In this episode, Dr Isabel Preeshagul and Dr Eric Singhi provide the benefit of their experience when discussing how to approach different treatment scenarios in HER2-mutant NSCLC.

 

The conversation unfolds to cover:

• Ways to distinguish HER2 alterations from other alterations on biomarker reports 

• The latest efficacy and safety data of currently approved and emerging treatments for HER2-altered NSCLC  

• The potential CNS activity of these treatments in patients with HER2-mutated NSCLC 

• How the treatment pathway may look in the near future 

   

Clinical takeaways

• In NSCLC, HER2-positivity includes mutations, amplifications and overexpression. It's important to distinguish HER2 alterations from EGFR mutations, particularly exon 20 insertions, when interpreting next-generation sequencing (NGS) results 

• Trastuzumab Deruxtecan (T-DXd) is currently the only approved targeted agent for HER2-altered NSCLC in the 2nd-line setting. It shows promising efficacy, especially in HER2-mutant cases, but has limited brain penetration and is associated with notable side effects, including pneumonitis, which requires close monitoring 

• Emerging TKIs, such as zongertinib, BAY 2927088 (sevabertinib), and NVL-330, target HER2-mutations and have shown high response rates and CNS activity in early studies, without ILD/pneumonitis. These treatments come with unique side effects like diarrhoea and rash, which can be managed with supportive care 

• CNS metastases are common, with up to 30% of HER2-altered NSCLC patients presenting with or quickly developing CNS metastases. Current large molecule therapies (like T-DXd) have limited brain penetration, making small-molecule TKIs, like zongertinib, BAY 2927088 (sevabertinib), and NVL-330, promising for their potential CNS activity

• Current standard 1st-line care for HER2-mutant NSCLC remains platinum-based chemotherapy ± immunotherapy. Targeted agents (like T-DXd) are generally reserved for 2nd-line use, but ongoing trials are evaluating the move toward frontline therapy

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