BNT327-06

1) Have given informed consent by signing and dating the ICF before initiation of

any trial-specific procedures.

2) 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 are able to understand and follow trial-related instructions.

3) Male or female, aged ≥18 years at the time of giving informed consent.

4) Have 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 Union Internationale contre le Cancer/American Joint Committee on Cancer staging system, 8th edition without actionable EGFR mutation or anaplastic lymphoma kinase rearrangement.

Note: Patients with non-squamous NSCLC will be enrolled to Substudy A and patients 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.

5) Have at least one measurable lesion as the targeted lesion based on RECIST v1.1. Lesions treated after prior local treatment (radiotherapy, ablation, interventional procedures, etc.) are generally not considered as target lesions. If the lesion with prior local treatment is the only targeted lesion, evidence-based radiology must be provided to demonstrate disease progression (the single bone metastasis or the single central nervous system metastasis should not be considered as a measurable lesion).

6) ECOG performance status of 0 or 1.

7) Have a minimum life expectancy of >3 months.

8) Adequate organ function, as defined below:

• Hematology:

− Absolute neutrophil count ≥1.5 × 10^9/L.

Note: Granulocyte colony-stimulating factor usage is not allowed before Cycle 1 Day 1 treatment.

− Platelet count ≥100 × 10^9/L.

− Hemoglobin ≥90 g/L or 5.6 mmol/L.

Note: Packed red blood cell transfusion is allowed 4 weeks prior to Cycle 1 Day 1 and criterion must be met without erythropoietin treatment.

• Liver function:

− Bilirubin

o Total bilirubin ≤1.5 × ULN.

o With Gilbert’s syndrome total bilirubin <3 mg/dL and direct bilirubin ≤ULN. Note, Gilbert’s syndrome must be documented appropriately as past medical history.

− ALT and AST

o Participants without liver metastasis: ≤2 × ULN.

o Participants with liver metastasis: ≤5 × ULN.

− Albumin ≥3.0 g/dL.

• Renal function:

− Creatinine clearance ≥50 mL/min. Cockcroft Gault formula, creatinine clearance from 24-hour urine collection or scintigraphic glomerular filtration rate calculations can be used.

• Qualitative urine protein ≤1+. If qualitative urine protein ≥2+, a 24-h urine protein quantitative test is required. If the 24-h urine protein result is <1 g, participant can be enrolled.

• Coagulation function: International normalized ratio or prothrombin time and activated partial thromboplastin time ≤1.5 × ULN unless the participant is receiving anticoagulation therapy as long as prothrombin or activated partial thromboplastin is within therapeutic range of intended

use of anticoagulant.

9) Are WOCBP who have a negative serum beta-human chorionic gonadotropin test at screening and before each IMP dose. Women born female that are postmenopausal (defined as 12 months with no menses without an alternative medical cause) or permanently sterilized (verified by medical records) will not be considered WOCBP and therefore will not be required to undergo pregnancy testing.

10) Are WOCBP 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 IMP.

For guidance on highly effective forms of contraception, see Section 10.5.2.

11) Are men who are sterile or if they are potentially fertile (i.e., are not surgically [e.g., have had a vasectomy] or congenitally sterile) 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. For guidance on highly effective forms of contraception, see Section 10.5.2.

12) 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. 

1) 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.

2) Have 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.

3) Have histologically or cytologically confirmed NSCLC with small-cell lung cancer histologic component.

4) Have received any of the following therapies or drugs within the noted time

intervals prior to trial treatment:

• 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 platinumbased chemotherapy and/or anti-PD(L)-1 as part of adjuvant or neoadjuvant treatment

• Have received systemic corticosteroids (at a dosage greater than 10 mg/day of prednisone or an equivalent dose of other corticosteroids) within 14 days prior to the initiation of trial treatment. Note: local, intranasal, intraocular, intra-articular or inhaled corticosteroids, short-term use (≤7 days) of corticosteroids for prophylaxis (e.g., prevention of contrast agent allergy) or treatment of non-autoimmune conditions (e.g., delayed hypersensitivity reactions caused by exposure to allergens) are allowed.

• 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.

5) Have undergone major organ surgery (core needle biopsies are allowed >7 days prior trial start), significant trauma, or invasive dental procedures (such as dental implants) within 28 days prior to the trial treatment or plan to undergo elective surgery during the trial. Placement of vascular infusion devices are allowed.

6) Have received allogeneic hematopoietic stem cell transplantation or organ transplantation.

7) 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 10 days before initiating trial treatment.

• Participants with known metastases in spinal cord, or leptomeningeal carcinomatosis.

8) 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 thyroid disease or type 1 diabetes.

9) Have had other malignant tumors within 2 years prior to the trial treatment are not allowed. Except for those who have been cured with local treatment (such as basal cell or squamous cell carcinoma of the skin, superficial or non-invasive bladder cancer, carcinoma in situ of the cervix, ductal carcinoma in situ of the breast, papillary carcinoma of thyroid, and early-stage prostate

cancer).

10) 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, or other Grade 3 and above cardiovascular and cerebrovascular events.

• New York Heart Association functional classification ≥II heart failure or left ventricular ejection fraction <50%.

• Those who have ventricular arrhythmias requiring clinical intervention, second- to third-degree atrioventricular block, or congenital long QT syndrome. Participants with treated cardiac arrythmia/atrial fibrillation are allowed.

• Mean QT interval corrected by QTcF >480 ms.

• Use of cardiac pacemaker.

• Cardiac troponin I or N >2 x ULN.

11) Have any of the following hypertension or diabetic conditions prior to trial treatment:

• Uncontrolled hypertension (systolic BP ≥150 mmHg and/or diastolic BP ≥90 mmHg) while on antihypertensive medicine.

• 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]).

12) Have a serious non-healing wound, ulcer, or bone fracture. This includes history (within 6 months prior to trial entry) or risk of abdominal fistula, tracheoesophageal fistula, gastrointestinal perforation, or intra-abdominal abscess. In addition, the participant must have undergone correction (or spontaneous healing) of the perforation/fistula and/or the underlying process causing fistula/perforation.

13) Participants with evidence of major coagulation disorders or other significant risks of hemorrhage such as:

• History of intracranial or intraspinal hemorrhage.

• Tumor lesions invading large vessels or the pericardium, and with significant risk of bleeding.

• Had clinically significant hemoptysis or tumor hemorrhage within 1 month prior to the trial treatment.

14) Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently). However, participants who are clinically stable following treatment for these conditions

(including therapeutic thoracentesis or paracentesis or with indwelling catheters, e.g., PleurX) are allowed.

15) Participants with a history of serious Grade 3 or higher irAEs that led to treatment discontinuation of a prior immunotherapy. Participants with a history of Grade 3 or higher irAEs that did not lead to treatment discontinuation of a prior immunotherapy should be discussed with the sponsor.

16) Have a known or suspected hypersensitivity to the trial treatments including any active ingredient or excipients thereof.

17) 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.

18) Participants with past hepatitis B virus infection or resolved hepatitis B virus infection (defined as the presence of hepatitis B core antibody and absence of hepatitis B virus antigen are eligible only if they are negative for hepatitis B virus DNA).

19) 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.

20) Participants with AEs from prior antitumor therapy whose AE(s) have not returned to Grade 1 (graded by CTCAE 5.0 criteria) or below (unless the investigator determines that certain AEs pose no safety risk to participants, such as hair loss, Grade 2 peripheral neuropathy or stable hypothyroidism under hormone replacement therapy) are not eligible for the trial.

21) Have superior vena cava syndrome or symptoms of spinal cord compression.

22) 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.

Exception: asymptomatic interstitial changes caused by previous radiation

therapy, chemotherapy, or other factors such as smoking are acceptable.

23) Those with active tuberculosis.

24) Have underlying condition 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. 

Research Nurse: Lizzie Coates (x2031) Elizabeth.Coates@LTHTR.nhs.uk