Non Small Cell Lung Cancer (NSCLC)
Conditions
Keywords
Cetuximab, Non small cell lung cancer, Lung cancer, Cisplatin/vinorelbine, Monoclonal antibody, Erbitux
Brief summary
The purpose of this trial is to investigate the efficacy of cetuximab in combination with chemotherapy in comparison to chemotherapy alone in patients with advanced non small cell lung cancer who did not received prior chemotherapy. Overall survival will be taken as primary measure of efficacy.
Interventions
DRUGcetuximab + cisplatin + vinorelbine
cetuximab given as an intravenous (i.v.) infusion every week (400mg/m\^2 initial dose and 250mg/m\^2 subsequent doses) until progressive disease (PD) + cisplatin 80mg/m\^2 i.v. infusion on day 1 of each 3-week cycle + vinorelbine 25mg/m\^2 i.v. infusion on days 1 and 8 of each 3-week cycle.
DRUGcisplatin + vinorelbine
cisplatin 80mg/m\^2 i.v. infusion on day 1 of each 3-week cycle + vinorelbine 25mg/m\^2 i.v. infusion on days 1 and 8 of each 3-week cycle.
Sponsors
Merck KGaA, Darmstadt, Germany
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Diagnosis of histologically or cytologically confirmed NSCLC, stage IIIb with documented malignant pleural effusion or stage IV * Immunohistochemical evidence of EGFR expression on tumor tissue * Presence of at least 1 bi-dimensionally measurable index lesion, whereby index lesions must not lie in an irradiated area
Exclusion criteria
* Previous exposure to monoclonal antibodies, signal transduction inhibitors or EGFR-targeting therapy * Previous chemotherapy for NSCLC * Documented or symptomatic brain metastasis * Superior vena cava syndrome contra-indicating hydration * Previous malignancy in the last 5 years except basal cell carcinoma of the skin or pre-invasive carcinoma of the cervix
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival Time (OS) | Time from randomisation to death or last day known to be alive, reported between day of first patient randomised, Oct 2004, until cut-off date 18 Jul 2007 | Time from randomization to death. Patients without event are censored at the last date known to be alive or at the clinical cut-off date, whatever is earlier. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Best Overall Response Rate | Evaluations were performed every 6 weeks until progression, reported between day of first patient randomised, Oct 2004, until cut-off date 18 Jul 2007 | The best overall response rate is defined as the proportion of subjects having achieved confirmed Complete Response + Partial Response as the best overall response according to radiological assessments (based on modified WHO criteria). |
| Disease Control Rate | Evaluations were performed every 6 weeks until progression, reported between day of first patient randomised, Oct 2004, until cut-off date 18 Jul 2007 | The disease control rate is defined as the proportion of subjects having achieved confirmed Complete Response + Partial Response + Stable Disease as best overall response according to radiological assessments (based on modified WHO criteria). |
| Quality of Life (QOL) Assessment European Organisation for the Research and Treatment of Cancer (EORTC) QLQ-C30 Global Health Status | at baseline, at cycle 3, at month 6, reported between day of first patient randomised, Oct 2004, until cut-off date 18 Jul 2007 | Mean global health status scores (EORTC QLQ-C30) against time for each treatment group. Scores were derived from mutually exclusive sets of items, with scale scores ranging from 0 to 100 after a linear transformation. Higher scores indicate a better QoL. |
| Progression-free Survival Time | Time from randomization to disease progression, death or last tumor assessment, reported between day of first patient randomised, Oct 2004, until cut-off date 18 Jul 2007 | Duration from randomization until radiological progression (based on modified World Health Organisation (WHO) criteria) or death due to any cause. Only deaths within 60 days of last tumor assessment are considered. Patients without event are censored on the date of last tumor assessment. |
| A Population Pharmacokinetic (PK) Analysis for Cetuximab in Non-Small Cell Lung Cancer (NSCLC) - Serum Cetuximab Concentrations | Week 1, Day 1: baseline and end of infusion; Week 7, Day 43: within 12 h after cetuximab administration. | Population PK analysis was conducted using non-linear mixed effects modeling (NONMEM) software, integrating the PK data from this study and the Phase II study EMR 62 202-011. |
| Safety - Number of Patients Experiencing Any Adverse Event | time from first dose up to 30 after last dose of study treatment, reported between day of first patient randomised, Oct 2004, until cut-off date 18 Jul 2007 | Please refer to Adverse Events section for further details |
| Quality of Life Assessment (EORTC QLQ-C30) Social Functioning | at baseline, at cycle 3, at month 6, reported between day of first patient randomised, Oct 2004, until cut-off date 18 Jul 2007 | Mean social functioning scores (EORTC QLQ-C30) against time for each treatment group. Scores were derived from mutually exclusive sets of items, with scale scores ranging from 0 to 100 after a linear transformation. Higher scores indicate a higher level of functioning. |
Countries
Argentina, Australia, Austria, Belgium, Brazil, Bulgaria, Chile, Czechia, France, Germany, Hong Kong, Hungary, Ireland, Italy, Mexico, Netherlands, Poland, Russia, Singapore, Slovakia, South Korea, Spain, Sweden, Switzerland, Taiwan, Turkey (Türkiye), Ukraine, United Kingdom
Participant flow
Recruitment details
First/last subject (informed consent): October 2004/January 2006. Clinical data cut-off: 18 July 2007. Last subject completed 16 May 2012. Subjects randomized at 155 centers; Asia/Australia: 21; Europe: 120; South America: 14.
Pre-assignment details
Enrolled: 1,861 after consent to epidermal growth factor receptor (EGFR) assessment; 603 excluded (mainly non-fulfillment of inclusion or exclusion criteria). 1,258 screened for eligibility after consent for study procedures; 143 excluded (mainly non-fulfillment of inclusion or exclusion criteria). 1,125 subjects randomized.
Participants by arm
| Arm | Count |
|---|---|
| Cetuximab Plus Chemotherapy cetuximab given as an intravenous (i.v.) infusion every week (400mg/m\^2 initial dose and 250mg/m\^2 subsequent doses) until progressive disease (PD) + cisplatin 80mg/m\^2 i.v. infusion on day 1 of each 3-week cycle + vinorelbine 25mg/m\^2 i.v. infusion on days 1 and 8 of each 3-week cycle.
Safety population: includes all treated subjects. | 557 |
| Chemotherapy Alone cisplatin 80mg/m\^2 i.v. infusion on day 1 of each 3-week cycle + vinorelbine 25mg/m\^2 i.v. infusion on days 1 and 8 of each 3-week cycle.
Safety population: includes all treated subjects. | 568 |
| Total | 1,125 |
Baseline characteristics
| Characteristic | Cetuximab Plus Chemotherapy | Chemotherapy Alone | Total |
|---|---|---|---|
| Age, Continuous | 59 years | 60 years | 59 years |
| Age, Customized <18 years | 0 participants | 0 participants | 0 participants |
| Age, Customized >=65 years | 172 participants | 179 participants | 351 participants |
| Age, Customized Between 18 and 65 years | 385 participants | 389 participants | 774 participants |
| Region of Enrollment Argentina | 5 participants | 2 participants | 7 participants |
| Region of Enrollment Australia | 20 participants | 23 participants | 43 participants |
| Region of Enrollment Austria | 9 participants | 7 participants | 16 participants |
| Region of Enrollment Belgium | 3 participants | 10 participants | 13 participants |
| Region of Enrollment Brazil | 48 participants | 51 participants | 99 participants |
| Region of Enrollment Bulgaria | 12 participants | 12 participants | 24 participants |
| Region of Enrollment Chile | 10 participants | 16 participants | 26 participants |
| Region of Enrollment Czech Republic | 12 participants | 17 participants | 29 participants |
| Region of Enrollment France | 25 participants | 25 participants | 50 participants |
| Region of Enrollment Germany | 91 participants | 88 participants | 179 participants |
| Region of Enrollment Hong Kong | 2 participants | 2 participants | 4 participants |
| Region of Enrollment Hungary | 21 participants | 23 participants | 44 participants |
| Region of Enrollment Ireland | 3 participants | 4 participants | 7 participants |
| Region of Enrollment Italy | 18 participants | 23 participants | 41 participants |
| Region of Enrollment Korea, Republic of | 28 participants | 26 participants | 54 participants |
| Region of Enrollment Mexico | 9 participants | 8 participants | 17 participants |
| Region of Enrollment Netherlands | 10 participants | 10 participants | 20 participants |
| Region of Enrollment Poland | 59 participants | 50 participants | 109 participants |
| Region of Enrollment Portugal | 3 participants | 0 participants | 3 participants |
| Region of Enrollment Russian Federation | 23 participants | 16 participants | 39 participants |
| Region of Enrollment Singapore | 5 participants | 5 participants | 10 participants |
| Region of Enrollment Slovakia | 8 participants | 12 participants | 20 participants |
| Region of Enrollment Spain | 16 participants | 13 participants | 29 participants |
| Region of Enrollment Sweden | 6 participants | 3 participants | 9 participants |
| Region of Enrollment Switzerland | 10 participants | 6 participants | 16 participants |
| Region of Enrollment Taiwan | 21 participants | 22 participants | 43 participants |
| Region of Enrollment Turkey | 1 participants | 2 participants | 3 participants |
| Region of Enrollment Ukraine | 56 participants | 71 participants | 127 participants |
| Region of Enrollment United Kingdom | 23 participants | 21 participants | 44 participants |
| Sex: Female, Male Female | 172 Participants | 163 Participants | 335 Participants |
| Sex: Female, Male Male | 385 Participants | 405 Participants | 790 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 532 / 548 | 537 / 562 |
| serious Total, serious adverse events | 325 / 548 | 244 / 562 |
Outcome results
Primary
Overall Survival Time (OS)
Time from randomization to death. Patients without event are censored at the last date known to be alive or at the clinical cut-off date, whatever is earlier.
Time frame: Time from randomisation to death or last day known to be alive, reported between day of first patient randomised, Oct 2004, until cut-off date 18 Jul 2007
Population: ITT
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cetuximab Plus Chemotherapy | Overall Survival Time (OS) | 11.3 months |
| Chemotherapy Alone | Overall Survival Time (OS) | 10.1 months |
Comparison: Primary efficacy analysis: To test equality of OS time between treatment groups, applying the two-sided stratified log-rank test (Stage IIIb vs IV, ECOG 0/1 vs 2) (α=5%).p-value: 0.0441Stratified Log Rank
Secondary
A Population Pharmacokinetic (PK) Analysis for Cetuximab in Non-Small Cell Lung Cancer (NSCLC) - Serum Cetuximab Concentrations
Population PK analysis was conducted using non-linear mixed effects modeling (NONMEM) software, integrating the PK data from this study and the Phase II study EMR 62 202-011.
Time frame: Week 1, Day 1: baseline and end of infusion; Week 7, Day 43: within 12 h after cetuximab administration.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cetuximab Plus Chemotherapy | A Population Pharmacokinetic (PK) Analysis for Cetuximab in Non-Small Cell Lung Cancer (NSCLC) - Serum Cetuximab Concentrations | 223.1 ug/mL | Standard Deviation 64.6 |
| Chemotherapy Alone | A Population Pharmacokinetic (PK) Analysis for Cetuximab in Non-Small Cell Lung Cancer (NSCLC) - Serum Cetuximab Concentrations | 51.5 ug/mL | Standard Deviation 33.1 |
Secondary
Best Overall Response Rate
The best overall response rate is defined as the proportion of subjects having achieved confirmed Complete Response + Partial Response as the best overall response according to radiological assessments (based on modified WHO criteria).
Time frame: Evaluations were performed every 6 weeks until progression, reported between day of first patient randomised, Oct 2004, until cut-off date 18 Jul 2007
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cetuximab Plus Chemotherapy | Best Overall Response Rate | 36.4 percentage of participants |
| Chemotherapy Alone | Best Overall Response Rate | 29.2 percentage of participants |
Comparison: The best overall response rate was compared in the Cochran-Mantel-Haenszel test (two-sided with α=5%).p-value: 0.0101Cochran-Mantel-Haenszel
Secondary
Disease Control Rate
The disease control rate is defined as the proportion of subjects having achieved confirmed Complete Response + Partial Response + Stable Disease as best overall response according to radiological assessments (based on modified WHO criteria).
Time frame: Evaluations were performed every 6 weeks until progression, reported between day of first patient randomised, Oct 2004, until cut-off date 18 Jul 2007
Population: ITT
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cetuximab Plus Chemotherapy | Disease Control Rate | 72.5 percentage of participants |
| Chemotherapy Alone | Disease Control Rate | 71.5 percentage of participants |
Comparison: The disease control rate was compared in the Cochran-Mantel-Haenszel test (two-sided with α=5%).p-value: 0.6801Cochran-Mantel-Haenszel
Secondary
Progression-free Survival Time
Duration from randomization until radiological progression (based on modified World Health Organisation (WHO) criteria) or death due to any cause. Only deaths within 60 days of last tumor assessment are considered. Patients without event are censored on the date of last tumor assessment.
Time frame: Time from randomization to disease progression, death or last tumor assessment, reported between day of first patient randomised, Oct 2004, until cut-off date 18 Jul 2007
Population: ITT
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cetuximab Plus Chemotherapy | Progression-free Survival Time | 4.8 months |
| Chemotherapy Alone | Progression-free Survival Time | 4.8 months |
Comparison: To test equality of progression free survival time between treatment groups, applying the two-sided stratified log-rank test (α=5%).p-value: 0.3869Stratified Log Rank
Secondary
Quality of Life Assessment (EORTC QLQ-C30) Social Functioning
Mean social functioning scores (EORTC QLQ-C30) against time for each treatment group. Scores were derived from mutually exclusive sets of items, with scale scores ranging from 0 to 100 after a linear transformation. Higher scores indicate a higher level of functioning.
Time frame: at baseline, at cycle 3, at month 6, reported between day of first patient randomised, Oct 2004, until cut-off date 18 Jul 2007
Population: 670 subjects completed (348 in the cetuximab + chemotherapy arm and 322 in the chemotherapy alone arm) at least 1 evaluable QLQ-C30 questionnaire and were included in the Evaluable population. Numbers at each timepoint were (Cetuximab + chemotherapy/Chemotherapy alone, respectively): baseline 280/275; cycle 3 185/153; 6 month 101/97
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Cetuximab Plus Chemotherapy | Quality of Life Assessment (EORTC QLQ-C30) Social Functioning | At baseline | 66.17 scores on a scale | Standard Error 2.836 |
| Cetuximab Plus Chemotherapy | Quality of Life Assessment (EORTC QLQ-C30) Social Functioning | At cycle 3 | 58.05 scores on a scale | Standard Error 2.995 |
| Cetuximab Plus Chemotherapy | Quality of Life Assessment (EORTC QLQ-C30) Social Functioning | At month 6 | 67.36 scores on a scale | Standard Error 3.449 |
| Chemotherapy Alone | Quality of Life Assessment (EORTC QLQ-C30) Social Functioning | At baseline | 64.73 scores on a scale | Standard Error 2.825 |
| Chemotherapy Alone | Quality of Life Assessment (EORTC QLQ-C30) Social Functioning | At cycle 3 | 67.13 scores on a scale | Standard Error 3.138 |
| Chemotherapy Alone | Quality of Life Assessment (EORTC QLQ-C30) Social Functioning | At month 6 | 66.47 scores on a scale | Standard Error 3.515 |
Secondary
Quality of Life (QOL) Assessment European Organisation for the Research and Treatment of Cancer (EORTC) QLQ-C30 Global Health Status
Mean global health status scores (EORTC QLQ-C30) against time for each treatment group. Scores were derived from mutually exclusive sets of items, with scale scores ranging from 0 to 100 after a linear transformation. Higher scores indicate a better QoL.
Time frame: at baseline, at cycle 3, at month 6, reported between day of first patient randomised, Oct 2004, until cut-off date 18 Jul 2007
Population: 670 subjects completed (348 in the cetuximab + chemotherapy arm and 322 in the chemotherapy alone arm) at least 1 evaluable QLQ-C30 questionnaire and were included in the Evaluable population. Numbers at each timepoint were (Cetuximab + chemotherapy/Chemotherapy alone, respectively): baseline 278/274; cycle 3 184/153; 6 month 102/96
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Cetuximab Plus Chemotherapy | Quality of Life (QOL) Assessment European Organisation for the Research and Treatment of Cancer (EORTC) QLQ-C30 Global Health Status | At baseline | 45.72 scores on a scale | Standard Error 2.164 |
| Cetuximab Plus Chemotherapy | Quality of Life (QOL) Assessment European Organisation for the Research and Treatment of Cancer (EORTC) QLQ-C30 Global Health Status | At cycle 3 | 48.33 scores on a scale | Standard Error 2.325 |
| Cetuximab Plus Chemotherapy | Quality of Life (QOL) Assessment European Organisation for the Research and Treatment of Cancer (EORTC) QLQ-C30 Global Health Status | At month 6 | 54.71 scores on a scale | Standard Error 2.729 |
| Chemotherapy Alone | Quality of Life (QOL) Assessment European Organisation for the Research and Treatment of Cancer (EORTC) QLQ-C30 Global Health Status | At baseline | 46.36 scores on a scale | Standard Error 2.138 |
| Chemotherapy Alone | Quality of Life (QOL) Assessment European Organisation for the Research and Treatment of Cancer (EORTC) QLQ-C30 Global Health Status | At cycle 3 | 51.55 scores on a scale | Standard Error 2.464 |
| Chemotherapy Alone | Quality of Life (QOL) Assessment European Organisation for the Research and Treatment of Cancer (EORTC) QLQ-C30 Global Health Status | At month 6 | 52.92 scores on a scale | Standard Error 2.787 |
Secondary
Safety - Number of Patients Experiencing Any Adverse Event
Please refer to Adverse Events section for further details
Time frame: time from first dose up to 30 after last dose of study treatment, reported between day of first patient randomised, Oct 2004, until cut-off date 18 Jul 2007
Population: Safety Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cetuximab Plus Chemotherapy | Safety - Number of Patients Experiencing Any Adverse Event | 545 participants |
| Chemotherapy Alone | Safety - Number of Patients Experiencing Any Adverse Event | 549 participants |