Navigating the Evolving Treatment Landscape in HER2 Non–Small Cell Lung Cancer

On July 24, 2025, during the International Lung Cancer Congress in Huntington Beach, California, a panel of thoracic oncology experts met for a live workshop on HER2-mutated NSCLC. Moderated by Sandip Patel, MD, the discussion covered diagnostic strategies, use of antibody-drug conjugates (ADCs), and the development of HER2-targeted TKIs. Faculty shared practical insights, debated sequencing, and identified opportunities to improve care for this rare, but important, disease.

Session Overview and Highlights

Testing Recommendations for Diagnosing HER2-Mutant NSCLC

Faculty agreed that HER2 mutation testing should be incorporated into broad NGS panels, with HER2 IHC typically ordered after first-line progression. While tissue NGS is standard, many centers also perform liquid biopsy—alone or with tissue—to shorten turnaround and avoid inadequate samples.

Concurrent testing can uncover alterations missed by 1 method and accelerate treatment initiation, but cost and reimbursement limit use in some settings. Faculty called for clearer, standardized reports—labeling pathogenic variants without outdated drug suggestions and avoiding variants of uncertain significance.

ADC Class Review for the Treatment of HER2-Mutant NSCLC

T-DXd was identified as the preferred second-line option, although some faculty consider it frontline therapy for select patients with untreated brain metastases or leptomeningeal disease. Faculty reported meaningful systemic and intracranial responses but noted the need for lung cancer–specific CNS data. Even a small trial in untreated brain metastases was viewed as valuable.

Most preferred the 5.4-mg/kg dose to balance efficacy with tolerability and reduce the risk of interstitial lung disease. Common adverse events (AEs) included fatigue, nausea, cytopenias, and other chemotherapy-like toxicities. Sequencing decisions considered CNS status, comorbidities, patient goals, trial eligibility, anticipated AEs, and insurance coverage. The groupgenerally was cautious about combining ADCs with TKIs without supporting data.

Looking Ahead: TKIs in Development for HER2-Mutant NSCLC

Zongertinib and sevabertinib were viewed as promising TKIs. Zongertinib drew attention for its favorable gastrointestinal (GI) and skin toxicity profile, although both agents may be chosen based on CNS activity, resistance patterns, and availability.

The role of TKIs in earlier lines remains under debate, with durability of response and CNS efficacy seen as key. Management of low-grade diarrhea and other AEs that limit quality of life (QOL) was emphasized. Approval timing and prescriber familiarity were also noted as adoption factors.

Discussion Themes and Expert Insights

Without head-to-head ADC-TKI comparisons, treatment selection relies on clinical judgment, patient-specific factors, and access. The 2 new TKIs were viewed positively for early activity and tolerability, prompting interest in earlier use. Given the high incidence of brain metastases, faculty stressed enrolling patients with untreated CNS disease and exploring whether higher doses could improve intracranial outcomes.

Sequencing preferences varied. Some favored adding chemotherapy in high-burden or curative cases; others preferred single agents to preserve later options and reduce toxicity. Understanding resistance, identifying rare immunotherapy responders, and noting control-arm activity in non–kinase domain mutations were considered important. In slower-access markets, expanded access programs were seen as a way to build familiarity and collect real-world evidence, with first entrants potentially gaining a durable advantage.

Unmet Needs and Recommendations

Priorities include data on CNS durability, guidance on ADC-TKI sequencing, and evidence in non–kinase domain mutations. Universal molecular testing—regardless of histology or smoking status—and clear reporting are needed to avoid inappropriate treatment selection.

Proactive management of ILD and GI, and dermatologic toxicities was advised to maintain QOL and therapy duration. Addressing reimbursement and policy barriers, including limits on dual testing and early access, was viewed as critical to equitable care.

Conclusion

HER2-mutated NSCLC treatment is evolving rapidly. Faculty emphasized CNS control, thoughtful sequencing, and comprehensive testing to improve outcomes. Overall, there is interest in moving T-DXd to first-line therapy in certain cases (eg, CNS disease) and a shared excitement for emerging TKIs. As zongertinib and sevabertinib enter practice, effective toxicity oversight, broader access, and ongoing research will be key to refining strategies and expanding precision oncology benefits for this rare malignancy.

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