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

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

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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

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 reviewed data from the phase 2 HERTHENA-Lung01 trial evaluating the HER3-directed antibody-drug conjugate (ADC) patritumab deruxtecan (HER3-DXd) in EGFR-mutant non-small cell lung cancer (NSCLC) after progression on osimertinib and platinum chemotherapy.

HER3-DXd was given at 5.6 mg/kg intravenously every 3 weeks. A dose escalation arm was discontinued due to increased toxicity without added efficacy versus the fixed 5.6 mg/kg dose in 225 treated patients. These heavily pretreated patients had substantial tumor burden and most had baseline central nervous system (CNS) metastases.

Efficacy was promising, with an overall response rate of 30%, median progression-free survival of 5.5 months, and median overall survival of 12 months, comparing favorably to single agent chemotherapy in this setting. Importantly, intracranial response rate was 33% in those with baseline measurable CNS lesions without prior radiotherapy, indicating blood-brain barrier penetration.

Dr. Patel highlighted surprise at the level of CNS activity for an ADC and relatively prolonged duration of systemic and intracranial responses given the lack of HER3 biomarker selection. He advocated for combinations with EGFR inhibitors that may further enhance efficacy.

Dr. Yu agreed, noting that HER3-DXd showed efficacy across a spectrum of resistance mechanisms like EGFR C797S mutations and MET amplification. She raised interesting points around sequencing multiple ADCs sharing the same deruxtecan payload, like HER3-DXd and the TROP2-targeting datopotamab deruxtecan. Dr. Patel indicated that switching between these would unlikely overcome payload-mediated resistance, and that real-world data will help inform optimal sequencing as these ADCs see increasing clinical use.

In summary, the HERTHENA-Lung01 study indicates HER3-DXd has promising single agent activity in later-line EGFR-mutant NSCLC, including intracranially. Ongoing and planned trials will evaluate combinations with EGFR tyrosine kinase inhibitors, move into earlier treatment lines, and expand assessment in NSCLC without oncogenic drivers. Definition of resistance mechanisms and optimal sequencing with other ADCs remains an open question requiring further research.

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