Targeting HER2 Alterations with ADCs in NSCLC

Dr. Ritu Salani and Dr. Martin Dietrich discuss the use of antibody-drug conjugates (ADCs) in HER2-positive non-small cell lung cancer (NSCLC) and the challenges of retesting HER2 expression in breast cancer.

Regarding retesting HER2 expression in breast cancer, Dr. Dietrich acknowledges the importance of reconfirming receptors (estrogen, progesterone, and HER2) in the recurrent setting. However, he notes that trials used archival tissues, and obtaining fresh biopsies may not always be feasible. While fresh biopsies are preferable, he does not exclude patients if archival tissue shows HER2 positivity.

Moving on to NSCLC, Dr. Dietrich explains that HER2 in lung cancer is not as well understood as in breast cancer. The current approval of trastuzumab deruxtecan (T-DXd) in NSCLC is based on intracellular kinase domain mutations rather than amplification or overexpression. The DESTINY-Lung01 and DESTINY-Lung02 studies evaluated different alterations of HER2 and dosing schedules, with the 5.4 mg/kg dose eventually being approved.

HER2 in close connection to EGFR (HER1) has been challenging, as these subtypes do not respond well to immunotherapy. Off-label use of trastuzumab emtansine (T-DM1) showed modest responses (around 20%) and short durability. The DESTINY-Lung01 study demonstrated promising efficacy of T-DXd in HER2-mutant NSCLC, with a median progression-free survival of around 10 months and a more favorable toxicity profile at the lower dose.

T-DXd is currently the only approved therapy for HER2-mutant lung cancer and is a firmly established second-line standard of care. However, its role compared to standard therapies and the potential for combination with immunotherapy in the first-line setting remains to be determined. Ongoing confirmatory and combination studies will provide further insights.

Summary generated by Claude AI.