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RecruitingInterventionalPhase 2

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

NCT ID: NCT04302025Sponsor: Genentech, Inc.Last updated: 2026-06-09

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.

Arms & 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.

Outcome measures

Primary

  • 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.

    Time frame: 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.

    Time frame: After surgical resection (approximately study Week 8)

  • KRAS G12C Cohort: Percentage of Participants With 3-5 Grade Adverse Events (AEs)

    Time frame: 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

    Time frame: After surgical resection (approximately study Week 8)

Secondary

  • Proportion of Participants With MPR

    Time frame: After surgical resection (approximately study Week 8)

  • Proportion of Participants With pCR

    Time frame: After surgical resection (approximately study Week 8)

  • Pathological Regression Based on Weighted % Viable Tumor Cell Assessment

    Time frame: 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)

    Time frame: After neoadjuvant treatment (after approximately study Week 8)

  • Disease-free Survival (DFS)

    Time frame: 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)

    Time frame: 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)

    Time frame: 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 AEs

    Time frame: Up to 9 years

  • Nodal Downstaging

    Time frame: After surgical resection (approximately study Week 8)

  • Circulating tumor DNA (ctDNA) Clearance Rate

    Time frame: Prior to surgery (before study Week 8)

  • KRAS G12C Cohort: Plasma Concentration of Divarasib at Specified Timepoints

    Time frame: 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);

Eligibility criteria

Sex: AllAge: 18 Years and olderHealthy 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 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 locations (38)

City of Hope Comprehensive Cancer Center

Duarte, California, 91010

Withdrawn

City of Hope - Orange County Lennar Foundation Cancer Center

Irvine, California, 92618

Withdrawn

USC Norris Cancer Center

Los Angeles, California, 90033

Withdrawn

Cedars-Sinai Medical Center

Los Angeles, California, 90048

Withdrawn

University of California Los Angeles - Jonsson Comprehensive Cancer Center

Los Angeles, California, 90095

Recruiting

The Center for Cancer Prevention and Treatment at St.Joseph Hospital of Orange

Orange, California, 92868

Recruiting

UC Davis Comprehensive Cancer Center

Sacramento, California, 95817

Recruiting

UCSF Helen Diller Family CCC

San Francisco, California, 94158

Withdrawn

University of Colorado - Anschutz Medical Campus (University of Colorado Health Sciences Center)

Aurora, Colorado, 80045

Withdrawn

Yale Cancer Center

New Haven, Connecticut, 06511

Recruiting

MedStar Georgetown University Hospital (Lombardi Comprehensive Cancer Center)

Washington D.C., District of Columbia, 20007

Recruiting

Moffitt Cancer Center

Tampa, Florida, 33612

Recruiting

Northwestern University

Chicago, Illinois, 60611

Recruiting

Northwestern Medicine Cancer Center Kishwaukee

DeKalb, Illinois, 60115

Recruiting

Northwestern Medicine Cancer Center Delnor

Geneva, Illinois, 60134

Recruiting

Northwestern Medicine Cancer Center Warrenville

Warrenville, Illinois, 60555

Recruiting

Boston Medical Center

Boston, Massachusetts, 02118

Withdrawn

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215

Recruiting

University of Michigan

Ann Arbor, Michigan, 48109

Recruiting

Karmanos Cancer Institute - Farmington Hills/Weisberg Cancer Treatment Center

Farmington Hills, Michigan, 48334

Withdrawn

Mayo Clinic

Rochester, Minnesota, 55905

Recruiting

Ellis Fischel Cancer Center

Columbia, Missouri, 65201

Recruiting

Siteman Cancer Center - Washington University Medical Campus

St Louis, Missouri, 63108

Recruiting

Dartmouth Hitchcock Medical Center

Lebanon, New Hampshire, 03756

Recruiting

Laura and ISAAC Perlmutter Cancer Center at NYU Langone.

New York, New York, 10016

Recruiting

Columbia University Medical Center

New York, New York, 10032

Recruiting

Memorial Sloan Kettering Cancer Center

New York, New York, 10065

Recruiting

University Hospitals Cleveland Medical Center

Cleveland, Ohio, 44016

Withdrawn

Ohio State University

Columbus, Ohio, 43210

Recruiting

AHN Cancer Institute ? Allegheny General Hospital

Pittsburgh, Pennsylvania, 15212

Completed

Baptist Clinical Research Institute

Memphis, Tennessee, 38120

Recruiting

Tennessee Oncology - Nashville

Nashville, Tennessee, 37203

Withdrawn

Kelsey Seybold Clnic

Houston, Texas, 77025

Withdrawn

University of Texas MD Anderson Cancer Center

Houston, Texas, 77030-4008

Recruiting

Baylor College of Medicine

Houston, Texas, 77030

Withdrawn

Lumi Research

Kingwood, Texas, 77339

Withdrawn

Virginia Cancer Specialists (Fairfax) - USOR

Fairfax, Virginia, 22031

Recruiting

Seattle Cancer Care Alliance

Seattle, Washington, 98109

Withdrawn