Dr Moore on the Relationship Between Biomarker Expression and Efficacy With ADCs in Ovarian Cancer

Kathleen N. Moore, MD, MS, associate director, clinical research, Stephenson Cancer Center, director, Oklahoma TSET Phase I Program, professor, Section of Gynecologic Oncology, Oklahoma University (OU) College of Medicine, OU Health, discusses the relationship between biomarker expression and efficacy with antibody-drug conjugates (ADCs) in ovarian cancer.

The activity of mirvetuximab soravtansine-gynx (Elahere) is associated with the level of folate receptor–alpha (FRα) in ovarian cancer, and although it has shown the highest activity in patients with high expression levels, the drug is also active in patients with medium expression, Moore says. However, for other targets such as TROP2, it remains unclear whether response is associated with expression level. Findings from a phase 2 trial (NCT04152499) presented at the 2024 ESMO Congress seemed to suggest that immunohistochemical (IHC) H score may help stratify responders from nonresponders with sacituzumab tirumotecan. However, those data were exploratory, and small numbers of patients were evaluated, so no definitive statements can be drawn yet, Moore says.

In terms of other targets, data are anticipated with the cadherin-6 (CDH6)-directed ADC raludotatug deruxtecan. Previously, data from the first-in-human study (NCT04707248) of the agent showed an objective response rate of 46% (95% CI, 32%-61%) and a median duration of response of 11.2 months (95% CI, 3.0-not estimable) in pretreated patients with advanced and metastatic ovarian cancer. This suggests favorable responses in an all-comer population, Moore says. In April 2024, Merck announced that the first patient had been dosed in the phase 2/3 REJOICE-Ovarian01 trial (NCT06161025), which is evaluating the agent in patients with platinum-resistant ovarian cancer and will likely shed light on whether a biomarker is needed, Moore adds.

For B7-H4–directed ADCs, there are limited data that prevent any conclusions from being drawn, and for Claudin 6 (CLDN6)–directed ADCs, TORL-1-23 has shown the greatest activity in CLDN6-positive tumors. Time will tell whether different thresholds are associated with variable responses, Moore explains. Other targets with data gaps include HER2, although fam-trastuzumab deruxtecan-nxki (Enhertu) has shown significant activity in the HER2 3+ IHC population in the DESTINY-PanTumor trials, albeit in a small patient subset, Moore notes.

Moore concludes that expression level is associated with response for FRα and HER2, although obstacles with accurate scoring of the latter marker remain, and that more data are needed to tease out whether response is tied to expression level with these other agents under investigation.