Zongertinib Demonstrates Clinical Activity in HER2-Mutant Solid Tumors


The BEAMION Lung-1 trial of zongertinib in HER2–mutant solid tumors is advancing to phase 1b following encouraging preliminary results.

3d rendered Digital illustration of lung cancer cells in color background. Generative AI | Image Credit: © Owen - www.stock.adobe.com

Image Credit: © Owen - www.stock.adobe.com

In patients with HER2–mutant non–small cell lung cancer (NSCLC) treated in a cohort of the phase 1a/b BEAMION Lung-1 trial (NCT04886804), treatment with zongertinib (BI 1810631) showed preliminary efficacy signals and acceptable, according to results of the the dose-escalation portion of the study.1

Treatment with zongertinib in the study will proceed to phase 1b evaluation at doses of 120 mg and 240 mg once daily in patients with HER2–mutant NSCLC.

Data from the trial, which were presented at the 2023 IASLC World Conference on Lung Cancer, demonstrated that at the data cutoff date of July 17, 2023, the maximum tolerated dose (MTD) had not been reached. On-treatment dose-limiting toxicities (DLTs) included grade 2 edema (n = 1; 60 mg twice daily); grade 2 diarrhea (n = 1; 150 mg twice daily); grade 3 platelet count decrease (n = 1; 360 mg once daily); and grade 3 alanine aminotransferase (ALT) increase, grade 2 blood bilirubin increase, and grade 2 aspartate aminotransferase (AST) increase (n = 1; 180 mg once daily).

About the BEAMION Lung-1 Trial

Trial Name: ABEAMION-Lung 1: An Open Label, Phase I Dose Escalation Trial, With Dose Confirmation and Expansion, of BI 1810631 as Monotherapy in Patients With Advanced or Metastatic Solid Tumors With HER2 Aberrations

ClinicalTrials.gov Identifier: NCT04886804

Sponsor: Boehringer Ingelheim

Recruitment Contact: Boehringer Ingelheim, 1-800-243-0127, clintriage.rdg@boehringer-ingelheim.com

Completion Date: December 31, 2025

“Zongertinib demonstrated encouraging preliminary antitumor activity in various tumors with HER2 aberrations in phase 1a, [and] very promising initial efficacy results were observed in phase 1b in pretreated patients with NSCLC harboring HER2 TKD mutations,” lead study author Noboru Yamamoto, MD, PhD, deputy director of the National Cancer Center Hospital and chief of the Department of Experimental Therapeutics in Tokyo, Japan, said in a presentation of the data.

Many solid tumors harbor HER2 mutations, approximately half of which are found in TKD. However, 90% of HER2 TKD mutations are exon 20 insertion mutations, which do not respond well to available TKIs and result in added gastrointestinal and skin toxicities as a result of wild-type EGFR inhibition.

Zongertinib is a novel, covalent, wild-type EGFR–sparing TKI that binds selectively to the HER2 TKD mutation, resulting in fewer adverse effects (AEs). The agent is under investigation in BEAMION Lung-1 in patients with NSCLC harboring HER2 TKD mutations, including exon 20 insertions.

The study consisted of a phase 1a dose-escalation and phase 1b expansion cohort. In phase 1a, patients with advanced, HER2-aberrant solid tumors received either twice-daily doses of zongertinib ranging from 15 mg to 150 mg (n = ~36) or once-daily doses of between 60 mg and 360 mg of zongertinib (n = ~30) in 3-week cycles. Phase 1b dose expansion was subdivided into 5 cohorts: pretreated, HER2 TKD–mutant NSCLC (cohort 1); treatment-naïve, HER2 TKD–mutant NSCLC (cohort 2); NSCLC with a non–HER2 TKD mutation (cohort 3); NSCLC with active brain metastases (cohort 4); and NSCLC previously treated with a HER2-directed antibody-drug conjugate (cohort 5).

The primary end points of phase 1a were identification of the MTD and any DLTs. The primary objective of phase 1b was efficacy characterized by objective response rate (ORR) in all expansion cohorts.2

In phase 1a, (n = 50) the median age was 60.5 years (range, 31-79). Most patients were male (52.0%), Asian (64.0%), had an ECOG performance status of 1 (66.0%), and had received more than 2 prior lines of therapy (52.0%). Most patients had received a diagnosis of NSCLC (62.0%), although those with unspecified lung cancer (8.0%), colorectal cancer (6.0%), endometrial cancer (4.0%), and other tumors (16.0%) were also included. Identified HER2 aberrations included mutations (58.3%), amplifications (80.0%), overexpression (75.0%), and rearrangement involving HER2 or NRG1 (21.0%).1

In this cohort, one case of serious grade 3 ALT increase led to treatment discontinuation.

Overall treatment-related AEs (TRAEs) with twice-daily (n = 17) and once-daily (n = 33) zongertinib (n = 50) were diarrhea (any grade, 40.0%), AST increase (grade 1/2, 14.0%; grade ≥3, 2.0%), rash (any grade, 14.0%), ALT increase (grade 1/2, 12.0%; grade ≥3, 6.0%), paronychia (any grade, 10.0%), dry skin (any grade, 8.0%), and anemia (any grade, 8.0%).

“Zongertinib was well tolerated with low rates of EGFR-mediated AEs,” the authors wrote.

In the overall phase 1a cohort (n = 46), the ORR was 41.3%, all of which were partial responses (PRs); 50.0% of patients experienced stable disease, leading to a disease control rate (DCR) of 91.3%. Among patients with NSCLC (n = 34), the ORR consisting of all PRs was 50.0%; 47.1% of patients experienced stable disease, resulting in a DCR rate of 97.1%.

The median number of treatment cycles received was 7.5 (range, 1-24), and 62% patients remained on treatment at data cutoff. Among 11 patients who had an A775-G776 insertion YVMA mutation, 63.6% achieved PR, 27.3% experienced stable disease, and 9.1% developed progressive disease.

In phase 1b (n = 42), median patient age was 62.0 years (range, 34-80) and most patients were female (52.4%). Any-grade TRAEs occurred in 66.7% of patients (grade ≥3, 9.5%), the most common of which was diarrhea (28.6%), followed by rash (21.4%), AST increase (grade 1/2, 9.5%; grade ≥3, 2.4%), decreased appetite (9.5%), and dysgeusia (9.5%).

DLTs occurred in 3 patients at the 240 mg dose. Two DLTs––grade 3 febrile neutropenia and grade 4 immune thrombocytopenia––occurred in the MTD evaluation period. On treatment, one patient experienced grade 3 ALT and AST increase and grade 4 neutrophil count decrease.

One dose reduction occurred owing to grade 3 febrile neutropenia and neutrophil count decrease. Discontinuations due to AEs were not needed in this cohort, although 2 patients experienced serious AEs of grade 3 ALT/AST increase and grade 4 immune thrombocytopenia and neutrophil count decrease.

Among patients evaluable for efficacy in phase 1b (n = 23) who had received between 2 and 5 cycles of treatment at data cutoff, the ORR was 73.9% (95% CI, 53.5%-87.5%) and the DCR was 91.3%. Median best percentage change from baseline in target lesions was –41.2%.

The trial is ongoing, and phase 1b is open for enrollment in countries in Europe and the Middle East, Australia and Asia, and North America.


1. Yamamoto N, Opdam F, Barve M, et al. Beamion Lung-1, a phase 1a/b trial of the HER2 TKI, zongertinib (BI 1810631), in patients with advanced solid tumors with HER2 aberrations. Presented at: 2023 IASLC World Conference on Lung Cancer; September 9-12, 2023; Singapore, Republic of Singapore. Abstract MA13.08.

2. A study to test different doses of BI 1810631 in people with different types of advanced cancer (solid tumors with changes in the HER2 gene). ClinicalTrials.gov. Updated September 6, 2023. Accessed September 11, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT04886804

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