Dr O’Malley on What to Reach for Outside of a Clinical Trial in Platinum-Resistant Ovarian Cancer

“It is an ADC world, but really we're not even close to where we're going to be.”

David O’Malley, MD, a professor in the Department of Obstetrics and Gynecology at The Ohio State University College of Medicine and the director of the Division of Gynecologic Oncology at The Ohio State University Comprehensive Cancer Center––James, discussed how antibody-drug conjugates (ADCs) have reshaped the treatment paradigm for patients with platinum-resistant ovarian cancer (PROC).

Clinical trials are often the first line of defense in the PROC setting, O’Mally explained. Several clinical trials are ongoing in this setting, one of which includes the phase 3 MAESTRA 2 trial (NCT07214779) in patients with PROC and cyclin E1 overexpression. Outside of clinical trials, ADCs represent a novel treatment strategy, some of which are biomarker driven-strategies. However, the field’s biomarker framework and the evidence underlying it remains a work in progress, O’Malley noted. Folate receptor alpha (FRα) and HER2 expression are the two markers guiding ADC selection today, he said. For FRα, National Comprehensive Cancer Network (NCCN) guidelines support treatment at expression levels as low as 25%, though a positive result is conventionally defined as 75% or greater at 2+ scoring. Published data, including 2 papers for which O’Malley serves as corresponding senior author, support this more inclusive threshold. However, large prospective trials validating it remain absent, in part due to prior limitations in agent development by smaller biotech sponsors.

For HER2, accelerated approval is in place for patients with immunohistochemistry (IHC) 3+ expression, while NCCN guidelines also list IHC 2+ per data suggesting activity at lower expression levels. The phase 2 DESTINY-PanTumor02 trial (NCT04482309) further illustrated that central retesting reclassified many locally HER2-positive ovarian and gastrointestinal cancers to IHC 0, 1+, or 2+, yet similar overall response rates were observed across those expression levels. This reinforces that the meaningful drop-off in activity by expression tier has not been fully characterized in ovarian cancer, O’Malley noted.

O’Malley relayed routinely performing next-generation sequencing in his practice to identify eligibility for ongoing clinical trials, with results prioritized early to preserve access if a relevant trial becomes available. With respect to payload sequencing, topoisomerase I payload ADCs should be used only once, given the absence of data supporting sequential sequencing of the same payload. Anti-microtubule payload ADCs are similarly limited to one use. However, the same tumor target may be revisited if the subsequent ADC carries a different payload class, O’Malley concluded.

This video was supported in part by Incyte. Content independently developed and published by OncLive.