Dr Levy on Challenges With TROP2-Directed ADCs in NSCLC

“For better or for worse, [regarding] TROP2-directed ADCs, we had a lot of promise with those, but we now know that datopotamab deruxtecan will not move forward in the second line, based on an FDA decision.”

Benjamin P. Levy, MD, associate professor, oncology, Johns Hopkins University School of Medicine; clinical director, Medical Oncology, Sibley Memorial Hospital, Johns Hopkins Sidney Kimmel Cancer Center, shares insight on challenges regarding antibody-drug conjugates (ADCs) in the non–small cell lung cancer (NSCLC) landscape at the 42nd Annual CFS, specifically highlighting research with TROP2-directed ADCs.

In recent years, ADCs have emerged in the NSCLC field; however, there are still some roadblocks along the way for certain agents, Levy says. Fam-trastuzumab deruxtecan (Enhertu) was approved by the FDA in 2022 as a second-line treatment for patients with unresectable or metastatic NSCLC harboring activating HER2 mutations. Approval was sought patritumab deruxtecan, a HER3-directed ADC, for the treatment of patients with locally advanced or metastatic NSCLC harboring EGFR mutations who previously received 2 or more systemic therapies; however, in June 2024, the FDA issued a complete response letter to the biologics license application to seek approval for patritumab deruxtecan.

Although TROP2-directed ADCs previously demonstrated promise, in November 2024, a BLA seeking the approval of datopotamab deruxtecan (Dato-DXd) for the treatment of patients with advanced or metastatic nonsquamous NSCLC was withdrawn. Additionally, he estimates that the data for sacituzumab govitecan-hziy (Trodelvy) in the phase 3 EVOKE-01 trial (NCT05089734) will be similar to the outcome of Dato-DXd deruxtecan in NSCLC.

Although these roadblocks are present, Levy emphasizes that this may be an opportunity to pause and reflect upon what isn’t working. He hypothesizes that these setbacks could be resolved with additional research into biomarkers and the development of novel agents. Hope remains for ADCs in NSCLC, and work completed thus far could provide an opportunity to learn from these findings and improve moving forward, Levy concludes.