Early Lung Cancer Data Show Why FDA Approved HER2 Agent in First-Line

First-line treatment with a recently approved targeted agent demonstrated durable efficacy in advanced or metastatic HER2-mutant non-small cell lung cancer (NSCLC), results of the phase I Beamion LUNG-1 trial showed.

In 74 previously untreated patients, zongertinib (Hernexeos) induced responses in 76%, including complete responses in 11%, with a median response duration of 15.2 months. Treatment-related toxicities were mostly low-grade, reported researchers led by John Heymach, MD, PhD, of the University of Texas MD Anderson Cancer Center in Houston.

“This oral, targeted agent appears to be an effective alternative primary treatment option to chemotherapy for an aggressive disease,” they wrote in the New England Journal of Medicine.

The FDA last year granted accelerated approval to zongertinib as a second- or later-line option for HER2-mutant NSCLC. The irreversible tyrosine kinase inhibitor (TKI) selectively inhibits HER2 while sparing wild-type EGFR, which minimizes associated toxicities.

And in February of this year, based on the current study results, the agency granted accelerated approval for previously untreated patients with advanced or metastatic HER2-mutant NSCLC. An ongoing confirmatory phase III trial in the first-line setting is comparing zongertinib alone against chemotherapy plus pembrolizumab (Keytruda).

Mutations in HER2, most commonly within the tyrosine kinase domain, occur in approximately 2% to 4% of NSCLCs. It marks an aggressive disease with a poor prognosis, with a median progression-free survival (PFS) of less than 7 months and a high incidence of brain metastases.

In the current study, Heymach and co-authors reported, the median PFS with zongertinib reached 14.4 months, and the TKI showed an intracranial response rate of 47% in a separate cohort involving patients with active brain metastases.

While multiple generations of effective targeted therapies over the past two decades have made their way into the first-line care of lung cancers driven by EGFR, ALK, ROS, RET, and BRAF, drug development in HER2 has been an outlier, according to David Carbone, MD, PhD, of the Ohio State University in Columbus.

He noted in an accompanying editorial — dubbed “EGFR‘s Poor Sibling” — that while trastuzumab (Herceptin) was shown to effectively target HER2 in breast cancer as far back as the late 1990s, trials in lung cancer were disappointing.

The first breakthrough in HER2-mutant NSCLC was with the antibody-drug conjugate trastuzumab deruxtecan (Enhertu), which in a phase II study showed a response rate of 58% and a median duration of response of 8.7 months in the second-line, supporting an approval in 2022.

“But chemotherapy remained the recommended and most effective first-line therapy for HER2-mutant tumors,” Carbone wrote. “Until now.”

Following the first-line approval, zongertinib “will certainly now become the standard first-line therapy for HER2 tyrosine kinase domain–mutant lung cancer, as osimertinib [Tagrisso] is for tumors with its older relative EGFR,” he added.

The TKI sevabertinib (Hyrnuo) is also approved for previously treated HER2-mutant disease, and is being evaluated in first-line, but its efficacy and safety profile appears to be less favorable than zongertinib, according to Heymach and colleagues, though they included the standard cautionary language about cross-trial comparisons.

The researchers reported data on 74 patients with previously untreated HER2-mutant advanced or metastatic NSCLC (cohort 2) who received a 120-mg daily dose of zongertinib at 53 sites in Australia, Europe, Asia, and the U.S., as well as 30 previously treated and untreated patients with brain metastases (cohort 4) from the multicohort open-label Beamion LUNG-1 trial.

Median age of the participants in cohort 2 was 67 years, 50% were women, 45% were non-Asian, and 35% had a history of tobacco exposure. Metastases at baseline included those in the brain (30%) and liver (16%).

The primary outcome was confirmed objective response. Median time to response was 1.4 months with zongertinib, and median tumor shrinkage in terms of target lesion diameter was 59% from baseline.

Grade 3 or higher adverse events (AEs) were reported in 45% of patients, with 19% considered treatment related — the most common of which were increased alanine aminotransferase levels (4%) and decreased ejection fraction (4%). Grade 3 or higher AEs typically associated with EGFR inhibitors such as diarrhea (3%) and rash (0%) were infrequent. AEs of any grade leading to dose reductions or treatment discontinuation occurred in 16% and 9%, respectively.

In cohort 4, the median duration of intracranial response was 6.9 months, median intracranial PFS was 8.2 months, and responses were observed in those without previous brain radiotherapy. The safety profile in this subset “was consistent with that in the the overall Beamion LUNG-1 patient population,” wrote Heymach and colleagues.