Non-Small Cell Lung Cancer
Conditions
Keywords
Lung, cancer, EGFR, Epidermal Growth Factor Receptor, tyrosine kinase, Tarceva®, Erlotinib
Brief summary
A Phase III, multicenter, open-label, randomized trial of Erlotinib (Tarceva®) versus chemotherapy in patients with advanced NSCLC with mutations in the Tyrosine Kinase (TK) domain of the EGFR.
Detailed description
This is a multicenter, phase III, randomized, open-label clinical trial. 146 patients with a diagnosis of advanced (stage IIIB and stage IV), non-squamous-cell, non-small-cell pulmonary carcinoma not treated previously for their disease with chemotherapy who present mutation in the tyrosine kinase domain of the epidermal growth factor receptor, EGFR will be recluted. The primary objective is to compare the progression-free survival in both treatment arms of the study (conventional chemotherapy vs. erlotinib) in patients with non-squamous-cell, non-small-cell lung cancer (NSCLC) in advanced stage (stages IIIB and stage IV) who have not received previous chemotherapy for their disease and who present mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR).
Interventions
DRUGErlotinib
150 mg/day Patients will receive treatment until disease progression or unacceptable toxicity. For all practical effects a treatment cycle will be defined as three weeks of continuous treatment with erlotinib
DRUGCarboplatin
Gemcitabine 1000 mg/m2 days 1 and 8 and Carboplatin AUC = 5 day 1, every 21 days. Docetaxel (75 mg/m2) /carboplatin (AUC=6); Gemcitabine (1000 mg/m2; day 1 and 8) / Carboplatin (AUC=5) Patients in the chemotherapy arm will receive the treatment until disease progression or unacceptable toxicity occurs, or until a maximum of 4 treatment cycles are given.
DRUGGemcitabin
Cisplatin (75 mg/m2) / Gemcitabine (1250 mg/m2; day 1 and 8) Patients in the chemotherapy arm will receive the treatment until disease progression or unacceptable toxicity occurs, or until a maximum of 4 treatment cycles are given.
DRUGDocetaxel
Cisplatin (75 mg/m2) / Docetaxel (75 mg/m2) Patients in the chemotherapy arm will receive the treatment until disease progression or unacceptable toxicity occurs, or until a maximum of 4 treatment cycles are given.
DRUGCisplatin
Cisplatin (75 mg/m2) / Docetaxel (75 mg/m2) Patients in the chemotherapy arm will receive the treatment until disease progression or unacceptable toxicity occurs, or until a maximum of 4 treatment cycles are given.
Sponsors
Spanish Lung Cancer Group
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
* Informed consent * Histologically confirmed diagnosis of NSCLC, non epidermoid, stage IV or IIIB with pleural effusion, or N3 tumours not candidate for thoracic radiotherapy, harbouring deletions in the exon 19 or mutation in the exon 21 in the TK of the EGFR. * Either measurable or evaluable disease. * Age \> 18 years. * ECOG performance status \< 2. * Adequate bone marrow function * Adequate renal function * Adequate hepatic function * Patients must be accessible for treatment and follow-up. * Patients capable of following an adequate therapeutic compliance * Women of child bearing potential: negative pregnancy test. * Patients of both genders at a fertile age, including those women having their last menstruation within the two previous years, must follow effective contraceptive measures. * Ability to swallow. * Patients with asymptomatic brain metastasis and stable with medical treatment will be eligible for the study. Patients having received radiotherapy for their brain metastasis prior to the systemic treatment for the NSCLC will be also eligible. * Absence of gastrointestinal tract problems
Exclusion criteria
* Pregnant or lactating women. * Women of child bearing potential having a positive pregnancy test in the basal visit or not accomplishing the test. * Patients of both genders sexually active (at a fertile age) not following contraceptive measures during the study. * Prior chemotherapy for metastatic disease. Both prior neoadjuvant and adjuvant chemotherapy allowed provided that completed ≥ 6 months before entering the study. * Prior treatment with EGFR targeted therapies. * Patients may have received radiotherapy, provided that the irradiated lesion is not the only evaluable lesion for response and completed before entering the study. * Prior experimental pharmacological agent within the 3 weeks prior to the inclusion of the study. * Any significant ophthalmologic impairment of the eye surface. Use of contact lenses is not recommended. * Pre-existing motor or sensorial neurotoxicity grade \> 2, according to the NCI-CTC criteria. * Evidence of spinal cord compression. * Inability to take oral medication and surgical procedures affecting the absorption or implying intravenous or parenteral feeding. * Any other severe disease or clinical conditions, as, but not only: * Unstable cardiopathy despite treatment, myocardial infarction within the 6 months before entering the study * History of significant neurological or psychiatric disorders, including dementia and epileptic seizures. * Uncontrolled active infection. * Uncontrolled peptic ulcer. * Unstable diabetes mellitus or any other contraindication for treatment with corticosteroids. * AST and/or ALT \> 1.5 x UNL associated to alkaline phosphatase \> 2.5 x UNL. * Any other underlying severe process affecting the ability to take part in the study. * Absolute contraindication for steroids. * Dementia or significant mental disorder interfering the understanding and giving the informed consent. * History of other malignancy except adequately treated basal cell or squamous cell skin cancer, carcinoma in situ of the cervix, radically treated prostatic carcinoma with good prognostic (Gleason = 6). History of other curatively treated malignancy and no evidence of disease within the past 5 years.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free-survival | From the date of randomization to the date of last follow up, assessed up to 24 months | The time from enrollment in the study to tumor progression or death from any cause (whichever occurs first) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response | From the date of randomization to the date of last follow up, assessed up to 24 months | The objective response rate is defined as the percentage of patients who attain complete response (CR) or partial response (PR); response will be evaluated following RECIST criteria version 1.0. Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Progressive disease (PD): at least a 20% increase in the sum of diameters of target lesions. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as reference the smallest sum of diameters recorded on study. |
| Overall Survival | From the date of randomization to the date of last follow up, assessed up to 24 months | Overall Survival (OS) is defined as the time, in months, from the inclusion date to the death date. A patient is censored at the last contact date if he/she does not die.Overall survival will be assessed from the date of enrollment in the study until the date of death from any cause. Patients lost to follow-up will be censured on the date of the last follow-up visit. |
| Molecular Markers Related to EGFR and Study Pathology | At baseline | The study of mutations in serum (serum DNA). This exploratory analysis was performed to determine whether EGFR mutations can reliably be detected in serum thereby reducing the requirement for invasive techniques as well as to enable detection of mutations in patients where no tumor biopsy samples are available. |
Countries
France, Italy, Spain
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| A: Erlotinib Group Erlotinib (Tarceva)150 mg /day
Patients will receive treatment until disease progression or unacceptable toxicity.
For all practical effects a treatment cycle will be defined as three weeks of continuous treatment with erlotinib
Erlotinib: 150 mg/day Patients will receive treatment until disease progression or unacceptable toxicity.
For all practical effects a treatment cycle will be defined as three weeks of continuous treatment with erlotinib | 86 |
| B: Standard Chemotherapy Group 4 cycles of Chemotherapy:
Cisplatin / Gemcitabine; Cisplatin /Docetaxel; Carboplatin / Gemcitabine; Carboplatin / Docetaxel.
3 week cycles of standard intravenous chemotherapy
* 75 mg/m² cisplatin plus 75 mg/m² docetaxel on day 1 or
* 75 mg/m² cisplatin on day 1 plus 1250 mg/m² gemcitabine on days 1 and 8
Patients who were ineligible for cisplatin treatment received intra venous carboplatin chemotherapy instead:
* 3 week cycles of carboplatin AUC 6 on day 1 with 75 mg/m² docetaxel on day 1 or
* 3 week cycles carboplatin AUC 5 on day 1 with 1000 mg/m² gemcitabine on days 1 and 8
Patients in the chemotherapy arm will receive the treatment until disease progression or unacceptable toxicity occurs, or until a maximum of 4 treatment cycles are given. | 87 |
| Total | 173 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Protocol Violation | 1 | 0 |
Baseline characteristics
| Characteristic | A: Erlotinib Group | B: Standard Chemotherapy Group | Total |
|---|---|---|---|
| Age, Continuous | 65 years | 65 years | 65 years |
| Bone metastasis No | 58 Participants | 58 Participants | 116 Participants |
| Bone metastasis Yes | 28 Participants | 29 Participants | 57 Participants |
| Brain metastasis No | 77 Participants | 76 Participants | 153 Participants |
| Brain metastasis Yes | 9 Participants | 11 Participants | 20 Participants |
| Clinical stage Stage II C | 1 Participants | 0 Participants | 1 Participants |
| Clinical stage Stage IIIA | 1 Participants | 0 Participants | 1 Participants |
| Clinical stage Stage IIIB (malignant pleural effusion) | 6 Participants | 5 Participants | 11 Participants |
| Clinical stage Stage IV | 78 Participants | 82 Participants | 160 Participants |
| ECOG Performance Status Scale ECOG 0 | 27 Participants | 30 Participants | 57 Participants |
| ECOG Performance Status Scale ECOG 1 | 47 Participants | 45 Participants | 92 Participants |
| ECOG Performance Status Scale ECOG 2 | 12 Participants | 12 Participants | 24 Participants |
| ECOG Performance Status Scale ECOG 3 | 0 Participants | 0 Participants | 0 Participants |
| ECOG Performance Status Scale ECOG 4 | 0 Participants | 0 Participants | 0 Participants |
| Histological diagnosis Adenocarcinoma | 82 Participants | 78 Participants | 160 Participants |
| Histological diagnosis Adenosquamous carcinoma | 0 Participants | 1 Participants | 1 Participants |
| Histological diagnosis Bronchoalveolar adenocarcinoma | 0 Participants | 2 Participants | 2 Participants |
| Histological diagnosis Large-cell carcinoma | 3 Participants | 1 Participants | 4 Participants |
| Histological diagnosis Pleomorphic carcinoma | 0 Participants | 1 Participants | 1 Participants |
| Histological diagnosis Squamous-cell carcinoma | 1 Participants | 0 Participants | 1 Participants |
| Histological diagnosis Undifferentiated carcinomas | 0 Participants | 4 Participants | 4 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) White | 86 Participants | 85 Participants | 171 Participants |
| Region of Enrollment France | 21 participants | 18 participants | 39 participants |
| Region of Enrollment Italy | 11 participants | 8 participants | 19 participants |
| Region of Enrollment Spain | 54 participants | 61 participants | 115 participants |
| Sex: Female, Male Female | 58 Participants | 68 Participants | 126 Participants |
| Sex: Female, Male Male | 28 Participants | 19 Participants | 47 Participants |
| Smoking status Current smoker | 7 Participants | 12 Participants | 19 Participants |
| Smoking status Never smoked | 57 Participants | 63 Participants | 120 Participants |
| Smoking status Previous smoker | 22 Participants | 12 Participants | 34 Participants |
| Type of EGFR mutation Deletion of exon 19 | 57 Participants | 58 Participants | 115 Participants |
| Type of EGFR mutation L858R mutation in exon 21 | 29 Participants | 29 Participants | 58 Participants |
| Type of EGFR mutation Other | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 55 / 86 | 54 / 87 |
| other Total, other adverse events | 70 / 86 | 65 / 87 |
| serious Total, serious adverse events | 27 / 86 | 25 / 87 |
Outcome results
Primary
Progression Free-survival
The time from enrollment in the study to tumor progression or death from any cause (whichever occurs first)
Time frame: From the date of randomization to the date of last follow up, assessed up to 24 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| A: Erlotinib Group | Progression Free-survival | 9.4 months |
| B: Standard Chemotherapy Group | Progression Free-survival | 5.2 months |
p-value: 0.000195% CI: [0.27, 0.64]Log Rank
Secondary
Molecular Markers Related to EGFR and Study Pathology
The study of mutations in serum (serum DNA). This exploratory analysis was performed to determine whether EGFR mutations can reliably be detected in serum thereby reducing the requirement for invasive techniques as well as to enable detection of mutations in patients where no tumor biopsy samples are available.
Time frame: At baseline
Population: Intention to treat. Serum sample taken at baseline
| Arm | Measure | Group | Value (COUNT_OF_UNITS) |
|---|---|---|---|
| A: Erlotinib Group | Molecular Markers Related to EGFR and Study Pathology | Mutated | 30 Sample of serum |
| A: Erlotinib Group | Molecular Markers Related to EGFR and Study Pathology | Wild type | 24 Sample of serum |
| A: Erlotinib Group | Molecular Markers Related to EGFR and Study Pathology | Not enough sample | 32 Sample of serum |
| B: Standard Chemotherapy Group | Molecular Markers Related to EGFR and Study Pathology | Mutated | 29 Sample of serum |
| B: Standard Chemotherapy Group | Molecular Markers Related to EGFR and Study Pathology | Wild type | 23 Sample of serum |
| B: Standard Chemotherapy Group | Molecular Markers Related to EGFR and Study Pathology | Not enough sample | 35 Sample of serum |
Secondary
Objective Response
The objective response rate is defined as the percentage of patients who attain complete response (CR) or partial response (PR); response will be evaluated following RECIST criteria version 1.0. Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Progressive disease (PD): at least a 20% increase in the sum of diameters of target lesions. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as reference the smallest sum of diameters recorded on study.
Time frame: From the date of randomization to the date of last follow up, assessed up to 24 months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| A: Erlotinib Group | Objective Response | Complete Response (CR) | 2.3 percentage of participants |
| A: Erlotinib Group | Objective Response | Stable Disease (SD) | 18.6 percentage of participants |
| A: Erlotinib Group | Objective Response | Partial Response (PR) | 62.8 percentage of participants |
| A: Erlotinib Group | Objective Response | Missing (No Response Assessment) | 9.3 percentage of participants |
| A: Erlotinib Group | Objective Response | Progressive Disease (PD) | 7 percentage of participants |
| B: Standard Chemotherapy Group | Objective Response | Missing (No Response Assessment) | 21.8 percentage of participants |
| B: Standard Chemotherapy Group | Objective Response | Stable Disease (SD) | 49.4 percentage of participants |
| B: Standard Chemotherapy Group | Objective Response | Complete Response (CR) | 0 percentage of participants |
| B: Standard Chemotherapy Group | Objective Response | Partial Response (PR) | 16.1 percentage of participants |
| B: Standard Chemotherapy Group | Objective Response | Progressive Disease (PD) | 12.6 percentage of participants |
Secondary
Overall Survival
Overall Survival (OS) is defined as the time, in months, from the inclusion date to the death date. A patient is censored at the last contact date if he/she does not die.Overall survival will be assessed from the date of enrollment in the study until the date of death from any cause. Patients lost to follow-up will be censured on the date of the last follow-up visit.
Time frame: From the date of randomization to the date of last follow up, assessed up to 24 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| A: Erlotinib Group | Overall Survival | 33.4 months |
| B: Standard Chemotherapy Group | Overall Survival | 29.9 months |
p-value: 0.04395% CI: [0.36, 0.99]Log Rank