HER3-DXd and the Evolving Treatment Paradigm in EGFR-mutated NSCLC

EP: 1.The Evolving Treatment Landscape in EGFR Mutated NSCLC and the Role of Comprehensive Genetic Testing in Guiding Treatment

EP: 2.Unmet Needs and Emergent Studies in EGFR Mutated NSCLC

EP: 3.Targeting HER3 to Overcome Resistance in EGFR-mutated NSCLC: Patritumab Deruxtecan

EP: 4.HERTHENA-Lung01: Patritumab Deruxtecan (HER3-DXd) in Previously Treated Metastatic EGFR-Mutated NSCLC: Efficacy Data and Sequencing Considerations

EP: 5.HER3-DXd May Lead to an Additional Treatment Option in EGFR+ NSCLC

EP: 6.HER3-DXd Safety and Strategies to Optimize Patient Outcomes

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EP: 7.HER3-DXd and the Evolving Treatment Paradigm in EGFR-mutated NSCLC

This is a synopsis of an Insights series featuring Helena Yu, MD, of Memorial Sloan Kettering Cancer Center, and Sandip Patel, MD, of UCSD Moores Cancer Center.

The discussants reflected on how they envision integrating the HER3-targeting antibody-drug conjugate (ADC) patritumab deruxtecan (HER3-DXd) into management of EGFR-mutant non-small cell lung cancer (NSCLC) based on efficacy signals from the phase 2 HERTHENA-Lung01 trial.

Dr. Patel indicated osimertinib remains standard first-line therapy for metastatic NSCLC with common EGFR mutations like exon 19 deletions or L858R. The ideal sequence of novel agents like amivantamab, lazertinib, HER3-DXd, and chemotherapy post-osimertinib progression is unclear currently and will likely involve shared decision-making based on factors like brain metastases status, side effect tolerance, and patient lifestyle considerations around oral versus intravenous therapy.

Dr. Yu agreed, highlighting intriguing data on improved outcomes with amivantamab combinations in NSCLC with MET-dependent osimertinib resistance. This exemplifies the hope that optimal sequencing soon becomes guided by molecular profiles from plasma or tissue biopsy at resistance rather than empiric. However, HER3-DXd showed efficacy across various alteration patterns in HERTHENA-Lung01, supporting use when resistance mechanisms are unclear.

Both discussants advocated for emerging biomarker-directed and immune-based combination strategies in EGFR-mutant NSCLC. Dr. Patel specifically mentioned interest in making traditionally “cold” tumors like these immunologically responsive, particularly through cellular immunotherapy approaches.

In summary, while osimertinib remains the cornerstone of care, the growing array of effective later-line treatments heralds an era of personalized sequencing based on predictive biomarkers, side effect profiles, patient factors, and practical considerations in this population. Ongoing research aims to further augment and appropriately select targeted and immunotherapies in EGFR-driven NSCLC.

*Video synopsis is AI-generated and reviewed by Cancer Network editorial staff.