This trial will evaluate the efficacy and safety of various therapies in participants with Stage IB, IIA, IIB, IIIA, or selected IIIB resectable and untreated NSCLC tumors that meet protocol-specified biomarker criteria.
Newly diagnosed early-stage NSCLC stages IB, IIA, IIB, IIIA, or selected IIIB (T3N2 only) NSCLC of squamous or non-squamous histology. Staging should be based on the 8th edition of the American Joint Committee on Cancer (AJCC)/Union Internationale Contre le Cancer (UICC) NSCLC staging system
T4 primary NSCLC will be allowed only on the basis of size. Invasion of the diaphragm, mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, carina, and separate tumor nodules in a different ipsilateral lobe is not permitted
All participants will undergo clinical staging using computed tomography (CT) and positron emission tomography (PET) scanning, as well as brain imaging using magnetic resonance imaging (MRI). Invasive mediastinal staging by either mediastinoscopy or endo-bronchial ultrasonography is highly encouraged for participants with radiographically suspected mediastinal nodal disease (i.e., N2) but not mandated if the CT or PET scans showed no evidence of N2 disease
Molecular testing results from clinical laboratory improvement amendments (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 expression in ≥ 1% tumor cells as determined by Food and Drug Administration (FDA)-approved test, KRAS G12C mutation
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
Major surgical procedure within 28 days prior to Cycle 1, Day 1
Single group
Alectinib
DrugParticipants will receive oral alectinib twice per day (BID).
Entrectinib
DrugParticipants will receive oral entrectinib daily.
Vemurafenib
DrugParticipants will receive oral vemurafenib BID.
Cobimetinib
DrugParticipants will receive oral cobimetinib daily.
Pralsetinib
DrugParticipants will receive oral pralsetinib daily.
Atezolizumab
DrugAtezolizumab will be administered by intravenous (IV) infusion.
SBRT
DrugParticipants will receive SBRT given concurrently, starting with the first dose of atezolizumab.
Resection
Procedure/SurgeryParticipants will receive surgical resection of the primary tumor along with selected lymph nodes per SOC.
Chemotherapy
DrugParticipants will receive SOC chemotherapy as determined by the treating physician.
Divarasib
DrugParticipants in the KRAS G12C cohort will receive oral divarasib for approximately 8 weeks until the day before surgery as neoadjuvant therapy up to 3 years as adjuvant therapy.
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Treatment groupsSee each treatment group below.
Tyrosine Kinase Inhibitor (TKI) Cohort: Proportion of Participants With Major Pathologic Response (MPR)
MPR is defined as ≤ 10% residual viable tumor cells as scored by local pathologists.
Checkpoint Inhibitor (CPI) Cohort: Pathological Complete Response (pCR)
Scored by local pathologists; defined as lack of any viable tumor cells on review of hematoxylin and eosin (H\&E) slides after complete evaluation of a resected lung cancer specimen including all sampled regional lymph nodes.
KRAS G12C Cohort: Percentage of Participants With 3-5 Grade Adverse Events (AEs)
KRAS G12C Cohort: Percentage of Participants Without Delays of Surgery due to Treatment-related AEs as Reported by the Investigator
Proportion of Participants With MPR
Defined as ≤10% residual viable tumor cells) based on surgical resection as defined by Hellmann et al. (2014) and Travis et al. (2020). TKI cohorts: MPR will be scored by a central pathology committee consensus read. CPI cohort: MPR will be scored by local pathologists and central pathology committee consensus read. KRAS G12C cohort: MPR will be scored by local pathologists and central pathology committee consensus read.
Proportion of Participants With pCR
Defined as lack of any viable tumor cells on review of H\&E slides after complete evaluation of a resected lung cancer specimen, including all sampled regional lymph nodes. TKI cohorts: pCR will be scored by local pathologists and a central pathology committee consensus read. CPI cohort: pCR will be scored by a central pathology committee consensus read. KRAS G12C cohort: pCR will be scored by a central pathology committee consensus read.
Pathological Regression Based on Weighted % Viable Tumor Cell Assessment
Investigator-assessed Response Objective Response Rate (ORR) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1)
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