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

Phase 3

Completed

Conditions: Non-small Cell Lung Cancer

Interventions: Drug: Alectinib
Drug: Docetaxel
Drug: Pemetrexed

Registration Number: NCT02604342

Lead Sponsor: Hoffmann-La Roche

Brief Summary: 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).

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 119

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 & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Alectinib	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.
Premetrexed/Docetaxel	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.
Premetrexed/Docetaxel	Pemetrexed	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.

Primary Outcome Measures

Name	Time	Method
Progression-Free Survival (PFS) Using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 as Assessed by Investigator	Randomization to first documented disease progression, death from any cause, or study end (up to 33 months)	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.

Secondary Outcome Measures

Name	Time	Method
Percentage of Participants With CNS Objective Response Rate (ORR) With Measurable CNS Metastases at Baseline Using RECIST Version 1.1 as Assessed By IRC	Baseline through study end (up to 33 months)	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.
PFS Using RECIST Version 1.1 as Assessed by IRC	Approximately 15 months (Tumor assessments at baseline, every 6 weeks until progressive disease (PD), death or withdrawal from study prior to PD)	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.
Percentage of Participants With Objective Response of CR or PR Using RECIST Version 1.1 as Assessed by Investigator and IRC	Approximately 15 months (Tumor assessments at baseline, every 6 weeks until progressive disease (PD), death or withdrawal from study prior to PD)	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.
Percentage of Participants With Disease Control Using RECIST Version 1.1 as Assessed by Investigator and IRC	Approximately 15 months (Tumor assessments at baseline, every 6 weeks until progressive disease (PD), death or withdrawal from study prior to PD)	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.
Duration of Response (DOR) Using RECIST Version 1.1 as Assessed by Investigator and IRC	From the first documented CR or PR to the first documented disease progression, death, or study end (up to 33 months)	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.
PFS in C-ITT Population Using RECIST Version 1.1 as Assessed by Investigator and IRC	Approximately 15 months (Tumor assessments at baseline, every 6 weeks until progressive disease (PD), death or withdrawal from study prior to PD)	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.
Time to CNS Progression in C-ITT Population Using RECIST Version 1.1 as Assessed by IRC	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 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.
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
Percentage of Participants With Disease Control in C-ITT Population Using RECIST Version 1.1 as Assessed by IRC	From first documented CR, PR, or SD lasting at least 5 weeks through study end (up to 33 months)	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.
Percentage of Participants With ORR in C-ITT Population Using RECIST Version 1.1 as Assessed by IRC	Baseline through study end (up to 33 months)	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.
Duration of Response for Lesions in the CNS (C-DOR) Using RECIST Version 1.1 as Assessed by IRC	From the first documented CR or PR to the first documented disease progression, death, or study end (up to 33 months)	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.
Overall Survival (OS)	Randomization to death from any cause, through study end (up to 33 months)	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.
Compliance of European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 (EORTC QLQ-C30) Over Time	Baseline through Week 138	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.
Compliance of European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Lung Cancer-13 (EORTC QLQ-LC13) Over Time	Baseline through Week 138	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.
Compliance of European Quality of Life (EuroQoL) 5 Dimension 5 Levels (EQ-5D-5L) Questionnaire Over Time	Baseline through Week 60	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.
Time to Deterioration (TTD) in Lung Cancer Symptoms Using EORTC QLQ-LC13 Score for ITT Population	Baseline through study end (up to 33 months)	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.
Time to Deterioration (TTD) in Lung Cancer Symptoms Using EORTC QLQ-LC13 Score for C-ITT Population	Baseline through study end (up to 33 months)	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.
Time to Deterioration (TTD) in Lung Cancer Symptoms Using EORTC QLQ-LC30 Score for ITT Population	Baseline through study end (up to 33 months)	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.
Time to Deterioration (TTD) in Lung Cancer Symptoms Using EORTC QLQ-LC30 Score for C-ITT Population	Baseline through study end (up to 33 months)	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.
TTD in Composite of Three Symptoms (Cough, Dyspnea, and Chest Pain) Using EORTC QLQ-LC13 Score for C-ITT Population	Baseline through study end (up to 33 months)	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.
TTD in Composite of Three Symptoms (Cough, Dyspnea, and Chest Pain) Using EORTC QLQ-LC13 Score for ITT Population	Baseline through study end (up to 33 months)	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.
Percentage of Participants With Adverse Events (AEs)	Baseline through study end (up to 33 months)	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.

Trial Locations

Locations (54): Azienda Ospedaliera Di Perugia Ospedale s. Maria Della Misericordia; Oncologia Medica
🇮🇹
Perugia, Umbria, Italy
Medical University of Gdansk
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Gdansk, Poland
Azienda Ospedaliera San Camillo Forlanini; U.O.C. Pneumologia Ad Indirizzo Oncologico 1
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Roma, Lazio, Italy
CHVNG/E_Unidade 1; Servico de Pneumologia
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Vila Nova De Gaia, Portugal
MBAL Serdika EOOD
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Sofia, Bulgaria
University сlinic of headaches
🇷🇺
Moscow, Moskovskaja Oblast, Russian Federation
IPO do Porto; Servico de Oncologia Medica
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Porto, Portugal
Inonu University Medical Faculty Turgut Ozal Medical Center Medical Oncology Department
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Malatya, Turkey
Oslo Universitetssykehus HF; Radiumhospitalet
🇳🇴
Oslo, Norway
City Clinical Oncology Dispensary
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Saint-Petersburg, Russian Federation
S-Pb clinical scientific practical center of specialized kinds of medical care (oncological)
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Saint-Petersburg, Russian Federation
Main Military Clinical Hospital named after N.N. Burdenko
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Moscow, Russian Federation
FSBI"National Medical Research Center of Oncology named after N.N.Petrov" MHRF
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St Petersburg, Leningrad, Russian Federation
FNsP F. D. Roosevelta Banska Bystrica, II.Ocna klinika SZU
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Banska Bystrica, Slovakia
Istanbul Uni Capa Medical Faculty; Inst. of Oncology
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Istanbul, Turkey
Ege University Medical Faculty; Chest Diseases
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Izmir, Turkey
Azienda Ospedaliera di Rilievo Nazionale e di Alta Specialita San Giuseppe Moscati
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Avellino, Campania, Italy
Irccs Ospedale San Raffaele;Oncologia Medica
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Milano, Lombardia, Italy
UZ Antwerpen
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Edegem, Belgium
GHdC Site Notre Dame
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Charleroi, Belgium
UZ Gent
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Gent, Belgium
Hopital Robert Schuman; Pneumologie
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Vantoux, France
Hopital Larrey; Pneumologie
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Toulouse, France
Hopital Bichat Claude Bernard ; Service de Pneumologie
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Paris, France
Vychodoslovensky onkologicky ustav
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Košice, Slovakia
Centre Francois Baclesse
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Caen, France
Hopital Du Haut Leveque; Service Des Maladies Respiratoires
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Pessac, France
Hopital Foch; Pneumologie
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Suresnes, France
Hopital Sainte Musse; Pneumologie
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Toulon, France
Zentralklinik Bad Berka GmbH; Abteilung Onkologie und Hämatologie
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Bad Berka, Germany
Asklepios-Fachkliniken Muenchen-Gauting; Onkologie
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Gauting, Germany
Evang. Lungenklinik Berlin Klinik für Pneumologie
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Berlin, Germany
AORN Ospedali dei Colli Ospedale Monaldi; UOC Pneumologia ad indirizzo Oncologico
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Napoli, Campania, Italy
Pius-Hospital; Klinik fuer Haematologie und Onkologie
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Oldenburg, Germany
Fachklinik für Lungenerkrankungen
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Immenhausen, Germany
Semmelweis Egyetem X; Pulmonologiai Klinika
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Budapest, Hungary
Ospedale Provinciale Santa Maria Delle Croci; Oncologia Medica
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Ravenna, Emilia-Romagna, Italy
Istituto Nazionale Tumori Fondazione G. Pascale; U.O.C. Oncologia Medica Toraco Polmonare
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Napoli, Campania, Italy
A.O. Universitaria Pisana-Ospedale Cisanello; Dipartimento Cardio Toracico-Pneumologia Ii
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Pisa, Toscana, Italy
Irccs Istituto Europeo Di Oncologia (IEO); Oncologia Medica
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Milano, Lombardia, Italy
POLICLINICO RODOLICO, U.O. di Oncologia Medica
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Catania, Sicilia, Italy
Korea University Guro Hospital; Oncology
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Seoul, Korea, Republic of
Chonnam National University Hwasun Hospital
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Jeollanam-do, Korea, Republic of
Hospital Geral; Servico de Pneumologia
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Coimbra, Portugal
City Clinical Oncology Hospital
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Moscow, Russian Federation
Hospital de Cruces; Servicio de Oncologia
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Bilbao, Vizcaya, Spain
Hospital Universitario La Paz; Servicio de Oncologia
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Madrid, Spain
Hospital Universitario de Torrejon
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Torrejon de Ardoz, Madrid, Spain
Hospital Clinico Universitario Virgen de la Victoria; Servicio de Oncologia
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Malaga, Spain
Hospital Universitari i Politecnic La Fe de Valencia
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Valencia, Spain
Hacettepe Uni Medical Faculty Hospital; Oncology Dept
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Ankara, Turkey
Adana Acıbadem Hospital Oncology Department
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Adana, Turkey
Queen Elizabeth Hospital; Clinical Oncology
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Hong Kong, Hong Kong
Queen Mary Hospital; Dept. of Clinical Oncology
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Hong Kong, Hong Kong