A Study of Multiple Therapies in Biomarker-selected Participants With Resectable Stages IB-III Non-small Cell Lung Cancer (NSCLC) (NAUTIKA1)

NAUTIKA1: A Multicenter, Phase II, Neoadjuvant and Adjuvant Study of Multiple Therapies in Biomarker-selected Patients With Resectable Stages IB-III Non-small Cell Lung Cancer

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.

Study Overview

• Status: Recruiting
• Conditions: Non-small Cell Lung Cancer
• Intervention / Treatment: Drug: Alectinib; Procedure: Resection; Drug: Chemotherapy; Drug: Entrectinib; Drug: Vemurafenib; Drug: Cobimetinib; Drug: Pralsetinib; Drug: Atezolizumab; Drug: SBRT; Drug: Divarasib

• Study Type: Interventional
• Enrollment (Estimated): 99
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Reference Study ID Number: ML41591 https://forpatients.roche.com/; Phone Number: 888-662-6728; Email: global-roche-genentech-trials@gene.com

Study Locations

• United States
  • California
    • Duarte, California, United States, 91010
      • Withdrawn
      • City of Hope Comprehensive Cancer Center
    • Irvine, California, United States, 92618
      • Withdrawn
      • City of Hope - Orange County Lennar Foundation Cancer Center
    • Los Angeles, California, United States, 90033
      • Withdrawn
      • USC Norris Cancer Center
    • Los Angeles, California, United States, 90048
      • Withdrawn
      • Cedars-Sinai Medical Center
    • Los Angeles, California, United States, 90095
      • Recruiting
      • University of California Los Angeles - Jonsson Comprehensive Cancer Center
    • Orange, California, United States, 92868
      • Recruiting
      • The Center for Cancer Prevention and Treatment at St.Joseph Hospital of Orange
    • Sacramento, California, United States, 95817
      • Recruiting
      • UC Davis Comprehensive Cancer Center
    • San Francisco, California, United States, 94158
      • Withdrawn
      • UCSF Helen Diller Family CCC
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Withdrawn
      • University of Colorado - Anschutz Medical Campus (University of Colorado Health Sciences Center)
  • Connecticut
    • New Haven, Connecticut, United States, 06511
      • Recruiting
      • Yale Cancer Center
  • District of Columbia
    • Washington D.C., District of Columbia, United States, 20007
      • Recruiting
      • MedStar Georgetown University Hospital (Lombardi Comprehensive Cancer Center)
  • Florida
    • Tampa, Florida, United States, 33612
      • Recruiting
      • Moffitt Cancer Center
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Recruiting
      • Northwestern University
    • DeKalb, Illinois, United States, 60115
      • Recruiting
      • Northwestern Medicine Cancer Center Kishwaukee
    • Geneva, Illinois, United States, 60134
      • Recruiting
      • Northwestern Medicine Cancer Center Delnor
    • Warrenville, Illinois, United States, 60555
      • Recruiting
      • Northwestern Medicine Cancer Center Warrenville
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Recruiting
      • Dana-Farber Cancer Institute
    • Boston, Massachusetts, United States, 02118
      • Withdrawn
      • Boston Medical Center
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • Recruiting
      • University of Michigan
    • Farmington Hills, Michigan, United States, 48334
      • Withdrawn
      • Karmanos Cancer Institute - Farmington Hills/Weisberg Cancer Treatment Center
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Recruiting
      • Mayo Clinic
  • Missouri
    • Columbia, Missouri, United States, 65201
      • Recruiting
      • Ellis Fischel Cancer Center
    • St Louis, Missouri, United States, 63108
      • Recruiting
      • Siteman Cancer Center - Washington University Medical Campus
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756
      • Recruiting
      • Dartmouth Hitchcock Medical Center
  • New York
    • New York, New York, United States, 10065
      • Recruiting
      • Memorial Sloan Kettering Cancer Center
    • New York, New York, United States, 10032
      • Recruiting
      • Columbia University Medical Center
    • New York, New York, United States, 10016
      • Recruiting
      • Laura and ISAAC Perlmutter Cancer Center at NYU Langone.
  • Ohio
    • Cleveland, Ohio, United States, 44016
      • Withdrawn
      • University Hospitals Cleveland Medical Center
    • Columbus, Ohio, United States, 43210
      • Recruiting
      • Ohio State University
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15212
      • Completed
      • AHN Cancer Institute ? Allegheny General Hospital
  • Tennessee
    • Memphis, Tennessee, United States, 38120
      • Recruiting
      • Baptist Clinical Research Institute
    • Nashville, Tennessee, United States, 37203
      • Withdrawn
      • Tennessee Oncology - Nashville
  • Texas
    • Houston, Texas, United States, 77030-4008
      • Recruiting
      • University of Texas MD Anderson Cancer Center
    • Houston, Texas, United States, 77030
      • Withdrawn
      • Baylor College of Medicine
    • Houston, Texas, United States, 77025
      • Withdrawn
      • Kelsey Seybold Clnic
    • Kingwood, Texas, United States, 77339
      • Withdrawn
      • Lumi Research
  • Virginia
    • Fairfax, Virginia, United States, 22031
      • Recruiting
      • Virginia Cancer Specialists (Fairfax) - USOR
  • Washington
    • Seattle, Washington, United States, 98109
      • Withdrawn
      • Seattle Cancer Care Alliance

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 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
• 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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

7

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: ALK Cohort (Enrolment Closed); Participants will receive up to 8 weeks of alectinib neoadjuvant treatment before undergoing surgical resection per standard of care (SOC). 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. Enrolment Closed.	Drug: Alectinib; Participants will receive oral alectinib twice per day (BID).; Other Names: CH5424802; RO5424802; Procedure: Resection; Participants will receive surgical resection of the primary tumor along with selected lymph nodes per SOC.; Drug: Chemotherapy; Participants will receive SOC chemotherapy as determined by the treating physician.
Experimental: ROS 1 Cohort (Enrolment Closed); Participants will receive up to 8 weeks of entrectinib neoadjuvant treatment before undergoing surgical resection per SOC. 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. Enrolment Closed.	Procedure: Resection; Participants will receive surgical resection of the primary tumor along with selected lymph nodes per SOC.; Drug: Chemotherapy; Participants will receive SOC chemotherapy as determined by the treating physician.; Drug: Entrectinib; Participants will receive oral entrectinib daily.; Other Names: Rozlytrek®; RXDX-101
Experimental: NTRK Cohort (Enrolment Closed); Participants will receive up to 8 weeks of entrectinib neoadjuvant treatment before undergoing surgical resection per SOC. 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. Enrolment Closed.	Procedure: Resection; Participants will receive surgical resection of the primary tumor along with selected lymph nodes per SOC.; Drug: Chemotherapy; Participants will receive SOC chemotherapy as determined by the treating physician.; Drug: Entrectinib; Participants will receive oral entrectinib daily.; Other Names: Rozlytrek®; RXDX-101
Experimental: BRAF Cohort (No Participants Enrolled, Cohort Closed); Participants will receive up to 8 weeks of vemurafenib plus cobimetinib neoadjuvant treatment before undergoing surgical resection per SOC. 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. Cohort closed.	Procedure: Resection; Participants will receive surgical resection of the primary tumor along with selected lymph nodes per SOC.; Drug: Chemotherapy; Participants will receive SOC chemotherapy as determined by the treating physician.; Drug: Vemurafenib; Participants will receive oral vemurafenib BID.; Other Names: Zelboraf®; Drug: Cobimetinib; Participants will receive oral cobimetinib daily.; Other Names: Cotellic®
Experimental: RET Cohort (Cohort closed); Participants will receive up to 8 weeks of pralsetinib neoadjuvant treatment before undergoing surgical resection per SOC. 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. Cohort closed.	Procedure: Resection; Participants will receive surgical resection of the primary tumor along with selected lymph nodes per SOC.; Drug: Chemotherapy; Participants will receive SOC chemotherapy as determined by the treating physician.; Drug: Pralsetinib; Participants will receive oral pralsetinib daily.; Other Names: Gavreto®
Experimental: PD-L1 Cohort (Enrolment Closed); Participants with positive programmed death-ligand 1 (PD-L1) in ≥1% tumor cells will receive 4 cycles of atezolizumab neoadjuvant treatment. During neoadjuvant Cycle 1 of atezolizumab, participants will also receive low-dose stereotactic body radiation therapy (SBRT) (8 gray [Gy] X 3). Adjuvant treatment consists of SOC treatment as determined by the investigator, per National Comprehensive Cancer Network (NCCN) guidelines. Enrolment Closed.	Procedure: Resection; Participants will receive surgical resection of the primary tumor along with selected lymph nodes per SOC.; Drug: Atezolizumab; Atezolizumab will be administered by intravenous (IV) infusion.; Other Names: Tecentriq®; Drug: SBRT; Participants will receive SBRT given concurrently, starting with the first dose of atezolizumab.
Experimental: KRAS G12C Cohort; Participants will receive up to 8 weeks of divarasib as neoadjuvant treatment before undergoing surgical resection per SOC. PD-L1 negative participants whose tumors have pathological response or lack radiographic progression will be have the option of continuing divarasib alone for up to 3 years or 1-4 cycles of SOC chemotherapy followed by divarasib for 3 years as adjuvant therapy. For participants who test positive PD-L1, they will have the option to receive 1-4 cycles of SOC chemotherapy followed by atezolizumab for up to 16 cycles or SOC alone.	Procedure: Resection; Participants will receive surgical resection of the primary tumor along with selected lymph nodes per SOC.; Drug: Chemotherapy; Participants will receive SOC chemotherapy as determined by the treating physician.; Drug: Divarasib; 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.; Other Names: GDC-6036

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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 G12C Cohort: Percentage of Participants With 3-5 Grade Adverse Events (AEs)		After surgical resection (approximately study Week 8)
KRAS G12C Cohort: Percentage of Participants Without Delays of Surgery due to Treatment-related AEs as Reported by the Investigator		After surgical resection (approximately study Week 8)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pathological Regression Based on Weighted % Viable Tumor Cell Assessment		After surgical resection (approximately study Week 8)
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 a central pathology committee consensus read.	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)
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)
Nodal Downstaging	Defined as percentage of participants with reduced stages in regional lymph nodes at surgery.	After surgical resection (approximately study Week 8)
Circulating tumor DNA (ctDNA) Clearance Rate		Prior to surgery (before study Week 8)
Percentage of Participants With AEs		Up to 9 years
KRAS G12C Cohort: Plasma Concentration of Divarasib at Specified Timepoints	Treatment completion/discontinuation;; Disease Progression or Recurrence during Neoadjuvant treatment or Surveillance;; Unscheduled (Tumor Evaluation and Response) [Anytime up to 3 years]	Neo-adjuvant: pre-dose & 2 hours post-dose on Day 1 of Cycles 1 & 2; Pre-surgery (before Week 8): pre-dose; Adjuvant treatment: pre-dose & 2 hours post-dose on Day 1 of Cycles 1-6, pre-dose on Day 1 of Cycle 9 (each cycle=28 days);

Collaborators and Investigators

• Sponsor: Genentech, Inc.
• Collaborators: Blueprint Medicines Corporation
• Investigators: Study Director: Clinical Trials, Hoffmann-La Roche

Study record dates

Study Major Dates

• Study Start (Actual): November 6, 2020
• Primary Completion (Estimated): November 30, 2026
• Study Completion (Estimated): May 30, 2030

Study Registration Dates

• First Submitted: March 6, 2020
• First Submitted That Met QC Criteria: March 6, 2020
• First Posted (Actual): March 10, 2020

Study Record Updates

• Last Update Posted (Actual): May 22, 2026
• Last Update Submitted That Met QC Criteria: May 19, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Respiratory Tract Diseases; Lung Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Carcinoma, Non-Small-Cell Lung; Sulfur Compounds; Organic Chemicals; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Therapeutics; Amides; Indoles; Sulfonamides; Sulfones; Vemurafenib; Drug Therapy; atezolizumab; cobimetinib; entrectinib; alectinib; pralsetinib
• Other Study ID Numbers: ML41591

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: For eligible studies, qualified researchers may request access to individual patient level clinical data. See Roche's commitment to transparency of clinical study information here: https://go.roche.com/data_sharing

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No