Trial: Beamion BCGC-1: A Study to Find a Suita…

Trial Details

Sponsor: Boehringer Ingelheim (industry)

Phase: 1/2

Start date: June 28, 2024

Planned enrollment: 582

Trial ID: NCT06324357

More trial details at ClinicalTrials.gov

Show Summary from Sponsor

Investigational Drug AI Analysis

Show for: Zongertinib (BI-1810631, NSC-854531)

Overview

Zongertinib (BI-1810631; NSC-854531) is an oral, irreversible tyrosine kinase inhibitor (TKI) that selectively targets HER2 (ERBB2). In August 2025, the US FDA granted accelerated approval for zongertinib (brand name Hernexeos) for adults with unresectable or metastatic, nonsquamous NSCLC with HER2 tyrosine kinase domain (TKD) activating mutations who have received prior systemic therapy. The approval was based on objective response rate and duration of response from the Beamion LUNG-1 trial, with continued approval contingent on confirmatory evidence. (fda.gov)

Mechanism of action

Zongertinib is a covalent, HER2-selective TKI designed to inhibit HER2 signaling while sparing EGFR, aiming to reduce EGFR-related toxicities seen with less selective pan-ERBB inhibitors. Preclinical studies showed potent anti-tumor activity in HER2-driven models (including HER2 exon 20 insertions) and synergy with other agents; early clinical cases outside NSCLC also suggested activity. (aacrjournals.org)

Efficacy

Key data come from the phase Ia/Ib, multi-cohort Beamion LUNG-1 trial (NCT04886804):

Phase Ia dose-escalation (various HER2-altered solid tumors, including NSCLC; data cutoff May 23, 2024): confirmed ORR 30% overall and 35% in NSCLC; median duration of response (DoR) 12.7 months. Recommended once-daily doses for expansion were 120 mg and 240 mg. Activity was observed across common HER2 TKD variants (e.g., A775_G776insYVMA) and in patients previously treated with HER2-directed therapy. (ascopubs.org)
Phase Ib (HER2-mutant NSCLC): at the AACR Annual Meeting 2025, updated cohort results reported ORR 71% (95% CI 60–80), including 7% complete responses; median DoR 14.1 months and median PFS 12.4 months; disease control rate 96%. Intracranial activity was reported in patients with measurable brain metastases. These data were presented as Abstract CT050 and highlighted by AACR and institutional releases. (aacrjournals.org)

The FDA’s approval summary described ORR 75% in a subset previously treated with platinum-based chemotherapy but no HER2-targeted ADC/TKI, and ORR 44% in those previously treated with a HER2-targeted ADC, both assessed by blinded independent central review. (ons.org)

Safety

In early-phase studies, zongertinib showed a generally manageable tolerability profile:

Phase Ia: treatment-related adverse events (TRAEs) occurred in 82% of patients; grade ≥3 TRAEs in 10%. Most common TRAEs included diarrhea (50%; grade ≥3, 1%), rash (16%; grade ≥3, 2%), anemia (10%), decreased appetite (10%), and elevated ALT (10%; grade ≥3, 4%). MTD was not reached. (ascopubs.org)
Phase Ib (interim/updated): low incidence of grade ≥3 drug-related AEs was reported; diarrhea was typically grade 1–2. (ascopubs.org)

The FDA label includes warnings/precautions for hepatotoxicity, left ventricular dysfunction, interstitial lung disease/pneumonitis, and embryo-fetal toxicity. (fda.gov)

HealthScout AI Analysis

Goal: Identify safe, tolerable, and biologically active dose levels of the oral HER2-selective tyrosine kinase inhibitor zongertinib when given alone or in combination with trastuzumab deruxtecan (T-DXd), trastuzumab emtansine (T-DM1), or trastuzumab plus capecitabine, and to preliminarily evaluate antitumor activity across advanced HER2-positive solid tumors (metastatic breast cancer and metastatic gastric/GEJ/esophageal adenocarcinoma).

Patients: Adults ≥18 years with unresectable, metastatic HER2-overexpressing and/or amplified breast cancer or metastatic gastric, gastroesophageal junction, or esophageal adenocarcinoma with documented progression after prior therapy. ECOG 0–1, at least one measurable lesion by RECIST 1.1, recovery of prior treatment toxicities to ≤CTCAE grade 1 (specified exceptions). Key exclusions include recent or significant cardiovascular disease, QTcF >470 ms, LVEF <50%, and recent serious thromboembolic or ischemic events. For Phase II, archival tumor tissue from non-irradiated sites is requested when feasible.

Design: Multicenter, randomized, open-label, Phase Ib/II study with dose-escalation cohorts to define safety, DLTs, and a recommended dose, followed by randomized dose-optimization cohorts to compare different zongertinib dose levels across combination and monotherapy settings. Imaging-based tumor assessments are performed serially per RECIST 1.1, and safety is continuously monitored. Planned enrollment is 582.

Treatments: Zongertinib (BI 1810631) administered orally as monotherapy or in combination with T-DXd, T-DM1, trastuzumab plus capecitabine, or trastuzumab alone across Phase Ib (dose escalation) and Phase II (dose optimization and extensions). Zongertinib is a highly selective, covalent HER2 tyrosine kinase inhibitor that targets wild-type and mutant HER2 while sparing EGFR, aiming to reduce EGFR-related toxicities. Early-phase data in HER2-mutant NSCLC have shown promising activity, including objective response rates around 49–74% in dose-finding cohorts with a manageable safety profile dominated by mostly low-grade diarrhea and few serious treatment-related events, and no maximum tolerated dose reached to date. Standard components include T-DXd and T-DM1, antibody-drug conjugates targeting HER2, and trastuzumab with capecitabine, a commonly used regimen in HER2-positive disease.

Outcomes: Primary outcomes: Phase Ib—occurrence of dose-limiting toxicities during the first 21 days to inform maximum tolerated dose; Phase II—objective response rate per RECIST 1.1 by investigator. Secondary outcomes include ORR in Phase Ib, DLTs over the entire treatment period, pharmacokinetics of zongertinib (Cmax, AUC), progression-free survival, disease control rate, and safety/tolerability measures such as dose reductions. Patient-reported outcomes include PRO-CTCAE symptom burden and EORTC items for treatment burden and physical functioning.

Burden on patient: Moderate to high. Patients will undergo frequent clinic visits typical of Phase I/II trials, including intensive safety monitoring, serial CT/MRI per RECIST, and multiple pharmacokinetic blood draws, especially during early cycles and dose-escalation cohorts. Combination arms with antibody-drug conjugates or capecitabine require infusion visits and oral dosing adherence, along with laboratory monitoring for hematologic, hepatic, cardiac (including LVEF assessment and ECGs for QTc), and gastrointestinal toxicities. Archival tissue submission is requested for Phase II; fresh biopsies are not mandated but may be required if archival tissue is inadequate at some sites. Overall visit frequency and PK sampling exceed standard-of-care schedules, contributing to travel and time burden.

Last updated: Oct 2025

Eligibility

Show Criteria

Inclusion Criteria:

* Signed and dated written Informed consent form (ICF) in accordance with International Council for Harmonisation-Good Clinical Practice (ICH-GCP) and local legislation prior to admission to the trial.

* Patients ≥18 years of age or over the legal age of consent in countries where that is greater than 18 years at the time of signature of the ICF.

* Documented Human epidermal growth factor receptor 2 overexpressing and/or amplified (HER2+), metastatic breast cancer (mBC) or metastatic gastric adenocarcinoma, gastroesophageal junction adenocarcinoma, or esophageal adenocarcinoma (mGEAC).

* For dose optimization (Phase II): Patient must provide tumor tissue from locations not radiated prior to biopsy, if possible, collected through archival tissue.

* Documented investigator assessed progression.

* Recovered from any previous therapy-related toxicity to ≤ Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 at start of treatment (except for alopecia, stable sensory neuropathy, and hypothyroidism (patients on thyroid replacement therapy) which must be ≤ CTCAE Grade 2).

* Presence of at least one measurable lesion according to Response evaluation criteria in solid tumors (RECIST) 1.1, as determined by the local site investigator/radiology assessment.

* Eastern Cooperative Oncology Group (ECOG) score of 0 or 1. Further inclusion criteria apply.

Exclusion Criteria:

* Previous or concomitant malignancies other than the one treated in this trial within the previous 2 years, which require current systemic therapy except:

* effectively treated non-melanoma skin cancers

* effectively treated carcinoma in situ of the cervix

* effectively treated ductal carcinoma in situ

* other effectively treated malignancy that is considered cured by local treatment

* History or presence of cardiovascular abnormalities such as uncontrolled hypertension, congestive heart failure New York Heart Association (NYHA) classification of ≥ III or IV, unstable angina or poorly controlled arrhythmia which are considered as clinically relevant by the investigator. Myocardial infarction (or troponin levels consistent with myocardial infarction within 28 days of randomization), stroke, or pulmonary embolism within 6 months prior to randomization.

* Any clinically important abnormalities (as assessed by the investigator) in rhythm, conduction, or morphology of resting electrocardiograms, e.g. complete left bundle branch block, third degree heart block.

* Mean resting corrected QT interval (QT interval corrected for heart rate by Fridericia´s formula (QTcF)) \>470 msec.

* Any factors that increase the risk of QT interval corrected for heart rate (QTc) prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, personal or family history of long QT syndrome or unexplained sudden death under 40 years-of-age.

* Ejection fraction \<50% or the lower limit of normal of the institutional standard within 28 days prior to randomization.

* Women who are pregnant or nursing or who plan to become pregnant or nurse during the trial or within 7 months after the last dose of trial treatment with T-DXd, T-DM1, trastuzumab or capecitabine and trastuzumab.

Orange, California, 92868, United States

Trial Details

Show Summary from Sponsor

Investigational Drug AI Analysis

Show for: Zongertinib (BI-1810631, NSC-854531)

Overview

Mechanism of action

Efficacy

Safety

Further reading

HealthScout AI Analysis

Eligibility

Show Criteria

Sites (100)

CHU UCL Namur

Centre Hospitalier Universitaire de Liège

Edegem - UNIV UZ Antwerpen

Hôpital Vivalia De Libramont

UZ Leuven

Fudan University Shanghai Cancer Center

Harbin Medical University Cancer Hospital

Henan Cancer Hospital

Jiangsu Province Hospital

Jilin Province Cancer Hospital

Sir Run Run Shaw Hospital, Zhejiang University, School of Medicine

Tianjin Cancer Hospital

IRCCS San Raffaele

Istituto Clinico Humanitas

Istituto Europeo di Oncologia

Japanese Foundation for Cancer Research

Kyoto University Hospital

National Cancer Center Hospital East

Osaka International Cancer Institute

CIO Clara Campal

Fundación Jiménez Díaz

Hospital Clínic de Barcelona

Hospital Universitari Vall D Hebron

University of California Irvine

Valkyrie Clinical Trials

Yale University School of Medicine

Tennessee Oncology, Pllc

Cliniques Universitaires Saint-Luc

The First Hospital of Jilin University

CTR Eugène Marquis

CTR François Baclesse

CTR Georges-François Leclerc

CTR Leon Berard

HOP Tenon

INS Bergonie

INS Claudius Regaud IUCT-Oncopole

INS Gustave Roussy

INS Paoli-Calmettes

Institut de Cancérologie de Strasbourg

Institut de Cancérologie de l'Ouest

Asklepios Kliniken GmbH & Co. KGaA

Evang. Kliniken Essen-Mitte gGmbh

Universitätsklinikum Carl Gustav Carus Dresden

Universitätsklinikum Erlangen

Universitätsklinikum Mannheim GmbH

Universitätsklinikum Ulm

Az.Osp. Universitaria "Ospedali Riuniti"

Humanitas Istituto Clinico Catanese S.p.A.

Istituto Di Candiolo

Istituto Nazionale IRCCS Tumori Fondazione Pascale

Istituto Scientifico Romagnolo

Aichi Cancer Center Hospital

Hakuaikai Sagara Hospital

Kanagawa Cancer Center

Tokai University Hospital

Asan Medical Center

CHA Bundang Medical Center

Korea University Anam Hospital

Seoul National University Bundang Hospital

Seoul National University Hospital

Severance Hospital, Yonsei University Health System

The Catholic University of Korea, Seoul St.Mary's Hospital

Clínica Universidad de Navarra - Madrid

Hospital Clínico San Carlos

Hospital Duran i Reynals

Hospital General Universitario Gregorio Marañón

Hospital Teresa Herrera