medwireNews: Phase 1b trial data point to the potential of zongertinib, a novel HER2 inhibitor, for previously treated patients with HER2-mutant non-small-cell lung cancer (NSCLC).
“[Z]ongertinib showed durable clinical activity, had a manageable safety profile, and resulted in notably low levels of grade 3 or higher drug-related adverse events, including those associated with EGFR inhibitors (e.g., diarrhea and rash),” notes the research team in The New England Journal of Medicine.
Giving the background for the trial, the investigators say that trastuzumab deruxtecan “is recommended as the standard of care in HER2-mutant NSCLC but can be associated with potentially serious adverse events,” and pan-HER tyrosine kinase inhibitors (TKIs) “have only shown marginal benefit” in this patient population.
“Therefore, an effective, oral, HER2-targeted treatment option with improved safety is needed,” they continue.
The researchers evaluated zongertinib – “an oral, irreversible TKI that selectively inhibits HER2 while sparing EGFR, thereby limiting associated toxic effects” – in the multicohort phase 1a/1b Beamion LUNG-1 trial comprising patients with HER2-mutant locally advanced or metastatic NSCLC.
The current report focuses on previously treated patients who received zongertinib at a dose of 120 mg/day, specifically:
- those with a mutation in the tyrosine kinase domain (TKD; cohort 1);
- those with a TKD mutation who had received prior treatment with a HER2-directed antibody–drug conjugate (cohort 5); and
- those with a non-TKD mutation (cohort 3).
At a median follow-up of 11.3 months in cohort 1, the primary endpoint of an objective response, as assessed by blinded independent central review, was achieved by 71% of the 75 participants, which was significantly higher than the 30% benchmark rate.
Responses lasted for a median of 14.1 months and, at the time of analysis, 40% of the 53 responders had an ongoing response. The median progression-free survival (PFS) time was 12.4 months.
In cohort 5, at a median follow-up of 6.8 months, just under half (48%) of the 31 participants had an objective response by blinded review. The median duration of response was 5.3 months and the median PFS was 6.8 months.
Zongertinib also showed activity in cohort 3, with an objective response rate, as evaluated by investigator review, among the 20 participants of 30%. The data for median duration of response and PFS were not mature at the time of analysis.
John Heymach (The University of Texas MD Anderson Cancer Center, Houston, USA) and associates report that zongertinib was active across various TKD mutations, “with a promising confirmed objective response observed in patients with A775_G776insYVMA (81%) and P780_Y781insGSP (75%) insertions.”
The findings were also promising for patients with non-TKD mutations, “including known activating mutations in the extracellular (S310X) and transmembrane (V659E) domains,” they add, but caution that “this cohort was highly heterogeneous and included some mutations that are not considered to be activating (i.e., S113F and P1199S), so further research is required.”
With regard to the safety, the authors say that “[t]he safety profile of zongertinib was consistent with its mechanism of action and previous clinical experience.”
Treatment-related adverse events (TRAEs) of grade 3 or higher occurred in 17% of patients in cohort 1, 3% of those in cohort 5, and 25% in cohort 3.
The most common TRAEs of any grade in cohort 1 were diarrhea and rash, observed at rates of 56% and 33%, respectively, but except for one case of grade 3 diarrhea, all were of grade 1 or 2. The most frequent TRAEs of grade 3 or worse were increased alanine aminotransferase and aspartate aminotransferase levels, in a respective 8% and 5%.
Just five (7%) cohort 1 participants required a dose reduction of zongertinib due to AEs and two (3%) discontinued. Seven (9%) patients died due to AEs, but none were considered related to zongertinib.
Of note, there were no cases of drug-related interstitial lung disease, which is a known toxicity of trastuzumab deruxtecan, in any cohort.
Heymach and colleagues acknowledge the limitations of the study, such as “the open-label design and the lack of a standard-of-care comparator group.”
And they conclude: “The ongoing phase 3 Beamion LUNG-2 trial is evaluating the efficacy and safety of first-line zongertinib as compared with the standard of care in patients with unresectable, locally advanced or metastatic HER2-mutant nonsquamous NSCLC.”
These data were simultaneously presented at the AACR Annual Meeting 2025, held in Chicago, Illinois, USA.
medwireNews is an independent medical news service provided by Springer Healthcare Ltd. © 2025 Springer Healthcare Ltd, part of the Springer Nature Group
N Engl J Med 2025; doi:10.1056/NEJMoa2503704
AACR Annual Meeting 2025; Chicago, Illinois, USA: 25–30 April
