Zongertinib (BI 1810631), an investigational oral HER2-specific tyrosine kinase inhibitor (TKI), has shown continued efficacy and a manageable safety profile in patients with pretreated advanced non-small cell lung cancer (NSCLC) harboring HER2 mutations. These findings, from the phase 1 Beamion LUNG-1 study (NCT04886804), were presented at the 2024 ESMO Asia Congress.
Efficacy of Zongertinib in Pretreated NSCLC
At the data cutoff of August 29, 2024, patients receiving zongertinib at 120 mg (n = 75) achieved a confirmed objective response rate (ORR) of 71% (95% CI, 60%-80%; P < .0001). The disease control rate (DCR) was 93%, with 55% of responders remaining on treatment. The 6-month duration of response (DOR) rate was 73%, and the 6-month progression-free survival (PFS) rate was 69%.
Dr. Noboru Yamamoto, from the National Cancer Center Hospital in Tokyo, Japan, highlighted the clinical significance of these results, stating, "Zongertinib demonstrated significant and clinically meaningful activity in patients with pretreated advanced NSCLC harboring HER2 mutations," and emphasized the agent's manageable safety profile.
Addressing Unmet Needs in HER2-Mutant NSCLC
HER2 mutations are present in 2% to 4% of NSCLC cases and are associated with poor prognosis and a higher incidence of brain metastases. The current treatment landscape includes trastuzumab deruxtecan, an antibody-drug conjugate approved for second-line use and beyond. However, there remains a need for effective oral targeted therapies that can improve patient quality of life.
Study Design and Dosage Optimization
The phase 1a portion of the Beamion LUNG-1 study involved dose escalation to identify the optimal dose for phase 1b. Ultimately, 120 mg once daily was selected for further evaluation. The primary endpoint of the phase 1b study was confirmed ORR, with secondary endpoints including DCR, DOR, and PFS.
Safety and Tolerability
The majority of treatment-related adverse events (TRAEs) were mild and manageable. No fatal TRAEs or cases of interstitial lung disease were reported. Dose reductions due to AEs occurred in 5% of patients, and treatment discontinuation in 3%. Common TRAEs included diarrhea (51%), rash (27%), increased aspartate aminotransferase (21%), and increased alanine aminotransferase (20%).
Ongoing Phase 3 Trial
The randomized, phase 3 Beamion LUNG-2 study (NCT06151574) is currently enrolling patients to compare zongertinib with standard of care as a first-line treatment for HER2-mutant advanced NSCLC.
Expert Commentary
Dr. Edgardo S. Santos Castillero, with The Oncology Institute (TOI) of Hope and Innovation, noted zongertinib's favorable toxicity profile, stating it has "the best toxicity profile that I have seen on any HER2 TKI." He also highlighted the importance of a selective HER2 TKI in minimizing off-target effects and improving patient quality of life.
