Elise C Kohn

A working group report from the 2024 National Cancer Institute / Gynecologic Cancer Steering Committee endometrial cancer clinical trials planning meeting: refining the approach to endometrial cancer in the immunotherapy era

Abstract Endometrial cancer is now the leading cause of gynecologic cancer death in the United States. Recognizing the urgent need to improve outcomes for patients diagnosed with endometrial cancer, the National Cancer Institute Gynecologic Cancer Steering Committee convened a clinical trials planning meeting, Refining the Approach to Endometrial Cancer in the Immunotherapy Era, on January 8 and 9, 2024. Multidisciplinary experts were charged with addressing critical challenges to optimize treatment of endometrial cancer in the new immunotherapy landscape. As part of the clinical trials planning meeting, working groups were assembled to address several important aspects of clinical trial design. Working group 1 focused on translational science and was tasked with reviewing the scientific literature for data on validated discriminants of response to immunotherapy to inform trial concept development by the therapy-focused groups. The working group established that molecular subtyping of endometrial cancer is now the standard approach for classifying endometrial tumors. Molecular subtyping for prognostic and predictive applications should be considered when assessing biomarkers as well as therapeutic targets. Additionally, strategies to improve immune response like incorporation of radiation as well as therapy sequencing considerations should continue to be explored. A major key observation from working group 1 was lack of validated discriminants for immunotherapy response beyond mismatch repair status, and tumor mutational burden and exploration of additional discriminants of response and resistance will be critical with the increasing use of immunotherapy in endometrial cancer.

The Diverse Aspects of Uterine Serous Cancer: an NCI workshop on the status of and opportunities for advancement of research

Abstract The marked increase in the incidence and mortality associated with endometrial cancer over the past 2 decades is driven in part by rising rates of higher-grade, more aggressive endometrial cancers with variations in TP53, uterine serous cancers and their dedifferentiated component, uterine carcinosarcomas. Uterine serous cancer rates have been increasing among all racial and ethnic groups, with higher rates of this aggressive uterine cancer in Black women. The National Cancer Institute hosted a workshop in June 2023 to examine the diverse aspects of uterine serous cancers across epidemiology, biology, and molecular genetics and to advance knowledge from basic to preclinical and translational efforts. Key stakeholders, including basic scientists, clinical investigators, and patient advocates, came together to identify critical research gaps that, when addressed, would facilitate more comprehensive and rapid progress in understanding and ultimately treating uterine serous cancers across all patients. The National Cancer Institute released a supplemental funding opportunity (NOT-CA-24-044) in spring 2024 to facilitate rapid translation of these recommendations.

Ovarian cancer

Epithelial ovarian cancer (EOC) describes a group of diseases characterized by differing pathogeneses, molecular profiles, histologies and prognoses. The low incidence of each distinct histological type of EOC poses challenges for obtaining an accurate diagnosis, robust evidence to guide management, and a mechanistic understanding to ensure availability of effective therapies. Most EOCs, including high-grade serous ovarian cancer, predominantly originate from the fimbriated ends of the fallopian tube, whereas low-grade serous, clear cell, endometrioid and mucinous EOCs are thought to originate from other tissues. Despite recognized genetic susceptibilities for the disease, no effective screening is available and late-stage diagnosis remains common. Known genetic susceptibilities are addressed by risk reduction surgery including removal of both fallopian tubes and both ovaries. Management is predominantly based on adequate surgery and chemotherapy with carboplatin and paclitaxel, with the addition of anti-angiogenic therapy as indicated. The incorporation of poly(ADP-ribose) polymerase inhibitors into first-line therapy has considerably altered outcomes in some women with EOC who have defective homologous recombination DNA repair, including in those with BRCA1 and/or BRCA2 mutations. Other molecular characteristics are important in distinct types of EOC, but the use of matched targeted therapies remains under investigation, as does the role of immunotherapy for EOC, for which trial data have been disappointing to date. Translationally enriched clinical trials will be important to further explore and validate accurate biomarkers to better guide clinical care.

Comparing Durvalumab, Olaparib, and Cediranib Monotherapy, Combination Therapy, or Chemotherapy in Patients with Platinum-Resistant Ovarian Cancer with Prior Bevacizumab: The Phase II NRG-GY023 Trial

Abstract Purpose: We assessed the efficacy of anti–PD-L1 durvalumab in combination with olaparib and cediranib (DOC), compared with the standard-of-care chemotherapy (SOC) in patients with platinum-resistant ovarian cancer (PROC), who had prior bevacizumab. Patients and Methods: NRG-GY023 was the first randomized four-arm superiority phase II trial enrolling patients with high-grade serous/endometrioid or clear-cell PROC with prior bevacizumab exposure. Patients were randomized 1:2:2:2 to SOC (weekly paclitaxel, topotecan, or pegylated liposomal doxorubicin), DOC, durvalumab + cediranib (DC), or olaparib + cediranib (OC). The primary endpoint was progression-free survival (PFS). The secondary endpoints included overall survival, overall response rate, and safety. The design had 80% power to detect an HR of 0.5 using a one-sided, α = 0.1-level test for each comparison with the SOC with a preplanned interim analysis. Experimental arms with HR estimates (vs. SOC) >0.87 could be discontinued. Results: A total of 153 patients were enrolled between April 4, 2021, and February 1, 2023. Accrual was permanently closed on February 1, 2023, due to futility. With a data cutoff of September 9, 2024, the median PFS was 3.4, 2.9, 2.5, and 2.8 months, and median overall survival was 7.5, 8.3, 5.7, and 10.2 months for SOC, DOC, DC, and OC, respectively. The overall response rate was 4.3% [95% confidence interval (CI), 0.00–0.19], 15.9% (95% CI, 0.07–0.29), 11.9% (95% CI, 0.05–0.24), and 9.1% (95% CI, 0.03–0.20) for SOC, DOC, DC, and OC, respectively. Compared with SOC, the PFS HR estimates were 1.003 (95% CI, 0.56–1.80), 1.108 (95% CI, 0.63–1.96), and 1.021 (95% CI, 0.57–1.82) for DOC, DC, and OC, respectively. No new safety signals were observed. Conclusions: In patients with PROC with prior bevacizumab, all experimental arms failed to reach the primary objective of improving PFS compared with SOC.