Week 5, July 2024: ADCs & Gynecologic Cancer

A recent editorial by researchers at Yale University School of Medicine describes how we are entering the golden age for antibody-drug conjugates (ADCs) in gynecologic cancer, which includes difficult to treat tumors such as uterine carcinosarcomas and platinum-resistant ovarian cancer. Gynecologic cancer refers to any cancer that starts in a woman's reproductive organs. The five main types are: cervical, ovarian, uterine, vaginal, and vulvar. A recent study the researchers described was the remarkable preclinical results of trastuzumab-deruxtecan (T-DXd), a HER2-directed ADC against biologically aggressive uterine tumors.

There are several ADCs under investigation with validated targets like HER2/neu, TROP-2, CDH6, and folate receptor, such as DHES08151, sacituzumab govitcan, and datopotomab-deruxtecan. These ADCs target epithelial ovarian cancer, uterine serous carcinoma, uterine and ovarian carcinosarcoma, and cervical tumors, all with significant bystander killing. Research into combining ADCs with other treatments are only just beginning, but multimodal therapy (with immunotherapies, PARP inhibitors, and traditional chemotherapy), allows for stronger efficacy and could be used to overcome resistance to chemotherapy. 

Meanwhile, an insightful review published this week from Humanitas San Pio X describes the clinical landscape of ADCs in endometrial cancer specifically. Clinical outcomes remain challenging in advanced or recurrent endometrial cancer due to tumor heterogeneity and therapy resistance, but there are promising ADC targets under clinical investigation. Future development directions include agents targeting multiple antigens, combinatorial strategies, and sequential use of agents targeting the same antigen but using different payloads. 

Also this month, Astrazeneca’s Imfinzi (durvalumab) and Lynparza (olaparib) combination was recommended for approval in the EU by CHMP for patients with mismatch repair proficient advanced or recurrent endometrial cancer. Durvalumab is a human monoclonal antibody that binds to the PD-L1 protein and blocks the interaction of PD-L1 with the PD-1 and CD80 proteins, countering the tumor's immune-evading tactics and releasing the inhibition of immune responses. While not an ADC, this multimodal therapy provides another example of its potential in gynecologic cancer treatments.