Non-Squamous Non-Small Cell Lung Cancer
Conditions
Brief summary
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.
Interventions
DRUGPlacebo
Placebo will be administered PO once daily as first-line maintenance until disease progression, death, or unacceptable toxicity.
DRUGErlotinib
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.
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.
Sponsors
Hoffmann-La Roche
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Died During the Overall Study | 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) | 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. |
| Overall Survival (OS) as Median Time to Event During the Overall Study | 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) | 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. |
| Percentage of Participants Event-Free (Alive) at 1 Year During the Overall Study | At 1 year | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Complete Response (CR) or Partial Response (PR) According to RECIST During Blinded Treatment | 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) | 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. |
| Percentage of Participants Who Died or Experienced Disease Progression During Blinded Treatment | 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) | 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. |
| Percentage of Participants With CR, PR, or SD According to RECIST During Blinded Treatment | 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) | 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. |
| Percentage of Participants by Best Overall Response According to RECIST During Blinded Treatment | 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) | 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. |
| Progression-Free Survival (PFS) as Median Time to Event During Blinded Treatment | 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) | 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. |
| Percentage of Participants Event-Free (Alive and No Disease Progression) at 6 Months During Blinded Treatment | At 6 months | 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. |
Countries
Brazil, Bulgaria, Canada, China, Czechia, France, Hungary, Italy, Latvia, Lithuania, Netherlands, Poland, Romania, Slovakia, South Africa, South Korea, Taiwan, Thailand, Ukraine, United States
Participant flow
Pre-assignment details
The study consisted of three periods: a Blinded Phase (BP), an Open-Label Phase (OLP), and final Survival Follow-Up (SFU). These periods were not necessarily sequential, because the OLP could be skipped in select participants. Therefore, the reasons for discontinuation are presented altogether within the Overall Study.
Participants by arm
| Arm | Count |
|---|---|
| Late Erlotinib Participants received blinded placebo tablets PO once daily during the BP in the maintenance setting until disease progression, death, or unacceptable toxicity. Those who demonstrated disease progression were unblinded and could receive second-line erlotinib tablets during the OLP as 150 mg PO once daily, provided by the Sponsor. This treatment continued until disease progression, death, or unacceptable toxicity. If disease progression or unacceptable toxicity occurred during the OLP, the participant entered a final SFU period. Participants could also enter the SFU period directly after the BP if they were unable to receive second-line treatment per protocol. | 321 |
| Early Erlotinib Participants received blinded erlotinib tablets, 150 mg PO once daily during the BP in the maintenance setting until disease progression, death, or unacceptable toxicity. Those who demonstrated disease progression were unblinded and could receive an approved second-line therapy (but not EGFR targeted therapies) or BSC as chosen by the investigator during the OLP. This treatment continued until disease progression, death, or unacceptable toxicity. If disease progression or unacceptable toxicity occurred during the OLP, the participant entered a final SFU period. Participants could also enter the SFU period directly after the BP if they were unable to receive second-line treatment per protocol. | 322 |
| Total | 643 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 0 |
| Overall Study | Death | 243 | 258 |
| Overall Study | Disease Progression | 17 | 14 |
| Overall Study | Lost to Follow-up | 6 | 7 |
| Overall Study | Other | 11 | 6 |
| Overall Study | Study Closed by the Sponsor | 36 | 31 |
| Overall Study | Withdrawal by Subject | 6 | 6 |
Baseline characteristics
| Characteristic | Late Erlotinib | Early Erlotinib | Total |
|---|---|---|---|
| Age, Continuous | 60.6 years STANDARD_DEVIATION 9.1 | 60.8 years STANDARD_DEVIATION 8.8 | 60.7 years STANDARD_DEVIATION 8.9 |
| Sex: Female, Male Female | 77 Participants | 84 Participants | 161 Participants |
| Sex: Female, Male Male | 244 Participants | 238 Participants | 482 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 107 / 319 | 206 / 322 | 1 / 1 | 0 / 0 |
| serious Total, serious adverse events | 27 / 319 | 36 / 322 | 23 / 248 | 8 / 162 |
Outcome results
Primary
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.
Time frame: 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)
Population: ITT Population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Late Erlotinib | Overall Survival (OS) as Median Time to Event During the Overall Study | 9.46 months |
| Early Erlotinib | Overall Survival (OS) as Median Time to Event During the Overall Study | 9.72 months |
Comparison: Unstratified Analysis.p-value: 0.818395% CI: [0.85, 1.22]Log Rank
Comparison: Stratified Analysis: Stratified according to tumor histology, stage of disease, objective response at Baseline, bevacizumab use, smoking status, and region of enrollment.p-value: 0.525695% CI: [0.87, 1.32]Log Rank
Primary
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.
Time frame: At 1 year
Population: ITT Population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Late Erlotinib | Percentage of Participants Event-Free (Alive) at 1 Year During the Overall Study | 41.75 percentage of participants |
| Early Erlotinib | Percentage of Participants Event-Free (Alive) at 1 Year During the Overall Study | 42.15 percentage of participants |
p-value: 0.920795% CI: [-8.25, 7.45]Chi-squared
Primary
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.
Time frame: 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)
Population: ITT Population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Late Erlotinib | Percentage of Participants Who Died During the Overall Study | 73.2 percentage of participants |
| Early Erlotinib | Percentage of Participants Who Died During the Overall Study | 75.2 percentage of participants |
Secondary
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.
Time frame: 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)
Population: ITT Population.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Late Erlotinib | Percentage of Participants by Best Overall Response According to RECIST During Blinded Treatment | PR | 3.1 percentage of participants |
| Late Erlotinib | Percentage of Participants by Best Overall Response According to RECIST During Blinded Treatment | PD | 38.6 percentage of participants |
| Late Erlotinib | Percentage of Participants by Best Overall Response According to RECIST During Blinded Treatment | SD | 55.5 percentage of participants |
| Late Erlotinib | Percentage of Participants by Best Overall Response According to RECIST During Blinded Treatment | Missing | 2.2 percentage of participants |
| Late Erlotinib | Percentage of Participants by Best Overall Response According to RECIST During Blinded Treatment | CR | 0.6 percentage of participants |
| Early Erlotinib | Percentage of Participants by Best Overall Response According to RECIST During Blinded Treatment | Missing | 6.5 percentage of participants |
| Early Erlotinib | Percentage of Participants by Best Overall Response According to RECIST During Blinded Treatment | CR | 0.9 percentage of participants |
| Early Erlotinib | Percentage of Participants by Best Overall Response According to RECIST During Blinded Treatment | PR | 5.6 percentage of participants |
| Early Erlotinib | Percentage of Participants by Best Overall Response According to RECIST During Blinded Treatment | SD | 54.7 percentage of participants |
| Early Erlotinib | Percentage of Participants by Best Overall Response According to RECIST During Blinded Treatment | PD | 32.3 percentage of participants |
Secondary
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.
Time frame: At 6 months
Population: ITT Population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Late Erlotinib | Percentage of Participants Event-Free (Alive and No Disease Progression) at 6 Months During Blinded Treatment | 24.22 percentage of participants |
| Early Erlotinib | Percentage of Participants Event-Free (Alive and No Disease Progression) at 6 Months During Blinded Treatment | 27.11 percentage of participants |
p-value: 0.406995% CI: [-9.7, 3.93]Chi-squared
Secondary
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.
Time frame: 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)
Population: ITT Population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Late Erlotinib | Percentage of Participants Who Died or Experienced Disease Progression During Blinded Treatment | 95.0 percentage of participants |
| Early Erlotinib | Percentage of Participants Who Died or Experienced Disease Progression During Blinded Treatment | 94.1 percentage of participants |
Secondary
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.
Time frame: 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)
Population: ITT Population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Late Erlotinib | Percentage of Participants With Complete Response (CR) or Partial Response (PR) According to RECIST During Blinded Treatment | 3.7 percentage of participants |
| Early Erlotinib | Percentage of Participants With Complete Response (CR) or Partial Response (PR) According to RECIST During Blinded Treatment | 6.5 percentage of participants |
p-value: 0.109795% CI: [-0.78, 6.35]Chi-squared
95% CI: [0.87, 3.72]
Secondary
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.
Time frame: 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)
Population: ITT Population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Late Erlotinib | Percentage of Participants With CR, PR, or SD According to RECIST During Blinded Treatment | 59.2 percentage of participants |
| Early Erlotinib | Percentage of Participants With CR, PR, or SD According to RECIST During Blinded Treatment | 61.2 percentage of participants |
p-value: 0.606295% CI: [-5.74, 9.72]Chi-squared
95% CI: [0.79, 1.49]
Secondary
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.
Time frame: 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)
Population: ITT Population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Late Erlotinib | Progression-Free Survival (PFS) as Median Time to Event During Blinded Treatment | 12.00 weeks |
| Early Erlotinib | Progression-Free Survival (PFS) as Median Time to Event During Blinded Treatment | 13.00 weeks |
Comparison: Unstratified Analysis.p-value: 0.475995% CI: [0.8, 1.11]Log Rank
Comparison: Stratified Analysis: Stratified according to tumor histology, stage of disease, objective response at Baseline, bevacizumab use, smoking status, and region of enrollment.p-value: 0.163595% CI: [0.72, 1.06]Log Rank