Looking Forward: Combination Therapy for HER2 Mutation mNSCLC

Clinical Pearls for Testing and Treatment of HER2-Mutation Metastatic NSCLC in Community Settings

Future combination strategies in HER2-mutated non–small cell lung cancer (NSCLC) draw heavily from EGFR treatment paradigms, recognizing HER2 mutations as high-risk factors associated with highly metastatic and aggressive disease behavior. Recent FLORA-2 trial data combining chemotherapy plus osimertinib and amivantamab plus lazertinib in first-line EGFR-mutated disease decisively outperformed single-agent targeted therapy, suggesting that similar combination approaches may benefit HER2-mutated patients. The biological similarities between EGFR and HER2 as closely related receptors in the same gene family support predictions that combination therapies will become critical for optimal outcomes in this aggressive disease subset.

HER2-targeted therapy development offers unique advantages over EGFR combination strategies, particularly leveraging precedents from breast cancer where antibodies, antibody drug conjugates, and targeted therapies have been successfully combined. Anti-VEGF approaches represent promising combination strategies, as HER2-mutated tumors demonstrate active VEGF proliferation pathways. Emerging combinations include trastuzumab deruxtecan with tislelizumab and bevacizumab, plus HER2-targeted agents with PD-L1 and anti-VEGF combinations. However, questions remain about the individual contribution of anti-PD1/PD-L1 targeting in this subset, despite its incorporation into current treatment paradigms.

Clinical development considerations emphasize the importance of 3-arm trial designs incorporating combination therapies up front rather than simple targeted therapy vs chemoimmunotherapy comparisons. Patient subset analyses will become increasingly important, including distinctions between YVMA mutations vs non–tyrosine kinase domain mutations, presence of liver or brain metastases, and circulating tumor DNA clearance patterns. Zongertinib’s excellent tolerability profile makes it particularly suitable for combination approaches, while concerns exist about combining trastuzumab deruxtecan or less HER2-specific agents like sevabertinib due to potentially prohibitive toxicity profiles. The field remains in its infancy with current second-line approvals, but rapid development toward first-line positioning and combination strategies appears imminent, following developmental pathways established in EGFR-mutated disease management.