HER2-Altered Non-Small Cell Lung Cancer — An Interview with Dr John V Heymach

·1 hr 5 min·5 clips

Dr. John Heymach explains the two main buckets of HER2 alterations in lung cancer and where recent progress has been made.

Dr. Neil Love hosts Dr. John Heymach to discuss the current and future management of HER2-altered non-small cell lung cancer. Dr. Heymach begins by categorizing HER2 alterations into two main buckets: HER2 overexpression/amplification (similar to breast cancer) and HER2 mutations, which are more common in lung cancer. He explains that HER2 mutations account for about 3-4% of lung cancers, comparable to ALK fusions. These mutations are subdivided into tyrosine kinase domain (TKD) mutations, like exon 20 insertions (e.g., YVMA), and non-TKD mutations. For TKD mutations, the oral TKI zongirtinib is approved, analogous to EGFR inhibitors. For non-TKD mutations and HER2 overexpression (IHC 3+), the antibody-drug conjugate trastuzumab deruxtecan (TDXD) is approved. Dr. Heymach clarifies that HER2 mutations are driver mutations, typically occurring in non-smokers and mutually exclusive with other drivers like EGFR or KRAS, while HER2 amplification is not a driver and co-occurs with other mutations. The conversation explores the poor response of HER2 mutants to immunotherapy, with a median progression-free survival of about three months. Dr. Heymach compares the development of HER2 TKIs to the evolution of EGFR inhibitors, referencing historical trials like IPASS. He details the mechanisms of zongirtinib (covalent, irreversible) and sevabirtinib (reversible), noting differences in toxicity (e.g., diarrhea with sevabirtinib) and efficacy. Clinical cases illustrate the spectrum of disease, from aggressive cases with bony or liver metastases to prolonged responses exceeding three years. Dr. Heymach discusses sequencing of therapies, potential combinations (e.g., TKIs with ADCs or CAR T-cells), and future directions like T-cell engagers and bispecific antibodies. The episode also touches on AI applications in predicting treatment responses and toxicities, and an intriguing finding that COVID-19 vaccination may enhance immunotherapy efficacy. The program concludes with a note on the recent accelerated approval of sevabirtinib.

As heard by us

A clear guide to the HER2 test results that shape lung cancer care.

HER2-altered non-small-cell lung cancer is framed as a set of distinct alteration types, each carrying different testing readouts and clinical implications.

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Why you'd press play

If you want the HER2 alteration map before the treatment talk, start here.

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