FDA Approves Zongertinib for HER2-Mutated NSCLC

The FDA has granted accelerated approval to zongertinib (Hernexeos, Boehringer Ingelheim Pharmaceuticals, Inc.) for certain adults with unresectable or metastatic nonsquamous non-small cell lung cancer (NSCLC).

Specifically, the TKI was approved for patients whose tumors harbor HER2 (ERBB2) tyrosine kinase domain-activating mutations as detected by an FDA-approved test and who have received prior systemic therapy, according to the approval notice. 

The novel agent is the first orally administered, targeted therapy for previously treated patients with HER2 (ERBB2)-mutant NSCLC, who have poor prognosis and limited treatment options, Boehringer Ingelheim noted in a February 2025 press release announcing the agent having been granted priority review. Zongertinib had previously received breakthrough therapy and fast track designation.

The FDA also approved the Oncomine DX Target Test (Life Technologies Corporation) to help detect the target mutations and identify patients who may be eligible for zongertinib treatment. 

“With the approval of zongertinib, we have an effective, targeted, orally administered treatment option for patients with HER2 (ERBB2)-mutant non-small cell lung cancer in the U.S. that not only elicits a durable response but, importantly, has a manageable safety profile,” said John Heymach, MD, PhD, chair of thoracic/head and neck medical oncology at The University of Texas MD Anderson Cancer Center, Houston, and coordinating investigator for the Beamion-LUNG 1 trial, stated in a press release. “In a patient population where there are currently limited treatment options, this approval represents a significant advancement in cancer care.”

Zongertinib approval was based on efficacy demonstrated in the open-label phase 1b Beamion LUNG-1 dose escalation trial.

Among 71 patients who had received prior platinum-based chemotherapy but who had not received a HER2-targeted TKI or antibody-drug conjugate, 75% had an objective response and 58% had duration of response of at least 6 months. Among 34 patients who had received both platinum-based chemotherapy and a HER2-targeted antibody-drug conjugate, the objective response and duration of response rates were 44% and 27%, respectively. 

Boehringer Ingelheim reported that dose reductions occurred in only 5% of patients, and only 2.9% discontinued treatment. Most treatment-related adverse events were manageable, with diarrhea, hepatotoxicity, and rash occurring most commonly. The prescribing information, which will be posted at Drugs@FDA, includes warnings and precautions for hepatotoxicity, left ventricular dysfunction, interstitial lung disease, and embryo-fetal toxicity.

The recommended zongertinib dose is 120 mg given orally once daily for patients who weigh less than 90 kg and 180 mg given orally once daily for those who weigh 90 kg or greater. Zongertinib can be taken with or without food and can be continued until disease progression or unacceptable toxicity, according to the full prescribing information. 

Sharon Worcester, MA, is an award-winning medical journalist based in Birmingham, Alabama, writing for Medscape, MDedge, and other affiliate sites. She currently covers oncology, but she has also written on a variety of other medical specialties and healthcare topics. She can be reached at [email protected] or on X: @SW_MedReporter.