BNT327 (bispecific antibody against vascular endothelial growth factor A and programmed death-ligand 1) for Non-small cell lung cancer

Inclusion criteria

• {"criterion_text":"- Are able to give informed consent and have given written consent in accordance with ICH GCP and local legislation prior to the start of any trial-specific procedures."}
• {"criterion_text":"- Have adequate organ function regarding hematology, liver, renal, and coagulation."}
• {"criterion_text":"- Are a person of child-bearing potential (POCBP) who have a negative serum beta-human chorionic gonadotropin test at screening and before each IMP dose."}
• {"criterion_text":"- Are a POCBP who agree to practice a highly effective form of contraception and require their male sexual partners to use barrier contraception methods (preferably condoms) starting at the Screening Visit and continuously until 6 months after receiving the last dose of investigational medicinal product (IMP)."}
• {"criterion_text":"- Are men who are sterile or if they are potentially fertile and sexually active with a partner of childbearing potential, who agree to use condoms and to ask their sexual partners to practice a highly effective form of contraception during the trial, starting at the time of giving informed consent and continuously until 6 months after receiving the last dose of IMP."}
• {"criterion_text":"- Agree not to donate and/or cryopreserve germ cells (sperm, oocytes, ova) for the purposes of assisted reproduction during trial, starting at screening and continuously until 6 months after the last dose of IMP."}
• {"criterion_text":"- Are willing and able to comply with scheduled visits, treatment schedule, the planned trial assessments, laboratory tests, lifestyle restrictions, and other requirements of the trial. This includes that they can understand and follow trial-related instructions. Participants must provide a tumor tissue specimen and a documented PD-L1 status prior to randomization."}
• {"criterion_text":"- Male or female, aged ≥18 years at the time of giving informed consent."}
• {"criterion_text":"- Have systemic treatment naïve, histologically or cytologically confirmed diagnosis of Stage IIIB or IIIC (who are not amenable to curative surgery or radiotherapy) or Stage IV NSCLC per the UICC/AJCC staging system, 8th edition . • Participants with non-squamous NSCLC will be enrolled to Substudy A. − Participants must be tested for EGFR mutations and ALK rearrangements; those with actionable results should not be enrolled. − If locally approved targeted first-line therapies are available, participants with known actionable mutations (other than EGFR and ALK alterations) should not be enrolled. Note: Testing for other genomic mutations is not mandated if not done as part of standard local practice. • Participants with squamous NSCLC will be enrolled to Substudy B. Mixed tumors which involve squamous tumor cells will be categorized as squamous cell NSCLC; if small cell elements are present, the participant is ineligible. − If the participant is <50 years old or has never smoked or quit smoking >15 years ago then they should be tested for EGFR mutations and ALK rearrangements; those with actionable results should not be enrolled."}
• {"criterion_text":"- Have at least one measurable lesion as the targeted lesion based on RECIST v1.1."}
• {"criterion_text":"- Have ECOG performance status of 0 or 1."}

Exclusion criteria

• {"criterion_text":"- Are pregnant or breastfeeding or are planning pregnancy or to father children during the trial or within 6 months after the last dose of IMP."}
• {"criterion_text":"- Have active autoimmune disease or history of autoimmune diseases with anticipated relapse (such as systemic lupus erythematosus, rheumatoid arthritis, vasculitis, etc.) are not allowed, except for those with clinically stable autoimmune diseases such as autoimmune thyroid disease or Type 1 diabetes, or skin disorders including psoriasis, vitiligo, or alopecia."}
• {"criterion_text":"- Have had other malignant tumours within 3 years prior to the trial treatment are not allowed. Except for those who have been cured with local treatment"}
• {"criterion_text":"- Have a serious or non-healing wound or (incompletely healed) bone fracture."}
• {"criterion_text":"- Participants with significant risk of hemorrhage, (per investigator clinical judgment) indicated by any of the following criteria: -Tumors with clear radiographic evidence of major blood vessel invasion -Tumor lesions with clear invasion of major airways (such as tracheal invasion) or vital organs (such as the heart, pericardium, and esophagus). -At least one major cavitation posing hemorrhage risk. -Clinically significant hemoptysis -Intracranial or intraspinal hemorrhage within 3 months before randomization. -Gastrointestinal bleeding within 3 months before the first dose of trial treatment. -Vascular diseases (such as aortic aneurysm) with a risk of rupture within 3 months prior to randomization. -Therapeutic anticoagulation or antiplatelet therapy within 10 days before randomization. However, prophylactic use of anticoagulants is allowed."}
• {"criterion_text":"- Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently)."}
• {"criterion_text":"- Participants with a history of serious Grade 3 or higher immune-related adverse events (irAEs) that led to treatment discontinuation of a prior immunotherapy."}
• {"criterion_text":"- Have a known or suspected hypersensitivity to the trial treatments including any active ingredient or excipients thereof."}
• {"criterion_text":"- Have known human immunodeficiency virus infection or known acquired immunodeficiency syndrome, with the following exceptions: • Participants with CD4+ T-cell counts ≥350 cells/mL per local laboratory should generally be eligible for the trial. • Participants who have not had an opportunistic infection within the past 12 months."}
• {"criterion_text":"- Participants with past hepatitis B virus infection or resolved hepatitis B virus infection."}
• {"criterion_text":"- Have an active hepatitis C virus infection; individuals who have completed curative antiviral treatment with hepatitis C virus viral load below the limit of quantification are allowed."}
• {"criterion_text":"- Have any of the following heart conditions within 6 months prior to the trial treatment: • Acute coronary syndrome, coronary artery bypass grafting, congestive heart failure, aortic dissection, stroke, arterial thrombosis, or other Grade 3 and above cardiovascular and cerebrovascular events. • New York Heart Association functional classification ≥II heart failure or left ventricular ejection fraction less than 50%. • Those who have ventricular arrhythmias requiring clinical intervention, second- to third-degree atrioventricular block, or congenital long QT syndrome. • Mean QT interval corrected by QTcF more than 480 ms."}
• {"criterion_text":"- Participants with an adverse event (AE) from prior antitumor therapy whose AE(s) have not returned to Grade 1 or below are not eligible for the trial."}
• {"criterion_text":"- Have superior vena cava syndrome or symptoms of spinal cord compression."}
• {"criterion_text":"- Those with active, or a history of, pneumonitis requiring treatment with steroids, or has active, or a history of, interstitial lung disease. Those with a history of pulmonary fibrosis, or currently diagnosed with severe lung diseases such as interstitial pneumonia, pneumoconiosis, chemical pneumonitis, or any other condition resulting in significant impairment in lung function."}
• {"criterion_text":"- Those with active tuberculosis or have active syphilis infection."}
• {"criterion_text":"- Have an underlying condition that may increase risk of the combination treatment or complicate the interpretation of AEs, as judged by the investigator, or other scenarios that the investigators consider the participant is not eligible for the trial."}
• {"criterion_text":"- Have any of the following hypertension or diabetic conditions prior to trial treatment: • Uncontrolled hypertension (systolic blood pressure (BP) ≥160 mmHg and/or diastolic BP ≥100 mmHg) while on antihypertensive medicine within 7 days prior to the first dose of trial treatment. • Those with a history of hypertensive crisis or hypertensive encephalopathy. • Poorly controlled diabetes (fasting blood glucose ≥13.3 mmol/L [240 mg/dL] or HbA1C ≥8.5% [69 mmol/mol]) within 7 days prior to the first dose of trial treatment."}
• {"criterion_text":"- Having a medical, psychological, or social condition which, in the opinion of the investigator, could compromise their wellbeing if they participate in the trial, or that could prevent, limit, or confound the protocol-specified assessments or procedures, or that could impact adherence to protocol-described requirements."}
• {"criterion_text":"- Have histologically or cytologically confirmed NSCLC with small cell lung cancer or neuroendocrine histologic component."}
• {"criterion_text":"- Have received any of the following therapies or drugs within the noted time intervals prior to trial treatment: • Previous chemotherapy (platinum-based) or PD(L)-1 for treating NSCLC in either neoadjuvant/adjuvant or locally advanced/metastatic setting. • Receipt of an investigational drug or device within 30 days of screening or within five half-lives of the investigational drug (whichever is shorter). • Participants who received prior treatment with anti-VEGF monoclonal antibody, or PD(L)-1/VEGF bispecific antibody or received platinum-based chemotherapy and/or anti-PD(L)-1 as part of adjuvant or neoadjuvant treatment • Have received systemic corticosteroids within 7 days prior to the initiation of trial treatment. • Have been vaccinated with live attenuated vaccine(s) within 4 weeks prior to initiation of the trial treatment. • Received broad-spectrum intravenous antibiotics therapy within 2 weeks prior to initiation of trial treatment."}
• {"criterion_text":"- Have undergone major organ surgery, significant trauma, or invasive dental procedures within 21 days prior to the trial treatment or plan to undergo elective surgery during the trial."}
• {"criterion_text":"- Have received allogeneic hematopoietic stem cell transplantation or organ transplantation."}
• {"criterion_text":"- Have the following central nervous system metastases: • Participants with untreated brain metastases that are symptomatic. • Participants with treated central nervous system metastases who are not neurologically stable or on steroids (prednisone equivalent more than 10 mg/day) within 7 days before initiating trial treatment. • Participants with known metastases in spinal cord, or leptomeningeal carcinomatosis."}

Primary endpoints

• {"endpoint_text":"- For the Phase II parts of sub-studies A and B: Occurrence of treatment-emergent adverse events (TEAE) (including Grade ≥3), adverse events of special interest (AESIs), treatment-related TEAEs, treatment emergent serious adverse events (SAE), and treatment-related treatment-emergent SAEs in the combination treatment regimen from the first dose of investigational medicinal product (IMP) to the 90-day Follow-Up Visit.","definition_or_measurement_approach":"Safety and tolerability endpoints measured as occurrence and grading (including Grade ≥3) of TEAEs, AESIs, treatment-related TEAEs, treatment-emergent SAEs, and treatment-related SAEs from first IMP dose to 90-day follow-up."}
• {"endpoint_text":"- For the Phase II parts of sub-studies A and B: Occurrence of dose interruptions, reductions, and discontinuations of IMP due to TEAEs (including related TEAEs) from the first dose of IMP to the 90-day Follow-Up Visit.","definition_or_measurement_approach":"Measured as counts/incidence of dose interruptions, dose reductions, and discontinuations of IMP attributed to TEAEs from first dose to 90-day follow-up."}
• {"endpoint_text":"- For the Phase II parts of sub-studies A and B: Objective response rate (ORR) defined as the proportion of participants in whom a confirmed complete response (CR) or confirmed partial response (PR) (per RECIST v1.1 based on the investigator’s assessment) is observed as best overall response.","definition_or_measurement_approach":"ORR defined as proportion of participants with confirmed CR or PR per RECIST v1.1 assessed by investigator as best overall response."}
• {"endpoint_text":"- For the Phase II parts of sub-studies A and B: Best percentage change from baseline in tumor size (based on investigator’s tumor assessment according to RECIST 1.1).","definition_or_measurement_approach":"Measured as best (maximum) percent change from baseline in sum of target lesion diameters per RECIST v1.1 assessed by investigator."}
• {"endpoint_text":"- For the Phase III parts of sub-studies A and B: Progression-free survival (PFS) defined as the time from randomization to first documented tumour progression (progressive disease assessed by blinded independent central review (BICR) per RECIST v1.1), or death from any cause, whichever occurs first.","definition_or_measurement_approach":"PFS measured as time (days) from randomization to first documented tumor progression by BICR per RECIST v1.1 or death from any cause."}

Secondary endpoints

• {"endpoint_text":"- For the Phase II parts of sub-studies A and B: Duration of response (DOR) defined as the time from first objective response (CR or PR per RECIST v1.1) to first occurrence of objective tumour progression (progressive disease per RECIST v1.1) or death from any cause, whichever occurs first.","definition_or_measurement_approach":"DOR measured as time from first confirmed CR/PR to objective tumor progression per RECIST v1.1 or death."}
• {"endpoint_text":"- For the Phase II parts of sub-studies A and B: Disease control rate (DCR) defined as the proportion of participants in whom a confirmed CR or confirmed PR or stable disease (per RECIST v1.1, stable disease assessed at least 6 weeks after randomization) is observed as best overall response.","definition_or_measurement_approach":"DCR measured as proportion with confirmed CR or PR or stable disease (stable disease assessed ≥6 weeks post-randomization) per RECIST v1.1."}
• {"endpoint_text":"- For the Phase III parts of sub-studies A and B: Progression-free survival (PFS) defined as the time from randomization to first documented tumour progression (progressive disease assessed by investigator per RECIST v1.1), or death from any cause, whichever occurs first.","definition_or_measurement_approach":"Investigator-assessed PFS per RECIST v1.1 measured as time from randomization to progression or death."}
• {"endpoint_text":"- For the Phase III parts of sub-studies A and B: Objective response rate (ORR) defined as the proportion of participants in whom a confirmed CR or confirmed PR (per RECIST v1.1) is observed as best overall response.","definition_or_measurement_approach":"ORR per RECIST v1.1 as proportion with confirmed CR or PR."}
• {"endpoint_text":"- For the Phase III parts of sub-studies A and B: Progression-free survival (PFS) rate as assessed by blinded independent central review (BICR) at 6, 12, and 18 months.","definition_or_measurement_approach":"PFS rates at fixed timepoints (6,12,18 months) assessed by BICR per RECIST v1.1."}
• {"endpoint_text":"- For the Phase III parts of sub-studies A and B: PFS rate as assessed by investigator at 6, 12, and 18 months.","definition_or_measurement_approach":"Investigator-assessed PFS rates at 6, 12, 18 months."}
• {"endpoint_text":"- For the Phase III parts of sub-studies A and B: Overall survival (OS) rate at 6, 12, 18, and 24 months.","definition_or_measurement_approach":"OS rate at given timepoints measured as proportion alive at 6,12,18,24 months."}
• {"endpoint_text":"- For the Phase III parts of sub-studies A and B: Change from baseline in EORTC QLQ-C30 Global Health status/Quality-of-Life score (Items 29 and 30).","definition_or_measurement_approach":"Change from baseline in EORTC QLQ-C30 global health/QoL items (29,30)."}
• {"endpoint_text":"- For the Phase III parts of sub-studies A and B: Change from baseline in EORTC QLQ-C30 physical functioning.","definition_or_measurement_approach":"Change from baseline in EORTC QLQ-C30 physical functioning domain score."}
• {"endpoint_text":"- For the Phase III parts of sub-studies A and B: Change from baseline in the “coughing” scale of the EORTC QLQ-LC29.","definition_or_measurement_approach":"Change from baseline in EORTC QLQ-LC29 coughing scale."}
• {"endpoint_text":"- For the Phase III parts of sub-studies A and B: Change from baseline in the “shortness of breath” scale of the EORTC QLQ-LC29.","definition_or_measurement_approach":"Change from baseline in EORTC QLQ-LC29 shortness of breath scale."}
• {"endpoint_text":"- For the Phase III parts of sub-studies A and B: Change from baseline in the “coughed-up blood” item of the EORTC QLQ-LC29.","definition_or_measurement_approach":"Change from baseline in EORTC QLQ-LC29 haemoptysis/coughed-up blood item."}
• {"endpoint_text":"- For the Phase III parts of sub-studies A and B: Change from baseline in the “fatigue domain” score scale of the NSCLC-SAQ.","definition_or_measurement_approach":"Change from baseline in NSCLC-SAQ fatigue domain score."}
• {"endpoint_text":"- For the Phase III parts of sub-studies A and B: Change from baseline in the “pain domain” score of the NSCLC-SAQ.","definition_or_measurement_approach":"Change from baseline in NSCLC-SAQ pain domain score."}
• {"endpoint_text":"- For the Phase III parts of sub-studies A and B: Change from baseline in FACT-G overall bother item (FACT-GP5).","definition_or_measurement_approach":"Change from baseline in FACT-G overall bother item (FACT-GP5)."}
• {"endpoint_text":"- For the Phase III parts of sub-studies A and B: Occurrence of treatment-emergent adverse events (TEAEs) including Grade ≥3, serious, and fatal TEAEs by relationship, according to CTCAE v5.0.","definition_or_measurement_approach":"Safety events graded using CTCAE v5.0, categorized by relationship to treatment."}
• {"endpoint_text":"- For the Phase III parts of sub-studies A and B: Occurrence of dose interruptions, reductions, and discontinuations of IMP due to TEAEs (including related TEAEs) from the first dose of IMP to the 90-day Follow-Up Visit.","definition_or_measurement_approach":"Counts/incidence of dose interruptions/reductions/discontinuations due to TEAEs from first dose to 90-day follow-up."}
• {"endpoint_text":"- For the Phase III parts of sub-studies A and B: Overall survival (OS) defined as the time from randomization to death from any cause.","definition_or_measurement_approach":"OS measured as time from randomization to death from any cause."}

Methods

• Patient-facing recruitment materials: Flyers (K2_Flyer) — country-specific flyers available (e.g. EN, FR, NL, RO, BG) as listed in recruitment documents.
• Posters (K2_Poster) — country-specific posters available as listed in recruitment documents.
• Patient letters / recruitment brochures (K2 Recruitment Material_Patient Letter / Brochure) — used to inform potential participants.
• Recruitment procedure documents / instructions (K1_Recruit-ICF Process, K1_Patient recruit procedure) describing local recruitment workflow and site-level procedures.
• Patient-facing reminders and cards (Thank-you / Reminder cards, Emergency cards) and BP monitoring diaries provided as part of subject information materials.

Poland

Earliest CTIS Part Ii Submission Date

21-03-2025

Latest Decision Or Authorization Date

17-03-2026

Processing Time Days

361

Number Of Sites

18

Number Of Participants

220

Italy

Earliest CTIS Part Ii Submission Date

28-03-2025

Latest Decision Or Authorization Date

14-04-2026

Processing Time Days

382

Number Of Sites

36

Number Of Participants

61

Belgium

Earliest CTIS Part Ii Submission Date

28-03-2025

Latest Decision Or Authorization Date

08-04-2026

Processing Time Days

376

Number Of Sites

7

Number Of Participants

21

Spain

Earliest CTIS Part Ii Submission Date

06-03-2025

Latest Decision Or Authorization Date

27-02-2026

Processing Time Days

358

Number Of Sites

27

Number Of Participants

114

France

Earliest CTIS Part Ii Submission Date

17-03-2025

Latest Decision Or Authorization Date

11-03-2026

Processing Time Days

359

Number Of Sites

22

Number Of Participants

50

Germany

Earliest CTIS Part Ii Submission Date

17-03-2025

Latest Decision Or Authorization Date

04-03-2026

Processing Time Days

352

Number Of Sites

24

Number Of Participants

150

Romania

Earliest CTIS Part Ii Submission Date

28-03-2025

Latest Decision Or Authorization Date

04-05-2026

Processing Time Days

402

Number Of Sites

15

Number Of Participants

40

Bulgaria

Earliest CTIS Part Ii Submission Date

04-05-2026

Latest Decision Or Authorization Date

11-05-2026

Processing Time Days

7

Number Of Sites

5

Number Of Participants

35

Hungary

Earliest CTIS Part Ii Submission Date

27-03-2026

Latest Decision Or Authorization Date

04-05-2026

Processing Time Days

38

Number Of Sites

7

Number Of Participants

35

Primary sponsor

Full Name

BioNTech SE

Organisation Type

Pharmaceutical company

Country Of Registered Address

Germany

Contract research organisations

Name

Icon Clinical Research Limited

Responsibilities

Clinical operations and study management functions (listed sponsor duties include codes for typical CRO activities).

Name

Almac Clinical Services Limited

Responsibilities

Packaging, labelling, QP-release, importer/manufacturer tasks for IMPs.

Name

Labcorp Central Laboratory Services LP

Responsibilities

Central laboratory services.

Name

4g Clinical LLC

Responsibilities

Clinical support and services.

Third parties

• {"country":"United States","full_name":"Bioagilytix Labs LLC","duties_or_roles":"Biomarkers","organisation_type":"Pharmaceutical company"}
• {"country":"Germany","full_name":"Azenta Germany GmbH","duties_or_roles":"Long-term sample storage","organisation_type":"Pharmaceutical company"}
• {"country":"United Kingdom (Northern Ireland)","full_name":"Almac Clinical Services Limited","duties_or_roles":"Importer and manufacturer, performs packaging, labelling, and QP-release of finished IMP (BNT327, carboplatin, paclitaxel, pemetrexed, and pembrolizumab).","organisation_type":"Pharmaceutical company"}
• {"country":"Germany","full_name":"Foundation Medicine GmbH","duties_or_roles":"Specialised biomarker assays, ct DNA detection","organisation_type":"Pharmaceutical company"}
• {"country":"Ireland","full_name":"Icon Clinical Research Limited","duties_or_roles":"Clinical operations and study management functions (CRO services)","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Labcorp Central Laboratory Services LP","duties_or_roles":"Laboratory services","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"4g Clinical LLC","duties_or_roles":"Clinical data and related services","organisation_type":"Non-Pharmaceutical company"}