A Study of Multiple Therapies in Biomarker-Selected Patients With Resectable Stages IB-III Non-Small Cell Lung Cancer

Study Overview
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Brief Summary
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This trial will evaluate the efficacy and safety of various therapies in patients with Stage IB, IIA, IIB, IIIA, or selected IIIB resectable and untreated non-small cell lung cancer (NSCLC) tumors that meet protocol-specified biomarker criteria

Official Title
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NAUTIKA1: Multicenter, Phase II, Neoadjuvant and Adjuvant Study of Multiple Therapies in Biomarker-Selected Patients With Resectable Stages IB-III Non-Small Cell Lung Cancer

Conditions
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Non-small Cell Lung Cancer

Intervention / Treatment
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* Drug: Alectinib
* Drug: Entrectinib
* Drug: Vemurafenib
* Drug: Cobimetinib
* Drug: Pralsetinib
* Drug: Atezolizumab
* Drug: SBRT
* Procedure: Resection
* Drug: Chemotherapy
* Drug: Divarasib


Participation Criteria
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Eligibility Criteria
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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 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 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ALK Cohort<br>Participants will receive up to 8 weeks of alectinib neoadjuvant treatment before undergoing surgical resection per standard of care. All participants that undergo surgical resection and whose tumors have pathological response or lack radiographic progression will be eligible for the Adjuvant Treatment Phase with alectinib. Adjuvant therapy will consist of 4 cycles of chemotherapy followed by up to 2 years of alectinib. | Drug: Alectinib<br>* Participants will receive oral alectinib twice per day (BID)<br>Procedure: Resection<br>* Participants will receive surgical resection of the primary tumor along with selected lymph nodes<br>Drug: Chemotherapy<br>* Participants will receive standard of care (SOC) chemotherapy as determined by the treating physician<br>|
| Experimental: ROS 1 Cohort<br>Participants will receive up to 8 weeks of entrectinib neoadjuvant treatment before undergoing surgical resection per standard of care. All participants that undergo surgical resection and whose tumors have pathological response or lack radiographic progression will be eligible for the Adjuvant Treatment Phase with entrectinib. Adjuvant therapy will consist of 4 cycles of chemotherapy followed by up to 2 years of entrectinib. | Drug: Entrectinib<br>* Participants will receive oral entrectinib daily<br>Procedure: Resection<br>* Participants will receive surgical resection of the primary tumor along with selected lymph nodes<br>Drug: Chemotherapy<br>* Participants will receive standard of care (SOC) chemotherapy as determined by the treating physician<br>|
| Experimental: NTRK Cohort<br>Participants will receive up to 8 weeks of entrectinib neoadjuvant treatment before undergoing surgical resection per standard of care. All participants that undergo surgical resection and whose tumors have pathological response or lack radiographic progression will be eligible for the Adjuvant Treatment Phase with entrectinib. Adjuvant therapy will consist of 4 cycles of chemotherapy followed by up to 2 years of entrectinib. | Drug: Entrectinib<br>* Participants will receive oral entrectinib daily<br>Procedure: Resection<br>* Participants will receive surgical resection of the primary tumor along with selected lymph nodes<br>Drug: Chemotherapy<br>* Participants will receive standard of care (SOC) chemotherapy as determined by the treating physician<br>|
| Experimental: BRAF Cohort<br>Participants will receive up to 8 weeks of vemurafenib plus cobimetinib neoadjuvant treatment before undergoing surgical resection per standard of care. All participants that undergo surgical resection and whose tumors have pathological response or lack radiographic progression will be eligible for the Adjuvant Treatment Phase with vemurafenib plus cobimetinib. Adjuvant therapy will consist of 4 cycles of chemotherapy followed by up to 2 years of of vemurafenib plus cobimetinib. | Drug: Vemurafenib<br>* Participants will receive oral vemurafenib BID<br>Drug: Cobimetinib<br>* Participants will receive oral cobimetinib daily<br>Procedure: Resection<br>* Participants will receive surgical resection of the primary tumor along with selected lymph nodes<br>Drug: Chemotherapy<br>* Participants will receive standard of care (SOC) chemotherapy as determined by the treating physician<br>|
| Experimental: RET Cohort<br>Participants will receive up to 8 weeks of pralsetinib neoadjuvant treatment before undergoing surgical resection per standard of care. All participants that undergo surgical resection and whose tumors have pathological response or lack radiographic progression will be eligible for the Adjuvant Treatment Phase with pralsetinib. Adjuvant therapy will consist of 4 cycles of chemotherapy followed by up to 2 years of pralsetinib. | Drug: Pralsetinib<br>* Participants will receive oral pralsetinib daily<br>Procedure: Resection<br>* Participants will receive surgical resection of the primary tumor along with selected lymph nodes<br>Drug: Chemotherapy<br>* Participants will receive standard of care (SOC) chemotherapy as determined by the treating physician<br>|
| Experimental: PD-L1 Cohort<br>Participants with positive PD-L1 in ≥1% tumor cells will receive 4 cycles of atezolizumab neoadjuvant treatment. During neoadjuvant Cycle 1 of atezolizumab, patients will also receive low-dose SBRT (8Gy X 3). Adjuvant treatment consists of SOC treatment as determined by the investigator, per NCCN guidelines | Drug: Atezolizumab<br>* Atezolizumab will be administered by intravenous (IV) infusion<br>Drug: SBRT<br>* Patients will receive SBRT given concurrently starting with the first dose of atezolizumab<br>Procedure: Resection<br>* Participants will receive surgical resection of the primary tumor along with selected lymph nodes<br>|
| Experimental: KRAS G12C Cohort<br>Participants will receive up to 8 weeks of GDC-6036 as neoadjuvant treatment before undergoing surgical resection per standard of care. PD-L1 negative patients whose tumors have pathological response or lack radiographic progression will be have the option of continuing GDC-6036 for up to 2 years as adjuvant therapy | Procedure: Resection<br>* Participants will receive surgical resection of the primary tumor along with selected lymph nodes<br>Drug: Divarasib<br>* Participants in the KRAS G12C cohort will receive GDC-6036 for approximately 8 weeks until the day before surgery.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tyrosine kinase inhibitor (TKI): Proportion of Participants with Major Pathologic Response (MPR) | MPR is defined as </=10% residual viable tumor cells as scored by local pathologists | After surgical resection (approximately study Week 8) | 
| 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 | After surgical resection (approximately study Week 8) | 
| KRAS cohort: Percentage of participants with 3-5 grade Adverse Events |  | 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | After surgical resection (approximately study Week 8) | 
| 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 local pathologists and a central pathology committee consensus read | After surgical resection (approximately study Week 8) | 
| Pathological Regression Based on Weighted % Viable Tumor Cell Assessment |  | After surgical resection (approximately study Week 8) | 
| Investigator-Assessed Response Objective Response Rate (ORR) per RECIST v1.1 |  | After neoadjuvant treatment (after approximately study Week 8) | 
| Pathological Complete Response (pCR) as Assessed by Local and Central Pathology Laboratories | 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 | At the time of surgical resection (approximately study Week 8) | 
| 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 8 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 8 years) | 
| Overall Survival (OS) |  | From the first dose of study medication to death from any cause, through the end of the study (up to 8 years) | 
| Percentage of Participants with Adverse Events (AEs) |  | Up to 8 years | 
| Nodal downstaging, defined as percentage of patients with reduced stages in mediastinal nodes at surgery |  | After surgical resection (approximately study Week 8) | 
| Circulating tumor DNA ctDNA Clearance Rate |  | Prior to surgery (before study Week 8) | 
| KRAS G12C cohort: Plasma concentration of GDC-6036 at specified timepoints |  | Cycle 1 Day 1, Cycle 2 Day 1 (Cycle= 28 days) |