This is the second episode of a two-part series on the HER2 diagnostic and treatment landscape in non-small cell lung cancer (NSCLC), hosted by the Oncology Brothers, Drs Rohit and Rahul Gosain. 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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