My Treatment Approach: HER2-Mutant mNSCLC - Episode 9
Emerging Treatment Options in 2L Treatment of mNSCLC With HER2 Mutations
Panelists discuss how emerging second-line treatment options for HER2-mutant non–small cell lung cancer (NSCLC) include sevabertinib (a dual HER2/EGFR exon 20 inhibitor with higher gastrointestinal toxicity but similar efficacy to zongertinib) and other brain-penetrant tyrosine-kinase inhibitors (TKIs) in development, while noting that multiple ongoing phase 3 trials are studying frontline comparisons of these targeted therapies vs chemotherapy plus immunotherapy, creating a complex treatment landscape where the principle of using the best therapy first must consider efficacy, tolerability, and quality-of-life factors.
Emerging Treatment Options in Second-Line mNSCLC With HER2 Mutations
The HER2 therapeutic landscape continues to evolve with multiple agents in development, though significant refinement remains needed in areas including line placement and mutation type considerations. Zongertinib has established a high efficacy bar, receiving National Comprehensive Cancer Network (NCCN) guideline updates within 1 week of FDA approval as a preferred option upon first-line progression. While the FDA label restricts use primarily to tyrosine kinase domain mutations, NCCN guidelines provide broader coverage including non–tyrosine kinase domain mutations, offering expanded treatment opportunities despite limited data in this subset.
Sevabertinib (BAY88) represents the most mature alternative agent in development, functioning as a dual EGFR/HER2 inhibitor with response rates approaching 70%. However, this dual targeting approach produces more classical EGFR-mediated toxicities, particularly significantly higher rates of gastrointestinal toxicity compared with zongertinib’s cleaner, HER2-specific targeting profile. Additional agents, including IAM1363 from Iambic, show positive responses in HER2 mutations but demonstrate less durability. The therapeutic window advantage appears to favor zongertinib’s selective approach, though brain metastasis efficacy data continue to evolve across all agents. Given HER2’s high propensity for brain metastases similar to EGFR, central nervous system coverage remains critical for optimal outcomes.
The treatment paradigm faces complexity with 3 ongoing phase 3 frontline trials comparing zongertinib, trastuzumab deruxtecan, and sevabertinib against chemoimmunotherapy regimens. Clinical considerations extend beyond simple efficacy to encompass patient convenience, adverse effect profiles, and quality-of-life factors. The principle of using best agents first becomes paramount, particularly considering real-world attrition rates of 25-33% between treatment lines. While accelerated approvals exist for both zongertinib and trastuzumab deruxtecan in second-line settings, with potential sevabertinib approval anticipated in the fall based on American Society of Clinical Oncology data, the optimal sequencing and positioning of these agents require careful evaluation of efficacy, tolerability, and patient-specific factors. Additional brain-penetrant TKIs from Cogent and Nuvalent (NVL-330) are advancing through development, further expanding future treatment options.
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