New data for Boehringer Ingelheim’s investigational oncology candidate, zongertinib, shows sustained clinical benefits in non-small cell lung cancer (NSCLC) patients with HER2 mutations in the tyrosine kinase domain (TKD).
Updated findings from the Phase Ib Beamion LUNG-1 trial included durability of response, building on the clinical evidence supporting zongertinib’s efficacy.
Among patients across five cohorts, cohort 1, with 75 previously treated patients, took the orally administered tyrosine kinase inhibitor (TKI) zongertinib 120 mg once a day. This cohort was powered as the primary analysis cohort.
In cohort 1, patients achieved a median duration of response (DoR) of 14.1 months and a median progression-free survival (PFS) of 12.4 months among previously treated patients.
HER2 mutations, present in approximately 2% to 4% of NSCLC cases, have historically been associated with limited treatment options and poor prognoses.
Lung cancer is the second most commonly diagnosed cancer in the US, affecting approximately 250,000 people annually. Among those with metastatic NSCLC, the outlook remains grim — only about 8% survive beyond five years post-diagnosis.
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The FDA granted zongertinib Priority Review status in February 2025, after which Boehringer filed a drug application for it. The Prescription Drug User Fee Act (PDUFA) action date is anticipated in the third quarter of 2025.
If approved, zongertinib would offer a convenient, once-daily oral therapy for patients with HER2-mutated NSCLC, potentially transforming the treatment landscape for this challenging cancer subtype.
The latest trial data for the drug was presented at the American Association for Cancer Research (AACR) Annual Meeting 2025 and published in The New England Journal of Medicine.
In an AACR press release on the data, coordinating trial investigator John V. Heymach, MD, PhD, explained: “Until recently, there were no effective targeted therapies for HER2-mutated NSCLC,” and that “this practice-changing approval of zongertinib would provide access to a highly efficacious treatment option with a manageable safety profile and would be the first oral therapy and only tyrosine kinase inhibitor approved for patients with HER2-mutated NSCLC.”
Building on Past Trial Data
Boehringer’s previous data from Beamion LUNG-1 showed that zongertinib led to an objective response rate (ORR) of 71% in patients with TKD HER2 mutations, including a 7% complete response rate and a 64% partial response rate.
The disease control rate (DCR) reached 96%, indicating that nearly all patients experienced some clinical benefit.
Zongertinib’s efficacy extended to various patient subgroups.
Among patients with advanced NSCLC with TKD HER2 mutations who had previously received platinum-based chemotherapy and HER2-targeted antibody-drug conjugates (ADCs), zongertinib achieved a 48% ORR and a 97% DCR. Among patients with non-TKD HER2 mutations, the ORR was 30%.
Notably, patients with brain metastases achieved a 41% intracranial response rate and an 81% DCR, highlighting zongertinib’s potential in managing central nervous system involvement.
The safety profile of zongertinib was generally favorable. In cohort 1, grade 3 or higher drug-related adverse events occurred in 17% of patients, with no reported cases of interstitial lung disease or cardiotoxicity. This tolerability is particularly significant given the limited treatment options and potential toxicities associated with existing therapies for HER2-mutated NSCLC.
Related: FDA Approves Ensacove (Ensartinib) for Advanced NSCLC in Crowded ALK Inhibitor Market
NSCLC Contenders
In the press release on the new data, Boehringer noted that AstraZeneca and Daiichi Sankyo’s Enhertu (trastuzumab deruxtecan) was approved as the first treatment for HER2-mutated NSCLC only three years ago in the US in 2022, followed by a European approval in October 2023.
The company said a potential advantage of zongertinib over Enhertu is its selective targeting of HER2 while sparing EGFR. This reduces the risk of adverse events like interstitial lung disease (ILD), which has been associated with Enhertu.
The approval of Enhertu was based on data from the Phase II DESTINY-Lung02 trial, in which among 52 patients, the confirmed ORR was 57.7%, with 1.9% achieving a complete response and 55.8% showing partial responses. The median duration of response was 8.7 months.
Boehringer said zongertinib is also being evaluated in the Phase III Beamion LUNG-2 trial (NCT06151574) against current standard of care as a first-line option for HER2-mutated NSCLC.
There has been notable activity in the NSCLC space since last year.
In December, Xcovery Holdings received FDA approval for its ALK inhibitor Ensacove (ensartinibi) for ALK-positive locally advanced or metastatic NSCLC.
Meanwhile, Akeso and Summit Therapeutics completed enrollment for a Phase III trial of PD-1/VEGF bispecific antibody ivonescimab, which is looking to challenge Merck’s Keytruda in NSCLC.
And Janssen’s Rybrevant (amivantamab) and lazertinib won FDA approval last summer as the first chemotherapy-free treatment for advanced NSCLC with EGFR exon 19 deletions or L858R mutations.
Nuvation Bio shared promising data for its TKI taletrectinib last year in extending PFS for NSCLC patients with ROS1 fusions.
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