My Treatment Approach: HER2-Mutant mNSCLC

Panelists discuss how HER2 mutations in metastatic non–small cell lung cancer (mNSCLC) require comprehensive molecular testing including both next-generation sequencing and immunohistochemistry, and how the recent FDA approval of zongertinib as a HER2-specific tyrosine kinase inhibitor provides a new targeted therapy option with superior tolerability compared with trastuzumab deruxtecan, emphasizing the importance of proper treatment sequencing and the evolving landscape from chemotherapy-based approaches to precision medicine in this patient population.

EP. 1: The Clinical Importance of HER2 Testing in mNSCLC

September 3rd 2025

EP. 2: HER2 Alteration Prevalence and Testing Best Practices in mNSCLC

September 3rd 2025

EP. 3: Distinguishing HER2 Alterations in mNSCLC

September 10th 2025

Panelists discuss how HER2 alterations in lung cancer differ from other cancers like breast cancer, where overexpression is more common and targetable with antibody-drug conjugates (ADCs), while in lung cancer the focus is primarily on HER2 exon 20 insertion mutations and other tyrosine kinase domain mutations, requiring both next-generation sequencing (NGS) and immunohistochemistry (IHC) testing since liquid biopsies can detect mutations but not overexpression.

EP. 4: The Clinical Utility of ctDNA Testing in HER2- Mutation mNSCLC

September 10th 2025

Panelists discuss how circulating tumor DNA (ctDNA) testing is valuable for up-front molecular profiling in all locally advanced or metastatic lung cancer patients to accelerate treatment decisions, but longitudinal ctDNA monitoring is not yet standard practice for assessing treatment response in HER2 mutations, though it can be useful at disease progression to identify resistance mechanisms and guide subsequent therapy decisions.

EP. 5: Opportunities for HER2 Molecular Testing Education in mNSCLC

September 17th 2025

Panelists discuss how community oncologists can best serve patients by understanding that lung cancer is no longer 1 disease requiring uniform treatment, emphasizing that comprehensive molecular testing including both next-generation sequencing and immunohistochemistry (IHC) is critical for identifying targetable alterations like HER2 mutations that now have FDA-approved targeted therapies, making broad panel testing essential for optimal patient outcomes in 2025.

EP. 6: Frontline Treatment Options for mNSCLC With HER2 Mutations

September 17th 2025

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.

EP. 7: Second-Line Treatment Options for mNSCLC With HER2 Mutations

September 24th 2025

Panelists discuss how second-line treatment options for HER2-mutant non–small cell lung cancer (NSCLC), particularly trastuzumab deruxtecan (T-DXd), require careful management of significant adverse effects, including interstitial lung disease/pneumonitis (especially concerning after prior immunotherapy due to the antibody’s immune-active properties), topoisomerase inhibitor–related gastrointestinal toxicity requiring strong antiemetic protocols, and cytopenias leading to fatigue and infection risk, making it more complex to manage than traditional precision medicine targeted therapies.

EP. 8: Beamion LUNG-1: Examining the Efficacy and Safety of Zongertinib in 2L Treatment of mNSCLC With HER2 Mutations

September 24th 2025

Panelists discuss how the Beamion LUNG-1 trial demonstrated zongertinib’s impressive efficacy in second-line treatment of HER2–mutant non–small cell lung cancer (NSCLC)with a 75% response rate and 14.1-month duration of response in previously treated patients, while showing a favorable safety profile as a true targeted therapy with mainly low-grade diarrhea and minimal toxicities compared with chemotherapy-like side effects, and maintaining activity even after prior trastuzumab deruxtecan treatment with a 50% response rate.

EP. 9: Emerging Treatment Options in 2L Treatment of mNSCLC With HER2 Mutations

October 1st 2025

Panelists discuss how emerging second-line treatment options for HER2-mutant non–small cell lung cancer (NSCLC) include sevabertinib (a dual HER2/EGFR exon 20 inhibitor with higher gastrointestinal toxicity but similar efficacy to zongertinib) and other brain-penetrant tyrosine-kinase inhibitors (TKIs) in development, while noting that multiple ongoing phase 3 trials are studying frontline comparisons of these targeted therapies vs chemotherapy plus immunotherapy, creating a complex treatment landscape where the principle of using the best therapy first must consider efficacy, tolerability, and quality-of-life factors.

EP. 10: Patient Clinical Scenario: 2L Treatment of mNSCLC With HER2 Mutations

October 1st 2025

Panelists discuss a clinical scenario involving a 73-year-old Asian woman with stage 4 lung adenocarcinoma harboring a HER2 exon 20 insertion mutation (A775-G776 YVMA) who initially responded to carboplatin, pemetrexed, and pembrolizumab for 4 cycles followed by maintenance therapy, but now presents with progressive cough and shortness of breath suggesting clinical progression, requiring decisions about next-step management in this fit patient with good performance status.