Alectinib Versus Pemetrexed or Docetaxel in Anaplastic Lymphoma Kinase (ALK)-Positive Advanced Non-Small Cell Lung Cancer (NSCLC) Participants Previously Treated With Platinum-Based Chemotherapy and Crizotinib

Randomized, Multicenter, Phase III, Open-Label Study of Alectinib Versus Pemetrexed or Docetaxel in Anaplastic Lymphoma Kinase-Positive Advanced Non Small Cell Lung Cancer Patients Previously Treated With Platinum-Based Chemotherapy and Crizotinib

This randomized active-controlled multicenter Phase III open-label study will evaluate and compare between treatment groups the efficacy of alectinib versus chemotherapy in participants with ALK-positive advanced NSCLC who were previously treated with chemotherapy and crizotinib, as measured by investigator-assessed progression-free survival (PFS) and to evaluate and compare between treatment groups the central nervous system (CNS) objective response rate (C-ORR) in participants with measurable CNS metastases at baseline, as assessed by an Independent Review Committee (IRC).

Study Overview

• Status: Completed
• Conditions: Non-small Cell Lung Cancer
• Intervention / Treatment: Drug: Alectinib; Drug: Docetaxel; Drug: Pemetrexed

• Study Type: Interventional
• Enrollment (Actual): 119
• Phase: Phase 3

Contacts and Locations

Study Locations

• Belgium
  • Charleroi, Belgium, 6000
    • GHdC Site Notre Dame
  • Edegem, Belgium, 2650
    • UZ Antwerpen
  • Gent, Belgium, 9000
    • UZ Gent
• Bulgaria
  • Sofia, Bulgaria, 1632
    • MBAL Serdika EOOD
• France
  • Caen, France, 14076
    • Centre Francois Baclesse
  • Paris, France, 75877
    • Hopital Bichat Claude Bernard ; Service de Pneumologie
  • Pessac, France, 33600
    • Hopital Du Haut Leveque; Service Des Maladies Respiratoires
  • Suresnes, France, 92151
    • Hopital Foch; Pneumologie
  • Toulon, France, 83056
    • Hopital Sainte Musse; Pneumologie
  • Toulouse, France, 31059
    • Hopital Larrey; Pneumologie
  • Vantoux, France, 57070
    • Hopital Robert Schuman; Pneumologie
• Germany
  • Bad Berka, Germany, 99437
    • Zentralklinik Bad Berka GmbH; Abteilung Onkologie und Hämatologie
  • Berlin, Germany, 13125
    • Evang. Lungenklinik Berlin Klinik für Pneumologie
  • Gauting, Germany, 82131
    • Asklepios-Fachkliniken Muenchen-Gauting; Onkologie
  • Immenhausen, Germany, 34376
    • Fachklinik für Lungenerkrankungen
  • Oldenburg, Germany, 26121
    • Pius-Hospital; Klinik fuer Haematologie und Onkologie
• Hong Kong
  • Hong Kong, Hong Kong
    • Queen Mary Hospital; Dept. of Clinical Oncology
  • Hong Kong, Hong Kong
    • Queen Elizabeth Hospital; Clinical Oncology
• Hungary
  • Budapest, Hungary, 1083
    • Semmelweis Egyetem X; Pulmonologiai Klinika
• Italy
  • Campania
    • Avellino, Campania, Italy, 83100
      • Azienda Ospedaliera di Rilievo Nazionale e di Alta Specialita San Giuseppe Moscati
    • Napoli, Campania, Italy, 80131
      • AORN Ospedali dei Colli Ospedale Monaldi; UOC Pneumologia ad indirizzo Oncologico
    • Napoli, Campania, Italy, 80131
      • Istituto Nazionale Tumori Fondazione G. Pascale; U.O.C. Oncologia Medica Toraco Polmonare
  • Emilia-Romagna
    • Ravenna, Emilia-Romagna, Italy, 48100
      • Ospedale Provinciale Santa Maria Delle Croci; Oncologia Medica
  • Lazio
    • Roma, Lazio, Italy, 00152
      • Azienda Ospedaliera San Camillo Forlanini; U.O.C. Pneumologia Ad Indirizzo Oncologico 1
  • Lombardia
    • Milano, Lombardia, Italy, 20141
      • Irccs Istituto Europeo Di Oncologia (IEO); Oncologia Medica
    • Milano, Lombardia, Italy, 20132
      • Irccs Ospedale San Raffaele;Oncologia Medica
  • Sicilia
    • Catania, Sicilia, Italy, 95100
      • POLICLINICO RODOLICO, U.O. di Oncologia Medica
  • Toscana
    • Pisa, Toscana, Italy, 56124
      • A.O. Universitaria Pisana-Ospedale Cisanello; Dipartimento Cardio Toracico-Pneumologia Ii
  • Umbria
    • Perugia, Umbria, Italy, 06156
      • Azienda Ospedaliera Di Perugia Ospedale s. Maria Della Misericordia; Oncologia Medica
• Korea, Republic of
  • Jeollanam-do, Korea, Republic of, 58128
    • Chonnam National University Hwasun Hospital
  • Seoul, Korea, Republic of, 152-703
    • Korea University Guro Hospital; Oncology
• Norway
  • Oslo, Norway, 0310
    • Oslo Universitetssykehus HF; Radiumhospitalet
• Poland
  • Gdansk, Poland, 80-952
    • Medical University of Gdansk
• Portugal
  • Coimbra, Portugal, 3041-801
    • Hospital Geral; Servico de Pneumologia
  • Porto, Portugal, 4200-072
    • IPO do Porto; Servico de Oncologia Medica
  • Vila Nova De Gaia, Portugal, 4434-502
    • CHVNG/E_Unidade 1; Servico de Pneumologia
• Russian Federation
  • Moscow, Russian Federation, 143423
    • City Clinical Oncology Hospital
  • Moscow, Russian Federation, 105229
    • Main Military Clinical Hospital named after N.N. Burdenko
  • Saint-Petersburg, Russian Federation, 197758
    • S-Pb clinical scientific practical center of specialized kinds of medical care (oncological)
  • Saint-Petersburg, Russian Federation, 197022
    • City Clinical Oncology Dispensary
  • Leningrad
    • St Petersburg, Leningrad, Russian Federation, 197758
      • FSBI"National Medical Research Center of Oncology named after N.N.Petrov" MHRF
  • Moskovskaja Oblast
    • Moscow, Moskovskaja Oblast, Russian Federation, 121467
      • University сlinic of headaches
• Slovakia
  • Banska Bystrica, Slovakia, 975 17
    • FNsP F. D. Roosevelta Banska Bystrica, II.Ocna klinika SZU
  • Košice, Slovakia, 040 01
    • Vychodoslovensky onkologicky ustav
• Spain
  • Madrid, Spain, 28046
    • Hospital Universitario La Paz; Servicio de Oncologia
  • Malaga, Spain, 29010
    • Hospital Clinico Universitario Virgen de la Victoria; Servicio de Oncologia
  • Valencia, Spain, 46026
    • Hospital Universitari i Politecnic La Fe de Valencia
  • Madrid
    • Torrejon de Ardoz, Madrid, Spain, 28850
      • Hospital Universitario De Torrejon
  • Vizcaya
    • Bilbao, Vizcaya, Spain, 48903
      • Hospital de Cruces; Servicio de Oncologia
• Turkey
  • Adana, Turkey, 01130
    • Adana Acıbadem Hospital Oncology Department
  • Ankara, Turkey, 06100
    • Hacettepe Uni Medical Faculty Hospital; Oncology Dept
  • Istanbul, Turkey, 34093
    • Istanbul Uni Capa Medical Faculty; Inst. of Oncology
  • Izmir, Turkey, 35040
    • Ege University Medical Faculty; Chest Diseases
  • Malatya, Turkey, 44280
    • Inonu University Medical Faculty Turgut Ozal Medical Center Medical Oncology Department

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Histologically or cytologically confirmed diagnosis of advanced or recurrent (Stage IIIB not amenable for multimodality treatment) or metastatic (Stage IV) NSCLC that is ALK-positive. ALK positivity must have been determined by a validated fluorescence in situ hybridization (FISH) test (recommended probe, Vysis ALK Break-Apart Probe) or a validated immunohistochemistry (IHC) test (recommended antibody, clone D5F3)
• Participant had received two prior systemic lines of therapy, which must have included one line of platinum-based chemotherapy and one line of crizotinib
• Prior CNS or leptomeningeal metastases allowed if asymptomatic
• Participants with symptomatic CNS metastases for whom radiotherapy is not an option will be allowed to participate in this study
• Measurable disease by RECIST Version 1.1 prior to the administration of study treatment
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
• For all females of childbearing potential, a negative pregnancy test must be obtained within 3 days before starting study treatment

Exclusion Criteria:

• Participants with a previous malignancy within the past 3 years are excluded (other than curatively treated basal cell carcinoma of the skin, early gastrointestinal [GI] cancer by endoscopic resection or in situ carcinoma of the cervix)
• Participants who have received any previous ALK inhibitor other than crizotinib
• Any GI disorder that may affect 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: Alectinib; Participants will receive oral alectinib at a dose of 600 milligrams (mg) twice daily, taken with food until disease progression, unacceptable toxicity, withdrawal of consent or death.	Drug: Alectinib; Participants will receive oral alectinib at a dose of 600 mg twice daily, taken with food until disease progression, unacceptable toxicity, withdrawal of consent or death.
Active Comparator: Premetrexed/Docetaxel; Participants will receive chemotherapy with either pemetrexed (500 milligrams per square meter [mg/m^2] of body surface area) or docetaxel (75 mg/m^2) intravenously.	Drug: Docetaxel; Participants will receive docetaxel at a dose of 75 mg/m^2 of body surface area intravenously every 3 weeks, until disease progression, unacceptable toxicity, withdrawal of consent or death.; Other Names: Taxotere®; Drug: Pemetrexed; Participants will receive pemetrexed at a dose of 500 mg/m^2 of body surface area intravenously every 3 weeks, until disease progression, unacceptable toxicity, withdrawal of consent or death.; Other Names: Alimta®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-Free Survival (PFS) Using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 as Assessed by Investigator	PFS was defined as the time from randomization to the first documented disease progression, as determined using RECIST v1.1, or death from any cause, whichever occurred first. As per RECIST v1.1, disease progression is a 20% increase in the sum of the diameters of target lesions, an increase in size of measurable lesions by at least 5 millimeter (mm) and the appearance of new lesions.	Randomization to first documented disease progression, death from any cause, or study end (up to 33 months)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With CNS Objective Response Rate (ORR) With Measurable CNS Metastases at Baseline Using RECIST Version 1.1 as Assessed By IRC	Overall response rate in subjects with confirmed CNS response (C-ORR) was defined as the percentage of subjects who attained Complete Response (CR) or Partial Response (PR) for lesions in the CNS. As per RECIST v1.1, CR: Disappearance of all target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm, PR: At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters.	Baseline through study end (up to 33 months)
PFS Using RECIST Version 1.1 as Assessed by IRC	PFS was defined as the time from randomization to the first documented disease progression, as determined using RECIST v1.1, or death from any cause, whichever occurred first. As per RECIST v1.1, disease progression is a 20% increase in the sum of the diameters of target lesions, an increase in size of measurable lesions by at least 5 mm and the appearance of new lesions. This outcome measure was assessed as part of the primary analysis and was not repeated during final analysis.	Approximately 15 months (Tumor assessments at baseline, every 6 weeks until progressive disease (PD), death or withdrawal from study prior to PD)
Percentage of Participants With Objective Response of CR or PR Using RECIST Version 1.1 as Assessed by Investigator and IRC	ORR was defined as the percentage of participants who attained CR or PR. As per RECIST v1.1, CR: Disappearance of all target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm, PR: At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters. The IRC assessment was part of the primary analysis and was not repeated during final analysis.	Approximately 15 months (Tumor assessments at baseline, every 6 weeks until progressive disease (PD), death or withdrawal from study prior to PD)
Percentage of Participants With Disease Control Using RECIST Version 1.1 as Assessed by Investigator and IRC	Disease control rate (DCR) was defined as the percentage of participants who attained CR, PR, or stable disease (SD) of at least 5 weeks. As per RECIST v1.1, CR: Disappearance of all target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm, PR: At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters, SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of diameters since the treatment started. The IRC assessment was part of the primary analysis and was not repeated during final analysis.	Approximately 15 months (Tumor assessments at baseline, every 6 weeks until progressive disease (PD), death or withdrawal from study prior to PD)
Duration of Response (DOR) Using RECIST Version 1.1 as Assessed by Investigator and IRC	DOR was defined as the time from when response (CR or PR) was first documented to first documented disease progression or death, whichever occurred first. DOR was evaluated for participants who had a best overall response (BOR) of CR or PR. The IRC assessment was part of the primary analysis and was not repeated during final analysis.	From the first documented CR or PR to the first documented disease progression, death, or study end (up to 33 months)
PFS in C-ITT Population Using RECIST Version 1.1 as Assessed by Investigator and IRC	PFS was defined as the time from randomization to the first documented disease progression, as determined using RECIST v1.1, or death from any cause, whichever occurred first. As per RECIST v1.1, disease progression is a 20% increase in the sum of the diameters of target lesions, an increase in size of measurable lesions by at least 5 mm and the appearance of new lesions. This outcome measure assessment was part of the primary analysis and was not repeated during final analysis.	Approximately 15 months (Tumor assessments at baseline, every 6 weeks until progressive disease (PD), death or withdrawal from study prior to PD)
Time to CNS Progression in C-ITT Population Using RECIST Version 1.1 as Assessed by IRC	Time to CNS progression was defined as the time from randomization until radiographic evidence of CNS progression. As per RECIST v1.1, disease progression is a 20% increase in the sum of the diameters of target lesions, an increase in size of measurable lesions by at least 5 mm and the appearance of new lesions. This outcome measure assessment was part of the primary analysis and was not repeated during final analysis.	Approximately 15 months (Tumor assessments at baseline, every 6 weeks until progressive disease (PD), death or withdrawal from study prior to PD)
Percentage of Participants With Disease Control in C-ITT Population Using RECIST Version 1.1 as Assessed by IRC	Disease Control Rate (DCR) was defined as the percentage of participants who attained CR, PR, or stable disease (SD) of at least 5 weeks. As per RECIST v1.1, CR: Disappearance of all target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm, PR: At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters, SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of diameters since the treatment started.	From first documented CR, PR, or SD lasting at least 5 weeks through study end (up to 33 months)
Percentage of Participants With ORR in C-ITT Population Using RECIST Version 1.1 as Assessed by IRC	ORR was defined as the percentage of participants who attained CR or PR. As per RECIST v1.1, CR: Disappearance of all target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm, PR: At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters.	Baseline through study end (up to 33 months)
Duration of Response for Lesions in the CNS (C-DOR) Using RECIST Version 1.1 as Assessed by IRC	DOR was defined as the time from when response (CR or PR) was first documented to first documented disease progression or death, whichever occurred first. C-DOR was defined in a similar way for lesions in the CNS, taking into account all lesions in the body. DOR was evaluated for participants who had a BOR of CR or PR.	From the first documented CR or PR to the first documented disease progression, death, or study end (up to 33 months)
Overall Survival (OS)	Overall survival (OS) was defined as the time from randomization to death from any cause. OS was confounded by cross-over of participants to the alectinib arm.	Randomization to death from any cause, through study end (up to 33 months)
Plasma Concentration of Alectinib		Predose (2 hours) at Baseline, Week 3 and Week 6
Plasma Concentration of Alectinib Metabolite		Predose (2 hours) at Baseline, Week 3 and Week 6
Compliance of European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 (EORTC QLQ-C30) Over Time	Percentage of participants who filled out an EORTC QLQ-C30 questionnaire at a visit. The EORTC QLQ-C30 questionnaire consisted of 30 questions generating five functional scores (physical, role, cognitive, emotional, and social); a global health status/global quality of life scale score; three symptom scale scores (fatigue, pain, and nausea and vomiting); and six stand alone one-item scores that capture additional symptoms (dyspnea, appetite loss, sleep disturbance, constipation, and diarrhea) and perceived financial burden.	Baseline through Week 138
Compliance of European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Lung Cancer-13 (EORTC QLQ-LC13) Over Time	Percentage of participants who filled out an EORTC QLQ-LC13 questionnaire at a visit. The EORTC QLQ-LC13 module generated one multiple-item scale score assessing dyspnea and a series of single item scores assessing chest pain, arm/shoulder pain, pain in other parts, coughing, sore mouth, dysphagia, peripheral neuropathy, alopecia, and hemoptysis.	Baseline through Week 138
Compliance of European Quality of Life (EuroQoL) 5 Dimension 5 Levels (EQ-5D-5L) Questionnaire Over Time	Percentage of participants who filled out an ED-5D-5L questionnaire at a visit. EQ-5D-5L: A generic preference-based health utility measure that provides a single index value for health status. The instrument consists of two parts. The first part, health-state classification, contains five dimensions of health: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression.	Baseline through Week 60
Time to Deterioration (TTD) in Lung Cancer Symptoms Using EORTC QLQ-LC13 Score for ITT Population	TTD in the overall population is defined as time from randomization to the earliest time with a ≥10-point increase from baseline for symptoms domains (or decrease for functioning domains from baseline for cough, dyspnea [single item and multi-item scales] chest pain [single item], pain in arm/shoulder and fatigue as measured by the EORTC QLQ-LC13.	Baseline through study end (up to 33 months)
Time to Deterioration (TTD) in Lung Cancer Symptoms Using EORTC QLQ-LC13 Score for C-ITT Population	TTD in the overall population is defined as time from randomization to the earliest time with a ≥10-point increase from baseline for symptoms domains (or decrease for functioning domains from baseline for cough, dyspnea [single item and multi-item scales] chest pain [single item], pain in arm/shoulder and fatigue as measured by the EORTC QLQ-LC13.	Baseline through study end (up to 33 months)
Time to Deterioration (TTD) in Lung Cancer Symptoms Using EORTC QLQ-LC30 Score for ITT Population	TTD in the overall population is defined as time from randomization to the earliest time with a ≥10-point increase from baseline for symptoms domains (or decrease for functioning domains from baseline for cough, dyspnea [single item and multi-item scales] chest pain [single item], pain in arm/shoulder and fatigue as measured by the EORTC QLQ-C30.	Baseline through study end (up to 33 months)
Time to Deterioration (TTD) in Lung Cancer Symptoms Using EORTC QLQ-LC30 Score for C-ITT Population	TTD in the overall population is defined as time from randomization to the earliest time with a ≥10-point increase from baseline for symptoms domains (or decrease for functioning domains from baseline for cough, dyspnea [single item and multi-item scales] chest pain [single item], pain in arm/shoulder and fatigue as measured by the EORTC QLQ-C30.	Baseline through study end (up to 33 months)
TTD in Composite of Three Symptoms (Cough, Dyspnea, and Chest Pain) Using EORTC QLQ-LC13 Score for C-ITT Population	TTD for a composite of three symptoms (cough, dyspnea, chest pain) in the overall population is defined as time from randomization to the earliest time with a ≥10-point increase from baseline for any component of the composite of the three following symptoms [cough, dyspnea [multi-item subscales QLQ-LC13] and chest pain]) as measured by the EORTC QLQ-LC13.	Baseline through study end (up to 33 months)
TTD in Composite of Three Symptoms (Cough, Dyspnea, and Chest Pain) Using EORTC QLQ-LC13 Score for ITT Population	TTD for a composite of three symptoms (cough, dyspnea, chest pain) in the overall population is defined as time from randomization to the earliest time with a ≥10-point increase from baseline for any component of the composite of the three following symptoms [cough, dyspnea [multi-item subscales QLQ-LC13] and chest pain]) as measured by the EORTC QLQ-LC13.	Baseline through study end (up to 33 months)
Percentage of Participants With Adverse Events (AEs)	An adverse event (AE) is any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.	Baseline through study end (up to 33 months)

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche

Publications and helpful links

General Publications

• Novello S, Mazieres J, Oh IJ, de Castro J, Migliorino MR, Helland A, Dziadziuszko R, Griesinger F, Kotb A, Zeaiter A, Cardona A, Balas B, Johannsdottir HK, Das-Gupta A, Wolf J. Alectinib versus chemotherapy in crizotinib-pretreated anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer: results from the phase III ALUR study. Ann Oncol. 2018 Jun 1;29(6):1409-1416. doi: 10.1093/annonc/mdy121.

Study record dates

Study Major Dates

• Study Start (Actual): November 3, 2015
• Primary Completion (Actual): January 26, 2017
• Study Completion (Actual): August 13, 2018

Study Registration Dates

• First Submitted: November 11, 2015
• First Submitted That Met QC Criteria: November 11, 2015
• First Posted (Estimate): November 13, 2015

Study Record Updates

• Last Update Posted (Actual): October 29, 2019
• Last Update Submitted That Met QC Criteria: October 7, 2019
• Last Verified: October 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Folic Acid Antagonists; Docetaxel; Pemetrexed
• Other Study ID Numbers: MO29750; 2015-000634-29 (EudraCT Number)

Drug and device information, study documents

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