Case 1: Sequencing Therapy in HER2 Mutant NSCLC After Immunochemotherapy and ADC Treatment

In this segment, Dr. Jacob Sands presents a detailed first case illustrating real-world decision-making in HER2 mutant non-small cell lung cancer. The patient is a 62-year-old man with metastatic adenocarcinoma, ECOG 1 status, and a HER2 exon 20 insertion, who initially received carboplatin, pemetrexed, and pembrolizumab per the Keynote-189 regimen. After approximately 10 months of disease control, he transitioned to second-line trastuzumab deruxtecan at the lung-specific dose of 5.4 mg/kg. The patient achieved a partial response but developed an asymptomatic grade 1 interstitial lung disease that resolved with observation. Dr. Sands uses this case to clarify how clinicians distinguish true progression from minimal radiographic changes, emphasizing careful scan review and the nuances between trial-defined versus clinically meaningful progression. As the patient ultimately shows confirmed interval worsening across multiple sites, Dr. Sands frames this as a classic scenario requiring a change in therapy and highlights key considerations for selecting the next line of treatment in HER2-driven NSCLC.