Zongertinib first, T-DXd second: experts map out the new HER2-mutated lung cancer playbook

The HER2-mutated NSCLC treatment landscape has rapidly evolved, with two FDA-approved TKIs — zongertinib (accelerated approval, February 2026) and sevabertinib (accelerated approval, September 2026) — and the antibody-drug conjugate T-DXd all now in play. At a recent OncLive Scientific Interchange and Workshop, thoracic oncologists reached broad consensus: for patients with HER2 exon 20 YVMA insertions, the preferred sequence is zongertinib first, then T-DXd. Zongertinib's oral dosing, CNS penetration, and more manageable side effect profile give it the edge over sevabertinib, whose daily diarrhea burden and limited intracranial activity are notable drawbacks.

The phase 3 DESTINY-Lung04 trial added important nuance. While T-DXd significantly improved progression-free survival over pembrolizumab plus platinum chemotherapy in the first-line setting, it did not translate to an overall survival benefit — a finding experts attribute to a high rate of interstitial lung disease (ILD) with T-DXd and a crossover-enriched control arm. Experts also flagged that ILD can foreclose future treatment options, making its management a critical concern.

Key Takeaways:

• Zongertinib is the preferred frontline agent due to CNS activity, oral administration, and tolerability
• Sevabertinib is an alternative, particularly for patients with liver toxicity concerns on zongertinib
• T-DXd is favored in the second-line setting; its first-line use is complicated by ILD risk
• Variant-specific differences (e.g., HER2 L755P, C805S) should guide sequencing decisions
• Repeat biopsy at progression is recommended to characterize resistance mechanisms

Why it matters: As more HER2-directed options become available, getting the sequencing right is critical — not just for efficacy, but to preserve future treatment options and quality of life for patients.