*April 2025*
The investigational oral tyrosine kinase inhibitor (TKI) zongertinib showed promise in patients with previously treated HER2-mutant non-small cell lung cancer (NSCLC) in a multicohort phase Ia/Ib study.
In the first cohort of 75 patients with tumors harboring a mutation in the tyrosine kinase domain, the confirmed objective response rate was 71% (64% partial responses, 7% complete responses), reported John V. Heymach, MD, PhD, of the University of Texas MD Anderson Cancer Center in Houston, at the American Association for Cancer Research annual meeting in Chicago.
The median duration of response was 14.1 months, and the median progression-free survival was 12.4 months, they noted in the New England Journal of Medicine, where the study was also published.
In the cohort of 31 patients with tumors harboring a mutation in the tyrosine kinase domain previously treated with a HER2-directed antibody-drug conjugate, 48% had a confirmed objective response, and in the cohort of 20 patients with tumors harboring a non-tyrosine kinase domain mutation, 30% had a confirmed objective response.
“Zongertinib provided clinically meaningful activity in previously treated patients with advanced non-small cell lung cancer with HER2 mutations, both within and outside the tyrosine kinase domain, including in patients with brain metastases,” Heymach said.
Grade 3 or higher drug-related adverse events occurred in 13 patients in the first cohort, and in one and five patients in the other two cohorts, respectively.
“I want to start out by acknowledging what an important study this is for our patients,” said invited discussant Charles Rudin, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York City. “An effective, well-tolerated, orally bioavailable therapy with HER2-driven lung cancer has long been an unmet need. In my opinion, zongertinib satisfies the primary criteria we would want to see for a drug of this class.”
Next-generation TKIs, as well as antibody-drug conjugates, are “looking better than chemotherapy or chemoimmunotherapy for this disease,” Rudin suggested. “That is great news for our patients with HER2-mutant lung cancer.”
He said an important next step is finding out which class of drugs should be given first line, and gave the edge to TKIs, “based on tolerability and the high response rate.”
“This is a highly competitive space — which, again, is good news for patients,” he added. “And there are other exciting and highly active TKIs hot on the heels of zongertinib.”
In explaining the rationale behind the study, Heymach noted that about 2% to 4% of NSCLCs harbor HER2 mutations, which are associated with a poor prognosis and a higher incidence of brain metastases. The most prevalent HER2 mutations are in exon 20, the active site of the tyrosine kinase domain.
“Historically, there has been a challenge in targeting HER2-mutated kinases, because these drugs typically also inhibit wild-type EGFR and cause a lot of EGFR-related toxicities,” he said. “Zongertinib was designed to be highly selective for HER2 and spare wild-type EGFR, therefore potentially limiting those EGFR-related toxicities.” Read more.
