Lung Cancer
Conditions
Keywords
non small cell lung cancer, advanced, non-squamous, EGFR, mutations
Brief summary
Rationale: Advanced non-small-cell lung cancer (NSCLC) patients harbouring epidermal growth factor receptor (EGFR) mutations (del19 or L858R) show an impressive progression-free survival between 9 and 14 months when treated with erlotinib. However, the presence of EGFR mutations can only imperfectly predict outcome. The investigators hypothesize that progression-free survival could be influenced both by the pretreatment EGFR T790M mutation and by components of DNA repair pathways. The investigators propose a model of treatment whereby patients with EGFR mutations (single or with T790M) can attain a benefit with longer overall PFS when treated with erlotinib plus bevacizumab. When the patients are grouped by BRCA1 mRNA levels and T790M the hypothesis is that the combination of erlotinib plus bevacizumab can improve the PFS in all subgroups.
Detailed description
Objectives: 1. To determine long-term outcome of patients with advanced non-squamous NSCLC harbouring EGFR mutations with or without T790M mutation at diagnosis and treated with the combination of erlotinib and bevacizumab. Primary endpoint: progression-free survival 2. To evaluate the efficacy and tolerability of the combination 3. To evaluate the correlation of BRCA1 mRNA and AEG-1 mRNA expression and T790M with progression-free survival 4. To monitor EGFR mutations (including T790M) in serum and plasma longitudinally 5. To evaluate molecular biomarkers related to EGFR TKI and bevacizumab Design: This is a multinational, multi-center phase II trial of erlotinib plus bevacizumab in patients with advanced non-squamous NSCLC harbouring EGFR mutations confirmed by central re-assessment. Patients will be stratified into two subgroups, with and without EGFR T790M mutation. The stratification will be done after the inclusion of patients. Sample size: 102 patients
Interventions
DRUGErlotinib
Patients will be treated with erlotinib, 150 mg p.o., daily
DRUGBevacizumab
Patients will be treated with bevacizumab 15 mg/kg i.v. on day 1 of each 3-week cycle (+/- 3 days)
Sponsors
ETOP IBCSG Partners Foundation
Spanish Lung Cancer Group
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age ≥ 18 years * ECOG performance status 0-2 * Adequate haematological function, coagulation, liver function and renal function * Pathological diagnosis of predominantly non-squamous, non-small-cell lung cancer (NSCLC) * TNM version 7 stage IV disease including M1a (malignant effusion) or M1b (distant metastasis), or locally advanced disease not amenable to curative treatment (including patients progressing after radiochemotherapy for stage III disease) * Measurable or evaluable disease (according to RECIST 1.1 criteria). * Centrally confirmed EGFR exon 19 deletion (del19) or exon 21 mutation (L858R)
Exclusion criteria
* Patients with increased risk of bleeding * Patients with clinically significant cardiovascular diseases * Patients with a history of thrombosis or thromboembolism in the 6 months prior to treatment * Patients with gastrointestinal problems * Patients with neurologic problems * Patients who have had in the past 5 years any previous or concomitant malignancy EXCEPT adequately treated basal or squamous cell carcinoma of the skin, in situ carcinoma of the cervix or bladder, in situ breast carcinoma. * Patients with any known significant ophthalmologic anomaly of the ocular surface * Patients who received prior chemotherapy for metastatic disease * Patients who received previous treatment for lung cancer with drugs targeting EGFR or VEGF * Pregnancy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival | From the date of enrollment until documented progression or death, whichever occurs first, assessed up to 48 months. | Time from the date of enrollment until an investigator-documented progression or death, whichever occurs first. Assessment of Progressive Disease (PD) is based on Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1): at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum recorded on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | From the date of enrollment until death, assessed up to 48 months. | Time from the date of enrollment until death from any cause. |
| Time to Treatment Failure | From the date of enrollment until discontinuation of treatment, assessed up to 48 months. | Time from the date of enrollment to discontinuation of treatment for any reason including progression of disease (based on RECIST v1.1), treatment toxicity (adverse events classified according to NCI CTCAE version 4.), refusal and death. |
| Objective Response | Assessed across all time-points from enrollment to termination of trial treatment (max 48 months). | Objective response is defined as best overall response (CR or PR) across all assessment time-points during the period from enrollment to termination of trial treatment. Objective response, along with progressive and stable disease, will be determined using RECIST 1.1 criteria: Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum of diameters. Progression (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum recorded on the trial. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. 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 the trial. |
| Disease Control | Assessed across all time-points from enrollment to termination of trial treatment (max 48 months). | Disease control is defined as achieving objective response (CR or PR, across all time-points from enrollment to termination of trial treatment) or stable disease for at least 6 weeks. Objective response, along with SD (disease control) and PD (no disease control), will be determined using RECIST 1.1 criteria: Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum of diameters.Progression (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum recorded on the trial. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.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 the trial. |
| Duration of Response | Assessed across all time-points from enrollment to to the date of first documented progression or relapse (max 48 months). | Interval from the date of first documentation of objective response (CR or PR) to the date of first documented progression or relapse. Assessment of Objective response and Progressive Disease (PD) is based on the RECIST 1.1 criteria: Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum of diameters. Progression (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum recorded on the trial. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. 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 the trial. |
| Adverse Events | Assessed across all time-points until end of treatment (30 +/-5 days following the last dose of study drug) (max 48 months). | Adverse events graded according to NCI CTCAE V4. |
Countries
France, Germany, Greece, Ireland, Italy, Spain, Switzerland, United Kingdom
Contacts
STUDY_CHAIRRafael Rosell, MD
Catalan Institute of Oncology, Hospital Germans Trias i Pujol
STUDY_CHAIRStahel Rolf, MD
Laboratory of Molecular Oncology, Clinic of Oncology, University Hospital Zuerich
STUDY_CHAIRMiquel Taron
Medical Oncology Service-ICO, Hospital Germans Trias i Pujol
Participant flow
Recruitment details
Between June 11, 2012 and Oct 28, 2014, 109 eligible patients were enrolled in 29 centers of eight European countries (Spain, Switzerland, UK, Greece, Italy, Ireland, France and Germany). All patients were included in the efficacy analysis.
Participants by arm
| Arm | Count |
|---|---|
| T790M Positive Treatment-naive patients with advanced non-small-cell lung cancer positive for an activating EGFR mutation (exon 19 deletion or L858R mutation), with T790M, treated with erlotinib (150 mg p.o., daily) and bevacizumab (15 mg/kg i.v. on day 1 of each 21 day cycle). | 37 |
| T790M Negative Treatment-naive patients with advanced non-small-cell lung cancer positive for an activating EGFR mutation (exon 19 deletion or L858R mutation), without T790M, treated with erlotinib (150 mg p.o., daily) and bevacizumab (15 mg/kg i.v. on day 1 of each 21 day cycle). | 72 |
| Total | 109 |
Baseline characteristics
| Characteristic | Total | T790M Positive | T790M Negative |
|---|---|---|---|
| AEG1 mRNA expression High (≥1) | 30 Participants | 12 Participants | 18 Participants |
| AEG1 mRNA expression Low (<1) | 31 Participants | 11 Participants | 20 Participants |
| AEG1 mRNA expression No material or no value | 48 Participants | 14 Participants | 34 Participants |
| Age, Continuous | 66.1 years | 69.5 years | 63 years |
| Brain metastasis No | 88 Participants | 30 Participants | 58 Participants |
| Brain metastasis Yes | 21 Participants | 7 Participants | 14 Participants |
| BRCA1 mRNA expression High (≥9.2) | 23 Participants | 10 Participants | 13 Participants |
| BRCA1 mRNA expression Low (<9.2) | 23 Participants | 10 Participants | 13 Participants |
| BRCA1 mRNA expression No material or no value | 63 Participants | 17 Participants | 46 Participants |
| ECOG performance status 0 | 53 Participants | 17 Participants | 36 Participants |
| ECOG performance status 1 | 50 Participants | 18 Participants | 32 Participants |
| ECOG performance status 2 | 6 Participants | 2 Participants | 4 Participants |
| Histological diagnosis Adenocarcinoma | 93 Participants | 34 Participants | 59 Participants |
| Histological diagnosis Adenosquamous carcinoma | 2 Participants | 1 Participants | 1 Participants |
| Histological diagnosis Not otherwise specified | 3 Participants | 1 Participants | 2 Participants |
| Histological diagnosis Unknown | 11 Participants | 1 Participants | 10 Participants |
| Race and Ethnicity Not Collected | 0 Participants | — | — |
| Sex: Female, Male Female | 67 Participants | 25 Participants | 42 Participants |
| Sex: Female, Male Male | 42 Participants | 12 Participants | 30 Participants |
| Smoking status Current smoker | 7 Participants | 0 Participants | 7 Participants |
| Smoking status Former smoker | 30 Participants | 10 Participants | 20 Participants |
| Smoking status Never smoked | 72 Participants | 27 Participants | 45 Participants |
| Type of EGFR mutation Deletion of exon 19 | 70 Participants | 23 Participants | 47 Participants |
| Type of EGFR mutation L858R mutation in exon 21 | 39 Participants | 14 Participants | 25 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 36 | 0 / 70 |
| other Total, other adverse events | 36 / 36 | 69 / 70 |
| serious Total, serious adverse events | 12 / 36 | 19 / 70 |
Outcome results
Primary
Progression Free Survival
Time from the date of enrollment until an investigator-documented progression or death, whichever occurs first. Assessment of Progressive Disease (PD) is based on Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1): at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum recorded on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.
Time frame: From the date of enrollment until documented progression or death, whichever occurs first, assessed up to 48 months.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| T790M Positive | Progression Free Survival | 16 months |
| T790M Negative | Progression Free Survival | 10.5 months |
Secondary
Adverse Events
Adverse events graded according to NCI CTCAE V4.
Time frame: Assessed across all time-points until end of treatment (30 +/-5 days following the last dose of study drug) (max 48 months).
Population: Three patients never started treatment (2 lost to follow-up, one from each arm and 1 withdrawal from T790M negative arm).
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| T790M Positive | Adverse Events | Experienced SAE | 12 Participants |
| T790M Positive | Adverse Events | Experienced AE/SAE | 36 Participants |
| T790M Positive | Adverse Events | No AE/SAE | 0 Participants |
| T790M Negative | Adverse Events | Experienced SAE | 19 Participants |
| T790M Negative | Adverse Events | Experienced AE/SAE | 69 Participants |
| T790M Negative | Adverse Events | No AE/SAE | 1 Participants |
Secondary
Disease Control
Disease control is defined as achieving objective response (CR or PR, across all time-points from enrollment to termination of trial treatment) or stable disease for at least 6 weeks. Objective response, along with SD (disease control) and PD (no disease control), will be determined using RECIST 1.1 criteria: Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum of diameters.Progression (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum recorded on the trial. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.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 the trial.
Time frame: Assessed across all time-points from enrollment to termination of trial treatment (max 48 months).
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| T790M Positive | Disease Control | Disease Control | 35 Participants |
| T790M Positive | Disease Control | No Disease Control | 2 Participants |
| T790M Negative | Disease Control | Disease Control | 66 Participants |
| T790M Negative | Disease Control | No Disease Control | 6 Participants |
Secondary
Duration of Response
Interval from the date of first documentation of objective response (CR or PR) to the date of first documented progression or relapse. Assessment of Objective response and Progressive Disease (PD) is based on the RECIST 1.1 criteria: Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum of diameters. Progression (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum recorded on the trial. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. 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 the trial.
Time frame: Assessed across all time-points from enrollment to to the date of first documented progression or relapse (max 48 months).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| T790M Positive | Duration of Response | NA months |
| T790M Negative | Duration of Response | 12 months |
Secondary
Objective Response
Objective response is defined as best overall response (CR or PR) across all assessment time-points during the period from enrollment to termination of trial treatment. Objective response, along with progressive and stable disease, will be determined using RECIST 1.1 criteria: Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum of diameters. Progression (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum recorded on the trial. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. 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 the trial.
Time frame: Assessed across all time-points from enrollment to termination of trial treatment (max 48 months).
Population: Patients with only 1 tumor assessment are classified as Non-Evaluable, because they cannot be accounted for the Objective Response rate.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| T790M Positive | Objective Response | Partial Response | 24 Participants |
| T790M Positive | Objective Response | Progressive Disease | 1 Participants |
| T790M Positive | Objective Response | Stable Disease | 8 Participants |
| T790M Positive | Objective Response | Non-Evaluable | 1 Participants |
| T790M Positive | Objective Response | Complete Response | 3 Participants |
| T790M Negative | Objective Response | Non-Evaluable | 3 Participants |
| T790M Negative | Objective Response | Complete Response | 3 Participants |
| T790M Negative | Objective Response | Partial Response | 54 Participants |
| T790M Negative | Objective Response | Stable Disease | 9 Participants |
| T790M Negative | Objective Response | Progressive Disease | 3 Participants |
Secondary
Overall Survival
Time from the date of enrollment until death from any cause.
Time frame: From the date of enrollment until death, assessed up to 48 months.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| T790M Positive | Overall Survival | NA months |
| T790M Negative | Overall Survival | 28.2 months |
Secondary
Time to Treatment Failure
Time from the date of enrollment to discontinuation of treatment for any reason including progression of disease (based on RECIST v1.1), treatment toxicity (adverse events classified according to NCI CTCAE version 4.), refusal and death.
Time frame: From the date of enrollment until discontinuation of treatment, assessed up to 48 months.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| T790M Positive | Time to Treatment Failure | 13.4 months |
| T790M Negative | Time to Treatment Failure | 8.3 months |