiation. In arm B, they received the same 3 doses but during chemoradiation. The primary endpoint was identifying biologic parameters that could predict long-term outcomes and determining whether parameters could help understand the impact of chemoradiation on immune response and immunotherapy plus chemoradiotherapy sequencing.

The PFS was 79% at 26 months in arm A and 59% in arm B. It is important to note that this study was not powered to show a difference in PFS or overall survival. The only thing we can say is that giving the priming dose did not adversely affect survival outcomes.

I think the most interesting outcome from that study was that the priming dose appeared to lead to an early systemic expansion of tumor-associated T-cell clones, which suggests an early systemic tumor-specific immune response. Of note, this was not seen in arm B, and in arm B, there appeared to be a tumor-associated T-cell clone contraction. Those findings are hypothesis generating and can potentially help us in study design as we continue to explore the idea of moving immunotherapy into the frontline for locally advanced cervical cancer.

I presented the second study. It is a randomized phase II trial of pembrolizumab during chemoradiotherapy or after chemoradiotherapy in patients with high-risk locally advanced cervical cancer (n = 96).  The primary endpoint for the study was change as a function of intervention in the ratio of CD8 T-cells divided by T-regulatory cells. Similar to the NRG GY017, we conducted multiple tissue biopsies and multiple blood biopsies. We also included data on PD-L1 staining and looked at PET scan response. This regimen is safe and tolerable, similar to NRG GY017, and safety and tolerability data have already been published. Unfortunately, our primary endpoint was not met. We did not see a difference in the ratio of CD8 T-cells to T-regulatory cells either in tissue or in blood between the 2 arms. However, we did see different patterns of change in E7 peptide in peripheral blood, and we saw increases in all of E7 and one E6 response only if pembrolizumab was given during chemoradiation.  Similar to the NRG GY017, we also saw both sequences altered multiple immune cell populations and ongoing work is continuing to explore that finding.

Low-Grade Serous Ovarian Cancer

Linda Duska, MD, MPH, FACOG, FACS, FASCO:
At SGO, Dr. Brian Slomovitz presented results from a single-arm, open-label phase II trial of letrozole and ribociclib in women with advanced and recurrent low-grade serous ovarian cancer (n = 51).  This is a rare disease that is in dire need of new therapies. In that study, patients were allowed to have unlimited prior lines of therapy, although no prior letrozole was allowed—most had previous chemotherapy (73%). The primary endpoint was overall response rate.

The overall response rate in this study was 23%. All responses were partial responses, but the duration of response was 19.1 months, median PFS of 19.1 months, and median overall survival had not been reached at the time of this presentation. The most common high-grade toxicities were hematologic, and patients did very well while receiving this combination. When compared with alternative therapies, the combination of letrozole and ribociclib had the longest PFS and duration of response. These findings suggested that this is a viable alternative for these women.

David Scott Miller, MD, FACOG, FACS:
Thank you for those excellent summaries. It is very encouraging to finally see something with actual activity in low-grade serous ovarian cancer.

Your summaries on the immune therapy for cervix cancer were very interesting. I do recall that, a decade or so ago, we used to hear a lot about using neoadjuvant chemotherapy in locally advanced cervix cancer and that eventually did not pan out. Are you a little more optimistic about the addition of immune therapy?

Linda Duska, MD, MPH, FACOG, FACS, FASCO:
I think we need to have a better understanding of the biology. The question is how to make the environment more conducive to immunotherapy success. Whether that’s giving the immunotherapy during radiation or after radiation because of concern that radiation is killing off all the T-cells that you’re trying to stimulate with the immunotherapy, or whether the best idea is to give the immunotherapy upfront. I think we do not fully understand the biology, and we need to better design these trials. That’s why the 2 trials that were presented at SGO are so important going forward.

David Scott Miller, MD, FACOG, FACS:
I encourage you to go online to learn more about the conference coverage program entitled “Key Findings and Expert Recommendations in Gynecologic Malignancies: Independent 2023 Conference/Congress Coverage,” to listen to a Podcast and download the slides associated with this discussion, and remember to return to the website for new content from ASCO, ESGO, ESMO, and IGCS as data from these meetings become available.

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