Non-Small Cell Lung Cancer (NSCLC) Clinical Trials

∙ Patients are eligible to be included in the study only if all of the following criteria apply:

• Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the Informed Consent Form (ICF) and in this protocol.

• Provision of signed and dated written ICF prior to any mandatory study specific procedures, sampling, and analyses - including collection of samples for genetic analysis, if applicable.

• Patients must be ≥18 years at the time of screening.

• Newly diagnosed and previously untreated patients with histologically or cytologically documented NSCLC. Patients should have resectable disease (Stage IIA to Stage IIIA; Stage IIIB - Nodal stage N2 after the first 40 patients \[cohort 2\]), according to Version 8 of IASLC Staging Manual in Thoracic Oncology (2016), and be candidates for lobectomy, sleeve resection, or bilobectomy at the time of screening. For patients with N2 disease, only those with 1 single nodal station ≤3 cm are eligible (only valid for Cohort 1).

• At screening, complete surgical resection of the primary NSCLC must be deemed achievable, as assessed by a multidisciplinary evaluation, which must include a thoracic surgeon who performs lung cancer surgery as a prominent part of his/her practice.

⁃ T4 tumors will only be eligible if they are defined as T4 based only on their size (more than 7 cm); any other reason for T4 (e.g., adherent to any of the following structures: diaphragm, mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, carina) will be considered ineligible.

⁃ Nodal status should be investigated with whole-body fluorodeoxyglucose-positron emission tomography (FDG-PET), plus contrast-enhanced CT. If PET/CT scan is positive in the mediastinum, or if the scan is negative but there is T \>3 cm, central tumor, or cN1, then it is recommended that nodal status be proven by biopsy via endobronchial ultrasound, mediastinoscopy, or thoracoscopy.

• WHO Performance Status (WHO PS) score or Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0 or 1 at enrollment.

• Adequate organ and marrow function as defined below:

‣ Hemoglobin ≥9.0 g/dL.

⁃ Absolute neutrophil count (ANC) ≥1.5 × 109/L.

⁃ Platelet count ≥100 × 109/L.

⁃ Serum bilirubin ≤1.5 × Upper limit of normal (ULN). This will not apply to patients with confirmed Gilbert's syndrome, who will be allowed upon consultation with their physician.

⁃ Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 × ULN.

⁃ Measured creatinine clearance (CrCL) \>40 mL/min or calculated CrCL \>40 mL/min as determined by Cockcroft-Gault formula using actual body weight (Cockroft-Gault, 1976) (https://www.kidney.org/professionals/KDOQI/gfr\_calculatorCoc).

• Must have a life expectancy of at least 12 weeks.

• Body weight \>35 kg.

• Male or female. Women of childbearing potential should use an acceptable method of contraception from the time of screening throughout the total duration of the study, and (for drugs that are potentially genotoxic) the drug washout period (180 days after the last dose of study drugs) to prevent pregnancy.

• A non-sterilized male partner of a woman of childbearing potential must use a male condom plus spermicide (or condom alone in countries where spermicides are not approved) throughout this period. Male patients who intend to be sexually active with a female partner of childbearing potential must be surgically sterile or using an acceptable method of contraception (from the time of screening throughout the total duration of the study and (for drugs that are potentially genotoxic) the drug washout period (180 days after the last dose of study drugs) to prevent pregnancy in a partner. Male patients must not donate or bank sperm during this same time period. For more details on contraceptive guidance of the study for both women of childbearing potential and non sterilized male patients.

⁃ Negative pregnancy test (serum or urine) for women of childbearing potential.

⁃ Provision of tumor samples (newly acquired \[preferred\] or archival tumor tissue \[≤6 months old\]) to confirm PD-L1 status, epidermal growth factor receptor (EGFR), or anaplastic lymphoma kinase (ALK) status, where required during screening and prior to nC1D1.

⁃ (a) PD-L1 status: (i) If the patient's PD-L1 status has already been assessed using the analytically validated Ventana PD-L1 (SP263) immunohistochemistry (IHC) assay, 22C3 PharmDx assay, or 28-8 PharmDx assay, this test result can be used. (ii) Local laboratory results can be used if performed using the analytically validated Ventana PD-L1 (SP263) IHC assay, 22C3 PharmDx assay, or 28-8 PharmDx assay (iii) If appropriate local testing and/or previous results are not available, PD-L1 testing using the Ventana PD-L1 (SP263) IHC assay will be performed centrally using either newly acquired tumor tissue (preferred) or archival tissue (≤6 months old). Note: For Cohort 2 (PD-L1-positive cohort), only patients with PD-L1 expression tumor proportion score (TPS) ≥1% will be enrolled. (b) ALK and EGFR status: (i) Local laboratory results for ALK and EGFR will be obtained using a well validated, local-regulatory-approved assay. Neither patients with EGFR/ALK mutations nor those with unknown EGFR/ALK status will be enrolled, with the following exceptions:

‣ Patients with documented Kirsten rat sarcoma virus (KRAS) mutations do not require EGFR/ALK status.

‣ Patients with squamous cell carcinoma do not require ALK status.

⁃ Provision of tumor samples appropriate for exploratory biomarker analyses

⁃ Patients are suitable for inclusion if the planned surgery is lobectomy, sleeve resection, or bilobectomy, as determined by the attending surgeon based on the baseline findings. Patients whose planned surgery at enrollment includes pneumonectomy, segmentectomies, or wedge resections are not eligible for this study.

⁃ A pre- or post-bronchodilator forced expiratory volume (FEV1) of 1.0 L and diffusing capacity of lung for carbon monoxide (DLCO) \>40% postoperative predicted value. Use of these cut-off values to assess candidacy for resection should be guided by the results of cardiopulmonary exercise testing as outlined in the European Society for Medical Oncology (ESMO) guidelines on pre-treatment risk assessment. Both an FEV1 and a DLCO test are required for assessing lung function at screening.