Takeaway
Use of PD-1 inhibitors improves clinical outcomes in both the upfront and recurrent treatment settings. The magnitude of benefit of treatment with PD-1 inhibitors is greater in patients with dMMR tumors.
Anti-HER2 therapies
HER2 is a cell surface protein that can become overexpressed and promote tumorigenesis. It is used as a prognostic biomarker and a therapeutic target in breast, stomach, and colon cancer, but it has also been identified at high rates (20%-30%) in the most aggressive histologic subtypes in endometrial cancer (serous, clear cell, and carcinosarcoma). Trastuzumab is a monoclonal antibody directed against HER2, most commonly used in HER2-positive breast cancer. In 2018, a phase 2 trial demonstrated that trastuzumab combined with standard chemotherapy improved PFS in serous endometrial cancers that overexpress HER2.7 These results were important and promising given both the poor prognosis associated with the aggressive serous histology and the relative lack of effective therapies at the time of recurrence.
Recently, antibody-drug conjugates (ADCs) have come to the forefront of cancer-directed therapies. ADCs deliver chemotherapy agents directly to cancer cells via a monoclonal antibody that binds to a specific target on the cancer cells. Trastuzumab-deruxtecan (T-DXd) is an ADC consisting of an anti-HER2 monoclonal antibody, a topoisomerase I inhibitor payload, and a cleavable linker. T-DXd was evaluated in the tumor-agnostic phase 2 DESTINY-PanTumor02 trial,8 which included endometrial, ovarian, and cervical cancer cohorts, in addition to four other nongynecologic malignancies. In this study, 40 patients with advanced or recurrent malignancies overexpressing HER2 in each cohort were treated with T-DXd.
The results within the endometrial cancer cohort were particularly promising. The overall response rate in endometrial cancer was an astounding 57.5% with a median PFS of over 11 months. Even higher response rates were seen in endometrial cancer patients whose tumors demonstrated higher rates of HER2 overexpression. These results are unprecedented in a cohort in which most patients had seen at least 2 prior lines of therapy. Ocular and pulmonary toxicities are of particular interest with use of ADCs, but they were mostly low grade and manageable in this study.
Takeaway
Anti-HER2 therapies, including antibody-drug conjugates, are effective in treating patients with some of the highest-risk endometrial cancers when they overexpress this protein.
Dr. Haag is a gynecologic oncology fellow in the Department of Obstetrics and Gynecology, University of North Carolina Hospitals, Chapel Hill. Dr. Tucker is assistant professor of gynecologic oncology at the University of North Carolina at Chapel Hill. They have no conflicts of interest.
References
1. Siegel R et al. CA Cancer J. 2024;74(1):12-49.
2. Marabelle A et al. J Clin Oncol. 2020;38(1):1-10.
3. Makker V et al. N Engl J Med. 2022;386(5):437-48.
4. Eskander RN et al. N Engl J Med. 2023;388(23):2159-70.
5. Mirza MR et al. N Engl J Med. 2023;388(23):2145-58.
6. Powell MA et al, editors. Society of Gynecologic Oncology Annual Meeting on Women’s Cancer, 2024; San Diego, CA.
7. Fader AN et al. J Clin Oncol. 2018;36(20):2044-51.
8. Meric-Bernstam F et al. J Clin Oncol. 2024;42(1):47-58.