A Study of Alectinib, Entrectinib, or Vemurafenib Plus Cobimetinib in Participants With Stages I-III Non-Small Cell Lung Cancer With ALK, ROS1, NTRK, or BRAF v600E Molecular Alterations

Inclusion Criteria for Neoadjuvant Therapy:

• Pathologically documented NSCLC: Stage IB, IIA, IIB, IIIA, or selected IIIB, including T3N2, or T4 (by size criteria, not by mediastinal invasion) NSCLC (based on the 8th edition of the American Joint Committee on Cancer [AJCC] Non-Small Cell Lung Cancer Staging system
• Adequate hematologic and end-organ function
• Negative hepatitis B surface antigen (HBsAg) test at screening
• Negative total hepatitits B core antibody (HBcAb) test at screening for cohort, or positive total HBcAb test followed by a negative hepatitis B virus (HBV) DNA test at screening
• Negative hepatitis C virus (HCV) antibody test at screening, or positive HCV antibody test followed by a negative HCV RNA test at screening
• T4 primary NSCLC will be allowed only on the basis of size
• All patients will undergo clinical staging using CT and PET scanning, as well as brain imaging using MRI. Invasive mediastinal staging by either mediastinoscopy or endo- bronchial ultrasonography is highly encouraged for patients with radiographically suspected mediastinal nodal disease (ie, N2) but not mandated if the CT or PET scans showed no evidence of N2 disease.
• Molecular testing results from CLIA-certified laboratories and showing at least one of the following abnormalities: ALK fusion, ROS1 fusion, NTRK1/2/3 fusion; BRAF V600 mutation; RET fusion, PD-L1, KRAS G12C expression in ≥ 1% tumor cells as determined by FDA-approved test
• Measurable disease, as defined by RECIST v1.1
• Evaluated by the attending surgeon prior to study enrollment to verify that the primary tumor and any involved lymph nodes are technically completely resectable and verify that the participant is medically operable
• Adequate pulmonary function to be eligible for surgical resection with curative intent
• Adequate cardiac function to be eligible for surgical resection with curative intent
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
• Male participants must be willing to use acceptable methods of contraception
• Female participants of childbearing potential must agree to use acceptable methods of contraception

Inclusion Criteria for Adjuvant Therapy

• Participants whose tumors lack radiographic progression
• ECOG Performance Status of 0 or 1
• Adequate hematologic and end-organ function

• NSCLC that is clinically T4 by virtue of mediastinal organ invasion or Stage IIIB by virtue of N3 disease
• Any prior therapy for lung cancer, including chemotherapy, targeted therapy, immunotherapy, or radiotherapy, within 2 years
• Participants with prior lung cancer that have been in remission for <2 years with the exception of minimally invasive adenocarcinoma or incidental typical carcinoid tumors
• Major surgical procedure within 28 days prior to Cycle 1, Day 1
• Malignancies other than the disease under study within 3 years prior to Cycle 1, Day 1, with the exception of patients with a negligible risk of metastasis or death and with expected curative outcome
• Treatment with an investigational agent for any condition within 4 weeks prior to Cycle 1, Day 1
• Participants known to be positive for HIV are excluded if they meet any of the following criteria: CD4+ T-cell count of <350 cells/microliters; detectable HIV viral load; history of an opportunistic infection within the past 12 months; on stable antiretroviral therapy for <4 weeks
• Severe infection within 4 weeks prior to initiation of study treatment, including but not limited to hospitalization for complications of infections, or any active infection that, in the opinion of the investigator, could impact participant safety
• Pregnant or lactating, or intending to become pregnant during the study