Dr Halmos on the FDA Approval of Zongertinib in HER2 TKD–Mutated NSCLC

“[Zongertinib] really quickly is becoming the first choice because of those favorable characteristics.”

Balazs Halmos, MD, MS, director of the Multidisciplinary Thoracic Oncology Program and of the Section of Thoracic Medical Oncology at Montefiore Health Systems, as well as the director of Clinical Cancer Genetics and a professor of clinical medicine at the Albert Einstein College of Medicine, discussed the evolving treatment landscape for patients with HER2-mutant non–small cell lung cancer (NSCLC) following the FDA approval of zongertinib (Hernexeos) in the first-line setting.

On February 26, 2026, the FDA granted accelerated approval to zongertinib for an expanded indication for adults with unresectable or metastatic nonsquamous NSCLC whose tumors have HER2 TKD activating mutations, as detected by an FDA-authorized test. Halmos emphasized that although HER2 alterations occur in only approximately 1% to 2% of patients with NSCLC, they represent an important molecular subset with meaningful therapeutic implications. He noted that HER2 mutations span a spectrum, with the most common alterations occurring in the tyrosine kinase binding domain, which is also where much of the available clinical evidence has been generated. Additional mutations may occur in the extracellular and transmembrane domains, further underscoring the heterogeneity of this patient population.

Historically, chemotherapy and chemoimmunotherapy have demonstrated activity in HER2-mutant disease and have served as standard approaches, Halmos explained. More recently, the antibody-drug conjugate fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) expanded treatment options in this space, demonstrating an approximate 50% response rate and median progression-free survival (PFS) of around 9 months, albeit with notable toxicities, including a risk of pneumonitis occurring in roughly 10% of patients.

Halmos highlighted that the accelerated FDA approval of zongertinib granted in August 2025 for pretreated patients represented a major advance, offering a third therapeutic option that may ultimately shift frontline practice. He described zongertinib as an oral, HER2-targeted TKI administered at 120 mg once daily, noting its ease of use and strong efficacy profile, with an overall response rate of approximately 70%, and responses potentially exceeding 75% in treatment-naive patients.

Importantly, Halmos stressed the favorable tolerability profile of zongertinib, reporting that grade 3 toxicities are uncommon, with the most frequent adverse effects including diarrhea and skin-related toxicity. He added that dose reductions are rarely needed and treatment discontinuations are uncommon, making the agent an attractive option compared with other available therapies.

Although zongertinib entered the treatment paradigm as a newer option following chemotherapy and T-DXd, Halmos noted that its high response rates and excellent safety may position it as a preferred frontline therapy moving forward. He added that the ongoing phase 3 Beamion LUNG-02 trial (NCT06151574) is directly evaluating this possibility by comparing zongertinib with chemoimmunotherapy in the first-line setting.