Dr Levy on the Development and Clinical Use of ADCs in NSCLC

“There’s a lot of movement here. Some of these drugs are not yet approved, so it’s going to be interesting to see how they’re leveraged, how they’re used, and how they’re sequenced in our clinics.”

Benjamin P. Levy, MD, clinical director, Medical Oncology, Johns Hopkins Sidney Kimmel Cancer Center at Sibley Memorial Hospital; and associate professor, oncology, Johns Hopkins University School of Medicine, discusses the current clinical and developmental statuses of several antibody-drug conjugates (ADCs) in non–small cell lung cancer (NSCLC).

Fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu), a HER2-directed ADC, is FDA approved for the treatment of patients with HER2-mutated NSCLC, as well as those with HER2-overexpressing NSCLC, defined as disease that is HER2 3+ by immunohistochemistry (IHC), Levy begins. These indications highlight the importance of both mutational analysis and IHC in guiding patient eligibility for treatment with T-DXd, he emphasizes.

Patritumab deruxtecan is an emerging ADC under investigation within the EGFR-mutated NSCLC treatment paradigm, Levy explains. A press release from September 2024 indicated that in the phase 3 HERTHENA-Lung02 trial (NCT05338970), this agent led to superior progression-free survival (PFS) outcomes compared with chemotherapy in patients with locally advanced or metastatic EGFR-mutated NSCLC who had progressed following treatment with a third-generation TKI, he says. Further readouts from this trial will provide additional insights into the clinical relevance of this agent, he notes.

Moreover, several trials have evaluated the efficacy of TROP2-directed ADCs in patients with NSCLC, Levy reports. The phase 3 EVOKE-01 trial (NCT05089734), which compared sacituzumab govitecan-hziy (Trodelvy) with docetaxel in patients with advanced or metastatic NSCLC, did not demonstrate an overall survival (OS) advantage with the ADC. Similarly, datopotamab deruxtecan-dlnk (Dato-DXd; Datroway) failed to provide an OS benefit over docetaxel in patients with previously treated advanced or metastatic NSCLC with or without genomic alterations in the phase 3 TROPION-Lung01 trial (NCT04656652). However, the phase 2 TROPION-Lung05 trial (NCT04484142) revealed the meaningful clinical activity of Dato-DXd in the EGFR-mutated NSCLC population, he states.

Overall, the role of ADCs in NSCLC is rapidly evolving, with several agents in various stages of clinical development, he notes. The optimal sequencing and integration of these therapies into clinical practice remain key areas of investigation, he concludes.