A Study to Compare the Efficacy and Safety of Entrectinib and Crizotinib in Participants With Advanced or Metastatic ROS1 Non-small Cell Lung Cancer (NSCLC) With and Without Central Nervous System (CNS) Metastases

Randomized, Open Label, Multicenter, Phase III Study of Entrectinib Versus Crizotinib in Patients With Locally-Advanced or Metastatic Non-Small Cell Lung Cancer Harboring ROS1 Gene Rearrangements With and Without Central Nervous System Metastases

The study will compare the efficacy and safety of entrectinib with crizotinib in participants with advanced or metastatic ROS1 non-small cell lung cancer (NSCLC). The participants will self-administer oral entrectinib or crizotinib as described in the protocol and local prescribing information. Treatments will continue until progressive disease, unacceptable toxicity, death, or withdrawal from the study, whichever occurs first.

Study Overview

• Status: Active, not recruiting
• Conditions: Carcinoma, Non-Small-Cell Lung
• Intervention / Treatment: Drug: Entrectinib; Drug: Crizotinib

• Study Type: Interventional
• Enrollment (Estimated): 220
• Phase: Phase 3

Contacts and Locations

Study Locations

• Brazil
  • Rio de Janeiro, Brazil, 22250-905
    • Oncoclinicas Rio de Janeiro S.A.
  • Ceará
    • Fortaleza, Ceará, Brazil, 60130-241
      • Oncocentro Serviços Médicos e Hospitalares Ltda
  • Estado de Bahia
    • Salvador, Estado de Bahia, Brazil, 41253-190
      • Hospital Sao Rafael - HSR
  • Federal District
    • Brasília, Federal District, Brazil, 70390-140
      • Hospitais Integrados da Gavea S/A
  • Santa Catarina
    • Florianópolis, Santa Catarina, Brazil, 88020-210
      • Centro de Pesquisa e Ensino em Oncologia de Santa Catarina - CEPEN
  • São Paulo
    • Barretos, São Paulo, Brazil, 14784-400
      • Hospital de Cancer de Barretos
    • São Paulo, São Paulo, Brazil, 01246-000
      • Instituto do Câncer do Estado de São Paulo - ICESP
• China
  • Changchun, China, 132013
    • Jilin Cancer Hospital
  • Changsha, China, 410013
    • Hunan Cancer Hospital
  • Changsha, China, 410011
    • The Second Xiangya Hospital of Central South University
  • Chengdu, China, 610041
    • West China Hospital, Sichuan University
  • Guangzhou, China, 510120
    • The First Affiliated Hospital of Guangzhou Medical University
  • Harbin, China, 150081
    • Harbin Medical University Cancer Hospital
  • Jining, China, 272029
    • Affiliated Hospital of Jining Medical University
  • Nanning, China, 530021
    • Guangxi Cancer Hospital of Guangxi Medical University
  • Shanghai, China, 200433
    • Shanghai Pulmonary Hospital
  • Shiyan, China, 442000
    • Taihe Hospital of Hubei University of Medicine
  • Wuhan, China, 430048
    • Union Hospital Tongji Medical College Huazhong University of Science and Technology
• Croatia
  • Zagreb, Croatia, 10000
    • Clinical Hospital Centre Zagreb
• France
  • Bordeaux, France, 33076
    • Institut Bergonie
  • Lille, France, 59037
    • CHRU LILLE
  • Lyon, France, 69008
    • Centre Leon Berard
  • Marseille, France, 13015
    • Hopital Nord AP-HM
  • Rennes, France, 35033
    • CHU Rennes - Hôpital Pontchaillou
  • Toulouse, France, 31059
    • Hôpital Larrey
  • Vantoux, France, 57070
    • Hopital Robert Schuman
• Germany
  • Berlin, Germany, 14165
    • HELIOS Klinikum Emil von Behring Klinik f.Pneumologie Onkologie u.Infektiologie
  • Oldenburg, Germany, 26121
    • Pius-Hospital
• Greece
  • Athens, Greece, 185 47
    • Metropolitan Hospital
• India
  • Kerala
    • Kozhikode, Kerala, India, 673601
      • MVR Cancer Centre and Research Institute
  • Maharashtra
    • Mumbai, Maharashtra, India, 400036
      • MOC Cancer Care & Research Centre (Unit of Cellcure Cancer Centre Pvt Ltd)
  • National Capital Territory of Delhi
    • New Delhi, National Capital Territory of Delhi, India, 110029
      • All India Institute of Medical Sciences (AIIMS)
  • Uttar Pradesh
    • Varanasi, Uttar Pradesh, India, 221005
      • Mahamana Pandit Madan Mohan Malaviya Cancer Centre-TMC
  • West Bengal
    • Kolkata, West Bengal, India, 700160
      • Tata Medical Center
• Italy
  • Lazio
    • Rome, Lazio, Italy, 00152
      • Azienda Ospedaliera San Camillo Forlanini
  • Liguria
    • Genoa, Liguria, Italy, 16132
      • IRCCS Istituto Nazionale Per La Ricerca Sul Cancro (IST)
  • Piedmont
    • Orbassano, Piedmont, Italy, 10043
      • Azienda Sanitaria Ospedaliera S Luigi Gonzaga
  • Veneto
    • Padova, Veneto, Italy, 35128
      • IRCCS Istituto Oncologico Veneto (IOV)
• Jordan
  • Amman, Jordan, 1269
    • King Hussein Cancer Center
• Lebanon
  • Beirut, Lebanon
    • Hotel Dieu de France
• Mexico
  • Jalisco
    • Guadalajara, Jalisco, Mexico, 44280
      • Hospital Civil de Guadalajara Fray Antonio Alcalde
  • Mexico CITY (federal District)
    • Mexico City, Mexico CITY (federal District), Mexico, 03100
      • Health Pharma Professional Research
• Netherlands
  • Amsterdam, Netherlands, 1066 CX
    • NKI/AvL
  • Nijmegen, Netherlands, 6525 GA
    • UMC St Radboud
  • Rotterdam, Netherlands, 3015 GD
    • Erasmus MC
• Romania
  • Cluj County, Romania, 407280
    • Amethyst Cluj
  • Ploieşti, Romania
    • Emergency County Clinical Hospital Ploiesti
• Slovakia
  • Bratislava, Slovakia, 826 06
    • Univerzitna nemocnica Bratislava
• Spain
  • A Coruña, Spain, 15006
    • Complejo Hospitalario Universitario A Coruña (CHUAC)
  • Barcelona, Spain, 08003
    • Hospital del Mar
  • Barcelona, Spain, 08908
    • Institut Catala d Oncologia Hospital Duran i Reynals
  • Madrid, Spain, 28034
    • Hospital Ramon y Cajal
  • Málaga, Spain, 29010
    • Hospital Regional Universitario Carlos Haya
• Sweden
  • Stockholm, Sweden, 171 76
    • Karolinska Universitetssjukhuset, Solna
• Thailand
  • Bangkok, Thailand, 10330
    • Chulalongkorn Hospital
  • Bangkok, Thailand, 10700
    • Faculty of Med. Siriraj Hosp.
  • Chanthaburi, Thailand, 22000
    • Prapokklao Hospital
  • Songkhla, Thailand, 90110
    • Songklanagarind Hospital
  • Wachira Phayaban, Thailand, 10300
    • Bangkok Metropolitan Administration Medical College and Vajira Hospital
• Turkey (Türkiye)
  • Ankara, Turkey (Türkiye), 06500
    • Gazi University Medical Faculty, Oncology Hospital
  • Ankara, Turkey (Türkiye), 06680
    • Liv Hospital Ankara

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Histologically or cytologically-confirmed diagnosis of advanced or recurrent (Stage IIIB/C not amenable for radical treatment) or metastatic (Stage IV) NSCLC that harbors a documented ROS1 gene rearrangement.
• No prior treatment with a ROS1 tyrosine kinase inhibitor, chemotherapy or other systemic therapy for advanced or recurrent (Stage IIIB/C not amenable for radical treatment) or metastatic (Stage IV) NSCLC
• Prior radiotherapy is allowed if more than 14 days have elapsed between the end of treatment and randomization
• Measurable systemic disease according to RECIST v1.1
• Participants with measurable and non-measurable CNS lesions per RECIST v1.1, including leptomeningeal carcinomatosis
• Life expectancy of at least 12 weeks
• Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2
• Adequate hematologic, renal, liver functions
• Participants must have recovered from effects of any major surgery or significant traumatic injury at least 28 days before the first dose of study treatment
• Ability to swallow entrectinib and crizotinib intact without chewing, crushing, or opening the capsules
• For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods with a failure rate of <1% per year during the treatment period and for up to 5 weeks after the last dose of entrectinib or for at least 90 days after the last dose of crizotinib
• For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm.

Exclusion Criteria:

• Prior treatment with a ROS1 tyrosine kinase inhibitor, chemotherapy or other systemic therapy for advanced or recurrent (Stage IIIB/C not amenable for radical treatment) or metastatic (Stage IV) NSCLC
• NCI-CTCAE v5.0 Grade 3 or higher toxicities due to any prior therapy (excluding alopecia, fatigue, nausea and lack of appetite), which have not shown improvement and are strictly considered to interfere with current study drug
• History of recent (within the past 3 months) symptomatic congestive heart failure or ejection fraction ≤ 50% observed during screening for the study
• History of prolonged corrected QTc interval
• Peripheral sensory neuropathy ≥ Grade 2
• Known interstitial lung disease, interstitial fibrosis, or history of tyrosine kinase inhibitor-induced pneumonitis
• Previous malignancy within the past 3 years
• Incomplete recovery from any surgery prior to the start of study treatment
• Active GI disease (e.g., Crohn's disease, ulcerative colitis or short gut syndrome) or other malabsorption syndrome that would reasonably impact drug absorption
• History of prior therapy-induced pneumonitis
• Any condition (in the past 3 months) e.g., myocardial infarction, unstable angina, coronary/peripheral artery bypass graft, cerebrovascular accident or transient ischemic attack, stroke, symptomatic bradycardia, or uncontrolled arrhythmias requiring medication
• Known active infections (bacterial, fungal or viral, including human immunodeficiency virus positive)
• History of hypersensitivity to any of the additives in the entrectinib and/or crizotinib drug formulations
• Pregnant or lactating women
• Known human immunodeficiency virus (HIV) positivity or acquired immunodeficiency syndrome (AIDS)-related illness
• Any clinically significant concomitant disease or condition that could interfere with, or for which the treatment might interfere with, the conduct of the study or the absorption of oral medications.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Entrectinib; Participants will be enrolled to receive 600 mg entrectinib orally once daily until progressive disease, unacceptable toxicity, death, or withdrawal from the study, whichever occurs first.	Drug: Entrectinib; Entrectinib will be self-administered orally at a dose of 600 mg (three 200 mg capsules per day) once daily with or without food.
Active Comparator: Crizotinib; Participants will be enrolled to receive 250 mg crizotinib orally twice daily until progressive disease, unacceptable toxicity, death, or withdrawal from the study, whichever occurs first.	Drug: Crizotinib; Crizotinib will be self-administered orally at a dose of 250 mg twice daily with or without food.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival (PFS) in participants with central nervous system (CNS) metastases at baseline	PFS is defined as the time from randomization to the first documented disease progression (extracranial or intracranial) or death from any cause whichever occurs first determined by a blinded independent review committee (BIRC) using Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1).	Up to 7 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival in the Central Nervous System (CNS-PFS)	CNS-PFS is defined as the time from randomization to the first documented disease progression in the CNS or death from any cause, whichever occurs first, as determined by the BIRC using RECIST v1.1	Up to 7 Years
Overall response rate (ORR)	ORR is defined as the percentage of participants who attain Complete Response (CR) or Partial Response (PR) as assessed by the BIRC and the investigator per RECIST v1.1	Up to 7 Years
Duration of response (DOR)	DOR is defined as the time from when response (CR or PR) is first documented to disease progression or death, whichever occurs first, as assessed by the BIRC and the investigator per RECIST v1.1	Up to 7 Years
Progression-free survival (PFS)	PFS is defined as the time from randomization to the first documented disease progression (extracranial or intracranial) or death from any cause, whichever occurs first, as determined by the BICR and investigator using RECIST v1.1	Up to 7 years
Overall survival (OS)	OS is defined as the time from randomization to death from any cause	Up to 7 Years
Percentage of participants with confirmed deterioration as assessed by the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30)		Up to 7 Years
Percentage of participants with impact on lung cancer-specific symptoms assessed by the EORTC QLQ-LC13		Up to 7 Years
Objective response rate in the CNS-ORR in participants with CNS metastases at baseline	CNS-ORR is defined as the percentage of participants who attain CR or PR for lesions in the CNS, as determined by the BIRC per RECIST v1.1	Up to 7 Years
Duration of response in the CNS (CNS-DOR) in participants with CNS metastases at baseline	CNS-DOR is defined as the time from when a CNS response (CR or PR) is first documented to disease progression in the CNS, as determined by the BIRC per RECIST v1.1	Up to 7 Years
Percentage of participants with Adverse Events and Serious Adverse Events and Adverse Events leading to dose modifications/interruptions, study drug withdrawal or death	Assessed by the investigator according to the NCI CTCAE v5.0	Up to 7 Years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in the scores of EuroQol 5-Dimension Questionnaire, 5-level version (EQ-5D-5L)	To evaluate health status utility scores of participants to inform pharmacoeconomic modeling using the EuroQol 5-Dimension Questionnaire (5-level version; EQ-5D-5L) index-based and visual analog scale (VAS) scores	Up to 7 Years

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche
• Investigators: Study Director: Clinical Trials, Hoffmann-La Roche

Study record dates

Study Major Dates

• Study Start (Actual): September 30, 2021
• Primary Completion (Estimated): June 26, 2028
• Study Completion (Estimated): June 26, 2028

Study Registration Dates

• First Submitted: October 22, 2020
• First Submitted That Met QC Criteria: October 22, 2020
• First Posted (Actual): October 27, 2020

Study Record Updates

• Last Update Posted (Actual): May 28, 2026
• Last Update Submitted That Met QC Criteria: May 27, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: ROS1 Non-small-cell lung
• 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; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Piperidines; Aminopyridines; Crizotinib; entrectinib
• Other Study ID Numbers: MO41552; 2019-003859-11 (EudraCT Number); 2023-507494-18-00 (Ctis)

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
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

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