Non-Small Cell Lung Cancer
Conditions
Keywords
Tarceva, NSCLC
Brief summary
This was a Phase II, open-label, single-arm, single-stage, multicenter trial in patients with relapsed non-small cell lung cancer (NSCLC), with the objective of assessing the activity of the combination of erlotinib and pertuzumab on the basis of the endpoint of FDG-PET response rate.
Interventions
DRUGPertuzumab
After a single administration of a loading dose of 840 mg IV, patients received a maintenance dose of 420 mg IV every 3 weeks (q3w).
DRUGErlotinib
Patients received 150 mg orally once a day which was reduced to 100 mg orally once a day in a protocol amendment dated 19 May 2010.
Sponsors
Roche Pharma AG
Genentech, Inc.
Study design
Allocation
NON_RANDOMIZED
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 confirmed non-small cell lung cancer (NSCLC). * Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2. * Recurrent or progressive disease after receiving at least 1, but no more than two, chemotherapy regimens for advanced or metastatic NSCLC. * Recovery from reversible acute effects of prior anti-cancer therapy (chemotherapy, radiotherapy, or investigational treatment) to National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) Grade ≤ 1 (excluding alopecia). * Ability to comply with the study and follow-up procedures, including all specified imaging studies. * Ability to take oral medication. * Life expectancy ≥ 3 months. * Measurable disease on computed tomography (CT). * At least 1 extracerebral lesion on 2-deoxy-2-\[18F\]fluoro-D-glucose-positron emission tomography (FDG-PET) scan that is suitable for response assessment, that is measurable, and ≥ 15 mm on CT. * Left ventricular ejection fraction (LVEF) ≥ 50%, as determined by echocardiogram or MUltiple Gated Acquisition (MUGA) scan. * For women of childbearing potential and men with partners of childbearing potential, agreement to use a highly effective non-hormonal form of contraception or two effective forms of non-hormonal contraception by the patient and/or partner. * Availability and willingness to provide sufficient tumor tissue for testing for epidermal growth factor receptor (EGFR) mutations, and other human epidermal growth factor receptor (HER) pathway and NSCLC-related biomarkers.
Exclusion criteria
* Prior treatment with an investigational or marketed agent for the purpose of inhibiting HER family members (including HER1, HER2, HER3, and HER4). This includes, but is not limited to erlotinib, gefitinib, pertuzumab, cetuximab, and panitumumab. * Chemotherapy, radiotherapy, or investigational treatment within 28 days of start of study (ie, prior to Day 0) or from which patients have not yet recovered. * Inability to take oral medications, disease affecting gastrointestinal absorption, or prior surgical procedure affecting gastrointestinal absorption. * Uncontrolled diabetes. * Clinical or radiographic evidence of new or progression of pre-existing central nervous system (CNS) metastases. * Current severe, uncontrolled systemic disease (eg, clinically significant cardiovascular, pulmonary, or metabolic disease; wound-healing disorders; ulcers; or bone fractures). * Current uncontrolled hypertension or unstable angina. * History of congestive heart failure (CHF) of any New York Heart Association (NYHA) criteria, or serious cardiac arrhythmia requiring treatment (exceptions: atrial fibrillation, paroxysmal supraventricular tachycardia). * History of myocardial infarction within 6 months of enrollment or history of unstable angina. * Any evidence of an unstable infection as suggested by an infectious process, coupled with hypotension and/or tachycardia and/or fever and/or positive blood culture. * Known human immunodeficiency virus (HIV) infection. * Uncontrolled hypercalcemia. * Pregnancy or lactation. * History of another malignancy in the past 2 years, unless the malignancy has been adequately treated, is currently not detectable, and is associated with a 5-year survival \> 90%. * Claustrophobia. * Any other disease, condition, physical examination finding, or clinical laboratory finding that, in the opinion of the investigator, makes the patient inappropriate for the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients With a 2-deoxy-2-[18F]Fluoro-D-glucose-positron Emission Tomography (FDG-PET) Response at Day 56 in All Patients and in Epidermal Growth Factor Receptor (EGFR) Mutant and Wild-type Subgroups | Baseline to Day 56 | The assessment of FDG-PET response was performed by a central reading site. PET response was based on the maximum standard uptake value (SUVmax) of up to 5 regions of interest (ROI). The tumor ROIs were identified for each patient on pretreatment FDG-PET scans and corresponded to a subset of the target lesions identified for Response Evaluation Criteria for Solid Tumors (RECIST) analysis. Specifically, the SUVmax of each ROI on the on-treatment scans was compared with the SUVmax on the corresponding pretreatment scan and the percent change was calculated. When there was more than 1 ROI, the overall percent change in SUVmax was the arithmetic mean of the percent changes in SUVmax for each of the ROIs (mSUVmax). An PET response is defined as a decrease of ≥ 20% in mSUVmax. EGFR mutation status was assessed in tumor tissue samples taken from each patient. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) | Baseline to the end of the study (up to 3 years) | PFS was defined as the time from the first dosing with pertuzumab and erlotinib to the first occurrence of disease progression (PD), as determined by the investigator and based on computed tomography using Response Evaluation Criteria in Solid Tumors (RECIST), or death from any cause, whichever comes first. PD was defined as ≥ 20% increase in the sum of the longest diameter of target lesions (TL), taking as reference the smallest sum longest diameter recorded since treatment started, the unequivocal progression of existing non-target lesions (non-TL), or the appearance of 1 or more new lesions. TLs were selected on the basis of their size (those with the longest diameter) and their suitability for accurate repeated measurements by imaging techniques or clinically. All measurable lesions up to a maximum of 5 lesions per organ and 10 lesions in total, representative of all involved organs, were identified as TLs. All other lesions (or sites of disease) were identified as non-TLs. |
| Overall Survival (OS) | Baseline to the end of the study (up to 3 years) | Overall survival was defined as the time from the date of first dosing with pertuzumab and erlotinib until the date of patient death from any cause. |
| Percentage of Patients With an Objective Response (OR) | Baseline to the end of the study (up to 3 years) | OR was defined as a complete response (CR) or a partial response (PR) as determined by the investigator and based on computed tomography (CT) using Response Evaluation Criteria in Solid Tumors (RECIST) on 2 consecutive occasions at least 4 weeks apart. A complete response was defined as the disappearance of all target and non-target lesions and normalization of tumor marker level. A partial response was defined as ≥ 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter, or the persistence of 1 or more non-target lesions and/or the maintenance of a tumor marker level above the normal limits. |
| Percentage of Patients With Disease Control (DC) at Day 56 | Baseline to Day 56 | DC was defined as a CR, a PR, or stable disease (SD) as determined by the investigator and based on CT using RECIST. A CR was defined as the disappearance of all target (TL) and non-target lesions (nTL). A PR was defined as ≥ 30% decrease in the sum of the longest diameter (SLD) of TLs, taking as reference the baseline sum longest diameter, or the persistence of 1 or more nTLs and/or maintenance of a tumor marker level (TML) above normal limits. For TLs, SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum longest diameter (SSLD) since treatment started. For nTLs, SD was defined as the persistence of 1 or more lesions and/or maintenance of a TML above normal limits. PD was defined as ≥ 20% increase in the SLD of TLs, taking as reference the SSLD recorded since treatment started, the appearance of 1 or more new lesions, or the unequivocal progression of existing nTLs. |
Countries
Australia, United States
Participant flow
Pre-assignment details
Patients were considered to have completed the study if they were alive at their last survival follow-up visit prior to 10 Nov 2011, which was 1 year after the last patient was enrolled, or they were continuing treatment per Amendment 3 of the study protocol (1 patient).
Participants by arm
| Arm | Count |
|---|---|
| Pertuzumab + Erlotinib Patients received pertuzumab 840 mg intravenously (IV) 1 time (loading dose) followed by 420 mg IV (maintenance dose) every 3 weeks (q3w) plus erlotinib 150 mg orally once a day which was reduced to 100 mg orally once a day in a protocol amendment dated 19 May 2010. | 41 |
| Total | 41 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 31 |
| Overall Study | Disease progression | 1 |
| Overall Study | Patient's decision | 1 |
Baseline characteristics
| Characteristic | Pertuzumab + Erlotinib |
|---|---|
| Age Continuous | 60.7 years STANDARD_DEVIATION 8.3 |
| Sex: Female, Male Female | 17 Participants |
| Sex: Female, Male Male | 24 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 41 / 41 |
| serious Total, serious adverse events | 18 / 41 |
Outcome results
Primary
Percentage of Patients With a 2-deoxy-2-[18F]Fluoro-D-glucose-positron Emission Tomography (FDG-PET) Response at Day 56 in All Patients and in Epidermal Growth Factor Receptor (EGFR) Mutant and Wild-type Subgroups
The assessment of FDG-PET response was performed by a central reading site. PET response was based on the maximum standard uptake value (SUVmax) of up to 5 regions of interest (ROI). The tumor ROIs were identified for each patient on pretreatment FDG-PET scans and corresponded to a subset of the target lesions identified for Response Evaluation Criteria for Solid Tumors (RECIST) analysis. Specifically, the SUVmax of each ROI on the on-treatment scans was compared with the SUVmax on the corresponding pretreatment scan and the percent change was calculated. When there was more than 1 ROI, the overall percent change in SUVmax was the arithmetic mean of the percent changes in SUVmax for each of the ROIs (mSUVmax). An PET response is defined as a decrease of ≥ 20% in mSUVmax. EGFR mutation status was assessed in tumor tissue samples taken from each patient.
Time frame: Baseline to Day 56
Population: All 41 patients treated with pertuzumab and erlotinib were evaluable for analysis. Patients with a missing Day 56 assessment were deemed non-responders. Tumor tissue samples were only available for 32 patients for EGFR mutation status analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pertuzumab + Erlotinib | Percentage of Patients With a 2-deoxy-2-[18F]Fluoro-D-glucose-positron Emission Tomography (FDG-PET) Response at Day 56 in All Patients and in Epidermal Growth Factor Receptor (EGFR) Mutant and Wild-type Subgroups | In all patients | 19.5 Percentage of patients |
| Pertuzumab + Erlotinib | Percentage of Patients With a 2-deoxy-2-[18F]Fluoro-D-glucose-positron Emission Tomography (FDG-PET) Response at Day 56 in All Patients and in Epidermal Growth Factor Receptor (EGFR) Mutant and Wild-type Subgroups | In patients with EGFR mutation(s), n=9 | 66.7 Percentage of patients |
| Pertuzumab + Erlotinib | Percentage of Patients With a 2-deoxy-2-[18F]Fluoro-D-glucose-positron Emission Tomography (FDG-PET) Response at Day 56 in All Patients and in Epidermal Growth Factor Receptor (EGFR) Mutant and Wild-type Subgroups | In patients with wild-type EGFR, n=23 | 8.7 Percentage of patients |
Secondary
Overall Survival (OS)
Overall survival was defined as the time from the date of first dosing with pertuzumab and erlotinib until the date of patient death from any cause.
Time frame: Baseline to the end of the study (up to 3 years)
Population: All 41 patients treated with erlotinib and pertuzumab. Patients who had not died at the time of analysis for OS were censored at the date of last contact.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pertuzumab + Erlotinib | Overall Survival (OS) | 8.7 Months |
Secondary
Percentage of Patients With an Objective Response (OR)
OR was defined as a complete response (CR) or a partial response (PR) as determined by the investigator and based on computed tomography (CT) using Response Evaluation Criteria in Solid Tumors (RECIST) on 2 consecutive occasions at least 4 weeks apart. A complete response was defined as the disappearance of all target and non-target lesions and normalization of tumor marker level. A partial response was defined as ≥ 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter, or the persistence of 1 or more non-target lesions and/or the maintenance of a tumor marker level above the normal limits.
Time frame: Baseline to the end of the study (up to 3 years)
Population: All 41 patients treated with erlotinib and pertuzumab.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pertuzumab + Erlotinib | Percentage of Patients With an Objective Response (OR) | 7.3 Percentage of patients |
Secondary
Percentage of Patients With Disease Control (DC) at Day 56
DC was defined as a CR, a PR, or stable disease (SD) as determined by the investigator and based on CT using RECIST. A CR was defined as the disappearance of all target (TL) and non-target lesions (nTL). A PR was defined as ≥ 30% decrease in the sum of the longest diameter (SLD) of TLs, taking as reference the baseline sum longest diameter, or the persistence of 1 or more nTLs and/or maintenance of a tumor marker level (TML) above normal limits. For TLs, SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum longest diameter (SSLD) since treatment started. For nTLs, SD was defined as the persistence of 1 or more lesions and/or maintenance of a TML above normal limits. PD was defined as ≥ 20% increase in the SLD of TLs, taking as reference the SSLD recorded since treatment started, the appearance of 1 or more new lesions, or the unequivocal progression of existing nTLs.
Time frame: Baseline to Day 56
Population: All 41 patients treated with erlotinib and pertuzumab.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pertuzumab + Erlotinib | Percentage of Patients With Disease Control (DC) at Day 56 | 31.7 Percentage of patients |
Secondary
Progression-free Survival (PFS)
PFS was defined as the time from the first dosing with pertuzumab and erlotinib to the first occurrence of disease progression (PD), as determined by the investigator and based on computed tomography using Response Evaluation Criteria in Solid Tumors (RECIST), or death from any cause, whichever comes first. PD was defined as ≥ 20% increase in the sum of the longest diameter of target lesions (TL), taking as reference the smallest sum longest diameter recorded since treatment started, the unequivocal progression of existing non-target lesions (non-TL), or the appearance of 1 or more new lesions. TLs were selected on the basis of their size (those with the longest diameter) and their suitability for accurate repeated measurements by imaging techniques or clinically. All measurable lesions up to a maximum of 5 lesions per organ and 10 lesions in total, representative of all involved organs, were identified as TLs. All other lesions (or sites of disease) were identified as non-TLs.
Time frame: Baseline to the end of the study (up to 3 years)
Population: All 41 patients treated with erlotinib and pertuzumab. Patients who had not progressed or died at the time of analysis for PFS were censored at the date of their last tumor assessment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pertuzumab + Erlotinib | Progression-free Survival (PFS) | 1.9 Months |