Dr Rotow on the Updated Treatment Cadence for HER2-Mutant NSCLC

I suspect that in regions where both are available, we're primarily going to see things like zongertinib getting frontline use, and then T-DXd being used in the second-line setting, where absolutely I think it should be used prior to chemoimmunotherapy.

In the second segment of an interview at the IASLC 2026 World Conference on Lung Cancer (WCLC), Julia K. Rotow, MD, clinical director, Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute; assistant professor of medicine, Harvard Medical School, discussed frontline sequencing in HER2-mutant non–small cell lung cancer (NSCLC).

At WCLC 2026 in Seoul, Rotow presented primary results from the phase 3 DESTINY-Lung04 trial, in which first-line trastuzumab deruxtecan (T-DXd; Enhertu) improved progression-free survival over pembrolizumab (Keytruda) plus platinum chemotherapy in HER2-mutant metastatic NSCLC. The result lands alongside 2 oral HER2 TKIs with accelerated first-line approvals on single-arm data: zongertinib (Hernexeos) and, as of September 9, 2026, sevabertinib (Hyrnuo).

Rotow said she would not be surprised to see national guidelines list T-DXd, zongertinib, and sevabertinib as frontline options. On efficacy, she sees parity so far. Both the TKIs and T-DXd have reported median PFS in the 14-month range and response rates of 70-80%. Where they differ is toxicity and convenience.

The HER2 TKIs, and zongertinib in particular, have a favorable safety profile and oral dosing, so in regions with access to both Rotow expects TKI-first sequencing with T-DXd in the second line, ahead of chemoimmunotherapy. Where TKIs are not available, she advocates T-DXd over chemoimmunotherapy in the front line, reserving chemoimmunotherapy for second line.

How the agents perform in sequence is largely unknown, Rotow said. Resistance to a HER2 TKI, such as kinase domain or binding-site mutations, would not be expected to affect T-DXd, which binds the receptor externally and does not depend on kinase conformation. She hopes for preserved activity but would not be surprised by some drop-off; second-line response rates typically decline, and a tumor may become less HER2 dependent, with responses beginning to resemble those in HER2-overexpressing rather than HER2-mutant disease, where activity persists even without a kinase mutation.

Rotow called sequencing an area of real unmet need and urged resistance profiling at progression whenever possible so that the field can pool data and learn whether any findings predict more or less benefit from a given sequence.

Until then, she said, her approach remains TKI, then T-DXd, then chemoimmunotherapy.