My Treatment Approach: HER2-Mutant mNSCLC - Episode 10
Patient Clinical Scenario: 2L Treatment of mNSCLC With HER2 Mutations
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.
Patient Clinical Scenario: Second-Line Treatment of Metastatic NSCLC With HER2 Mutations
The clinical scenario involves a 73-year-old Asian female diagnosed with stage 4 non–small cell lung adenocarcinoma harboring a HER2 exon 20 insertion mutation, specifically, the most commonly observed A775_G776 insertion (YVMA). This patient represents a typical presentation for HER2-–mutated lung cancer, occurring in an older Asian female patient population. The molecular profile confirms the presence of the classic HER2 exon 20 insertion mutation that drives oncogenic signaling and represents the primary therapeutic target for HER2-directed interventions.
Initial treatment followed standard first-line approaches for metastatic non–small cell lung cancer (NSCLC) in the absence of approved HER2-targeted therapies, consisting of carboplatin, pemetrexed, plus pembrolizumab for 4 cycles with documented treatment response. Following the induction phase, the patient transitioned to maintenance therapy with pemetrexed and pembrolizumab, representing standard practice for maintaining disease control after initial chemotherapy response. The treatment course demonstrates the typical progression of care for HER2-mutated patients prior to the availability of targeted therapeutic options.
The patient now presents approximately 3 weeks after her last maintenance dose with concerning clinical symptoms, including new-onset persistent cough and progressively worsening shortness of breath over several months. Despite these respiratory symptoms, her vital signs remain stable and she maintains an ECOG performance status of 1, indicating preserved functional capacity. Her medical comorbidities are limited to hypertension and osteoporosis, suggesting she remains a suitable candidate for additional systemic therapy. The clinical presentation strongly suggests disease progression on chemotherapy and immunotherapy maintenance, necessitating immediate evaluation and consideration of second-line HER2-targeted therapy options including zongertinib or trastuzumab deruxtecan based on the recent therapeutic advances in this molecular subset.
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