Non-small Cell Lung Cancer
Conditions
Keywords
erlotinib, EGFR mutation, NSCLC
Brief summary
Erlotinib is a drug which targets non small cell lung cancer with a genetic change (mutation) in the epidermal growth factor receptor (EGFR). This drug has been used in other cancer research studies and information from those studies suggests that Erlotinib can control the growth of these cancer cells.
Detailed description
PRIMARY OBJECTIVE -To prospectively assess the frequency of different genetic mechanisms of secondary resistance in patients' tumors during treatment with erlotinib (e.g., T790M mutations, MET amplification). * Correlate these genetic changes with patient demographic data and clinical outcomes (time to progression, survival, sites of recurrence/progression). * Search for novel mechanisms of acquired resistance to erlotinib. * Identify whether these genetic changes are present at low levels in initial pretreatment tumor specimens. SECONDARY OBJECTIVE(S) 1. To measure the steady-state plasma concentrations of erlotinib during the course of patients' treatment. * Determine if the development and/or resolution of skin toxicity is related to plasma erlotinib concentrations. * Determine if the development of disease progression while on erlotinib is correlated with declines in plasma erlotinib concentrations. * Assess the plasma levels in patients whose smoking status has been biochemically verified to determine if smoking is associated with lower erlotinib plasma concentration. 2. To analyze from both free plasma DNA and DNA from circulating tumor cells of erlotinib-treated patients for the original sensitizing EGFR mutations and genetic changes associated with secondary resistance. 3. To measure clinical outcomes in patients with known sensitizing mutations in their tumor EGFR when treated with first-line erlotinib. * Response rate * Time to progression * Median overall survival
Interventions
DRUGErlotinib
Sponsors
Beth Israel Deaconess Medical Center
Brigham and Women's Hospital
Genentech, Inc.
David M. Jackman, MD
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
* Histologically or cytologically confirmed non-small cell lung cancer, stage IV or IIIB with a malignant pleural or pericardial effusion. Patients with stage I or II non-small cell lung cancer who have undergone surgical resection but who subsequently relapse with metastatic disease or a malignant pleural effusion are also eligible. * Documentation of a sensitizing mutation of the epidermal growth factor receptor. In addition, there must be a sufficient tissue for analysis of KRAS (the oncogene from the Kirsten rat sarcoma virus) mutations and MET amplification. * At least one measurable or evaluable site of disease as defined by revised RECIST (version 1.1) criteria. * 18 years of age or older * No more than one prior systemic therapy regimen for advanced non-small cell lung cancer. Chemotherapy delivered as part of concurrent chemoradiation will also count as a prior systemic therapy regimen. Adjuvant therapy for resected NSCLC will not count towards this total as long as it was completed at least 6 months prior to enrollment and did not include therapy with an EGFR-targeted agent. Adjuvant therapy completed less than 6 months prior to the time of screening will count as a prior regimen. * 3 or more weeks since prior major surgery * 2 or more weeks since prior radiation * ECOG performance status 0-1 * Life expectancy \> 8 weeks * Adequate hematologic, renal, and hepatic function * Willingness to undergo repeat tumor biopsy at the time of disease progression.
Exclusion criteria
* Untreated and/or uncontrolled central nervous system metastases. Patients with prior brain metastases must have had definitive treatment (radiation or surgery) and must be clinically stable off steroids for at least 1 week prior to enrollment. * More than one prior systemic chemotherapy for advanced non-small cell lung cancer. , Chemotherapy delivered as part of concurrent chemoradiation will also count as a prior systemic therapy regimen. Adjuvant therapy for resected NSCLC willnot count towards this total as long as it was completed at least 6 months prior to enrollment and did not include therapy with an EGFR-targeted agent. Adjuvant therapy completed less than 6 months prior to the time of screening will count as a prior regimen. * Prior exposure to erlotinib or other treatments targeting the HER family axis. * Active malignancies within the past 3 years, except for adequately treated carcinoma of the cervix or basal or squamous cell carcinomas of the skin. * Any process that compromises the ability to swallow and/or absorb oral medication. * Incomplete healing from previous surgery * A history of any of the following autoimmune skin disorders: Sjogren's syndrome, scleroderma, dermatomyositis, and systemic lupus erythematosus. * Significant medical history or unstable medical conditions. * Concurrent use of warfarin. Patients must be off warfarin for at least one week prior to initiation of erlotinib. Other non-warfarin anticoagulants are permitted. * Patients who require ongoing concomitant use of one of the strong inhibitors/inducers of CYP3A4. * Pregnant or breastfeeding. Women of child-bearing potential must agree to use adequate contraception prior to study entry and for the duration of study participation.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Resistance Mechanism | Participants were evaluated for incidence of genetic mechanisms of secondary resistance at time of disease progression at which point participants stopped treatment. Progression follow up was up to 3 years in this study cohort. | Participants were classified into 4 potential resistant mechanism groups (4 genetic/ 1 histologic) based on evaluation of rebiopsy tissue: EGFR mutations (T790M mutation, exon 20 insertion), KRAS mutations, MET amplification or small-cell lung cancer (SCLC) transform using established methods. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival | Disease was evaluated radiologically every 8 weeks on treatment (cycle duration=4 weeks). Participants were treated until evidence of disease progression or unacceptable toxicity. Progression follow-up was up to 3 years in this study cohort. | Progression-free survival based on the Kaplan-Meier method is defined as the duration of time from study entry to documented disease progression (PD) or death. Per RECIST 1.1 criteria: progressive disease (PD) is at least a 20% increase in the sum of longest diameter (LD) of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. PD for the evaluation of non-target lesions is the appearance of one or more new lesions and/or unequivocal progression of non-target lesions. |
Countries
United States
Participant flow
Recruitment details
Study activated December 2009. Patients enrolled from February 2010 - January 2015
Participants by arm
| Arm | Count |
|---|---|
| Erlotinib Patients receive standard dose of erlotinib 150mg daily with cycle length of 28 days; Patients are treated until disease progression or until unaccepted drug toxicity. | 60 |
| Total | 60 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 3 |
| Overall Study | Death | 2 |
| Overall Study | Ineligible | 1 |
| Overall Study | No lesion amenable | 1 |
| Overall Study | Patient non-compliance | 1 |
| Overall Study | still on therapy | 12 |
| Overall Study | Urgent Palliative Care | 2 |
| Overall Study | Withdrawal by Subject | 3 |
Baseline characteristics
| Characteristic | Erlotinib |
|---|---|
| Age, Continuous | 60 years |
| Region of Enrollment United States | 60 Participants |
| Sex: Female, Male Female | 44 Participants |
| Sex: Female, Male Male | 16 Participants |
| Smoking Status Never-Smoker | 34 Participants |
| Smoking Status Smoker | 26 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 59 / 60 |
| serious Total, serious adverse events | 5 / 60 |
Outcome results
Primary
Resistance Mechanism
Participants were classified into 4 potential resistant mechanism groups (4 genetic/ 1 histologic) based on evaluation of rebiopsy tissue: EGFR mutations (T790M mutation, exon 20 insertion), KRAS mutations, MET amplification or small-cell lung cancer (SCLC) transform using established methods.
Time frame: Participants were evaluated for incidence of genetic mechanisms of secondary resistance at time of disease progression at which point participants stopped treatment. Progression follow up was up to 3 years in this study cohort.
Population: The analysis dataset is comprised of all evaluable patients.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Erlotinib | Resistance Mechanism | Insufficient Tissue | 4 participants |
| Erlotinib | Resistance Mechanism | T790M mutation | 23 participants |
| Erlotinib | Resistance Mechanism | MET amplification | 1 participants |
| Erlotinib | Resistance Mechanism | SCLC Transformation | 3 participants |
| Erlotinib | Resistance Mechanism | Unknown | 4 participants |
Secondary
Progression-Free Survival
Progression-free survival based on the Kaplan-Meier method is defined as the duration of time from study entry to documented disease progression (PD) or death. Per RECIST 1.1 criteria: progressive disease (PD) is at least a 20% increase in the sum of longest diameter (LD) of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. PD for the evaluation of non-target lesions is the appearance of one or more new lesions and/or unequivocal progression of non-target lesions.
Time frame: Disease was evaluated radiologically every 8 weeks on treatment (cycle duration=4 weeks). Participants were treated until evidence of disease progression or unacceptable toxicity. Progression follow-up was up to 3 years in this study cohort.
Population: The analysis dataset is comprised of all treated patients.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Erlotinib | Progression-Free Survival | 11.1 months |
Post Hoc
Feasibility Rate
Feasibility in this study is defined as the percentage of patients who completed a repeated biopsy per protocol after evidence of disease progression.
Time frame: Disease was evaluated radiologically every 8 weeks on treatment (cycle duration=4 weeks). Participants were treated until evidence of disease progression or unacceptable toxicity. Progression follow-up was up to 3 years in this study cohort.
Population: The analysis dataset is comprised of all patients eligible for repeat biopsy.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Erlotinib | Feasibility Rate | 79.5 percentage of participants |
Post Hoc
Time to Repeat Biopsy
Time to repeat biopsy is the duration of time from clinical determination of progressive disease to time of repeat biopsy.
Time frame: At time of removal from study, patients were asked to undergo a repeat biopsy of their progressing or new tumor lesion. Progression follow up was up to 3 years in this study cohort.
Population: The analysis dataset is comprised of all evaluable patients.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Erlotinib | Time to Repeat Biopsy | 12 days |