Emerging Targeted Therapies for HER2-Mutant NSCLC.

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• HER2-mutant non-small cell lung cancer (NSCLC) is rare (2-5%) and linked to poor outcomes.
• Existing HER2-targeted therapies, including antibody-drug conjugates (ADCs) like trastuzumab deruxtecan (T-DXd), show efficacy but carry risks like interstitial lung disease (ILD).

Purpose of the Study:

• To review the molecular landscape and clinical features of HER2-mutant NSCLC.
• To summarize evidence for HER2-targeted therapies in NSCLC.
• To provide a future outlook on treatment strategies for HER2-mutant NSCLC.

Main Methods:

• Literature review of clinical trials and preclinical studies on HER2-targeted therapies for NSCLC.
• Analysis of efficacy and toxicity profiles of approved and investigational agents.
• Discussion of molecular characteristics and clinical presentation of HER2-mutant NSCLC.

Main Results:

• Trastuzumab deruxtecan (T-DXd) is an approved ADC for HER2-mutant NSCLC, achieving ~50% response rates but with a risk of ILD.
• Novel HER2-selective tyrosine kinase inhibitors (TKIs), such as sevabertinib and zongertinib, demonstrate deep and durable responses.
• TKIs exhibit improved safety profiles, with lower rates of ILD and toxicities mainly related to wild-type EGFR inhibition, particularly zongertinib.

Conclusions:

• HER2-mutant NSCLC treatment is evolving with effective targeted therapies.
• ADCs and TKIs offer distinct mechanisms and efficacy in HER2-mutant NSCLC.
• Novel HER2-targeted TKIs present a promising therapeutic avenue with favorable tolerability, potentially improving outcomes for NSCLC patients.