Zongertinib Displays Early Activity and Tolerability in HER2-Mutated Solid Tumors

The novel HER2-directed TKI zongertinib (BI 1810631) demonstrated preliminary efficacy and a manageable safety profile in patients with advanced or metastatic HER2-mutated solid tumors, according to findings from the phase 1a/b Beamion LUNG-1 study (NCT04886804) published in the Journal of Clinical Oncology.1

Efficacy-evaluable patients who received zongertinib across all dose levels and tumor types (n = 105) achieved a confirmed objective response rate (ORR) of 30% (95% CI, 23%-40%) and a disease control rate (DCR) of 83% (95% CI, 75%-89%). These responses were observed in patients with non–small cell lung cancer (NSCLC; n = 19), breast cancer (n = 4), colorectal cancer (n = 2), cervical cancer (n = 2), and cancers of the vulva, gastrointestinal tract, esophagus, ovary, and biliary tract (n = 1 each). Additionally, when accounting for unconfirmed responses, the ORR and DCR rates were 43% and 84%, respectively. No patients achieved a complete response. The median duration of response (DOR) was 12.7 months (95% CI, 6.9-not reached [NR]) and the median duration of disease control was 8.4 months (95% CI, 6.9-13.8).

Topline safety data revealed that 2 dose-limiting toxicities (DLTs) occurred during the maximum tolerated dose (MTD) evaluation period which included grade 3 diarrhea and grade 3 decreased platelet count. Six patients in the 60 mg twice daily, 150 mg twice daily, and above 180 mg once daily cohorts also experienced DLTs during the on-treatment period. Furthermore, most patients (95%) experienced any-grade treatment-emergent adverse effects (TEAEs) and 10% had grade 5 TEAEs. Three percent of patients discontinued treatment due to TEAEs; 30% and 11% of patients had a dose interruption or reduction of zongertinib due to TEAEs, respectively.

“The MTD of zongertinib was NR,” John V. Heymach, MD, PhD, and coauthors wrote in the study. Recommended doses of the agent for the expansion portion of the trial were determined to be 120 mg given once daily and 240 mg given once daily. Heymach and coauthors added that “There were low levels of typical EGFR-related toxicities [seen and] preliminary efficacy was observed across tumor types. The phase Ib part of trial, assessing the recommended doses for expansion of zongertinib in patients with HER2-mutant non–small cell lung cancer [NSCLC], is ongoing.”

Heymach is the David Bruton, Jr Chair in Cancer Research and is the chair of the Department of Thoracic/Head and Neck Medical Oncology as well as a professor at the University of Texas MD Anderson Cancer Center in Houston.

Beamion LUNG-1 Study Design and Baseline Characteristics

Beamion LUNG-1 enrolled adult patients with HER2-altered advanced, unresectable, and/or metastatic solid tumors who were refractory to or unsuitable candidates for standard therapy across 7 sites in the US, Japan, China, and the Netherlands. HER2 alterations consisted of overexpression (immunohistochemistry 2+/3+), gene amplification, nonsynonymous somatic mutations, or a gene rearrangement involving HER2 or NRG1. Eligible patients also needed to have measurable lesions per RECIST 1.1 criteria, an ECOG performance status of 0 or 1, adequate organ function, and a life expectancy of at least 12 weeks.

Patients received oral zongertinib once (n = 88) or twice (n = 17) daily via 21-day cycles. The starting dose in the twice-daily group was 15 mg (n = 3) and it was 60 mg (n = 5) in the once daily group. In the twice-daily group, other dose levels consisted of 30 mg (n = 3), 60 mg (n = 4), 100 mg (n = 4), and 150 mg (n = 3). Other dose levels in the once-daily group included 120 mg (n = 4), 180 mg (n = 25), 240 mg (n = 18), 300 mg (n = 25), and 360 mg (n = 11). Treatment in all groups continued until disease progression, patient withdrawal, or unacceptable toxicity.

The primary end point was determining the MTD based on the frequency of DLTs during the MTD evaluation period. Secondary end points included the number of DLTs over the entire treatment period and pharmacokinetics. ORR, DOR, DCR, and investigator assessed progression-free survival (PFS) were also assessed.

At baseline, the median age of the total population was 60 years (range, 31-81). Most patients were female (53.3%), Asian (50.5%), and had an ECOG performance status of 1 (60.0%). The primary tumor types were NSCLC (51.4%), breast (11.4%), colorectal (13.3%), esophageal (4.8%), cervical (2.9%), endometrial (2.9%), gastrointestinal tract (2.9%), biliary tract (1.9%), and other (8.6%) cancers. Approximately a quarter of patients had brain metastases (25.7%) and the median number of prior lines of treatment received was 4 (range, 1-17).

Additional Efficacy and Safety Data

Patients with NSCLC who received zongertinib (n = 54) achieved a confirmed ORR of 35% (95% CI, 24%-49%) and a DCR of 93% (95% CI, 82%-97%). The median PFS was 8.7 months (95% CI, 2.3-NR) with twice-daily dosing and 17.2 months (95% CI, 8.3-NR) with once-daily dosing. Efficacy evaluable patients with HER2-mutated NSCLC (n = 43) achieved a confirmed ORR of 35% and a DCR of 93%.

In February 2025, the FDA granted priority review to the new drug application (NDA) seeking the approval of zongertinib for the treatment of adult patients with unresectable or metastatic NSCLC harboring HER2 mutations who have received prior systemic therapy.2 The NDA was supported by prior findings from Beamion LUNG-1 and was given a Prescription Drug User Fee Act target action date in the third quarter of 2025.

In the overall population, the median PFS was 8.0 months (95% CI, 2.8-NR) among patients in the twice-daily dosing group and 8.3 months (95% CI, 5.5-13.8) in the once-daily group.1 Patients who received prior HER2-directed therapy (n = 46) achieved a confirmed ORR of 28% and DCR of 85%. These respective rates were 32% and 92% among patients who received prior antibody-drug conjugates. Furthermore, the agent demonstrated efficacy in patients with the exon 20 insertion A775_G776insYVMA (n = 24), yielding an ORR of 38%.

Additional safety data revealed that 30% of patients experienced grade 3 TEAEs and 2% had grade 4 TEAEs. Any-grade treatment-related AEs (TRAEs) were reported in 82% of patients. The most common any-grade TRAEs included diarrhea (50%), rash (16%), anemia (10%), decreased appetite (10%), and increased alanine transaminase levels (10%). Grade 3 or higher TRAEs occurred in 10% of patients and included grade 3 increased alanine transaminase levels (4%), increased aspartate aminotransferase levels (2%), and rash (2%), among others. Additionally, the sole grade 4 TRAE that occurred was thrombocytopenia and no grade 5 TRAEs were observed.

“In summary, the findings from this phase Ia trial indicate that zongertinib had a manageable tolerability profile with preliminary signals of efficacy in patients with HER2-altered solid tumors, including HER2-mutant NSCLC. These results support the ongoing recruitment into the phase Ib expansion portion of the trial,” the study authors wrote in conclusion.

References

1. Heymach JV, Opdam F, Barve M, et al. HER2-selective tyrosine kinase inhibitor, zongertinib (BI 1810631), in patients with advanced/metastatic solid tumors with HER2 alterations: a phase Ia dose-escalation study.J Clin Oncol. Published online March 3, 2025. doi:10.1200/JCO-24-01727
2. Boehringer’s zongertinib receives Priority Review from U.S. FDA for the treatment of HER2 (ERBB2)-mutant advanced non-small cell lung cancer. News Release. Boehringer Ingelheim. February 19, 2025. Accessed March 3, 2025. https://www.boehringer-ingelheim.com/us/zongertinib-granted-priority-review-us-fda