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

• ClinicalTrials.gov Identifier: NCT04302025
• Recruitment Status: Recruiting
• First Posted: March 10, 2020
• Last Update Posted: May 31, 2023
• Sponsor: Genentech, Inc.
• Collaborator: Blueprint Medicines Corporation
• Information provided by (Responsible Party): Genentech, Inc.

Tracking Information

• First Submitted Date: March 6, 2020
• First Posted Date: March 10, 2020
• Last Update Posted Date: May 31, 2023
• Actual Study Start Date: November 6, 2020
• Estimated Primary Completion Date: March 7, 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 25, 2023)

• Tyrosine kinase inhibitor (TKI): Proportion of Participants with Major Pathologic Response (MPR) [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: After surgical resection (approximately study Week 8) ]

Original Primary Outcome Measures (submitted: March 6, 2020)

Proportion of Participants with Major Pathologic Response (MPR) [ Time Frame: After surgical resection (approximately study Week 8) ]

MPR is defined as </=10% residual viable tumor cells

Current Secondary Outcome Measures (submitted: May 25, 2023)

• Proportion of Participants with MPR [ Time Frame: 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 [ Time Frame: 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 local pathologists and a central pathology committee consensus read
• 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 RECIST v1.1 [ Time Frame: After neoadjuvant treatment (after approximately study Week 8) ]
• Pathological Complete Response (pCR) as Assessed by Local and Central Pathology Laboratories [ Time Frame: 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) [ 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 8 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 8 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 8 years) ]
• Percentage of Participants with Adverse Events (AEs) [ Time Frame: Up to 8 years ]
• Nodal downstaging, defined as percentage of patients with reduced stages in mediastinal nodes at surgery [ 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 GDC-6036 at specified timepoints [ Time Frame: Cycle 1 Day 1, Cycle 2 Day 1 (Cycle= 28 days) ]

Original Secondary Outcome Measures (submitted: March 6, 2020)

• Pathological Regression Based on % Viable Tumor Cell Assessment [ Time Frame: After surgical resection (approximately study Week 8) ]
• Investigator-Assessed Response Objective Response Rate (ORR) per RECIST v1.1 [ Time Frame: After neoadjuvant treatment (after approximately study Week 8) ]
• Pathological Complete Response (pCR) as Assessed by Investigator Site Pathology Laboratory [ Time Frame: At the time of surgical resection (approximately study Week 8) ]
  pCR is defined as the absence of residual invasive in situ cancer and all sampled regional lymph nodes
• 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 8 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 8 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 8 years) ]
• Percentage of Participants with Adverse Events (AEs) [ Time Frame: Up to 8 years ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study of Multiple Therapies in Biomarker-Selected Patients With Resectable Stages IB-III Non-Small Cell Lung Cancer
• Official Title: 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
• Brief Summary: 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
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Non-small Cell Lung Cancer

Intervention

• Drug: Alectinib
  Participants will receive oral alectinib twice per day (BID)
• Drug: Entrectinib
  Participants will receive oral entrectinib daily
• Drug: Vemurafenib
  Participants will receive oral vemurafenib BID
• Drug: Cobimetinib
  Participants will receive oral cobimetinib daily
• Drug: Pralsetinib
  Participants will receive oral pralsetinib daily
• Drug: Atezolizumab
  Atezolizumab will be administered by intravenous (IV) infusion
• Drug: SBRT
  Patients will receive SBRT given concurrently starting with the first dose of atezolizumab
• Procedure: Resection
  Participants will receive surgical resection of the primary tumor along with selected lymph nodes
• Drug: Chemotherapy
  Participants will receive standard of care (SOC) chemotherapy as determined by the treating physician
• Drug: Divarasib
  Participants in the KRAS G12C cohort will receive GDC-6036 for approximately 8 weeks until the day before surgery.

Study Arms

• Experimental: ALK Cohort
  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.
  Interventions:

  • Drug: Alectinib
  • Procedure: Resection
  • Drug: Chemotherapy
• Experimental: ROS 1 Cohort
  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.
  Interventions:

  • Drug: Entrectinib
  • Procedure: Resection
  • Drug: Chemotherapy
• Experimental: NTRK Cohort
  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.
  Interventions:

  • Drug: Entrectinib
  • Procedure: Resection
  • Drug: Chemotherapy
• Experimental: BRAF Cohort
  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.
  Interventions:

  • Drug: Vemurafenib
  • Drug: Cobimetinib
  • Procedure: Resection
  • Drug: Chemotherapy
• Experimental: RET Cohort
  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.
  Interventions:

  • Drug: Pralsetinib
  • Procedure: Resection
  • Drug: Chemotherapy
• Experimental: PD-L1 Cohort
  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
  Interventions:

  • Drug: Atezolizumab
  • Drug: SBRT
  • Procedure: Resection
• Experimental: KRAS G12C Cohort
  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
  Interventions:

  • Procedure: Resection
  • Drug: Divarasib

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: May 25, 2023): 85
• Original Estimated Enrollment (submitted: March 6, 2020): 60
• Estimated Study Completion Date: March 6, 2029
• Estimated Primary Completion Date: March 7, 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

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
• 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 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
• 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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

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

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT04302025
• Other Study ID Numbers: ML41591
• Has Data Monitoring Committee: Not Provided

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: Qualified researchers may request access to individual patient level data through the clinical study data request platform (www.vivli.org). Further details on Roche's criteria for eligible studies are available here (https://vivli.org/ourmember/roche/). For further details on Roche's Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see here (https://www.roche.com/research_and_development/who_we_are_how_we_work/clinical_trials/our_commitment_to_data_sharing.htm).

• Current Responsible Party: Genentech, Inc.
• Original Responsible Party: Same as current
• Current Study Sponsor: Genentech, Inc.
• Original Study Sponsor: Same as current
• Collaborators: Blueprint Medicines Corporation

Investigators

• Study Director: Clinical Trials; Hoffmann-La Roche

• PRS Account: Genentech, Inc.
• Verification Date: May 2023