A Study to Evaluate the Efficacy and Safety of Multiple Targeted Therapies as Treatments for Participants With Non-Small Cell Lung Cancer (NSCLC)

Phase 2

Active, not recruiting

• Conditions: Non-Small Cell Lung Cancer
• Interventions: Drug: Alectinib; Drug: Entrectinib; Drug: Atezolizumab; Drug: Divarasib; Drug: Cisplatin; Drug: Pemetrexed; Drug: Docetaxel; Drug: Cobimetinib; Drug: Gemcitabine; Drug: Carboplatin; Drug: Vemurafenib; Drug: Bevacizumab

• Registration Number: NCT03178552
• Lead Sponsor: Hoffmann-La Roche

Brief Summary

This is a phase 2/3, global, multicenter, open-label, multi-cohort study designed to evaluate the safety and efficacy of targeted therapies or immunotherapy as single agents or in combination in participants with unresectable, advanced or metastatic NSCLC determined to harbor oncogenic somatic mutations or positive by tumor mutational burden (TMB) assay as identified by a blood-based next-generation sequencing (NGS) circulating tumor DNA (ctDNA) assay.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2017-06-05
• Study First Submitted QC: 2017-06-05
• Study First Posted: 2017-06-07
• Study Start: 2017-09-22
• Status Verified: 2025-06
• Last Update Submitted: 2025-06-11
• Last Update Posted: 2025-06-15
• Primary Completion: 2028-08-03
• Study Completion: 2028-08-03

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 1000

Inclusion Criteria

• Histologically or cytologically confirmed diagnosis of unresectable Stage IIIb not amenable to treatment with combined modality chemoradiation (advanced) or Stage IV (metastatic) NSCLC
• Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2
• Measurable disease
• Adequate recovery from most recent systemic or local treatment for cancer
• Adequate organ function
• Life expectancy greater than or equal to (>/=) 12 weeks
• For female participants of childbearing potential and male participants, willingness to use acceptable methods of contraception

Exclusion Criteria

• Inability to swallow oral medication
• Women who are pregnant or lactating
• Symptomatic, untreated CNS metastases
• History of malignancy other than NSCLC within 5 years prior to screening with the exception of malignancies with negligible risk of metastasis or death
• Significant cardiovascular disease, such as New York Heart Association cardiac disease (Class II or greater), myocardial infarction, or cerebrovascular accident within 3 months prior to randomization, unstable arrhythmias, or unstable angina
• Known active or uncontrolled human immunodeficiency virus (HIV) infection
• Either a concurrent condition or history of a prior condition that places the patient at unacceptable risk if he/she were treated with the study drug or confounds the ability to interpret data from the study
• Inability to comply with other requirements of the protocol

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Cohort A: Alectinib 600 Milligrams (mg)	Alectinib	This cohort includes participants with anaplastic lymphoma kinase (ALK) positive NSCLC. Participants will receive alectinib 600 mg orally twice in a day (BID) until disease progression, unacceptable toxicity, withdrawal of consent or death. Enrollment to Cohort A is complete.
Cohort C: Gemcitabine, Cisplatin or Carboplatin	Gemcitabine	This cohort includes participants with bTMB positive, squamous NSCLC. Participants will receive 4 or 6 cycles of treatment, with each cycle being 21 days in duration. Gemcitabine 1250 mg/m\^2 IV on Days 1 and 8 of every cycle and cisplatin 75 mg/m\^2 IV on Day 1 Q21D or gemcitabine 1000 mg/m\^2 IV on Days 1 and 8 of every cycle and carboplatin AUC 5 IV on Day 1 Q21D. Enrollment to Cohort C is complete.
Cohort D: Entrectinib 600 Milligrams (mg)	Entrectinib	This cohort includes participants with c-ros oncogene 1 positive (ROS1+) NSCLC. Participants will receive entrectinib 600 mg orally once a day (QD) until disease progression, unacceptable toxicity, withdrawal of consent or death. Enrollment to Cohort D is complete.
Cohort E: Atezolizumab, Vemurafenib, and Cobimetinib	Atezolizumab	This cohort includes participants with BRAF V600 mutation. Participants will receive: atezolizumab 1680 mg IV Q4W after the run-in period; cobimetinib 60 mg orally (PO) QD on Days 1-21 of each cycle during the run-in and triple-combination periods; and vemurafenib 960 mg PO twice daily (BID) on Days 1-21 of the initial run-in period, then 720 mg PO BID on Days 1-22 of the initial run-in period and on Days 1-28 of each cycle during the triple-combination period. Enrollment to Cohort E is complete.
Cohort F: Atezolizumab, Bevacizumab, Carboplatin, and Pemetrexed	Pemetrexed	This cohort includes participants with EGFR exon 20+ NSCLC. Participants will receive atezolizumab + bevacizumab + carboplatin + pemetrexed for 4 or 6 induction cycles (cycle = 21 days). After induction therapy, participants will continue maintenance treatment with atezolizumab + bevacizumab + pemetrexed until disease progression, unacceptable toxicity, withdrawal of consent, or death. Enrollment to Cohort F is complete.
Cohort F: Atezolizumab, Bevacizumab, Carboplatin, and Pemetrexed	Bevacizumab	This cohort includes participants with EGFR exon 20+ NSCLC. Participants will receive atezolizumab + bevacizumab + carboplatin + pemetrexed for 4 or 6 induction cycles (cycle = 21 days). After induction therapy, participants will continue maintenance treatment with atezolizumab + bevacizumab + pemetrexed until disease progression, unacceptable toxicity, withdrawal of consent, or death. Enrollment to Cohort F is complete.
Cohort G: Divarasib or Docetaxel	Divarasib	Experimental: Cohort G: GDC-6036 or Docetaxel This cohort includes participants with KRAS G12C mutation. Participants will receive GDC-6036 PO QD or IV docetaxel Q3W (75 mg/m\^2) until disease progression or unacceptable toxicity New participants will no longer receive docetaxel.
Cohort G: Divarasib or Docetaxel	Docetaxel	Experimental: Cohort G: GDC-6036 or Docetaxel This cohort includes participants with KRAS G12C mutation. Participants will receive GDC-6036 PO QD or IV docetaxel Q3W (75 mg/m\^2) until disease progression or unacceptable toxicity New participants will no longer receive docetaxel.
Cohort B: Dose Finding Phase (DFP) Alectinib	Alectinib	This cohort includes participants with rearranged during transfection (RET) positive NSCLC. Participants may receive alectinib 900 or 1200 mg orally BID until disease progression, unacceptable toxicity, withdrawal of consent or death if the recommended phase 2 dose (RP2D) is not established in any other clinical study. Participants may receive 750 mg or 600 mg, if it is unsafe to pursue the higher starting dose. Enrollment to Cohort B is complete.
Cohort B: Dose Expansion Phase (DEP) Alectinib	Alectinib	This cohort includes participants with RET positive NSCLC. Participants will receive alectinib at the RP2D established in the DFP of Cohort B or a separate clinical study. Participants will continue receiving study treatment until disease progression, unacceptable toxicity, withdrawal of consent or death. Enrollment to Cohort B is complete.
Cohort C: Atezolizumab 1200 mg	Atezolizumab	This cohort includes participants with bTMB positive NSCLC. Participants will receive atezolizumab at a dose of 1200 mg administered by IV infusion every 21 days (Q21D) until disease progression, loss of clinical benefit, unacceptable toxicity, withdrawal of consent or death. Enrollment to Cohort C is complete.
Cohort C: Pemetrexed, Cisplatin or Carboplatin	Pemetrexed	This cohort includes participants with bTMB positive, non-squamous NSCLC. Participants will receive 4 or 6 cycles of treatment, with each cycle being 21 days in duration. Carboplatin at a dose of area under the concentration-time curve (AUC) of 5 or 6 IV or cisplatin at a dose of 75 milligrams per meter square (mg/m\^2) IV on Day 1 of each cycle combined with pemetrexed at a dose of 500 mg/m\^2 IV on Day 1 of each cycle. Pemetrexed may be continued as maintenance therapy every 21 days (Q21D) as per local standard of care. Enrollment to Cohort C is complete.
Cohort C: Pemetrexed, Cisplatin or Carboplatin	Carboplatin	This cohort includes participants with bTMB positive, non-squamous NSCLC. Participants will receive 4 or 6 cycles of treatment, with each cycle being 21 days in duration. Carboplatin at a dose of area under the concentration-time curve (AUC) of 5 or 6 IV or cisplatin at a dose of 75 milligrams per meter square (mg/m\^2) IV on Day 1 of each cycle combined with pemetrexed at a dose of 500 mg/m\^2 IV on Day 1 of each cycle. Pemetrexed may be continued as maintenance therapy every 21 days (Q21D) as per local standard of care. Enrollment to Cohort C is complete.
Cohort C: Gemcitabine, Cisplatin or Carboplatin	Cisplatin	This cohort includes participants with bTMB positive, squamous NSCLC. Participants will receive 4 or 6 cycles of treatment, with each cycle being 21 days in duration. Gemcitabine 1250 mg/m\^2 IV on Days 1 and 8 of every cycle and cisplatin 75 mg/m\^2 IV on Day 1 Q21D or gemcitabine 1000 mg/m\^2 IV on Days 1 and 8 of every cycle and carboplatin AUC 5 IV on Day 1 Q21D. Enrollment to Cohort C is complete.
Cohort C: Pemetrexed, Cisplatin or Carboplatin	Cisplatin	This cohort includes participants with bTMB positive, non-squamous NSCLC. Participants will receive 4 or 6 cycles of treatment, with each cycle being 21 days in duration. Carboplatin at a dose of area under the concentration-time curve (AUC) of 5 or 6 IV or cisplatin at a dose of 75 milligrams per meter square (mg/m\^2) IV on Day 1 of each cycle combined with pemetrexed at a dose of 500 mg/m\^2 IV on Day 1 of each cycle. Pemetrexed may be continued as maintenance therapy every 21 days (Q21D) as per local standard of care. Enrollment to Cohort C is complete.
Cohort C: Gemcitabine, Cisplatin or Carboplatin	Carboplatin	This cohort includes participants with bTMB positive, squamous NSCLC. Participants will receive 4 or 6 cycles of treatment, with each cycle being 21 days in duration. Gemcitabine 1250 mg/m\^2 IV on Days 1 and 8 of every cycle and cisplatin 75 mg/m\^2 IV on Day 1 Q21D or gemcitabine 1000 mg/m\^2 IV on Days 1 and 8 of every cycle and carboplatin AUC 5 IV on Day 1 Q21D. Enrollment to Cohort C is complete.
Cohort E: Atezolizumab, Vemurafenib, and Cobimetinib	Vemurafenib	This cohort includes participants with BRAF V600 mutation. Participants will receive: atezolizumab 1680 mg IV Q4W after the run-in period; cobimetinib 60 mg orally (PO) QD on Days 1-21 of each cycle during the run-in and triple-combination periods; and vemurafenib 960 mg PO twice daily (BID) on Days 1-21 of the initial run-in period, then 720 mg PO BID on Days 1-22 of the initial run-in period and on Days 1-28 of each cycle during the triple-combination period. Enrollment to Cohort E is complete.
Cohort E: Atezolizumab, Vemurafenib, and Cobimetinib	Cobimetinib	This cohort includes participants with BRAF V600 mutation. Participants will receive: atezolizumab 1680 mg IV Q4W after the run-in period; cobimetinib 60 mg orally (PO) QD on Days 1-21 of each cycle during the run-in and triple-combination periods; and vemurafenib 960 mg PO twice daily (BID) on Days 1-21 of the initial run-in period, then 720 mg PO BID on Days 1-22 of the initial run-in period and on Days 1-28 of each cycle during the triple-combination period. Enrollment to Cohort E is complete.
Cohort F: Atezolizumab, Bevacizumab, Carboplatin, and Pemetrexed	Atezolizumab	This cohort includes participants with EGFR exon 20+ NSCLC. Participants will receive atezolizumab + bevacizumab + carboplatin + pemetrexed for 4 or 6 induction cycles (cycle = 21 days). After induction therapy, participants will continue maintenance treatment with atezolizumab + bevacizumab + pemetrexed until disease progression, unacceptable toxicity, withdrawal of consent, or death. Enrollment to Cohort F is complete.
Cohort F: Atezolizumab, Bevacizumab, Carboplatin, and Pemetrexed	Carboplatin	This cohort includes participants with EGFR exon 20+ NSCLC. Participants will receive atezolizumab + bevacizumab + carboplatin + pemetrexed for 4 or 6 induction cycles (cycle = 21 days). After induction therapy, participants will continue maintenance treatment with atezolizumab + bevacizumab + pemetrexed until disease progression, unacceptable toxicity, withdrawal of consent, or death. Enrollment to Cohort F is complete.

Primary Outcome Measures

Name	Time	Method
Cohort A: Percentage of Participants with Confirmed Objective Response as Assessed by the Investigator Based on the Response Evaluation Criteria in Solid Tumors (RECIST) Version (v) 1.1	Baseline up to disease progression or death (up to approximately 6 years)
Cohort B: Percentage of Participants with Confirmed Objective Response as Assessed by the Investigator Based on RECIST v1.1	Baseline up to disease progression or death (up to approximately 6 years)
Cohort C: Progression Free Survival (PFS) as Assessed by the Investigator Based on RECIST v1.1 in bTMB PP1	Baseline up to disease progression or death (up to approximately 6 years)
Cohort D: Percentage of Participants with Confirmed Objective Response as Assessed by the Investigator Based on RECIST v1.1	Baseline up to disease progression or death (up to approximately 6 years)
Cohort E: Time in Response (TIR) as Assessed by the Investigator Based on RECIST v1.1	Month 12
Cohort F: Investigator-Assessed Objective Response Rate (ORR) Based on RECIST v1.1	Baseline up to disease progression or death (up to approximately 6 years)
Cohort G: Incidence of Adverse Events (AEs)	Baseline to last dose of study treatment + 30 days or until initiation of new anticancer therapy, whichever occurs first (up to approximately 6 years)

Secondary Outcome Measures

Name	Time	Method
Cohort E: TIR as Assessed by IRF	Month 12
Cohorts A-F: Percentage of Participants with Adverse Events (AEs)	Baseline up to approximately 6 years
Cohorts C, E, F: Change from Baseline in Patient-Reported Lung Cancer Symptom (Cough, Dyspnea, Chest pain) Score as Measured by the SILC Scale	Baseline, every 4 weeks through Cycle 6 (1 Cycle = 21 or 28 days), every 8 weeks thereafter up to approximately 6 years
Cohorts A, B, D, E, F: Change from Baseline in HRQoL Scores as Measured by the SILC Scale	Baseline, every 4 weeks through Cycle 6 (1 Cycle = 21 or 28 days), every 8 weeks thereafter up to approximately 6 years
Cohorts A, B, D, E, F: Change from Baseline in Patient Functioning and Symptoms Score as Measured by the SILC Scale	Baseline, every 4 weeks through Cycle 6 (1 Cycle = 21 or 28 days), every 8 weeks thereafter up to approximately 6 years
Cohorts A-F: Duration of Response (DOR) as Assessed by the Investigator Based on RECIST v1.1	Baseline up to disease progression or death (up to approximately 6 years)
Cohorts A, B and D: Percentage of Participants with Clinical Benefit Response as Assessed by the Investigator Based on RECIST v1.1	Baseline up to disease progression or death (up to approximately 6 years)
Cohorts A, B, D, F: PFS as Assessed by the Investigator Based on RECIST v1.1	Baseline up to disease progression or death (up to approximately 6 years)
Cohorts A-F: Duration of Response as Assessed by the Independent Review Facility (IRF) Based on RECIST v1.1	Baseline up to disease progression or death (up to approximately 6 years)
Cohorts A, B and D: Percentage of Participants with Clinical Benefit Response as Assessed by IRF Based on RECIST v1.1	Baseline up to disease progression or death (up to approximately 6 years)
Cohorts A-F: PFS as Assessed by IRF Based on RECIST v1.1	Baseline up to disease progression or death (up to approximately 6 years)
Cohorts A-F: Percentage of Participants with Confirmed Objective Response as Assessed by IRF Based on RECIST v1.1	Baseline up to disease progression or death (up to approximately 6 years)
Cohorts A-F: Overall Survival (OS)	Baseline up to approximately 6 years
Cohorts A, B, D, E, F: Percentage of Participants with Improvement Compared with Baseline in Total Severity Symptom Score as Measured by Symptoms in Lung Cancer (SILC) Scale in Patient-Reported Lung Cancer Symptoms (Cough, Dyspnea and Chest Pain)	Baseline, every 4 weeks through Cycle 6 (1 Cycle = 21 or 28 days), every 8 weeks thereafter up to approximately 6 years
Cohorts A-F: Time to Deterioration in Patient-Reported Lung Cancer Symptoms (Cough, Dyspnea and Chest Pain) as Measured by the SILC Scale	Baseline, every 4 weeks through Cycle 6 (1 Cycle = 21 or 28 days), every 8 weeks thereafter up to approximately 6 years
Cohorts A-F: Change from Baseline in Health Related Quality of Life (HRQoL) Scores as Measured by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - C30 (EORTC QLQ-C30)	Baseline, every 4 weeks through Cycle 6 (1 Cycle = 21 or 28 days), every 8 weeks thereafter up to approximately 6 years
Cohorts A-F: Change from Baseline in Patient Functioning and Symptoms Score as Measured by the EORTC QLQ-C30	Baseline, every 4 weeks through Cycle 6 (1 Cycle = 21 or 28 days), every 8 weeks thereafter up to approximately 6 years
Cohort B: Metabolite to Parent Exposure Ratio for AUC0-last	DFP: pre-dose (0 hr) on Day 1 of Cycle 2; 0.5, 1, 2, 4, 6, 8 and 10 hr post-dose on Day 1 of Cycle 2 (1 Cycle=28 days)
Cohort B: Metabolite to Parent Exposure Ratio for Cmax	DFP: pre-dose (0 hr) on Day 1 of Cycle 2; 0.5, 1, 2, 4, 6, 8 and 10 hr post-dose on Day 1 of Cycle 2 (1 Cycle=28 days)
Cohort D: Time to CNS progression as Assessed by the Investigator Based on RECIST v1.1	Baseline up to CNS progression (up to approximately 6 years)
Cohort D: Time to CNS progression as Assessed by the IRF Based on RECIST v1.1	Baseline up to CNS progression (up to approximately 6 years)
Cohorts A-F: Health Status Assessed as an Index Score Using the European Quality of Life 5-Dimension 5-Level (EQ-5D-5L) Questionnaire	Baseline, every 4 weeks through Cycle 6 (1 Cycle = 21 or 28 days), every 8 weeks thereafter up to approximately 6 years
Cohort B: Percentage of Participants with Dose-Limiting Toxicities (DLTs)	Day 1 to Day 28 of Cycle 1 (cycle length = 28 days)
Cohort B: Maximum Plasma Concentration (Cmax) of Alectinib	DFP: pre-dose (0 hours [hr]) on Day 1 of Cycle 2; 0.5, 1, 2, 4, 6, 8 and 10 hr post-dose on Day 1 of Cycle 2 (1 Cycle=28 days)	DFP: Dose-Finding Phase; DEP: Dose-Expanding Phase.
Cohort B: Area Under the Concentration-Time Curve from Time Zero to the Last Measurable Concentration (AUC0-last) of Alectinib	DFP: pre-dose (0 hr) on Day 1 of Cycle 2; 0.5, 1, 2, 4, 6, 8 and 10 hr post-dose on Day 1 of Cycle 2 (1 Cycle=28 days)
Cohort B: Time to Reach Cmax (Tmax) of Alectinib	DFP: pre-dose (0 hr) on Day 1 of Cycle 2; 0.5, 1, 2, 4, 6, 8 and 10 hr post-dose on Day 1 of Cycle 2 (1 Cycle=28 days)
Cohort B: Half-Life (t1/2) of Alectinib	DFP: pre-dose (0 hr) on Day 1 of Cycle 2; 0.5, 1, 2, 4, 6, 8 and 10 hr post-dose on Day 1 of Cycle 2 (1 Cycle=28 days)
Cohort C: Percentage of Participants with Objective Response as Assessed by the Investigator Based on RECIST v1.1	Baseline up to disease progression or death (up to approximately 6 years)
Cohort C: Percentage of Participants Free from Disease Progression as Assessed by the Investigator Based on RECIST v1.1 at Months 6 and 12	Months 6, 12
Cohort C: PFS as Assessed by the Investigator based on RECIST v1.1 in bTMB PP2	Baseline up to disease progression or death (up to approximately 6 years)
Cohort C: OS in bTMB PP2	Baseline up to approximately 6 years
Cohort D: Percentage of Participants who have shown improvement compared with Baseline in patient-reported cognitive function, fatigue, HRQoL, headache and vision disorder per the EORTC QLQ-C30	Baseline, every 4 weeks until disease progression, up to approximately 6 years
Cohort D: Percentage of Participants who have shown improvement compared with Baseline in patient-reported cognitive function, fatigue, HRQoL, headache and vision disorder per the EORTC QLQ-BN20	Baseline, every 4 weeks until disease progression, up to approximately 6 years
Cohort D: Mean Plasma Concentration of Entrectinib Metabolite M5	Pre-dose (0 hr), 1.5 and 4 hr post-dose on Day 1 of Cycles 1, 2, 3, 4 and 5; and pre-dose on Day 1 of each subsequent treatment cycle (1 cycle = 28 days).
Cohorts E, F: Proportion of Participants who Improve Compared with Baseline in Participant-Reported Lung Cancer Symptoms of Cough, Dyspnea, and Chest Pain, as Measured by the SILC	Baseline up to approximately 6 years
Cohort D: Mean Plasma Concentration of Entrectinib	Pre-dose (0 hr), 1.5 and 4 hr post-dose on Day 1 of Cycles 1, 2, 3, 4 and 5; and pre-dose on Day 1 of each subsequent treatment cycle (1 cycle = 28 days).
Cohort E: TIR as Assessed by the Investigator Based on RECIST v1.1	Month 9
Cohorts E, F: Serum Concentration of Atezolizumab	Pre-dose (0 hr), 1.5 and 4 hr post-dose on Day 1 of Cycles 1, 2, 3, 4 and 5; and pre-dose on Day 1 of each subsequent treatment cycle (1 cycle = 28 days)
Cohorts E, F: Time to Confirmed Deterioration (TTCD) in Participant-Reported Lung Cancer Symptoms of Cough, Dyspnea, and Chest Pain, as Measured by the Symptoms in Lung Cancer (SILC)	Baseline up to approximately 6 years
Cohort G: Plasma Concentration of Divarasib	Baseline up to approximately 6 years
Cohorts E, F: Change from Baseline in Anti-Drug Antibodies (ADAs)	Baseline up to approximately 6 years

Trial Locations

Locations (157)

UC Davis; 🇺🇸 Sacramento, California, United States

Rocky Mountain Cancer Center; 🇺🇸 Denver, Colorado, United States

SCRI Florida Cancer Specialists South; 🇺🇸 Fort Myers, Florida, United States

Florida Cancer Specialist, North Region; 🇺🇸 Saint Petersburg, Florida, United States

University of Kentucky; 🇺🇸 Lexington, Kentucky, United States

Comprehensive Cancer Centers of Nevada; 🇺🇸 Las Vegas, Nevada, United States

Dartmouth Hitchcock Medical Center; 🇺🇸 Lebanon, New Hampshire, United States

Montefiore Medical Center; 🇺🇸 Bronx, New York, United States

Weill Cornell Medical College-New York Presbyterian Hospital; 🇺🇸 New York, New York, United States

Oregon HSU; 🇺🇸 Portland, Oregon, United States

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