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Our Thoughts on New Notable Results for Endometrial, Ovarian, and Cervical Cancers from ASCO 2021

Melissa M. Hardesty, MD, MPH

Affiliate Associate Professor
OB/GYN/GYN Oncology
University of Alaska Anchorage
Gynecologic Oncologist and Managing Partner
Alaska Women’s Cancer Care
Anchorage, Alaska

Melissa M. Hardesty, MD, MPH, has disclosed that she has received consulting fees and fees for non-CME/CE services from GlaxoSmithKline.

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David Scott Miller, MD, FACOG, FACS

Amy and Vernon E. Faulconer Distinguished Chair in Medical Science
Director and Dallas Foundation Chair in Gynecologic Oncology
Professor of Obstetrics & Gynecology
Fred F. Florence Bioinformation Center
University of Texas Southwestern Medical Center
Medical Director of Gynecologic Oncology
Cancer Committee
Parkland Health & Hospital System
Dallas, Texas

David Scott Miller, MD, FACOG, FACS, has disclosed that he has received funds for research support from Advenchen, Agenus, Akesobio, EMD Serono, Karyopharm, Merck Sharp & Dohme, Novocure, and Tesaro and consulting fees from AbbVie, AstraZeneca, Eisai Europe Limited, EMD Serono, Genentech, GlaxoSmithKline, Incyte, Iteos Belgium SA, Myriad Genetic Laboratories, Novocure, Serono, Seagen, Tarveda, and Tesaro.

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Released: July 8, 2021

At the 2021 American Society for Clinical Oncology (ASCO) annual meeting, important results were presented that may impact the treatment of endometrial, ovarian, and cervical cancers. In this commentary, Melissa M. Hardesty, MD, MPH, and David Scott Miller, MD, FACOG, FACS, share their thoughts on the clinical relevance of some of the most important findings.

Endometrial Cancer

Melissa M. Hardesty, MD, MPH:
Most women with endometrial cancer have a good prognosis and many undergo long-term follow-up monitoring. At the 2021 ASCO annual meeting, Zola and colleagues presented results from the multicenter, randomized TOTEM study comparing overall survival (OS) after 5 years for 1866 women with endometrial cancer who underwent either intensive or minimalist follow-up. In this study, follow-up tests such as CT scans, Pap smears, and regular pelvic ultrasounds did not improve OS or quality of life, even in patients with high-risk disease. The investigators suggested that, in clinical practice, frequent use of imaging and laboratory exams should be discouraged in patients in complete remission after surgery for endometrial cancer. This reflects my own practice, where we typically use less-intensive follow-up for most of my patients with endometrial cancer. If patients received either whole pelvic radiation or chemotherapy as adjuvant therapy beyond vaginal brachytherapy, I consider them high risk (pending histology). But even in the high-risk group of patients, the use of additional testing does not appear to be supported by the overall results from the TOTEM study.

David Scott Miller, MD, FACOG, FACS:
Management of recurrent endometrial cancer can be challenging, but the field has experienced significant progress in the last couple of years with the realization of personalized medicine. At ASCO 2021, a personalized approach was explored in a phase II pilot study of the PD‑1 inhibitor pembrolizumab in 25 patients with microsatellite instability (MSI)–high recurrent endometrial cancer. This study is important because it evaluated the heterogeneity in responses in patients with MSI status with either Lynch‑like characteristics vs sporadic (MLH1 methylation) endometrial cancer, which are much more common. Results from that study suggest that patients with endometrial cancer receiving pembrolizumab and Lynch‑like characteristics compared with those with methylated MLH1 status had a better objective response rate (100% vs 44%; P = .024), 3-year progression-free survival (100% vs 30%; P = .017), and 3-year OS (100% vs 43%; P = .043). If confirmed in a larger patient population, this discovery of heterogeneity in MSI‑high tumors should allow us to further refine our ability to prognosticate response and inform treatment decisions. For instance, patients with endometrial cancer and MLH1 methylation status may benefit from more aggressive combination therapy with the addition of lenvatinib.

Melissa M. Hardesty, MD, MPH:
Anecdotally, regarding ethnicity, in my clinic, some of the best responses to checkpoint inhibition are in Alaska natives. That said, I do not know of any studies in endometrial cancer that are examining results by race. I hope that with improving testing advances we will be able to further identify which patients will benefit most from these immunotherapies.

Ovarian Cancer

Melissa M. Hardesty, MD, MPH:
In the setting of ovarian cancer, Tanyi and colleagues presented a phase III open-label trial of a fluorescent folate receptor–targeted dye, pafolacianine sodium (OTL38), to detect lesions that would not be discernible by using only palpation and normal white light. Investigators showed that 33% of patients had ≥1 folate receptor–positive ovarian cancer lesion detected by intraoperative fluorescence imaging using pafolacianine sodium and fluorescence imaging not detected by normal white light/palpation on tissue not planned for resection. These are very thought-provoking results. Clearly, more-comprehensive tumor debulking may be associated with better outcomes, as seen in single‑institution studies that followed specific surgeons. Whether or not this particular tracking dye used in intraoperative imaging will facilitate that in everyday clinical practice is yet to be determined.

David Scott Miller, MD, FACOG, FACS:
I am also intrigued by this study of pafolacianine sodium imaging of folate receptor–positive ovarian cancer. I also agree with you that we do not have yet data regarding whether more robust debulking using this technology will result in OS benefit. Does excising microscopic, nearly invisible, disease make a difference? Or might it help further optimize a patient for systemic therapies?

Melissa M. Hardesty, MD, MPH:
I also think it’s worth noting that this technology would be difficult to implement in a resource-limited setting, even if a clinically relevant survival benefit is identified.

Another very important presentation at ASCO 2021 was regarding emerging challenges with the use of PARP inhibitors. Since PARP inhibitors are increasingly being used in the frontline setting and in platinum-sensitive recurrent ovarian cancer, one of the most clinically relevant questions to date is what to do in patients who experience disease relapse while receiving a PARP inhibitor.

At ASCO 2021, Westin and colleagues presented results from the noncomparative phase II EFFORT trial of adavosertib, a WEE1 inhibitor, with or without olaparib in 116 women with PARP inhibitor–resistant ovarian cancer. Preliminary results from that study suggest promising activity for single-agent adavosertib and in combination with olaparib. In my clinical practice, I encourage women to consider clinical trials like this because we lack robust data in the setting of relapse following a PARP inhibitor. Conversely, if a clinical trial is not an option, treatment is typically guided by whether patients are platinum sensitive, in which case, they typically receive a platinum doublet for recurrent disease. However, then there is the question of maintenance therapy. In this situation, next-generation sequencing can help guide decisions, along with homologous recombination deficiency status and other biomarkers. Regarding novel agents being investigated in ongoing clinical trials, I am particularly enthusiastic about WEE1 inhibitors, and folic acid receptor–targeting agents like mirvetuximab soravtansine, for which data were also presented at ASCO 2021 by O’Malley and colleagues.

Cervical Cancer

David Scott Miller, MD, FACOG, FACS:
In the setting of recurrent or metastatic cervical cancer, there has been a decades-long drought with no new significant treatment options. This may change in the relatively near future. At ASCO 2021, we saw data presented for several promising novel agents being evaluated in clinical trials. Tisotumab vedotin is an antibody–drug conjugate that targets cells expressing tissue factor, which is prevalent in cervical cancer. Based on promising results in the single-arm phase II innovaTV 204 study of tisotumab vedotin in patients with previously treated recurrent and/or metastatic cervical cancer, the phase III innovaTV 301 trial was initiated. The innovaTV 301 trial is comparing tisotumab vedotin vs chemotherapy as second-line or third-line treatment for relapsed or metastatic cervical cancer (N = 482). Cemiplimab is a monoclonal antibody targeting PD-1 that has shown encouraging preliminary antitumor activity in a phase I basket trial that included patients with recurrent cervical cancer. The phase III GOG-3016/EMPOWER-CERVICAL 1 study is currently comparing cemiplimab with chemotherapy in patients with platinum-refractory and/or metastatic cervical cancer who had progression within 6 months of their last platinum regimen (N = 608). Results from that study were recently presented at the 2021 virtual European Society for Medical Oncology meeting showing an improvement in OS (12.2 vs 8.5 months; HR: 0.69; P = .00011) in the overall population for cemiplimab when compared with investigator’s choice chemotherapy.

Melissa M. Hardesty, MD, MPH:
Another interesting trial looking at novel approaches to managing advanced and recurrent cervical cancer is the phase I/II of bintrafusp alfa, a bifunctional fusion protein comprised of a TGF-βRII (TGF-β trap) fused to a human monoclonal antibody blocking PD-L1. At ASCO 2021, Strauss and colleagues presented a pooled analysis of bintrafusp alfa in 39 women with heavily pretreated recurrent or metastatic cervix cancer who had not received treatment with an immune checkpoint inhibitor. Investigators reported an objective response rate of 28.2%, and the clinical response rate was 30.8%, which compares very favorably with PD‑L1 monotherapy. The median OS was 13.4 months, and one third of patients were alive at 2 years. Results are encouraging, given that this is a patient population with pretty difficult-to-treat disease, and the current approved agents do not have any more favorable results than this. Treatment‑related adverse events appear to be in line with what has been previously reported with anti–PD‑L1‑targeting agents.

Future Directions

Melissa M. Hardesty, MD, MPH:
I think we are starting to see a lot of progress in recent years, with exciting data being presented for patients with various types of gynecologic cancers, yet challenges remain for patients with relapsed or recurrent endometrial, ovarian, and cervical cancers. I think that it is important to try to get patients to enroll on clinical trials exploring novel agents in areas of high unmet clinical need.

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