Dr Dietrich on the FDA Approval of Zongertinib for HER2 TKD–Mutated Nonsquamous NSCLC

“It's the first time that we're seeing a HER2-targeting therapy that captures these most common exon 20 insertion mutations in HER2 with a specificity that doesn't overlap with EGFR. We don't see a lot of the on-target [adverse] effects on the skin or in the gastrointestinal tract.”

Martin F. Dietrich, MD, PhD, a medical oncologist with The US Oncology Network Cancer Care Centers of Brevard and an assistant professor of internal medicine at the University of Central Florida College of Medicine, discussed implications of the FDA accelerated approval of zongertinib (Hernexeos) for the treatment of adult patients with unresectable or metastatic nonsquamous non–small cell lung cancer (NSCLC) harboring HER2 tyrosine kinase domain (TKD) activating mutations, as detected by an FDA-approved test, who have received prior systemic therapy.

The regulatory decision was based on findings from the multicohort phase 1 Beamion LUNG-1 trial (NCT04886804), which evaluated zongertinib at a daily oral dose of 120 mg in patients with advanced NSCLC harboring HER2 alterations. Findings supporting the approval showed that evaluable patients who received prior platinum-based chemotherapy and had not been previously treated with a HER2-targeted TKI or antibody-drug conjugate (n = 71) experienced an overall response rate (ORR) of 75% (95% CI, 63%-83%) and a 6-month duration of response (DOR) rate of 58%. Among patients previously treated with platinum-based chemotherapy and a HER2-targeted ADC (n = 34), the ORR was 44% (95% CI, 29%-61%), with a 6-month DOR rate of 27%.

Additional activity was observed in other trial cohorts, including patients with non-TKD HER2 mutations and those with prior exposure to fam-trastuzumab deruxtecan-nxki (Enhertu), Dietrich said.

Dietrich noted that HER2-mutant NSCLC is a particularly aggressive subtype, often associated with high rates of central nervous system metastases and poor responsiveness to immunotherapy, similar to EGFR-mutant disease. Chemotherapy has been the historical standard of care in this setting. Zongertinib’s approval introduces a targeted treatment option with a favorable efficacy-to-toxicity ratio, he said, owing to its selectivity for HER2 exon 20 insertion mutations without overlapping EGFR inhibition, which reduces dermatologic and gastrointestinal on-target adverse effects.

The approval of zongertinib represents a meaningful advancement for patients with HER2-mutant NSCLC, Dietrich concluded. Future studies will be important to define optimal sequencing, evaluate potential combination strategies, and explore the role of zongertinib in earlier lines of therapy to maximize its clinical benefit.