My Treatment Approach: HER2-Mutant mNSCLC - Episode 6
Frontline Treatment Options for mNSCLC With HER2 Mutations
Panelists discuss how frontline treatment for HER2 mutant non–small cell lung cancer (mNSCLC) lacks FDA-approved targeted therapies, with current approaches varying between platinum-based chemotherapy with or without immunotherapy (such as the KEYNOTE-189 regimen), though some clinicians avoid immunotherapy in this population due to limited proven benefit in never-smokers who make up 60% of HER2-mutation patients, while considering whether to extrapolate from recently approved second-line targeted therapies like zongertinib.
Frontline Treatment Options for Metastatic NSCLC With HER2 Mutations
HER2 mutations represent a definitive oncogenic driver in NSCLC, exhibiting all the hallmarks of being the central genetic alteration–driving tumor biology. These mutations demonstrate significantly more clinical impact compared with HER2 overexpression or amplification, where data remain emerging and have primarily been studied in pan-tumor studies rather than lung cancer–specific investigations. The approval of zongertinib on August 8, 2025, added a new dimension to the therapeutic armamentarium, though this represents an accelerated approval in the second-line setting alongside the previously approved trastuzumab deruxtecan for second-line treatment.
The frontline treatment landscape for HER2 mutation–positive NSCLC remains undefined, with no FDA-approved matched targeted therapy available and no standard first-line treatment established in National Comprehensive Cancer Network guidelines. Historical approaches have varied widely, including the KEYNOTE-189 regimen (carboplatin, pemetrexed, and pembrolizumab) for standard practice. Clinical experience suggests that over 60% of patients with HER2 mutations are never-smokers, and for patients with low PD-L1 expression, chemotherapy alone with carboplatin and pemetrexed may be considered. However, chemotherapy demonstrates only modest activity with median time to progression averaging 7 to 8 months, resulting in unimpressive progression-free survival outcomes in this patient population.
Treatment approach considerations reveal important biological similarities between HER2 and EGFR mutations, as both occur more frequently in younger patients and never-smokers who typically derive limited benefit from immunotherapy. The available data suggest that immunotherapy rarely provides significant impact in HER2-mutated patients, leading some clinicians to favor platinum-based doublet chemotherapy alone in the frontline setting. This approach omits immunotherapy in the absence of proven benefit, avoiding potential toxicity and immune system alterations that might affect downstream treatment options. The field continues to evolve as clinicians consider whether to extrapolate from second-line accelerated approvals to use targeted agents like zongertinib or trastuzumab deruxtecan in the frontline setting.
Related Content:
