В recent webinar, Dr. Matthew Gubens and Dr. Estelamari Rodriguez discussed key questions about the management of HER2-altered advanced non-small cell lung cancer (NSCLC). They reviewed the rationale for targeting HER2 in NSCLC, optimal testing strategies for HER2, data on HER2-directed antibody-drug conjugates (ADCs) in NSCLC, and the practical applications of HER2-targeted therapy and emerging HER2-directed approaches in NSCLC.

Dr. Gubens noted that T-DXd, zongertinib, and sevabertinib are currently FDA-approved for patients with HER2-altered advanced NSCLC. T-DXd is the only HER2-directed agent with approval for use in patients with HER2-overexpressing (IHC 3+) advanced NSCLC. Zongertinib and sevabertinib are TKIs with approval for patients with HER2 mutation-positive NSCLC only.

For patients with HER2-overexpressing unresectable or metastatic NSCLC who have received prior systemic treatment, the clear-cut second-line treatment option is T-DXd, especially if the patient has no known or suspected cardiac dysfunction or interstitial lung disease (ILD)/pneumonitis.

Dr. Rodriguez emphasized the importance of monitoring patients for ILD/pneumonitis, which can be fatal if not appropriately managed. Any-grade ILD/pneumonitis was reported in approximately 15% of patients with NSCLC in the DESTINY-Lung02 trial with the use of T-DXd at the FDA-approved dose of 5.4 mg/kg (mostly grade 1/2). Grade ≥3 ILD/pneumonitis was reported in only 2% (2/101) of the patients.

For asymptomatic ILD/pneumonitis (grade 1), T-DXd should be interrupted until resolution to grade 0. If symptoms resolve ≤28 days from onset, T-DXd can be resumed at the same dose. However, if symptoms resolve >28 days from the time of onset, T-DXd dose should be reduced by 1 dose level as stated in the prescribing information.

Dr. Gubens agreed with Dr. Rodriguez's points about being very proactive and, of importance, doing due diligence while erring on the side of caution by holding T-DXd as soon as ILD/pneumonitis is suspected and carefully monitoring the patient until resolution to grade 0.

The selection of treatment needs to be personalized with careful considerations for each patient's preexisting comorbidities and concomitant drug use and interactions. The patient's preference and treatment goals also need to be considered before treatment recommendations are made. Of importance, all 3 agents have demonstrated central nervous system activity.