Zongertinib Demonstrates Clinically Meaningful Efficacy in HER2-Mutated NSCLC

Treatment with zongertinib (BI 1810631) led to clinically meaningful and statistically significant efficacy, as well as tolerable safety, in patients with previously treated non–small cell lung cancer (NSCLC) harboring HER2 tyrosine kinase domain (TKD) mutations, according to data from cohort 1 of the phase 1b Beamion LUNG-1 trial (NCT04886804) shared at the 2024 IASLC World Conference on Lung Cancer.¹

Among patients in the 120 mg cohort (n = 75), zongertinib elicited an objective response rate (ORR) of 66.7% (97.5% CI, 53.8%-77.5%; P <.0001) per blinded independent central review (BICR). Data showed that the primary end point of confirmed response by BICR was reached for patients who received the agent at 120 mg in cohort 1 during the phase 1b portion of the trial.

Additionally, 94% (n = 124/132) of patients experienced tumor shrinkage of any magnitude based on investigator assessment. Although duration of response (DOR) and progression-free survival (PFS) data were not yet mature at the time of the analysis, approximately two-thirds of the study population were still receiving treatment as of the data cutoff of May 23, 2024.

The confirmed ORR per central review was 72.4% (n = 42/58) in the 120 mg group compared with 78.2% (n = 43/55) in the 240 mg group. Data showed that 1.7% (n = 1/58) and 3.6% (n = 2/55) of each respective group achieved a complete response (CR), and 70.7% (n = 41/58) and 74.5% (n = 41/55) had a partial response (PR). Study treatment also yielded a disease control rate (DCR) of 94.8% (n = 55/58) and 100.0% (n = 55/55) in each respective group.

Regarding intracranial responses per BICR using Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria, the ORR was 33% (n = 9/27; 95% CI, 19%-52%) with zongertinib at 120 mg and 40% (n = 10/25; 95% CI, 23%-59%) at 240 mg. In each respective group, the CR rate was 15% (n = 4/27) and 20% (n = 5/25), and the PR rate was 19% (n = 5/27) and 20% (n = 5/20). Additionally, the DCR was 74% (n = 20/27; 95% CI, 55%-87%) and 92% (n = 23/25; 95% CI, 75%-98%).

“Zongertinib demonstrated significant and clinically meaningful activity in patients with pretreated [NSCLC] with a HER2 [TKD] mutation, including in those with brain metastases,” Gerrina Ruiter, MD, PhD, of the Department of Clinical Pharmacology and Department of Thoracic Oncology at Netherlands Cancer Institute in Amsterdam, the Netherlands, said in the presentation. “Zongertinib was very well tolerated, with no deaths attributed to treatment and a low incidence of dose reductions and treatment discontinuations.”

Ruiter further illustrated the potential efficacy of zongertinib in this population by highlighting a specific patient case involving a 67-year-old woman with stage IV HER2-mutated NSCLC. After disease progression at 7 months following frontline treatment consisting of carboplatin, pemetrexed, and pembrolizumab (Keytruda), second-line therapy with zongertinib at 120 mg elicited a PR lasting for 13 months to date; the patient currently remains on study treatment.

Developers designed zongertinib as an investigational, orally available HER2 tyrosine kinase inhibitor (TKI) that can selectively and covalently bind to the TKD of mutated and wild-type HER2 receptors. By sparing wild-type EGFR, treatment with zongertinib may avoid toxicities associated with this receptor.

Investigators of the Beamion LUNG-1 trial assessed treatment with zongertinib at the recommended expansion doses of 120 mg and 240 mg once daily. Cohort 1 included patients with previously treated NSCLC harboring a HER2 TKD mutation, where investigators selected the 120 mg dose at interim analysis.

The primary end point of the phase 1b portion of the trial was confirmed objective response per RECIST 1.1 criteria according to central independent review.

With a median follow-up of approximately 13 weeks for efficacy, 132 patients received treatment with zongertinib as of the data cutoff, including 75 in the 120 mg group and 57 in the 240 mg group. The median patient age was 62 years (range, 30-80) and 62 years (range, 36-82) in the 120 mg and 240 mg group, respectively, with most patients in each group being female (68% and 44%). Additionally, most patients in each group were Asian (53% and 58%), received 1 prior line of systemic therapy (56% and 49%), and had an ECOG performance status of 1 (63% and 70%). Of note, 37% and 46% of patients in each group had brain metastases.

Across the 120 mg group and 240 mg groups, respectively, 92% and 100% of patients had any-grade treatment-related adverse effects (TRAEs), with the most common including diarrhea (48% and 65%), rash (24% and 30%), and aspartate aminotransferase increases (21% and 25%). Additionally, grade 3 or higher TRAEs affected 17% and 19% of these groups, with the most common types including alanine aminotransferase increases (8% and 11%) and aspartate aminotransferase increases (5% and 7%).

Investigators reported no fatal TRAEs, and 11% (n = 14) of patients required dose reductions following toxicity. Additionally, 3% (n = 4) had AEs resulting in treatment discontinuation.

The FDA previously granted breakthrough therapy designation to zongertinib for adults with advanced, unresectable, or metastatic NSCLC harboring activating HER2 mutations following prior systemic therapy.²

Ruiter concluded by stating that the phase 3 Beamion LUNG-2 trial (NCT06151574) was open for enrollment. Investigators of Beamion LUNG-2 will compare zongertinib with standard-of-care therapy in the frontline treatment of patients with advanced HER2-mutant NSCLC.

References

1. Ruiter G, Tu H-Y, Ahn M-J, et al. Phase 1b analysis of Beamion LUNG-1: zongertinib (BI 1810631) in patients with HER2-mutant NSCLC. Presented at the 2024 World Conference on Lung Cancer; September 7-10, 2024; San Diego, CA. Abstract PL04.04.
2. Boehringer Ingelheim to unveil groundbreaking oncology research at WCLC, demonstrating strength of portfolio. News release. Boehringer Ingelheim. August 27, 2024. Accessed September 9, 2024. https://tinyurl.com/4nr9ntwy