Non-small Cell Lung Cancer
Conditions
Brief summary
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.
Interventions
DRUGAlectinib
Participants will receive oral alectinib twice per day (BID).
DRUGEntrectinib
Participants will receive oral entrectinib daily.
DRUGVemurafenib
Participants will receive oral vemurafenib BID.
DRUGCobimetinib
Participants will receive oral cobimetinib daily.
DRUGPralsetinib
Participants will receive oral pralsetinib daily.
DRUGAtezolizumab
Atezolizumab will be administered by intravenous (IV) infusion.
DRUGSBRT
Participants will receive SBRT given concurrently, starting with the first dose of atezolizumab.
PROCEDUREResection
Participants will receive surgical resection of the primary tumor along with selected lymph nodes per SOC.
DRUGChemotherapy
Participants will receive SOC chemotherapy as determined by the treating physician.
DRUGDivarasib
Participants 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.
Sponsors
Genentech, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
for Neoadjuvant Therapy: * Pathologically documented NSCLC: * 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 mediastinoscopyor endo- bronchial ultrasonography is highly encouraged for participants 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 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 FDA-approved test, KRAS G12C mutation * Measurable disease, as defined by RECIST v1.1 * NSCLC must have a solid or subsolid appearance on CT scan and cannot have a purely ground glass opacity appearance. For subsolid lesions, the tumor size (i.e., clinical T stage) should be measured based on the solid component only, exclusive of the ground glass opacity component * 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 * Adequate hematologic and end-organ function * Negative hepatitis B surface antigen (HBsAg) test at screening for cohort * 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) deoxyribonucleic acid (DNA) test at screening * Negative hepatitis C virus (HCV) antibody test at screening, or positive HCV antibody test followed by a negative HCV ribonucleic acid (RNA) test at screening * 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 (TKI Cohorts and KRAS G12C cohort \[if continuing on Divarasib\]): * Participants whose tumors lack radiographic progression * ECOG Performance Status of 0 or 1 * Adequate hematologic and end-organ function
Exclusion criteria
* 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 * Malignancies other than the disease under study within 3 years prior to Cycle 1, Day 1, with the exception of participants 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 human immunodeficiency virus (HIV) are excluded if they meet any of the following criteria: cluster of differentiation 4 (CD4)+ T-cell count of \<350 cells/microliters (cells/µL); 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Tyrosine Kinase Inhibitor (TKI) Cohort: Proportion of Participants With Major Pathologic Response (MPR) | After surgical resection (approximately study Week 8) | MPR is defined as ≤ 10% residual viable tumor cells as scored by local pathologists. |
| Checkpoint Inhibitor (CPI) Cohort: Pathological Complete Response (pCR) | After surgical resection (approximately study Week 8) | 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 Cohort: Percentage of Participants With 3-5 Grade Adverse Events (AEs) | After surgical resection (approximately study Week 8) | — |
| KRAS Cohort: Percentage of Participants Without Delays of Surgery due to Treatment-related Adverse Events as Reported by the Investigator | After surgical resection (approximately study Week 8) | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Participants With MPR | After surgical resection (approximately study Week 8) | 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 | After surgical resection (approximately study Week 8) | 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 | After surgical resection (approximately study Week 8) | — |
| Investigator-assessed Response Objective Response Rate (ORR) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | After neoadjuvant treatment (after approximately study Week 8) | — |
| Pathological Complete Response (pCR) as Assessed by Local and Central Pathology Laboratories | At the time of surgical resection (approximately study Week 8) | Defined as the absence of any viable tumor in main tumor bed at the time of surgical resection, as assessed by local and central pathology laboratories. |
| Disease-free Survival (DFS) | From the first date of no disease to local or distant recurrence or death from any cause, whichever occurs first, through the end of the study (up to 9 years) | — |
| Event-free Survival (EFS) | From first dose of study treatment to first documented disease progression per RECIST v1.1, or local or distant disease recurrence as determined by investigator, or death from any cause, whichever occurs first, through the end of study (up to 9 years) | — |
| Overall Survival (OS) | From the first dose of study medication to death from any cause, through the end of the study (up to 9 years) | — |
| Percentage of Participants With Adverse Events (AEs) | Up to 9 years | — |
| Nodal Downstaging | After surgical resection (approximately study Week 8) | Defined as percentage of participants with reduced stages in regional lymph nodes at surgery. |
| Circulating tumor DNA (ctDNA) Clearance Rate | Prior to surgery (before study Week 8) | — |
| KRAS G12C Cohort: Plasma Concentration of Divarasib at Specified Timepoints | Cycle 1 Day 1, Cycle 2 Day 1 (Cycle= 28 days) | — |
Countries
United States
Contacts
CONTACTReference Study ID Number: ML41591 https://forpatients.roche.com/
STUDY_DIRECTORClinical Trials
Hoffmann-La Roche
Outcome results
None listed