Lung Cancer
Conditions
Keywords
stage IIIB non-small cell lung cancer, stage IV non-small cell lung cancer, adenocarcinoma of the lung
Brief summary
RATIONALE: Erlotinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Bevacizumab also may stop the growth of non-small cell lung cancer by blocking blood flow to the tumor. Giving erlotinib together with bevacizumab may kill more tumor cells. PURPOSE: This phase II trial is studying how well giving erlotinib together with bevacizumab works in treating patients with stage IIIB or stage IV primary non-small cell lung cancer who have never smoked.
Detailed description
OBJECTIVES: Primary * Assess overall survival of patients with stage IIIB or IV primary non-small cell lung adenocarcinoma who have never smoked and are treated with erlotinib hydrochloride and bevacizumab. Secondary * Assess progression-free survival of patients treated with this regimen. * Assess the response rate (confirmed and unconfirmed, complete and partial) in a subset of patients with measurable disease treated with this regimen. * Evaluate the frequency and severity of toxicities associated with this regimen in these patients. OUTLINE: This is a multicenter study. Patients receive oral erlotinib hydrochloride daily on days 1-21 and bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed periodically for up to 3 years. PROJECTED ACCRUAL: A total of 80 patients will be accrued for this study.
Interventions
BIOLOGICALbevacizumab
DRUGerlotinib hydrochloride
Sponsors
National Cancer Institute (NCI)
SWOG Cancer Research Network
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 120 Years
Healthy volunteers
No
Inclusion criteria
DISEASE CHARACTERISTICS: * Histologically or cytologically confirmed non-small cell lung cancer (NSCLC) * Adenocarcinoma * No component of squamous cell carcinoma present * Incompletely resected or unresectable disease * Stage IIIB or IV disease as defined below: * Selected stage IIIB disease * T4 (cytologically confirmed malignant pleural effusion OR pleural tumor foci that are separate from direct pleural invasion by the primary tumor) * Any N * M0 * Stage IV disease * Any T * Any N * M1 (distant metastases present) * Recurrent lung cancer in a separate lobe after resection or radiotherapy within the past 5 years OR multifocal lesions in \> 1 lobe considered stage IV disease * New lesions occurring ≥ 5 years after resection may be considered a separate primary cancer and are not allowed if this is the only focus of lung cancer * Measurable and/or nonmeasurable disease by CT scan, positron emission tomography scan, or MRI * Disease must be present outside a previous radiotherapy field OR a new lesion must be inside the port * Measurable disease must be assessed within the past 28 days * Nonmeasurable disease must be assessed within the past 42 days * Pleural effusions, ascites, and laboratory parameters are not acceptable as the only evidence of disease * Must be a lifelong nonsmoker (\< 100 cigarettes in lifetime) * Treated brain metastases allowed provided the patient is asymptomatic and do not require steroids PATIENT CHARACTERISTICS: * Zubrod performance status 0-2 * Absolute neutrophil count ≥ 1,500/mm\^3 * Platelet count ≥ 100,000/mm\^3 * Total bilirubin normal * SGOT or SGPT ≤ 2.5 times upper limit of normal (ULN) (5 times ULN if liver metastases present) * Alkaline phosphatase ≤ 2.5 times ULN (5 times ULN if bone metastases present) * Creatinine ≤ 1.5 times ULN OR creatinine clearance ≥ 50 mL/min * Urine protein:creatinine ratio ≤ 0.5 OR urine protein \< 1,000 mg by 24-hour urine collection * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective contraception * Hypertension allowed if controlled on medication prior to study enrollment * Must be willing to provide prior smoking history * No immediate life-threatening complications from malignancies * No prior major medical condition, psychological condition, or social situation that would preclude study treatment * No hemoptysis ≥ ½ teaspoon within the past 28 days * No clinical history of pulmonary or upper respiratory hemorrhage ≥ grade 2 within the past 6 months or grade 1 within the past 28 days * No history of either thrombosis or hemorrhage, including hemorrhagic or thrombotic stroke, or other CNS bleeding * No serious nonhealing wound, ulcer, or bone fracture * No other prior malignancy except for the following: * Adequately treated basal cell or squamous cell skin cancer * Adequately treated stage I or II cancer from which the patient is currently in complete remission * In situ cervical cancer * Any other cancer from which the patient has been disease-free for 5 years PRIOR CONCURRENT THERAPY: * See Disease Characteristics * At least 7 days since prior fine-needle aspiration or core biopsy * At least 28 days since prior radiotherapy (14 days for palliative radiotherapy) and recovered * At least 28 days since prior surgery (e.g., thoracic or other major surgeries) and recovered * At least 28 days since prior systemic chemotherapy * Prior biologic therapy allowed * No prior gefitinib, erlotinib hydrochloride, bevacizumab, or other targeted therapies against the epidermal growth factor receptor or vascular endothelial growth factor axes * Concurrent stable, therapeutic anticoagulation therapy allowed (e.g., warfarin or low molecular weight heparin), provided the patient has no history of bleeding complications on anticoagulation or an inability to establish a stable therapeutic regimen for anticoagulation * No concurrent surgery * No other concurrent nonprotocol treatment (including chemotherapy, hormonal therapy, biological therapy, or radiotherapy) directed at this cancer
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | Disease assessment is performed every 6 weeks for 18 weeks, then every 9-12 weeks until progression up to 2 years. After disease progression, patients must be followed every 3 months for 1 year and then every 6 months for a maximum of 3 years. | From date of registration to date of death due to any cause. Patients last known to be alive are censored at date of last contact. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival | Disease assessment is performed every 6 weeks for 18 weeks, then every 9-12 weeks until progression up to 2 years. After disease progression, patients must be followed every 3 months for 1 year and then every 6 months for a maximum of 3 years. | From date of registration to date of first documentation of progression or symptomatic deterioration, or death due to any cause. Patients last known to be alive and progression-free are censored at date of last contact. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v 1.0), as a 20% increase in the sum of longest diameters of target measurable lesions over smallest sum observed (over baseline if no decrease during therapy) using the same techniques as baseline, or unequivocal progression of non-measurable disease in the opinion of the treating physician (an explanation must be provided) or appearance of any new lesion/site, or death due to disease without prior documentation of progression and without symptomatic deterioration. |
| Response Rate (Complete and Partial) | Disease assessment is performed every 6 weeks for 18 weeks, then every 9-12 weeks until progression up to 2 years. After disease progression, patients must be followed every 3 months for 1 year and then every 6 months for a maximum of 3 years. | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0): Complete Response (CR), Disappearance of all measurable and non-measurable disease; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. All target measurable lesions must be assessed using the same techniques as baseline. |
| Number of Patients With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Toxicity assessment was evaluated after each cycle (21 days) while on protocol therapy. | Adverse Events (AEs) are reported by CTCAE Version 3.0. Only adverse events that are possibly, probably or definitely related to study drug are reported. Any CTCAE 3.0 event of Grade 3 (serious), Grade 4 (life threatening) or Grade 5 (fatal) which were deemed to be related to protocol treatment are included. |
Countries
United States
Participant flow
Recruitment details
89 patients were enrolled. Four patients were excluded from the analysis: two patients were ineligible due to incorrect histology; two were no analyzable due to their not receiving any treatment on protocol.
Participants by arm
| Arm | Count |
|---|---|
| Erlotinib and Bevacizumab Patients received erlotinib 150 mg daily with bevacizumab at 15mg/kg until progression or prohibitive toxicity. | 85 |
| Total | 85 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 14 |
| Overall Study | Other-Not protocol specified | 5 |
| Overall Study | Progression | 62 |
| Overall Study | Withdrawal by Subject | 4 |
Baseline characteristics
| Characteristic | Erlotinib and Bevacizumab |
|---|---|
| Age, Continuous | 61 years |
| Performance Status 0/1 | 82 participants |
| Performance Status 2 | 3 participants |
| Race/Ethnicity, Customized African American | 4 participants |
| Race/Ethnicity, Customized Asian | 21 participants |
| Race/Ethnicity, Customized Caucasian | 56 participants |
| Race/Ethnicity, Customized Native American | 2 participants |
| Race/Ethnicity, Customized Unknown | 2 participants |
| Sex: Female, Male Female | 56 Participants |
| Sex: Female, Male Male | 29 Participants |
| Stage IIIB(pleural effusion) | 15 participants |
| Stage IV | 70 participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 83 / 85 |
| serious Total, serious adverse events | 17 / 85 |
Outcome results
Primary
Overall Survival
From date of registration to date of death due to any cause. Patients last known to be alive are censored at date of last contact.
Time frame: Disease assessment is performed every 6 weeks for 18 weeks, then every 9-12 weeks until progression up to 2 years. After disease progression, patients must be followed every 3 months for 1 year and then every 6 months for a maximum of 3 years.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Erlotinib and Bevacizumab | Overall Survival | 29.8 months |
Comparison: The overall survival rate at year 1 was estimated using Kaplan-Meier.95% CI: [0.67, 0.85]
Comparison: The overall survival rate at year 2 was estimated using Kaplan-Meier.95% CI: [0.46, 0.67]
Comparison: The overall survival rate at year 3 was estimated using Kaplan-Meier.95% CI: [0.32, 0.53]
Secondary
Number of Patients With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs
Adverse Events (AEs) are reported by CTCAE Version 3.0. Only adverse events that are possibly, probably or definitely related to study drug are reported. Any CTCAE 3.0 event of Grade 3 (serious), Grade 4 (life threatening) or Grade 5 (fatal) which were deemed to be related to protocol treatment are included.
Time frame: Toxicity assessment was evaluated after each cycle (21 days) while on protocol therapy.
Population: Eligible patients who had received the protocol treatments were included in the adverse event summaries.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Erlotinib and Bevacizumab | Number of Patients With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Pruritus/itching | 1 Participants |
| Erlotinib and Bevacizumab | Number of Patients With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Rash/desquamation | 5 Participants |
| Erlotinib and Bevacizumab | Number of Patients With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | ALT, SGPT (serum glutamic pyruvic transaminase) | 3 Participants |
| Erlotinib and Bevacizumab | Number of Patients With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | AST, SGOT | 4 Participants |
| Erlotinib and Bevacizumab | Number of Patients With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Anorexia | 1 Participants |
| Erlotinib and Bevacizumab | Number of Patients With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Bilirubin (hyperbilirubinemia) | 1 Participants |
| Erlotinib and Bevacizumab | Number of Patients With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Calcium, serum-low (hypocalcemia) | 1 Participants |
| Erlotinib and Bevacizumab | Number of Patients With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Colitis, infectious (e.g., Clostridium difficile) | 1 Participants |
| Erlotinib and Bevacizumab | Number of Patients With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Confusion | 2 Participants |
| Erlotinib and Bevacizumab | Number of Patients With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Dehydration | 1 Participants |
| Erlotinib and Bevacizumab | Number of Patients With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Dermatology/Skin-Other (Specify) | 1 Participants |
| Erlotinib and Bevacizumab | Number of Patients With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Diarrhea | 4 Participants |
| Erlotinib and Bevacizumab | Number of Patients With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Esophagitis | 1 Participants |
| Erlotinib and Bevacizumab | Number of Patients With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Fatigue (asthenia, lethargy, malaise) | 5 Participants |
| Erlotinib and Bevacizumab | Number of Patients With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Hemoglobin | 1 Participants |
| Erlotinib and Bevacizumab | Number of Patients With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Hemorrhage, GI - Stomach | 2 Participants |
| Erlotinib and Bevacizumab | Number of Patients With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Hemorrhage, pulmonary/upper respiratory - Lung | 1 Participants |
| Erlotinib and Bevacizumab | Number of Patients With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Hemorrhage, pulmonary/upper respiratory - Nose | 1 Participants |
| Erlotinib and Bevacizumab | Number of Patients With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Hypertension | 15 Participants |
| Erlotinib and Bevacizumab | Number of Patients With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Inf w/normal ANC or Gr 1-2 neutrophils - Lung | 1 Participants |
| Erlotinib and Bevacizumab | Number of Patients With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Mucositis/stomatitis (clinical exam) - Oral cavity | 1 Participants |
| Erlotinib and Bevacizumab | Number of Patients With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Mucositis/stomatitis (functional/symp) - Oral cav | 1 Participants |
| Erlotinib and Bevacizumab | Number of Patients With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Nail changes | 1 Participants |
| Erlotinib and Bevacizumab | Number of Patients With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Nausea | 2 Participants |
| Erlotinib and Bevacizumab | Number of Patients With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Neuropathy: motor | 1 Participants |
| Erlotinib and Bevacizumab | Number of Patients With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Pain - Abdomen NOS | 1 Participants |
| Erlotinib and Bevacizumab | Number of Patients With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Pain - Bone | 1 Participants |
| Erlotinib and Bevacizumab | Number of Patients With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Pain - Face | 1 Participants |
| Erlotinib and Bevacizumab | Number of Patients With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Pain - Joint | 1 Participants |
| Erlotinib and Bevacizumab | Number of Patients With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Potassium, serum-low (hypokalemia) | 1 Participants |
| Erlotinib and Bevacizumab | Number of Patients With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Proteinuria | 6 Participants |
| Erlotinib and Bevacizumab | Number of Patients With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Rash: acne/acneiform | 4 Participants |
| Erlotinib and Bevacizumab | Number of Patients With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Sodium, serum-low (hyponatremia) | 4 Participants |
| Erlotinib and Bevacizumab | Number of Patients With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Syncope (fainting) | 1 Participants |
| Erlotinib and Bevacizumab | Number of Patients With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Ulceration | 1 Participants |
| Erlotinib and Bevacizumab | Number of Patients With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Voice changes/dysarthria | 1 Participants |
| Erlotinib and Bevacizumab | Number of Patients With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs | Weight loss | 3 Participants |
Secondary
Progression-free Survival
From date of registration to date of first documentation of progression or symptomatic deterioration, or death due to any cause. Patients last known to be alive and progression-free are censored at date of last contact. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v 1.0), as a 20% increase in the sum of longest diameters of target measurable lesions over smallest sum observed (over baseline if no decrease during therapy) using the same techniques as baseline, or unequivocal progression of non-measurable disease in the opinion of the treating physician (an explanation must be provided) or appearance of any new lesion/site, or death due to disease without prior documentation of progression and without symptomatic deterioration.
Time frame: Disease assessment is performed every 6 weeks for 18 weeks, then every 9-12 weeks until progression up to 2 years. After disease progression, patients must be followed every 3 months for 1 year and then every 6 months for a maximum of 3 years.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Erlotinib and Bevacizumab | Progression-free Survival | 7.4 months |
Secondary
Response Rate (Complete and Partial)
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0): Complete Response (CR), Disappearance of all measurable and non-measurable disease; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. All target measurable lesions must be assessed using the same techniques as baseline.
Time frame: Disease assessment is performed every 6 weeks for 18 weeks, then every 9-12 weeks until progression up to 2 years. After disease progression, patients must be followed every 3 months for 1 year and then every 6 months for a maximum of 3 years.
Population: Only patients with measurable disease at baseline were included in the analysis. 66 of 85 patients (78%) had measurable disease at baseline.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Erlotinib and Bevacizumab | Response Rate (Complete and Partial) | Complete Response (CR) | 2 participants |
| Erlotinib and Bevacizumab | Response Rate (Complete and Partial) | Partial Response (PR) | 31 participants |
| Erlotinib and Bevacizumab | Response Rate (Complete and Partial) | Objective Response Rate (CR + PR) | 33 participants |
| Erlotinib and Bevacizumab | Response Rate (Complete and Partial) | Stable Disease (SD) | 23 participants |
| Erlotinib and Bevacizumab | Response Rate (Complete and Partial) | Non-Progression (ORR+SD) | 56 participants |
| Erlotinib and Bevacizumab | Response Rate (Complete and Partial) | Progressive Disease (PD) | 8 participants |
| Erlotinib and Bevacizumab | Response Rate (Complete and Partial) | Not Determinable/ Inadequate Assessment | 2 participants |