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New Results IGCS 2021
How We Will Apply New Results in Endometrial, Ovarian, and Cervical Cancers From IGCS 2021

Released: September 30, 2021

Expiration: September 29, 2022

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At the 2021 annual meeting of the International Gynecologic Cancer Society (IGCS), practice-changing data from various clinical trials were reported. Below, gynecologic cancer experts Alexandra Leary, MD, PhD, and Domenica Lorusso, MD, PhD, discuss some of the key results presented for endometrial, ovarian, and cervical cancers.

Endometrial Cancer

Alexandra Leary, MD, PhD:
IGCS 2021 was really exciting, particularly regarding the use of immune checkpoint inhibitors in endometrial cancer. A current focus in this setting is guiding treatment by microsatellite instability–high (MSI-H) or defective mismatch repair (dMMR) status. Subanalyses for 2 key studies of immunotherapy in endometrial cancer were presented at IGCS 2021: the GARNET trial of dostarlimab and the KEYNOTE-775 study of pembrolizumab plus lenvatinib.

Domenica Lorusso, MD, PhD:
I agree. At IGCS 2021, Oaknin and colleagues reported antitumor activity of dostarlimab by prior line of therapy in the GARNET study. And the results were quite interesting because, although the percentage of responders appears not to be influenced by whether the patients had received 1 vs ≥2 previous lines of treatment in the mismatch repair–proficient (pMMR)/microsatellite stable (MSS) cohort (13.9% vs 14.3%, respectively), response rate was increased from 35.9% to 50.0% in patients who had received only 1 prior line of therapy in the dMMR/MSI-H cohort. I think this is a great suggestion for when to incorporate this drug in patients with MSI-H status preferably after 1 prior line of therapy. And as you know, the FDA granted accelerated approval to dostarlimab for adult patients with dMMR recurrent or advanced solid tumors, and the European Medicines Agency has approved it for adult patients with dMMR/MSI-H recurrent or advanced endometrial cancer with progression on or after platinum-containing regimen.

Regarding the KEYNOTE-775 subgroup analyses in patients with dMMR status, Makker and colleagues reported that median PFS was significantly prolonged with lenvatinib and pembrolizumab vs treatment of physicians choice in the dMMR subgroup (10.7 vs 3.7 months; HR: 0.36; P <.0001), consistent with the overall population. Moreover, overall survival (OS) was not reached vs 8.6 months (HR: 0.37; P <.0001) and overall response rate (40.0% vs 12.3%) was also superior with lenvatinib plus pembrolizumab in the dMMR subgroup.

Alexandra Leary, MD, PhD:
Dr. Lorusso, it seems we have a rich woman’s problem with various options of immunotherapy in endometrial cancer. How do you approach treatment of your patients with MSI-H and MSS endometrial cancer? Do you prefer pembrolizumab alone, pembrolizumab plus lenvatinib, or dostarlimab?

Domenica Lorusso, MD, PhD:
This is the 1 million Euros question. The challenge is that to date, no trial in endometrial cancer has compared immune therapy alone to the combination of pembrolizumab plus lenvatinib, so I can only share my clinical experience. Patients with endometrial cancer tend to be fragile and older and have multiple comorbidities. In this population, the use of single-agent immunotherapy for patients with dMMR is very effective. In my practice, I usually treat patients with endometrial cancer and dMMR with immunotherapy alone, and reserve the combination for patients with pMMR, particularly clear cell, serous, and carcinosarcoma, where immunotherapy alone does not work as well. The tradeoff between efficacy and toxicity is an important consideration, particularly in endometrial cancer. The combination of lenvatinib and pembrolizumab may be effective, but it is also toxic: In KEYNOTE-775, 43.8% of patients in the combination arm discontinued due to toxicity and 71.9% had dose interruptions.

Alexandra Leary, MD, PhD:
The toxicity associated with the combination is a genuine concern, but as previously mentioned, it’s a nice problem to have, given the historical experience of no or few treatment options for women with endometrial cancer.

Domenica Lorusso, MD, PhD:
Agreed. The key point here is to identify those women with dMMR endometrial cancer for whom immunotherapy alone is not sufficient; in the dMMR subgroup of KEYNOTE-775, which was defined by both molecular and clinical characteristics, the combination with lenvatinib may perform better than single-agent immunotherapy.

Alexandra Leary, MD, PhD:
The randomized TOTEM study was designed to compare 5 years of intensive vs minimalist follow-up of patients with endometrial cancer to determine the risk of recurrence and survival benefit (N = 1866). Dr. Lorusso, what is your take on TOTEM?

Domenica Lorusso, MD, PhD:
The TOTEM trial clearly reported that intensive follow-up does not improve OS compared with minimalist follow-up (HR: 1.12). There also was no OS or relapse-free survival benefit evident when patients were stratified into low-risk and high-risk groups. The main caveat of this trial is that nearly 60% of patients had low‑risk (stage I, grade 1/2) tumors and molecular classification was not used. I’m not convinced that these results can be used to guide treatment in clinical practice. That said, it is now clear that during follow-up, we no longer require a Pap smear, ultrasound evaluation, or CA‑125 evaluation to determine relapse. As always, it remains important that patients be evaluated in the clinic, including a CT scan as needed due to symptoms.

Ovarian Cancer

Alexandra Leary, MD, PhD:
I wanted to briefly mention the post hoc analysis of the phase III NORA study of niraparib 300 mg/day as maintenance in platinum‑sensitive recurrent ovarian cancer (N = 265). This study, conducted in Asia, confirmed that niraparib maintenance in patients with a response to platinum chemotherapy decreases the risk of progression by 68% compared with placebo. In this analysis, the PFS benefit from niraparib was similar regardless of whether patients had received more or fewer than 4 cycles of platinum chemotherapy. To me, the take-home message is that if patients achieve complete response after 4 cycles, it is safe to stop, but if they have only achieved a partial response, it is preferable to continue through 6 cycles of platinum chemotherapy. This could be particularly helpful for patients who may not be able to continue platinum chemotherapy due to hematologic toxicities or allergies.

Domenica Lorusso, MD, PhD:
I agree; however, we know that patients of Asian descent seem to be genotyping differently from European patients. Do you think that these results also can be applied to European patients?

Alexandra Leary, MD, PhD:
I think this is a key question that needs to be addressed. We’ve been mistaken before when applying results from an Asian patient population to an European population, and we should always be cautious with the interpretation of these data. It is possible that certain treatments may have more efficacy just because the metabolism is different in these 2 populations. I think this is an important message and maybe one that we can try to answer with global studies that were conducted with a more diverse patient population.

Cervical Cancer

Alexandra Leary, MD, PhD:
One of the most important studies presented at IGCS 2021 was the phase III EMPOWER-CERVICAL 1 trial of the PD-1 inhibitor cemiplimab 350 mg every 3 weeks vs investigator’s choice of chemotherapy in patients with recurrent metastatic cervical cancer resistant to platinum-based chemotherapy and at least 1 prior line (N = 608). In the subset of patients with squamous cell carcinoma, cemiplimab showed such a strong OS benefit that the independent data and safety monitoring committee recommended the trial be stopped early for efficacy. The median OS in this subset of patients was 11.1 months for cemiplimab vs 8.8 months for chemotherapy (HR: 0.73; range: 0.36-0.85; P <.00306). These results represent a clinical breakthrough.

It has been many years since positive data were reported in a randomized phase III study in cervical cancer. Cemiplimab will be a significant step forward for our patients, and we are eagerly awaiting its approval. In the United States, the FDA has already approved immune checkpoint inhibitors for relapsed cervical cancer, but we do not yet have access in Europe.  

Domenica Lorusso, MD, PhD:
Absolutely. I think that immunotherapy in cervical cancer is changing the natural history of this disease. The earlier immunotherapy is used in this disease setting, I think there will be more potential for higher efficacy. At the 2021 European Society for Medical Oncology meeting, positive results were presented for the phase III KEYNOTE-826 trial of the combination of pembrolizumab with chemotherapy in the first‑line setting (NCT03635567). Then, in 1-2 years, results will be presented for a phase III trial evaluating the combination of pembrolizumab and chemoradiation in locally advanced disease (NCT04214067). We are living in a very exciting moment in endometrial cancer and cervical cancer treatment, in particular, with immunotherapy.

Alexandra Leary, MD, PhD:
Finally, some good news for our patients. It’s been a long time coming.

Your Thoughts
What are your thoughts on these near-future changes in endometrial, ovarian, and cervical cancer treatments? Please leave your thoughts in the comment box below.

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How often do you consider single-agent immunotherapy (dostarlimab or pembrolizumab) in patients with DNA dMMR endometrial cancer?
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