My Treatment Approach: HER2-Mutant mNSCLC - Episode 7
Second-Line Treatment Options for mNSCLC With HER2 Mutations
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.
Second-Line Treatment Options for Metastatic NSCLC With HER2 Mutations
T-DXd represents a complex therapeutic option in the second-line setting, functioning as an immune-active antibody-drug conjugate with an Fc fragment that engages the immune system. This immune-engaging mechanism necessitates careful consideration of potential immunogenic adverse effects, particularly interstitial lung disease and pneumonitis, which represent inflammatory mechanisms in the lung that are increasingly understood. The risk of these pulmonary complications becomes particularly concerning when T-DXd is administered subsequent to immunotherapy, requiring heightened vigilance and monitoring protocols.
The adverse effect profile of trastuzumab deruxtecan extends beyond pulmonary toxicities to encompass classical topoisomerase inhibitor–related adverse events. Gastrointestinal toxicity, including significant nausea and vomiting, represents a primary concern requiring robust antiemetic management approaches similar to those used with highly emetogenic chemotherapy regimens. The comprehensive supportive care strategy must account for the substantial symptomatic burden that can impact patient quality of life and treatment adherence.
Hematologic toxicities constitute another significant aspect of T-DXd management, with cytopenias including neutropenia and anemia being commonly observed. These blood count abnormalities result in secondary complications such as fatigue and increased infectious predisposition, requiring ongoing monitoring and potential dose modifications. While T-DXd demonstrates notable efficacy in the HER2-mutated NSCLC subset, the management complexity and toxicity profile require more intensive clinical oversight than typically expected from precision medicine-based targeted therapies. This necessitates careful patient selection and comprehensive supportive care planning to optimize therapeutic outcomes while managing the substantial adverse effect burden.
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