A Study of First-line Maintenance Erlotinib Versus Erlotinib at Disease Progression in Participants With Advanced Non-Small Cell Lung Cancer (NSCLC) Who Have Not Progressed Following Platinum-Based Chemotherapy

A Randomized, Double-Blind, Placebo-Controlled Phase III Study of First-Line Maintenance Tarceva Versus Tarceva at the Time of Disease Progression in Patients With Advanced Non-Small Cell Lung Cancer (NSCLC) Who Have Not Progressed Following 4 Cycles of Platinum-Based Chemotherapy

This double-blind, placebo-controlled study will evaluate the benefit of first-line maintenance erlotinib (Tarceva) versus erlotinib at the time of disease progression in participants with advanced NSCLC who have not progressed following 4 cycles of platinum based-chemotherapy and whose tumor does not harbor an epidermal growth factor receptor (EGFR)-activating mutation. Participants will be randomized to receive either erlotinib 150 milligrams (mg) orally (PO) once daily or placebo. Participants who progress on placebo will receive erlotinib 150 mg PO once daily as second-line therapy, and those who progress on erlotinib may switch to a non-investigational, second-line chemotherapy. Treatments will continue until disease progression, death, or unacceptable toxicity. Participants may also be entered into a final Survival Follow-Up (SFU) period upon treatment discontinuation.

Study Overview

• Status: Completed
• Conditions: Non-Squamous Non-Small Cell Lung Cancer
• Intervention / Treatment: Drug: Erlotinib; Drug: Second-Line Chemotherapy; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 643
• Phase: Phase 3

Contacts and Locations

Study Locations

• Brazil
  • MG
    • Belo Horizonte, MG, Brazil, 30150-281
  • RO
    • Ijuí, RO, Brazil, 98700-000
  • RS
    • Lajeado, RS, Brazil, 95900-000
    • Porto Alegre, RS, Brazil, 90035-003
    • Porto Alegre, RS, Brazil, 90430-090
    • Porto Alegre, RS, Brazil, 90020-090
    • Porto Alegre, RS, Brazil, 90470340
  • SC
    • Florianopolis, SC, Brazil, 88034-000
  • SP
    • Santo André, SP, Brazil, 09060-650
• Bulgaria
  • Gabrovo, Bulgaria, 5300
  • Haskovo, Bulgaria, 6300
  • Plovdiv, Bulgaria, 4004
  • Ruse, Bulgaria, 7000
  • Sofia, Bulgaria, 1756
  • Sofia, Bulgaria, 1784
  • Sofia, Bulgaria, 1233
  • Sofia, Bulgaria, 1606
  • Sofia, Bulgaria, 1527
  • Sofia, Bulgaria, 1303
  • Varna, Bulgaria, 9010
• Canada
  • Quebec, Canada, G1V 4G5
  • Ontario
    • Windsor, Ontario, Canada, N8W 2X3
  • Quebec
    • Montreal, Quebec, Canada, H3T 1E2
  • Saskatchewan
    • Regina, Saskatchewan, Canada, S4T 7T1
• China
  • Beijing, China, 100730
  • Beijing, China, 100142
  • Changchun, China, 130012
  • Fuzhou, China, 350014
  • Guangzhou, China
  • Guangzhou, China, 510515
  • Harbin, China, 150081
  • Shanghai, China, 200433
  • Shanghai, China, 200030
  • Shantou, China, 515041
  • Shenyang, China, 110001
  • Suzhou, China, 215004
  • Tianjin, China, 300060
  • Wuhan, China, 430071
  • Xi'an, China, 710061
• Czech Republic
  • Ceske Budejovice, Czech Republic, 370 87
  • Jindrichuv Hradec, Czech Republic, 377 01
  • Nymburk, Czech Republic, 288 01
  • Ostrava - Poruba, Czech Republic, 708 52
  • Praha, Czech Republic, 150 06
  • Praha 8, Czech Republic, 180 81
  • Tabor, Czech Republic, 390 03
• France
  • Bayonne, France, 64109
  • Compiegne, France, 60321
  • Gap, France, 05007
  • Libourne, France, 33505
  • Lille, France, 59020
  • Nantes, France, 44202
  • St Brieuc, France, 22027
  • Villefranche-sur-Saone, France, 69655
• Hungary
  • Budapest, Hungary, 1125
  • Budapest, Hungary, 1121
  • Budapest, Hungary, 1122
  • Budapest, Hungary, 1145
  • Deszk, Hungary, 6772
  • Farkasgyepu, Hungary, 8582
  • Gyor, Hungary, 9024
  • Gyula, Hungary, 5703
  • Matrahaza, Hungary, 3233
  • Miskolc, Hungary, 3526
  • Szolnok, Hungary, 5000
  • Székesfehérvár, Hungary, 8000
  • Torokbalint, Hungary, 2045
  • Zalaegerszeg, Hungary, 8900
• Italy
  • Campania
    • Avellino, Campania, Italy, 83100
  • Emilia-Romagna
    • Bologna, Emilia-Romagna, Italy, 40138
    • Parma, Emilia-Romagna, Italy, 43100
  • Lazio
    • Roma, Lazio, Italy, 00144
    • Roma, Lazio, Italy, 00168
    • Roma, Lazio, Italy, 00151
  • Lombardia
    • Legnago, Lombardia, Italy, 37045
    • Treviglio, Lombardia, Italy, 24047
  • Puglia
    • S. Giovanni Rotondo, Puglia, Italy, 71013
  • Toscana
    • Livorno, Toscana, Italy, 57124
    • Pisa, Toscana, Italy, 56100
  • Veneto
    • Verona, Veneto, Italy, 37134
• Korea, Republic of
  • Gyeonggi-do, Korea, Republic of, 463-707
  • Seoul, Korea, Republic of, 150-713
  • Seoul, Korea, Republic of, 06351
  • Seoul, Korea, Republic of, 03722
  • Suwon, Korea, Republic of, 442-723
• Latvia
  • Daugavpils, Latvia, 5417
  • Riga, Latvia, LV1002
  • Riga, Latvia, LV-1079
• Lithuania
  • Kaunas, Lithuania, 50009
  • Vilnius, Lithuania, 08660
• Netherlands
  • Arnhem, Netherlands, 6800 TA
  • Heerlen, Netherlands, 6419 PC
  • Hoorn, Netherlands, 1625 HV
  • Sittard-Geleen, Netherlands, 6162 BG
  • Zutphen, Netherlands, 7207 AE
• Poland
  • Brzozów, Poland, 36-200
  • Krakow, Poland, 31-115
  • Poznan, Poland, 60-569
  • Wodzislaw Slaski, Poland, 44-300
  • Zamosc, Poland, 22-400
• Romania
  • Baia Mare, Romania, 430031
  • Braila, Romania, 810325
  • Brasov, Romania, 500152
  • Brasov, Romania, 500091
  • Bucuresti, Romania, 022328
  • Bucuresti, Romania, 010976
  • Cluj-Napoca, Romania, 400058
  • Cluj-Napoca, Romania, 400015
  • Cluj-Napoca, Romania, 400132
  • Oradea, Romania, 410167
  • Ploiesti, Romania, 100337
  • Targu-Mures, Romania, 540136
• Slovakia
  • Banska Bystrica, Slovakia, 975 17
  • Bardejov, Slovakia, 085 01
  • Kosice, Slovakia, 04001
  • Nove Zamky, Slovakia, 940 02
  • Poprad, Slovakia, 058 01
  • Rimavska Sobota, Slovakia, 97901
• South Africa
  • Cape Town, South Africa, 7570
  • Cape Town, South Africa, 7700
  • George, South Africa, 6530
  • Port Elizabeth, South Africa, 6045
  • Pretoria, South Africa, 0002
• Taiwan
  • Kaohsiung, Taiwan, 00833
  • Taichung, Taiwan, 40447
  • Taichung, Taiwan, 40705
  • Taipei, Taiwan, 100
  • Taipei, Taiwan, 112
  • Taipei, Taiwan, 00112
  • Taipei, Taiwan, 11490
• Thailand
  • Bangkok, Thailand, 10700
  • Hat Yai, Thailand, 90110
  • Muang, Thailand, 50200
  • Muang, Thailand, 57000
• Ukraine
  • Dnipropetrovsk, Ukraine, 49102
  • Donetsk, Ukraine, 83092
  • Kharkiv, Ukraine, 61024
  • Kirovograd, Ukraine, 25011
  • Kyiv, Ukraine, 03115
  • Kyiv, Ukraine, 03022
  • Kyiv, Ukraine, 04107
  • Lutsk, Ukraine, 63000
  • Sumy, Ukraine, 40005
  • Uzhgorod, Ukraine, 88000
  • Vinnytsya, Ukraine, 21029
  • Zaporizhzhya, Ukraine, 69040
• United States
  • California
    • Gilroy, California, United States, 95020
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
  • Missouri
    • Kansas City, Missouri, United States, 64132
  • Montana
    • Missoula, Montana, United States, 59802
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756
  • Ohio
    • Dayton, Ohio, United States, 45420
  • Tennessee
    • Chattanooga, Tennessee, United States, 37404
  • Washington
    • Spokane, Washington, United States, 99218
    • Tacoma, Washington, United States, 98405

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:

• Adults greater than or equal to (≥) 18 years of age, or legal age of consent if greater than 18
• Advanced or recurrent (Stage IIIB) or metastatic (Stage IV) NSCLC
• Completion of 4 cycles of platinum-based chemotherapy without progression (end of last chemotherapy cycle less than or equal to [≤] 28 days prior to randomization)
• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1

Exclusion Criteria:

• Prior exposure to agents directed at human epidermal growth factor receptor (HER) axis (e.g. erlotinib, gefitinib, cetuximab)
• Participants whose tumors harbor an EGFR-activating mutation
• Prior chemotherapy or therapy with systemic anti-neoplastic therapy for advanced disease before Screening
• Use of pemetrexed in maintenance setting (pemetrexed allowed during the chemotherapy run-in)
• Participants who have undergone complete tumor resection after responding to the platinum-based chemotherapy during the Screening phase
• Any other malignancies within 5 years, except for curatively resected carcinoma in situ of the cervix, basal or squamous cell skin cancer, ductal carcinoma in situ, or organ-confined prostate cancer
• Central nervous system (CNS) metastases or spinal cord compression that has not been definitely treated with surgery and/or radiation, or treated CNS metastases or spinal cord compression without stable disease for ≥2 months
• Human immunodeficiency virus (HIV), hepatitis B, or hepatitis C infection
• Any inflammatory changes of the surface of the eye

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Early Erlotinib; Participants will receive blinded erlotinib as 150 mg PO once daily in the maintenance setting until disease progression, death, or unacceptable toxicity. Those who demonstrate disease progression may be unblinded to receive an approved second-line therapy (but not EGFR targeted therapies) until disease progression, death, or unacceptable toxicity. Participants may be observed during a final SFU period after discontinuation from study treatment.	Drug: Erlotinib; Erlotinib will be administered as 150 mg PO once daily until disease progression, death, or unacceptable toxicity, as first-line maintenance or as second-line therapy for those who progress while receiving placebo.; Other Names: Tarceva; Drug: Second-Line Chemotherapy; Participants who progress on first-line maintenance erlotinib may receive an approved second-line therapy (but not EGFR targeted therapies) until disease progression, death, or unacceptable toxicity. The selected chemotherapy will be non-investigational and chosen at the discretion of the Investigator.
Placebo Comparator: Late Erlotinib; Participants will receive blinded placebo tablets PO once daily in the maintenance setting until disease progression, death, or unacceptable toxicity. Those who demonstrate disease progression may be unblinded to receive second-line erlotinib as 150 mg PO once daily until disease progression, death, or unacceptable toxicity. Participants may be observed during a final SFU period after discontinuation from study treatment.	Drug: Erlotinib; Erlotinib will be administered as 150 mg PO once daily until disease progression, death, or unacceptable toxicity, as first-line maintenance or as second-line therapy for those who progress while receiving placebo.; Other Names: Tarceva; Drug: Placebo; Placebo will be administered PO once daily as first-line maintenance until disease progression, death, or unacceptable toxicity.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants Who Died During the Overall Study	Participants were followed for survival until death or premature withdrawal. The percentage of participants who died during the Overall Study (BP, OLP, or SFU) was calculated.	Up to approximately 3.5 years (visits at Baseline and Weeks 6, 12, and 18 and every 12 weeks until/at disease progression during BP; per local standards during OLP; then every 12 weeks during SFU until death)
Overall Survival (OS) as Median Time to Event During the Overall Study	Participants were followed for survival until death or premature withdrawal. OS was defined as the interval between date of randomization and date of death from any cause. Median time to event during the Overall Study (BP, OLP, or SFU) was estimated using the Kaplan-Meier method and expressed in months.	Up to approximately 3.5 years (visits at Baseline and Weeks 6, 12, and 18 and every 12 weeks until/at disease progression during BP; per local standards during OLP; then every 12 weeks during SFU until death)
Percentage of Participants Event-Free (Alive) at 1 Year During the Overall Study	Participants were followed for survival until death or premature withdrawal. The percentage of participants event-free (i.e., still alive) at 1 year during the Overall Study was calculated.	At 1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants Who Died or Experienced Disease Progression During Blinded Treatment	Tumor response was evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Disease progression was defined as a greater than or equal to (≥) 20 percent (%) and ≥5-millimeter (mm) increase in the sum of target lesion diameters in reference to the smallest sum on study and/or substantial worsening in non-target disease. The percentage of participants who died or experienced disease progression during the BP was calculated.	Up to approximately 3.5 years (visits at Baseline and Weeks 6, 12, and 18 and every 12 weeks until/at disease progression during BP)
Progression-Free Survival (PFS) as Median Time to Event During Blinded Treatment	Tumor response was evaluated using RECIST version 1.1. Disease progression was defined as a ≥20% and ≥5-mm increase in the sum of target lesion diameters in reference to the smallest sum on study and/or substantial worsening in non-target disease. PFS was defined as the interval between date of randomization and date of first documented death or disease progression. Median time to event during the BP was estimated using the Kaplan-Meier method and expressed in weeks.	Up to approximately 3.5 years (visits at Baseline and Weeks 6, 12, and 18 and every 12 weeks until/at disease progression during BP)
Percentage of Participants Event-Free (Alive and No Disease Progression) at 6 Months During Blinded Treatment	Tumor response was evaluated using RECIST version 1.1. Disease progression was defined as a ≥20% and ≥5-mm increase in the sum of target lesion diameters in reference to the smallest sum on study and/or substantial worsening in non-target disease. The percentage of participants event-free (i.e., still alive and without disease progression) at 6 months during the BP was calculated.	At 6 months
Percentage of Participants With Complete Response (CR) or Partial Response (PR) According to RECIST During Blinded Treatment	Tumor response was evaluated using RECIST version 1.1. CR was defined as disappearance of all target and non-target lesions and short-axis reduction to less than (<) 10 mm of any pathological lymph nodes. PR was defined as a ≥30% decrease in the sum of target lesion diameters in reference to the Baseline sum. The percentage of participants with a best overall response of either CR or PR (i.e., the objective response rate [ORR]) during the BP was calculated, and corresponding 95% CI was constructed using the Pearson-Clopper method.	Up to approximately 3.5 years (visits at Baseline and Weeks 6, 12, and 18 and every 12 weeks until/at disease progression during BP)
Percentage of Participants by Best Overall Response According to RECIST During Blinded Treatment	Tumor response was evaluated using RECIST version 1.1. CR was defined as disappearance of all target and non-target lesions and short-axis reduction to <10 mm of any pathological lymph nodes. PR was defined as a ≥30% decrease in the sum of target lesion diameters in reference to the Baseline sum. Stable disease (SD) was defined as neither sufficient shrinkage in target lesions to qualify for PR nor sufficient growth to qualify for disease progression. Disease progression (progressive disease/PD) was defined as a ≥20% and ≥5-mm increase in the sum of target lesion diameters in reference to the smallest sum on study and/or substantial worsening in non-target disease. The percentage of participants with each level of best tumor response during the BP was calculated, and corresponding 95% CI was constructed using the Pearson-Clopper method.	Up to approximately 3.5 years (visits at Baseline and Weeks 6, 12, and 18 and every 12 weeks until/at disease progression during BP)
Percentage of Participants With CR, PR, or SD According to RECIST During Blinded Treatment	Tumor response was evaluated using RECIST version 1.1. CR was defined as disappearance of all target and non-target lesions and short-axis reduction to <10 mm of any pathological lymph nodes. PR was defined as a ≥30% decrease in the sum of target lesion diameters in reference to the Baseline sum. SD was defined as neither sufficient shrinkage in target lesions to qualify for PR nor sufficient growth to qualify for disease progression. The percentage of participants with a best overall response of CR, PR, or SD (i.e., the disease control rate [DCR]) during the BP was calculated, and corresponding 95% CI was constructed using the Pearson-Clopper method.	Up to approximately 3.5 years (visits at Baseline and Weeks 6, 12, and 18 and every 12 weeks until/at disease progression during BP)

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche

Study record dates

Study Major Dates

• Study Start: September 1, 2011
• Primary Completion (Actual): December 1, 2015
• Study Completion (Actual): January 1, 2016

Study Registration Dates

• First Submitted: April 4, 2011
• First Submitted That Met QC Criteria: April 4, 2011
• First Posted (Estimate): April 5, 2011

Study Record Updates

• Last Update Posted (Estimate): October 28, 2016
• Last Update Submitted That Met QC Criteria: September 6, 2016
• Last Verified: June 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Disease Attributes; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Disease Progression; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Erlotinib Hydrochloride
• Other Study ID Numbers: BO25460