HER2-Selective Tyrosine Kinase Inhibitor, Zongertinib (BI 1810631), in Patients With Advanced/Metastatic Solid Tumors With HER2 Alterations: A Phase Ia Dose-Escalation Study

Abstract

PURPOSE

Human epidermal growth factor receptor 2 (HER2) alterations occur in many solid cancers, including non–small cell lung cancer (NSCLC). Beamion LUNG-1 (ClinicalTrials.gov identifier: NCT04886804) is assessing the safety/efficacy of zongertinib (BI 1810631), a novel HER2-selective tyrosine kinase inhibitor that spares epidermal growth factor receptor, in patients with HER2-altered solid tumors.

MATERIALS AND METHODS

Beamion LUNG-1 is an ongoing multicenter, multicohort phase Ia/Ib trial. Phase Ia assessed zongertinib administered twice a day (15-150 mg) or once daily (60-360 mg) in pretreated patients with various tumors, including NSCLC. Primary end points were maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs); tumor response was a secondary end point.

RESULTS

As of May 23, 2024, 105 patients were treated. Two DLTs occurred during the MTD evaluation period; MTD was not reached (NR). The recommended doses for expansion were 120 mg once daily and 240 mg once daily. Treatment-related adverse events (TRAEs; any/grade ≥3) occurred in 82%/10% of patients. The most common TRAEs (any/grade ≥3) included diarrhea (50%/1%), rash (16%/2%), anemia (10%/0%), decreased appetite (10%/1%), and increased alanine transaminase (10%/4%). The confirmed investigator-assessed overall response rate (ORR) across all doses/tumors was 30% (95% CI, 23 to 40); median duration of response was 12.7 months (95% CI, 6.9 to NR). In 54 patients with NSCLC, confirmed ORR was 35% (95% CI, 24 to 49). Activity was observed in patients with A775_G776insYVMA (ORR, 38%) and those who had received previous HER2-directed therapy (ORR, 28%). In patients with NSCLC receiving zongertinib once daily, median progression-free survival was 17.2 months (95% CI, 8.3 to NR).

CONCLUSION

Zongertinib had a manageable safety profile and demonstrated preliminary antitumor activity in patients with HER2-altered tumors, including those with HER2-mutant NSCLC.

INTRODUCTION

The human epidermal growth factor receptor 2 (HER2), a member of the ErbB family of transmembrane receptors, plays a critical role in the regulation of cell proliferation and survival.¹ HER2 alterations, including protein overexpression, gene amplification, and genetic mutations, occur frequently across many human malignancies including breast, gastric, and lung cancers.¹ HER2-targeted agents have transformed care for patients with breast and gastric cancers. Nevertheless, primary and acquired resistance to therapy remains a challenge in these settings.² To date, HER2-targeted agents have had less of an impact in non–small cell lung cancer (NSCLC) than in breast and gastric cancers. Only one HER2-targeted therapy, the antibody-drug conjugate trastuzumab deruxtecan, is approved for the treatment of NSCLC after previous systemic therapy in patients with HER2 mutations and, after a recent pan-tumor approval, patients with HER2-overexpressing tumors (immunohistochemistry of 3+).³ HER2-mutant NSCLC accounts for 2%-5% of all cases of NSCLC, is associated with poor prognosis and high rates of brain metastases, and is very challenging to treat.^4-11 Therefore, there remains an unmet need for novel HER2-targeted drugs in NSCLC and other tumor types.

CONTEXT

• Key Objective

• Zongertinib (BI 1810631) is a novel human epidermal growth factor receptor 2 (HER2)–selective tyrosine kinase inhibitor that spares epidermal growth factor receptor (EGFR). This ongoing, first-in-human, phase Ia/Ib trial is assessing the safety and efficacy of zongertinib in patients with HER2-altered tumors, including HER2-mutant non–small cell lung cancer (NSCLC).

• Knowledge Generated

• Data from phase Ia are reported. The maximum tolerated dose of zongertinib was not reached. There were low levels of typical EGFR-related toxicities. 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 NSCLC, is ongoing.

• Relevance (T.E. Stinchcombe)

• Future development of zongertinib in solid tumors with HER2 alterations is warranted.*

• *Relevance section written by JCO Associate Editor Thomas E. Stinchcombe, MD.

HER2 mutations in NSCLC mostly occur in the tyrosine kinase domain (TKD),⁵ and insertions in exon 20 predominate.^5-7,10,12 The most common exon 20 insertion is A775_G776insYVMA.^6,7,10 Other HER2 mutations are highly heterogeneous and occur across all exons.^8,13 Although HER2 exon 20 insertion mutations are sensitive to trastuzumab deruxtecan^14,15 and other antibody-drug conjugates, such as trastuzumab emtansine,¹⁶ they are generally resistant to HER2 tyrosine kinase inhibitors (TKIs); early-phase studies with agents including afatinib, dacomitinib, and neratinib demonstrated disappointing response rates.^13,17-19 Some pan-ErbB TKIs, such as pyrotinib and poziotinib, are active against exon 20 insertion mutations and have demonstrated activity in patients with HER2-mutant NSCLC, but are associated with high rates of off-target epidermal growth factor receptor (EGFR) wild-type related toxicities, such as diarrhea and, in the case of poziotinib, rash.^20-25

Zongertinib (BI 1810631) is a novel TKI that selectively and irreversibly inhibits HER2 and spares EGFR, thereby limiting associated toxicities.²⁶ In Ba/F3 cells, zongertinib has demonstrated a large difference in binding affinity to wild-type EGFR (half maximal inhibitory concentration [IC₅₀]: 1,540 nM) compared with HER2^YVMA (IC₅₀: 16 nM).²⁶ Furthermore, zongertinib induced tumor regressions in human xenograft models bearing HER2 aberrations.²⁶

Here, we report the phase Ia part of Beamion LUNG-1, an ongoing first-in-human, multicenter, multicohort phase Ia/Ib trial of zongertinib in patients with HER2-altered advanced solid tumors (ClinicalTrials.gov identifier: NCT04886804).

MATERIALS AND METHODS

Study Design

Phase Ia (dose escalation) of Beamion LUNG-1 was conducted at seven institutions across the United States, Japan, China, and the Netherlands, and assessed escalating doses of zongertinib, administered orally once daily or twice a day. The primary end point was maximum tolerated dose (MTD), on the basis of the number of dose-limiting toxicities (DLTs) during the MTD evaluation period. Secondary end points were the number of patients experiencing DLTs during the entire treatment period and pharmacokinetics (PKs). Further end points included objective response defined as best overall response of complete response (CR) or partial response (PR; RECIST version 1.1; applied to non-CNS lesions) as assessed by the investigator, disease control (CR, PR, or stable disease [SD]), duration of objective response, and duration of disease control. Investigator-assessed progression-free survival (PFS), defined as the time from first administration until tumor progression in non-CNS lesions, or death from any cause, was an exploratory end point. Phase Ib will assess the efficacy and safety of zongertinib at the recommended dose for expansion in patient cohorts with HER2-mutant NSCLC.

The study protocol was approved by institutional review boards at participating sites. The study was conducted according to the ethical principles of the Declaration of Helsinki. All patients provided written informed consent before enrollment.

Patients

Patients were age 18 years and older with a histologically or cytologically confirmed diagnosis of HER2-altered advanced, unresectable, and/or metastatic solid tumors refractory to, or unsuitable for, standard therapy. HER2 alterations were overexpression (2+ or 3+ by immunohistochemistry), gene amplification, nonsynonymous somatic mutation, or a gene rearrangement involving HER2 or neuregulin 1 (NRG1). NRG1 rearrangements were included because NRG1 is a ligand for HER3, which activates signaling via heterodimerization with HER2, and TKIs with HER2 activity have demonstrated activity in NRG1 fusion-driven preclinical models.²⁷

Other eligibility criteria included measurable or evaluable lesions as measured by RECIST version 1.1, Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1; adequate organ function, and life expectancy of ≥12 weeks. Patients with asymptomatic brain metastasis (no clinical neurologic symptoms) who were deemed stable by the investigator and were unlikely to require immediate CNS treatment were eligible for inclusion. Previous radiotherapy for brain lesions was permitted up to 1 week (for palliative intent) or 2 weeks (any other intent) before initiation of study treatment. Complete inclusion/exclusion criteria are provided in the Data Supplement (online only).

Treatment

Zongertinib was given orally twice a day or once daily on a 21-day cycle. The starting twice-a-day dose was 15 mg. Twice-a-day dosing was started first and continued until one dose level above the predicted human efficacious dose (40 mg twice a day) was considered safe. The once-daily schedule was opened at a starting dose of 60 mg. Subsequent dose-level cohorts were opened alternatively between twice-a-day and once-daily schedules, with twice-a-day cohorts filled first. The a priori dose levels of zongertinib to be tested were 15, 30, 60, 100, and 150 mg twice a day, and 60, 120, 180, 240, and 300 mg once daily. Patients continued treatment until disease progression (PD), withdrawal of consent, or unacceptable toxicity. Patients were allowed to stay on treatment beyond initial radiologic progression at the investigator's discretion.

Definition of DLTs, details of dose-escalation methodology, and stopping rules for MTD determination are provided in the Data Supplement. A maximum of one dose reduction by one dose level was allowed for adverse events (AEs) after treatment interruption, provided that toxicity had returned to grade ≤1. Treatment was permanently discontinued in the event of a second occurrence of toxicity.

Procedures and Outcomes

Tumor response in non-CNS lesions was evaluated by the investigator and/or the local radiologist. Assessment of safety included the reporting of AEs and documenting the occurrence of DLTs.

The PK parameters maximum plasma concentration (C_max) and AUC were evaluated after first and multiple dose administration of zongertinib on days 1 and 15 where feasible.

Statistical Analysis

Dose escalation and determination of the MTD were guided by the escalation with overdose control criterion on the basis of a three-parameter Bayesian logistic regression method (BLRM) including a binary covariate indicating the schedule (Data Supplement). Dose-escalation steps within the parameters of the BLRM and cohort size were overseen by a dose-escalation committee. Kaplan-Meier estimates with 95% CIs were used to analyze time-to-event end points using Greenwood's variance estimate. For objective response, 95% CIs were calculated with the Wilson method.

RESULTS

Patients and Treatment

As of May 23, 2024, 105 patients were treated. Median age was 60 years (range, 31-81); patients were predominantly Asian (n = 53, 50%) and female (n = 56, 53%; Table 1). Most patients had an ECOG PS of 1 (n = 63, 60%) and 27 (26%) had baseline brain metastases.

TABLE 1.

Baseline Demographic and Disease Characteristics

Characteristic	Zongertinib Twice Daily (n = 17)	Zongertinib Once Daily (n = 88)	Total (N = 105)
Age, years, median (range)	61 (47-79)	59 (31-81)	60 (31-81)
Sex, No. (%)
Female	9 (52.9)	47 (53.4)	56 (53.3)
Male	8 (47.1)	41 (46.6)	49 (46.7)
Race, No. (%)
White	7 (41.2)	33 (37.5)	40 (38.1)
Asian	10 (58.8)	43 (48.9)	53 (50.5)
Black	0	1 (1.1)	1 (1.0)
Missing	0	11 (12.5)	11 (10.5)
ECOG PS, No. (%)
0	5 (29.4)	37 (42.0)	42 (40.0)
1	12 (70.6)	51 (58.0)	63 (60.0)
Primary tumor, No. (%)
NSCLC	11 (64.7)	43 (48.9)	54 (51.4)
Breast	1 (5.9)	11 (12.5)	12 (11.4)
Colorectal	1 (5.9)	13 (14.8)	14 (13.3)
Esophageal	1 (5.9)	4 (4.5)	5 (4.8)
Cervical	0	3 (3.4)	3 (2.9)
Endometrial	1 (5.9)	2 (2.3)	3 (2.9)
GI tract	0	3 (3.4)	3 (2.9)
Biliary tract	0	2 (2.3)	2 (1.9)
Othera	2 (11.8)	7 (8.0)	9 (8.6)
Brain metastases at baseline, No. (%)	5 (29.4)	22 (25.0)	27 (25.7)
Number of previous lines of anticancer treatment, No. (%)
1	5 (29.4)	10 (11.4)	15 (14.3)
2‒4	7 (41.2)	45 (51.1)	52 (49.5)
5‒6	2 (11.8)	20 (22.7)	22 (21.0)
>6	3 (17.6)	13 (14.8)	16 (15.2)
HER2 aberration, n/N with result reported (%)
Mutation	12/17 (70.6)	45/86 (52.3)	57/103 (55.3)
Amplification	2/2 (100.0)	13/17 (76.5)	15/19 (78.9)
Overexpressionb	4/4 (100.0)	26/32 (81.3)	30/36 (83.3)
Rearrangement involving HER2	1/17 (5.9)	10/86 (11.6)	11/103 (10.7)
Rearrangement involving NRG1	0/17 (0)	7/86 (8.1)	7/103 (6.8)

Abbreviations: ECOG PS, Eastern Cooperative Oncology Group performance status; HER2, human epidermal growth factor receptor 2; NRG1, neuregulin 1; NSCLC, non–small cell lung cancer.

^a Genitourinary system and small intestine in the twice daily group, and head and neck, mediastinum, ovary, pancreas, uterine, vulva, and other in the once daily group.

^b 2+, or 3+ on immunohistochemistry.

Most patients had NSCLC (n = 54, 51%). Fourteen patients had colorectal cancer (13%) and 12 had breast cancer (11%). Of the 103 patients with genomic classification data, 57 (55%) had a HER2 mutation; 18 patients (17%) had a rearrangement involving either HER2 or NRG1. Some patients had HER2 amplification and/or overexpression, but the number of patients tested for these aberrations was limited. Of the 19 patients tested for HER2 amplification by in situ hybridization, 15 were positive (Table 1). Only one of these patients also had a HER2 mutation. Of the 36 patients tested for HER2 overexpression by immunohistochemistry, 30 were positive (Table 1). Five of these patients also had a HER2 mutation. Of the 54 patients with NSCLC, 43 had a HER2 mutation, three had an NRG1 fusion, two had HER2 amplification, two overexpressed HER2, and the HER2 alteration was not listed in four patients.

Median lines of previous treatment was 4 (range, 1-17). Forty-six patients (44%), 19 of whom had HER2-mutant NSCLC, received at least one previous HER2-targeted treatment including trastuzumab (n = 27), trastuzumab deruxtecan (n = 20), pertuzumab (n = 15), trastuzumab emtansine (n = 9), and pyrotinib (n = 7). Median duration of zongertinib treatment was 4.2 months (range, 0-28); treatment was ongoing in 47 patients at data cutoff (Fig 1).

FIG 1.

CONSORT diagram.

Dose Escalation, DLTs, and MTD

Two patients had a DLT during the MTD evaluation period (grade 3 diarrhea and grade 3 decreased platelet count with zongertinib 240 mg once daily and 360 mg once daily, respectively). A further six patients had DLTs during the on-treatment period across 60 mg twice a day, 150 mg twice a day, and once daily cohorts above 180 mg (Table 2). The MTD was not reached (NR) with either schedule.

TABLE 2.

Dose Escalation and DLTs

Zongertinib Dose and Schedule	Patients, No.	Patients With DLTs, No.	DLTs During MTD Evaluation Period (cycle 1)	DLTs After the MTD Evaluation Period
15 mg twice daily	3	—	—	—
30 mg twice daily	3	—	—	—
60 mg twice daily	4	1	—	Grade 2 edema
100 mg twice daily	4	—	—	—
150 mg twice daily	3	1	—	Grade 2 diarrhea
60 mg once daily	5	—	—	—
120 mg once daily	4	—	—	—
180 mg once daily	25	1	—	Grade 3 elevated ALT; grade 2 elevated AST; grade 2 elevated bilirubin
240 mg once daily	18	2	Grade 3 diarrhea	Grade 4 thrombocytopenia
300 mg once daily	25	1		Grade 2 ejection fraction decreased
360 mg once daily	11	2	Grade 3 decreased platelet count	Grade 3 elevated ALT; grade 3 elevated AST; grade 2 acute interstitial pneumonitis

Abbreviations: DLT, dose-limiting toxicity; MTD, maximum tolerated dose.

Safety and Tolerability

Treatment-emergent AEs (TEAEs) were reported in 100 patients (95%); 32 (30%) and two (2%) experienced grade 3 and 4 TEAEs, respectively (Data Supplement, Table S1). Eleven patients (10%) had grade 5 TEAEs. Thirty-two (30%) and 12 (11%) patients had a dose interruption or dose reduction of zongertinib due to TEAEs, respectively. Three patients (3%) discontinued zongertinib due to TEAEs.

Treatment-related AEs (TRAEs) were reported in 86 patients (82%; Table 3). The most common TRAEs were diarrhea (n = 53; 50%), rash (n = 17; 16%), and anemia (n = 11; 10%). Grade ≥3 TRAEs were reported in 11 patients (10%). These were grade 3 increased ALT (n = 4; 4%), grade 3 increased AST (n = 2; 2%), grade 3 rash (n = 2; 2%), and grade 3 hypocalcemia, diarrhea, lymphopenia, decreased appetite, decreased platelets, hypertension, and nausea (all n = 1; 1%). One patient had a grade 4 TRAE (thrombocytopenia). There were no grade 5 TRAEs.

TABLE 3.

Summary of AEs and Details of TRAEs Experienced by ≥Three Patients by Zongertinib Dosing Schedule

Summary of AEs	Zongertinib Twice Daily (n = 17), No. (%)	Zongertinib Once Daily (n = 88), No. (%)	Total (N = 105), No. (%)
Any AE	16 (94.1)	84 (95.5)	100 (95.2)
DLT	2 (11.8)	6 (6.8)	8 (7.6)
Serious AEs	8 (47.1)	31 (35.2)	39 (37.1)
AE leading to interruption	7 (41.2)	25 (28.4)	32 (30.5)
AE leading to dose reduction	2 (11.8)	10 (11.4)	12 (11.4)
AE leading to discontinuation	0	3 (3.4)	3 (2.9)

TRAE	Twice Daily			Once Daily			Total
	Grade 1, No. (%)	Grade 2, No. (%)	Grade 3, No. (%)	Grade 1, No. (%)	Grade 2, No. (%)	Grade 3, No. (%)	Grade 1, No. (%)	Grade 2, No. (%)	Grade 3,a No. (%)
Any TRAE	9 (52.9)	3 (17.6)	1 (5.9)	36 (40.9)	27 (30.7)	9 (10.2)	45 (42.9)	30 (28.6)	10 (9.5)
Diarrhea	6 (35.3)	2 (11.8)	0	38 (43.2)	6 (6.8)	1 (1.1)	44 (41.9)	8 (7.6)	1 (1.0)
Rashb	2 (11.8)	0	0	11 (12.5)	2 (2.3)	2 (2.3)	13 (12.4)	2 (1.9)	2 (1.9)
Anemia	1 (5.9)	1 (5.9)	0	4 (4.5)	5 (5.7)	0	5 (4.8)	6 (5.7)	0
ALT increased	0	0	1 (5.9)	5 (5.7)	1 (1.1)	3 (3.4)	5 (4.8)	1 (1.0)	4 (3.8)
Decreased appetite	0	0	0	8 (9.1)	1 (1.1)	1 (1.1)	8 (7.6)	1 (1.0)	1 (1.0)
AST increased	1 (5.9)	0	0	4 (4.5)	2 (2.3)	2 (2.3)	5 (4.8)	2 (1.9)	2 (1.9)
Fatigue	1 (5.9)	0	0	8 (9.1)	0	0	9 (8.6)	0	0
Nausea	0	0	0	4 (4.5)	4 (4.5)	1 (1.1)	4 (3.8)	4 (3.8)	1 (1.0)
Stomatitis	1 (5.9)	0	0	8 (9.1)	0	0	9 (8.6)	0	0
Dysgeusia	0	0	0	6 (6.8)	2 (2.3)	0	6 (5.7)	2 (1.9)	0
Paronychia	1 (5.9)	0	0	5 (5.7)	1 (1.1)	0	6 (5.7)	1 (1.0)	0
Nail disorder	0	0	0	6 (6.8)	0	0	6 (5.7)	0	0
Pruritus	1 (5.9)	0	0	5 (5.7)	0	0	6 (5.7)	0	0
Dry skin	2 (11.8)	0	0	3 (3.4)	0	0	5 (4.8)	0	0
Platelet count decreased	1 (5.9)	0	0	3 (3.4)	0	1 (1.1)	4 (3.8)	0	1 (1.0)
ALP increased	1 (5.9)	0	0	3 (3.4)	0	0	4 (3.8)	0	0
CPK increased	0	0	0	3 (3.4)	1 (1.1)	0	3 (2.9)	1 (1.0)	0
Muscle spasms	0	0	0	4 (4.5)	0	0	4 (3.8)	0	0
Neutrophil count decreased	0	0	0	1 (1.1)	3 (3.4)	0	1 (1.0)	3 (2.9)	0
Rhinitis	2 (11.8)	0	0	2 (2.3)	0	0	4 (3.8)	0	0
Vomiting	1 (5.9)	0	0	0	3 (3.4)	0	1 (1.0)	3 (2.9)	0
WBC decreased	0	0	0	0	4 (4.5)	0	0	4 (3.8)	0
Bilirubin conjugate increased	0	0	0	0	3 (3.4)	0	0	3 (2.9)	0
Bilirubin increased	0	0	0	1 (1.1)	2 (2.3)	0	1 (1.0)	2 (1.9)	0
Creatinine increased	1 (5.9)	0	0	2 (2.3)	0	0	3 (2.9)	0	0
Lymphocyte count decreased	0	0	0	1 (1.1)	1 (1.1)	1 (1.1)	1 (1.0)	1 (1.0)	1 (1.0)
Mouth ulceration	0	0	0	3 (3.4)	0	0	3 (2.9)	0	0

Abbreviations: AE, adverse event; ALP, alkaline phosphatase; CPK, creatine phosphokinase; DLT, dose-limiting toxicity; TRAE, treatment-related AE.

^a One patient had a grade 4 TRAE (thrombocytopenia).

^b Combined term, includes rash, rash maculopapular, and dermatitis acneiform.

Serious AEs were reported in 39 patients (37%). Three patients had serious AEs that were possibly related to treatment (grade 3 increased ALT and AST in one patient [240 mg once daily], grade 3 increased ALT, AST, and grade 2 pneumonitis in one patient [360 mg once daily], and grade 4 thrombocytopenia in one patient [240 mg once daily]). There were 15 deaths due to PD; none were considered related to treatment.

Efficacy

At data cutoff, 32 of all evaluable patients (n = 105) had a confirmed objective response (all PRs), giving a confirmed overall response rate (ORR) of 30% (95% CI, 23 to 40); the disease control rate (DCR) was 83% (95% CI, 75 to 89; Table 4). Including unconfirmed responses, the ORR and DCR were 43% and 84%, respectively. Of the 13 patients with unconfirmed responses, five were ongoing treatment at data cutoff. Confirmed responses occurred in patients with NSCLC (n = 19), breast cancer (n = 4), colorectal cancer (n = 2), cervical cancer (n = 2), and cancer of the vulva, GI tract, esophagus, ovary, and the biliary tract (all n = 1).

TABLE 4.

Confirmed Best Overall Tumor Response in Non-CNS Lesions per RECIST Version 1.1

Tumor Response	NSCLC (n = 54), No. (%)	All Patients (N = 105), No. (%)
Objective response rate	19 (35.2)	32 (30.5)
CR	0	0
PR	19 (35.2)	32 (30.5)
DCR	50 (92.6)	87 (82.9)
SD	31 (57.4)	55 (52.4)
PD	1 (1.9)	7 (6.7)
Not evaluable	3 (5.6)	11 (10.5)

Abbreviations: CR, complete response; DCR, disease control rate; NSCLC, non–small cell lung cancer; PD, progressive disease; PR, partial response; SD, stable disease.

Median duration of response (DoR) was 12.7 months (95% CI, 6.9 to NR) and median duration of disease control was 8.4 months (95% CI, 6.9 to 13.8; Fig 2). At data cutoff, treatment was ongoing in 23 of the 32 responding patients. Median PFS was 8.0 months (95% CI, 2.8 to NR), and 8.3 months (95% CI, 5.5 to 13.8) with zongertinib twice a day and once daily, respectively (Data Supplement, Fig S1A).

FIG 2.

(A) Swimmer plot of response assessments and duration of treatment by patient. (B) Best percentage change from baseline in target lesions according to RECIST version 1.1. Patients with ≥one postbaseline tumor assessment or who discontinued before first postbaseline assessment for any reason. PD, progressive disease; PR, partial response; SD, stable disease.

Among patients with NSCLC, the confirmed ORR was 35% (95% CI, 24 to 49) and the DCR was 93% (95% CI, 82 to 97; Table 4). Including unconfirmed responses, ORR and DCR were 54% and 93%, respectively. Median DoR was NR (95% CI, 6.9 to NR); median duration of disease control was 17.2 months (95% CI, 8.4 to NR). At data cutoff, treatment was ongoing in 13 of the 19 responding patients with NSCLC. Median PFS was 8.7 months (95% CI, 2.3 to NR) and 17.2 months (95% CI, 8.3 to NR) with twice-a-day and once-daily dosing, respectively (Data Supplement, Fig S1B). In evaluable patients with HER2-mutant NSCLC (n = 43), the confirmed ORR and DCR were 35% and 93%, respectively.

Twenty-four patients with NSCLC had the A775_G776insYVMA mutation (13 were ongoing treatment at data cutoff). In exploratory analysis, nine of these patients had a confirmed PR (38%) and 13 had SD (54%).

In patients with breast cancer (n = 12), four (33%) had a confirmed objective response and one had an unconfirmed response. Three of these patients had overexpression and/or amplification of HER2, one was HER2-mutant–positive, and one was HER2-mutant–positive and also had overexpression and amplification of HER2. All responding patients were heavily pretreated (four to nine previous lines of therapy); four had received previous HER2-targeted treatment.

In patients who had received previous HER2-directed therapy (n = 46), the confirmed ORR was 28% and the DCR was 85%. In patients who received previous antibody-drug conjugates (n = 25), the confirmed ORR was 32% and the DCR was 92%.

In the 83 patients (41 with NSCLC) who received zongertinib ≥120 mg once daily, the confirmed ORR was 34% (39% in patients with NSCLC). In the 31 patients with HER2-mutant NSCLC, the confirmed ORR was 39%. Including patients with unconfirmed responses, the ORR was 52%.

In the 27 patients with brain metastases at baseline, six (22%; all NSCLC) had a confirmed response, of whom five received zongertinib ≥120 mg once daily.

PK Analyses

At data cutoff, PK data for 87 patients across the 15-150 mg twice-a-day and 60-360 mg once-daily cohorts were available for analysis. Plasma concentration-time profiles were similar across different doses, with a fast absorption phase peaking between 1 and 3 hours after dose, followed by a monophasic to biphasic decline (Data Supplement, Fig S2). Overall, zongertinib plasma concentrations increased with increasing doses, but with high coefficients of variance (Data Supplement, Table S2). Steady state was reached by day 15, with accumulation of zongertinib after multiple dosing. After single dosing, high variability was observed for all PK parameters. At steady state, plasma exposure increased with increasing zongertinib doses (Data Supplement, Table S2) without any obvious deviation from dose proportionality. Because of the short time frame between doses, the terminal half-life of zongertinib could not be calculated in this study. Accumulation values for C_max and AUC were generally between one-fold and three-fold, but some dose groups had highly variable accumulation ratios of up to 7.4-fold for C_max and 8.1-fold for AUC with geometric coefficient of variation of 136% and 104%, respectively, possibly related to low absorption after the first dose.

On the basis of assessment of all available data, zongertinib at doses of 120 mg once daily and 240 mg once daily were selected as the recommended doses for expansion.

DISCUSSION

In this study, zongertinib had a manageable tolerability profile and demonstrated encouraging preliminary activity in patients with HER2-altered solid tumors, including HER2-mutant NSCLC. At data cutoff, 10% of patients had experienced grade ≥3 TRAEs. MTD of zongertinib was NR. The confirmed ORR across all dose levels was 30% overall and 35% in patients with NSCLC; treatment was ongoing in 47 patients. Median DoR was 12.7 months. Only three patients with NSCLC did not achieve disease control. The PK profile of zongertinib appeared to be compatible with once-daily dosing. On the basis of these encouraging data, phase Ib of Beamion LUNG-1 is ongoing.

The most common TRAE with zongertinib was diarrhea (50%); most cases were grade 1 (42%) or grade 2 (8%) with only one grade 3 event. Only three grade ≥3 TRAEs occurred in more than one patient (elevated ALT, elevated AST, and rash). Of note, liver enzyme elevations were reversible, and patients were able to continue on treatment after a dose interruption. As expected, on the basis of the high selectivity of zongertinib for HER2 over EGFR, there were low levels of typical EGFR TKI TRAEs, such as rash, stomatitis, and paronychia. There was one case of interstitial lung disease (ILD; grade 2).

The preliminary safety data for zongertinib are encouraging in the context of other HER2-targeted therapies. In the phase II DESTINY-Lung01 trial that assessed trastuzumab deruxtecan in 91 patients with metastatic, HER2-mutant NSCLC after standard therapy, the grade ≥3 TRAE rate was 46%.¹⁵ Treatment-related ILD (any grade) was observed in 26% of patients. In the subsequent phase II dose-optimization trial in patients with HER2-mutant NSCLC, DESTINY-Lung02, the grade ≥3 TRAE rate at the recommended dose of 5.4 mg/kg was 39%.¹⁴ Treatment-related ILD (any grade) was reported in 13% of patients. Pyrotinib and poziotinib have been associated with grade ≥3 TRAE rates of 20%-79% in pretreated patients, with high rates of grade ≥3 treatment-related diarrhea (17%-26%).^20-23 Poziotinib was associated with high rates of grade ≥3 rash (47%-49%), and dose discontinuations (3%-13%) due to TRAEs were often required.^22,23 Consequently, the US Food and Drug Administration's Oncology Drug Advisory Committee concluded that the current benefits of poziotinib do not outweigh its risks.²⁸

The preliminary efficacy observed with zongertinib in this study is encouraging, with a confirmed ORR of 35% in NSCLC (39% in patients who received ≥120 mg once daily). Responses appeared to be durable with a median DoR of 12.7 months. As this was a dose-finding study, across different tumor types, the efficacy data must be interpreted with caution. Nevertheless, the preliminary signals of antitumor activity in this study warrant further investigation. Recent studies of other HER2-targeted agents indicate that benchmark response rates of over 50% are now possible in patients with HER2-mutant NSCLC. In DESTINY-Lung01, ORR with trastuzumab deruxtecan was 55%, median DoR was 9.3 months, and median PFS was 8.2 months.¹⁵ In DESTINY-Lung02, ORR at the recommended dose was 49%, median DoR was 16.8 months, median PFS was 9.9 months, and median OS was 19.5 months.¹⁴ In phase II trials, pyrotinib has demonstrated ORRs of 19%-30% in patients with predominantly pretreated HER2-mutant NSCLC and 36% in a first-line setting.^20,21,24 Recently, the HER2/EGFR TKI, BAY 2927088, conferred an ORR of 72% in 43 patients with pretreated HER2-mutant NSCLC in the phase I/II SOHO-01 trial. The TRAE rate (any grade/grade ≥3) was 96%/43%.²⁹

Zongertinib also demonstrated activity in tumor types other than NSCLC. Of 12 patients with breast cancer included in the study, four had confirmed responses and one had an unconfirmed response. Responses were observed both in patients with HER2 overexpression and/or amplification as well as those who had HER2 mutations. At data cutoff, treatment was ongoing in three of the responding patients. Responses were noted in a range of other tumor types. Several clinical trials are planned, or are ongoing, that are assessing zongertinib across tumor types. Beamion LUNG-2 (ClinicalTrials.gov identifier: NCT06151574) is an open-label phase III randomized trial comparing first-line zongertinib versus standard of care in patients with HER2 TKD-mutant NSCLC. Beamion PANTUMOR-1 (ClinicalTrials.gov identifier: NCT06581432) is an ongoing phase II basket trial that will assess zongertinib in various HER2-mutant or HER2-amplified/HER2-overexpressing cancers. The phase Ib/II Beamion BCGC-1 trial (ClinicalTrials.gov identifier: NCT06324357) is assessing zongertinib plus trastuzumab deruxtecan or trastuzumab emtansine in patients with previously treated HER2-positive breast or gastroesophageal cancer.

We acknowledge that this study has some limitations. These are early-phase data in multiple tumor types with no comparator. The sample size was small and thus subgroup analyses were limited. The study was also constrained by the open-label design and the lack of independent central verification of tumor response. Finally, the total number of patients treated with currently available HER2 antibody-drug conjugates was rather low.

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.

DATA SHARING STATEMENT

A data sharing statement provided by the authors is available with this article at DOI https://doi.org/10.1200/JCO-24-01727. To ensure independent interpretation of clinical study results and enable authors to fulfill their role and obligations under the ICMJE criteria, Boehringer Ingelheim grants all external authors access to relevant clinical study data. In adherence with the Boehringer Ingelheim Policy on Transparency and Publication of Clinical Study Data, scientific and medical researchers can request access to clinical study data, typically 1 year after the approval has been granted by major regulatory authorities or after termination of the development program. Researchers should use the https://vivli.org/ link to request access to study data and visit https://www.mystudywindow.com/msw/datasharing for further information.

AUTHOR CONTRIBUTIONS

Conception and design: John V. Heymach, Hai-Yan Tu, Yi-Long Wu, Lukas Schröter, Yanick Botilde, Behbood Sadrolhefazi, Josep Serra, Noboru Yamamoto

Administrative support: Hai-Yan Tu

Provision of study materials or patients: Frans Opdam, Minal Barve, Hai-Yan Tu, Josep Serra, Noboru Yamamoto

Collection and assembly of data: John V. Heymach, Frans Opdam, Minal Barve, Hai-Yan Tu, Yi-Long Wu, Lukas Schröter, Yanick Botilde, Behbood Sadrolhefazi, Noboru Yamamoto

Data analysis and interpretation: John V. Heymach, Frans Opdam, Minal Barve, Hai-Yan Tu, Yi-Long Wu, David Berz, Lukas Schröter, Yanick Botilde, Behbood Sadrolhefazi, Kiyotaka Yoh, Noboru Yamamoto

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

HER2-Selective Tyrosine Kinase Inhibitor, Zongertinib (BI 1810631), in Patients With Advanced/Metastatic Solid Tumors With HER2 Alterations: A Phase Ia Dose-Escalation Study

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.

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