Beamion LUNG-2: A Study to Test Whether Zongertinib (BI 1810631) Helps People With Advanced Non-small Cell Lung Cancer With HER2 Mutations Compared With Standard Treatment

Study Overview
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Brief Summary
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This study is open to adults 18 years and older with advanced or metastatic non-small cell lung cancer. People can join the study if they have tumours with HER2 mutations and have not yet received any systemic therapy including chemotherapy for advanced or metastatic lung cancer. The purpose of this study is to find out whether a medicine called BI 1810631 (zongertinib) can slow down the worsening of advanced non-small cell lung cancer better than the standard treatment available. Zongertinib may slow cancer cell growth by inhibiting HER2. This would prolong cancer re-occurrence and increase survival. Current standard treatment is pembrolizumab plus platinum-pemetrexed chemotherapy. Participants are put into 2 groups by chance. One group receives zongertinib at regular times throughout the study and the other group receives infusions of pembrolizumab, pemetrexed and cisplatin or carboplatin (pembrolizumab plus platinum-pemetrexed chemotherapy) into a vein. Participants may be in the study up to a maximum of 70 months. During this time, they visit the study site about every 3 weeks for study procedures. The doctors regularly check the size of the tumour with a CT or MRI scan, at the beginning of the study and every 6 weeks. After 18 months they check the tumour size every 12 weeks. Doctors regularly check whether the cancer has spread to other parts of the body. The doctors also regularly check participants' health and take note of any unwanted effects. The time it takes for the cancer to worsen is compared between the 2 groups to see whether the treatment works. The participants also fill in questionnaires about their symptoms and quality of life.

Official Title
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Beamion LUNG-2: A Phase III, Open-label, Randomized, Active-controlled, Multi-centre Trial Evaluating Orally Administered BI 1810631 Compared With Standard of Care as First-line Treatment in Patients With Unresectable, Locally Advanced or Metastatic Nonsquamous Non-small Cell Lung Cancer Harbouring HER2 Tyrosine Kinase Domain Mutations

Conditions
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Lung Cancer, Non-squamous, Non-small Cell

Intervention / Treatment
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* Drug: zongertinib
* Drug: pembrolizumab
* Drug: cisplatin
* Drug: carboplatin
* Drug: pemetrexed


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Signed and dated written informed consent form (ICF) in accordance with International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use - 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. Histologically or cytologically confirmed diagnosis of an advanced and/or metastatic non-squamous Non-small cell lung cancer (NSCLC). Documented Human epidermal growth factor receptor 2 (HER2) mutation in the Tyrosine kinase domain (TKD) as per local lab results. An archival tumor tissue sample must be submitted to the central laboratory after inclusion of the patient to retrospectively confirm the HER2 status. If no archival tissue is available, this may be acceptable in exceptional cases after written agreement with the sponsor. Patients who have not received any systemic treatment for locally advanced or metastatic disease. 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. Eligible to receive treatment with the selected platinum-based doublet-chemotherapy (i.e. cisplatin/pemetrexed or carboplatin/pemetrexed) and pembrolizumab in accordance with the Summaries of Product Characteristics (SmPC)/Product Information. Further inclusion criteria apply. Exclusion criteria: Previous or concomitant malignancies other than the one treated in this trial within the last 5 years, 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 Tumors with targetable alterations with approved available therapy. Lung-specific intercurrent clinically significant severe illness based on investigators assessment. Patients who must or wish to continue the intake of restricted medications or any drug considered likely to interfere with the safe conduct of the trial. Major surgery (major according to the investigator's assessment) performed within 4 weeks prior to randomization or planned within 6 months after screening, e.g. hip replacement. Any history of or concomitant condition that, in the opinion of the investigator, would compromise the patient's ability to comply with the trial or interfere with the evaluation of the safety and efficacy of the test drug. 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, 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. Further exclusion criteria apply.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental treatment arm<br>zongertinib only | Drug: zongertinib<br>* zongertinib<br>* Other names: BI 1810631;|
| Active Comparator: Comparator arm<br>pembrolizumab plus platinum-pemetrexed chemotherapy | Drug: pembrolizumab<br>* pembrolizumab<br>* Other names: Keytruda®;Drug: cisplatin<br>* platinum-pemetrexed chemotherapy<br>Drug: carboplatin<br>* platinum-pemetrexed chemotherapy<br>Drug: pemetrexed<br>* platinum-pemetrexed chemotherapy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival (PFS) according to Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 determined by blinded central independent review | PFS is defined as the time from randomization until tumor progression according to RECIST 1.1 or death from any cause, whichever occurs earlier. | up to 4 years and 5 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Key secondary endpoint: Overall Response (OR) according to RECIST 1.1 determined by blinded central independent review | OR is defined as best overall response of complete response (CR) or partial response (PR), where best overall response is determined according to RECIST 1.1 from date of randomization until the earliest of disease progression, death, or last evaluable tumor assessment before start of subsequent anti-cancer therapy, loss to follow-up or withdrawal of consent. | up to 53 months | 
| Key secondary endpoint: Change from baseline to Week 25 of Non-small cell lung cancer Symptom Assessment Questionnaire (NSCLC-SAQ) total score | The NSCLC-SAQ is a 7-item patient-reported outcome measure for use in adults to assess symptoms of advanced NSCLC. It contains five domains and accompanying items that were identified as symptoms of NSCLC: cough (1 item), pain (2), dyspnea (1), fatigue (2), and appetite (1). The (total) lowest score possible is 0, and the highest (total) score possible is 20. Higher scores indicate more severe symptoms. | at baseline, at week 25 | 
| Key secondary endpoint: Overall Survival (OS) | OS is defined as the time from randomization until death from any cause. | up to 53 months | 
| Duration of response (DoR), determined by blinded central independent review | DoR is defined as the time from first documented complete response (CR) or partial response (PR) until the earliest of disease progression or death among patients with objective response. | up to 53 months | 
| PFS determined by blinded central independent review | PFS is defined as the time from randomization until tumor progression or death from any cause, whichever occurs earlier. | up to 53 months | 
| Bi-compartmental PFS, determined by blinded central independent review | Bi-compartmental PFS is defined as the time from randomization until tumor progression according to RECIST 1.1 or death from any cause, whichever occurs earlier. | up to 53 months | 
| OR determined by blinded central independent review | OR is defined as best overall response of CR or PR, from date of randomization until the earliest progression, death, or last evaluable tumor assessment before start of subsequent anti-cancer therapy, loss to follow-up or withdrawal of consent. | up to 53 months | 
| Change from baseline to Week 25 in the NSCLC-SAQ pain domain score | The individual NSCLC-SAQ items use a five-point verbal rating scale from No <symptom> At All to Very severe <symptom> or from Never to Always, corresponding to an (item) score of 0 to 4. A higher score indicates more severe symptoms. | at baseline, at week 25 | 
| Change from baseline to Week 25 in the NSCLC-SAQ dyspnea domain score |  | at baseline, at week 25 | 
| Change from baseline to Week 25 in the NSCLC-SAQ cough domain score |  | at baseline, at week 25 | 
| Change from baseline to Week 25 in the NSCLC-SAQ appetite domain score |  | at baseline, at week 25 | 
| Change from baseline to Week 25 in the NSCLC-SAQ fatigue domain score |  | at baseline, at week 25 | 
| Change from baseline to Week 25 in the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) physical functioning domain score | The EORTC QLQ-C30 is a quality of life questionnaire. It ranges from 0 to 100, higher scores equal worse outcome. | at baseline, at week 25 | 
| Occurrence of adverse events (AEs) during the on-treatment period, graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 |  | up to 53 months | 
| Occurrence of serious AEs (SAEs) during the on-treatment period, graded according to CTCAE version 5.0 |  | up to 53 months |