Erlotinib Hydrochloride With or Without Bevacizumab in Treating Patients With Stage IV Non-small Cell Lung Cancer With Epidermal Growth Factor Receptor Mutations

• Sponsor: Academic and Community Cancer Research United (Other)
• Overall Status: Completed
• CT.gov ID: NCT01532089
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 88
• Locations: 19
• Arms: 2
• Actual Duration (Months): 101.1
• Patients Per Site: 4.6
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This randomized phase II trial studies how well erlotinib hydrochloride (Tarceva) with or without bevacizumab (Avastin) works in treating patients with stage IV non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations. Erlotinib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as bevacizumab, may block tumor growth in different ways by targeting certain cells. Bevacizumab may also stop the growth of NSCLC by blocking the growth of new blood vessels necessary for tumor growth. It is not yet known whether erlotinib hydrochloride is more effective when given alone or with bevacizumab in treating patients with NSCLC.

Condition or Disease	Intervention/Treatment	Phase
EGFR Exon 19 Deletion Mutation; EGFR NP_005219.2:p.L858R; Lung Non-Squamous Non-Small Cell Carcinoma; Stage IV Lung Non-Small Cell Cancer AJCC v7	Biological: Bevacizumab; Drug: Erlotinib; Drug: Erlotinib Hydrochloride; Other: Laboratory Biomarker Analysis	Phase 2

Detailed Description

PRIMARY OBJECTIVE:

1. To determine the progression-free survival of erlotinib (erlotinib hydrochloride) and bevacizumab versus that of erlotinib alone for the purpose of deciding if the combination arm is worth pursuing in a phase III trial.

SECONDARY OBJECTIVES:

1. To investigate the overall survival of erlotinib and bevacizumab versus erlotinib alone.

2. To investigate the response rate of erlotinib and bevacizumab versus erlotinib alone.

3. To investigate the progression-free survival in patients with exon deletion 19 or exon 21 L858R point mutations.

4. To investigate the toxicity of erlotinib and bevacizumab versus erlotinib alone using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.

CORRELATIVE RESEARCH OBJECTIVES:

1. To correlate EGFR mutations detected in plasma deoxyribonucleic acid (DNA) with those detected in tumor DNA.

2. To estimate the prevalence of EGFR T790M resistance mutations from pretreatment tumor biopsies using more sensitive mutation detection methods.

3. To investigate progression free survival of EGFR mutant NSCLC patients with and without concurrent EGFR T790M detected from pre-treatment tumor specimen using allele specific quantitative polymerase chain reaction (PCR).

4. To prospectively evaluate the predictive value of plasma VEGF-A levels on progression free survival in patients treated with erlotinib alone or in combination with bevacizumab.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM A: Patients receive erlotinib hydrochloride orally (PO) once daily (QD) on days 1-21. (erlotinib will no longer be supplied and all patients will be removed from study treatment. No further follow-up by any study participants as of September 1, 2019)

ARM B: Patients receive erlotinib hydrochloride as in Arm A and bevacizumab intravenously (IV) over 30-90 minutes on day 1. (erlotinib will no longer be supplied and all patients will be removed from study treatment. No further follow-up by any study participants as of September 1, 2019)

In both arms, courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3-6 months for 6 years.

Study Design

• Study Type: Interventional
• Actual Enrollment: 88 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized Phase II Trial of Erlotinib Alone or in Combination With Bevacizumab in Patients With Non-Small Cell Lung Cancer and Activating Epidermal Growth Factor Receptor Mutations
• Actual Study Start Date: Mar 16, 2012
• Actual Primary Completion Date: Feb 13, 2018
• Actual Study Completion Date: Aug 18, 2020

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Arm A (erlotinib hydrochloride) Patients receive erlotinib hydrochloride PO QD on days 1-21. (erlotinib will no longer be supplied and all patients will be removed from study treatment. No further follow-up by any study participants as of September 1, 2019)	Drug: Erlotinib; Given PO; Drug: Erlotinib Hydrochloride; Given PO; Other Names: Cp-358,774 OSI-774 Tarceva ; Other: Laboratory Biomarker Analysis; Correlative studies
Experimental: Arm B (erlotinib hydrochloride, bevacizumab) Patients receive erlotinib hydrochloride as in Arm A and bevacizumab IV over 30-90 minutes on day 1. (erlotinib will no longer be supplied and all patients will be removed from study treatment. No further follow-up by any study participants as of September 1, 2019)	Biological: Bevacizumab; Given IV; Other Names: Anti-VEGF Anti-VEGF Humanized Monoclonal Antibody Anti-VEGF rhuMAb Avastin Bevacizumab awwb Bevacizumab Biosimilar BEVZ92 Bevacizumab Biosimilar BI 695502 Bevacizumab Biosimilar CBT 124 Bevacizumab Biosimilar CT-P16 Bevacizumab Biosimilar FKB238 Bevacizumab Biosimilar HD204 Bevacizumab Biosimilar HLX04 Bevacizumab Biosimilar IBI305 Bevacizumab Biosimilar LY01008 Bevacizumab Biosimilar MIL60 Bevacizumab Biosimilar QL 1101 Bevacizumab Biosimilar RPH-001 Bevacizumab Biosimilar SCT501 BP102 BP102 Biosimilar HD204 Immunoglobulin G1 (Human-Mouse Monoclonal rhuMab-VEGF Gamma-Chain Anti-Human Vascular Endothelial Growth Factor), Disulfide With Human-Mouse Monoclonal rhuMab-VEGF Light Chain, Dimer Recombinant Humanized Anti-VEGF Monoclonal Antibody rhuMab-VEGF SCT501 ; Drug: Erlotinib; Given PO; Drug: Erlotinib Hydrochloride; Given PO; Other Names: Cp-358,774 OSI-774 Tarceva ; Other: Laboratory Biomarker Analysis; Correlative studies

Outcome Measures

Primary Outcome Measures

1. Progression Free Survival (PFS) [Time from randomization to disease progression and death of any cause, whichever comes first, assessed up to 6 years]

   Progression free survival (PFS) is defined as the time from the date of randomization to the date of disease progression or death resulting from any cause, whichever comes first. Progression is defined according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 as at least a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. The median and 95% confidence intervals are estimated using the Kaplan-Meier estimator.

Secondary Outcome Measures

1. Overall Survival [Time from randomization to death of any causes, assessed up to 6 years]

   Overall survival time is defined as the time from randomization to death due to any cause. The median and 95% confidence intervals are estimated using the Kaplan-Meier estimator.

2. Response Rate (Complete or Partial) to Each Treatment, Evaluated Using the New International Criteria Proposed by the Revised Response Evaluation Criteria in Solid Tumors Guidelines (Version 1.1) [Up to 6 years]

   The response rate (percentage) is the percent of patients whose best response was Complete Response (CR) or Partial Response (PR) as defined by RECIST 1.1 criteria. Percentage of successes will be estimated by 100 times the number of successes divided by the total number of evaluable patients. (CR: Disappearance of all evidence of disease, PR: Regression of measurable disease and no new sites).

3. Progression Free Survival of Patients With Different Mutation Types (Exon Deletion 19 Versus Exon 21 L858R) [From the date of randomization to the date of disease progression or death of any cause, whichever comes first, assessed up to 6 years]

   Progression free survival (PFS) is defined as the time from the date of randomization to the date of disease progression or death resulting from any cause, whichever comes first. Progression is defined according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 as at least a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. The median and 95% confidence intervals are estimated using the Kaplan-Meier estimator by mutation type.

4. Number of Patients Experiencing Toxicity [Up to 42 days after treatment discontinuation]

   The number of patients experiencing toxicity defined as grade 3 or higher adverse events (using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0) considered at least possibly related to treatment is reported below.

Other Outcome Measures

1. EGFR Mutations Detected in Plasma Deoxyribonucleic Acid (DNA) [Up to 6 years]

   Agreement of EGFR mutations detected in plasma DNA with those detected in tumor DNA will be evaluated.

2. EGFR Mutations Detected in Tumor Deoxyribonucleic Acid (DNA) [Up to 6 years]

   Agreement of EGFR mutations detected in plasma DNA with those detected in tumor DNA will be evaluated.

3. Prevalence of EGFR T790M Resistance Mutations From Pretreatment > Tumor Biopsies Using More Sensitive Mutation Detection Methods [Baseline]

   Tested using Cox proportional hazard model after adjusting for treatment effect. The robustness of treatment effect in different subgroups will be examined in a Forest plot.

4. EGFR T790M Mutations [Up to 6 years]

   Detected from pre-treatment tumor specimen using allele specific quantitative polymerase chain reaction (PCR). The PFS of patients with EGFR T790M mutations will be estimated and the survival difference will be tested using Cox proportional hazard model after adjusting for treatment effect. The robustness of treatment effect in different subgroups will be examined in a Forest plot.

5. Predictive Value of Plasma VEGF-A Levels on Progression Free Survival in Patients Treated With Erlotinib Hydrochloride Alone or in Combination With Bevacizumab [Baseline]

   Evaluated using time-dependent receiver operating characteristic curve and area under curve.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Histologic documentation of primary lung carcinoma, non-squamous histology with activating epidermal growth factor receptor (defined as deletion 19 or exon 21 L858R mutation); Note: EGFR mutation testing must be performed at a Clinical Laboratory Improvement Amendments (CLIA) certified lab; either institutional or through a commercial laboratory (e.g. Genzyme, Response Genetics, etc); the laboratory report from the commercial laboratories report the specific mutations detected, and the method of detecting the exon 19 and exon 21 L858R point mutations must be available

• Stage IV disease according to the 7th Edition of the American Joint Committee on Cancer staging system

• Measurable disease

• Life expectancy of >= 12 months

• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1

• Absolute neutrophil count (ANC) >= 1,500/mm^3 obtained =< 14 days prior to randomization

• Platelet count >= 100,000/mm^3 obtained =< 14 days prior to randomization

• Hemoglobin >= 9.0 g/dL obtained =< 14 days prior to randomization

• Total bilirubin =< 1.5 x upper limit of normal (ULN) obtained =< 14 days prior to randomization

• Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) and serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 2.5 x ULN in patients without liver or bone metastases; < 5 x ULN in patients with liver or bone metastases obtained =< 14 days prior to randomization

• Cockcroft-Gault calculated creatinine clearance of >= 45 ml/min or creatinine =< 1.5 x ULN obtained =< 14 days prior to randomization

• Urine dipstick proteinuria < 2+ or urine protein/creatinine (UPC) ratio =< 1.0 obtained =< 14 days prior to randomization

• Note: patients discovered to have >= 2 + proteinuria on dipstick urinalysis at baseline should undergo a 24-hour urine collection and must demonstrate =< 1 g of protein in 24 hours

• Negative pregnancy test done =< 7 days prior to randomization, for women of childbearing potential only

• Provide informed written consent

• Willing to return to Academic and Community Cancer Research United (ACCRU) enrolling institution for follow-up

• Willing to provide tissue and blood samples for correlative research purposes

Exclusion Criteria:

• Mixed, non-small cell and small cell tumors or mixed adenosquamous carcinomas with a predominant squamous component

• Prior chemotherapy or treatment for metastatic non-small cell lung cancer

• Any of the following:

• Pregnant women

• Nursing women

• Men or women of childbearing potential who are unwilling to employ adequate contraception

• Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens

• Immunocompromised patients (other than that related to the use of corticosteroids) including patients known to be human immunodeficiency virus (HIV) positive, per medical doctor (MD) discretion

• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, or psychiatric illness/social situations, or any other medical condition that would limit compliance with study requirements

• Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm

• Other active malignancy =< 3 years prior to randomization; EXCEPTIONS: non melanotic skin cancer or carcinoma-in-situ of the cervix; Note: if there is a history of prior malignancy, they must not be receiving other specific treatment (i.e. hormonal therapy) for their cancer

• History of myocardial infarction or other evidence of arterial thrombotic disease (angina), symptomatic congestive heart failure (New York Heart Association >= grade 2), unstable angina pectoris, or cardiac arrhythmia; Note: allowed only if patient has no evidence of active disease for at least 6 months prior to randomization

• History of cerebral vascular accident (CVA) or transient ischemic attack (TIA) =< 6 months prior to randomization

• History of bleeding diathesis or coagulopathy

• Inadequately controlled hypertension (systolic blood pressure of > 150 mmHg or diastolic pressure > 100 mmHg on anti-hypertensive medications); Note: history of hypertensive crisis or hypertensive encephalopathy not allowed

• Current or recent (=< 10 days prior to randomization) use of aspirin (> 325 mg/day), clopidogrel (> 75 mg/day), or prasugrel (> 10 mg/day)

• Serious non-healing wound, ulcer, bone fracture, or have undergone a major surgical procedure, open biopsy, or significant traumatic injury =< 28 days or core biopsy =< 7 days prior to randomization

• History of abdominal fistula, gastrointestinal perforation, or intraabdominal abscess =< 6 months prior to randomization

• Known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies

• History of hemoptysis >= grade 2 (defined as bright red blood of at least 2.5 mL) =< 3 months prior to randomization

• Known central nervous system (CNS) disease, except for treated brain metastasis; Note: treatment for brain metastases may include whole brain radiotherapy (WBRT), radiosurgery (RS); gamma knife, linear accelerator (LINAC), or equivalent or a combination as deemed appropriate by the treating physician; patients with CNS metastases treated by neurosurgical resection or brain biopsy performed =< 3 months prior to randomization will be excluded; Note: craniotomy or intracranial biopsy site must be adequately healed, free of drainage or cellulitis, and the underlying cranioplasty must appear intact at the time of randomization; study treatment should be initiated > 28 days following the last surgical procedure (including biopsy, surgical resection, wound revision, or any other major surgery involving entry into a body cavity)

• Significant vascular disease (e.g. aortic aneurysm surgical repair or recent peripheral arterial thrombosis) =< 6 months prior to randomization

• Radiotherapy to any site for any reason =< 14 days prior to randomization

• Receiving any medications or substances that are strong or moderate inhibitors of CYP3A4; use of the following strong or moderate inhibitors are prohibited =< 7 days prior to randomization:

• Strong inhibitors of CYP3A4: indinavir (Crixivan), nelfinavir (Viracept), atazanavir (Reyataz), ritonavir (Norvir), clarithromycin (Biaxin, Biaxin XL), itraconazole (Sporanox), ketoconazole (Nizoral), nefazodone (Serzone), saquinavir (Fortovase, Invirase), telithromycin (Ketek)

• Moderate inhibitors of CYP3A4: aprepitant (Emend), erythromycin (Erythrocin, E.E.S, Ery-Tab, Eryc, EryPed, PCE, fluconazole (Diflucan), grapefruit juice, verapamil (Calan, Calan SR, Covera-HS, Isoptin SR, Verelan, Verelan PM), diltiazem (Cardizem, Cardizem CD, Cardizem LA, Cardizem SR, Cartia XT, Dilacor XR, Diltia XT, Taztia XT, Tiazac)

• Receiving any medications or substances that are strong or moderate inducers of

CYP3A4; use of the following inducers are prohibited =< 7 days prior to randomization:

efavirenz (Sustiva), nevirapine (Viramune), carbamazepine (Carbatrol, Epitol, Equetro, Tegretol, Tegretol-XR), modafinil (Provigil), phenobarbital (Luminal), phenytoin (Dilantin, Phenytek), pioglitazone (Actos), rifabutin (Mycobutin), rifampin (Rifadin), St. John?s wort

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UC San Diego Moores Cancer Center	La Jolla	California	United States	92093
2	Heartland Cancer Research NCORP	Decatur	Illinois	United States	62526
3	Illinois CancerCare-Peoria	Peoria	Illinois	United States	61615
4	Carle Cancer Center NCI Community Oncology Research Program	Urbana	Illinois	United States	61801
5	Michigan Cancer Research Consortium NCORP	Ann Arbor	Michigan	United States	48106
6	Cancer Research Consortium of West Michigan NCORP	Grand Rapids	Michigan	United States	49503
7	Mayo Clinic	Rochester	Minnesota	United States	55905
8	Coborn Cancer Center at Saint Cloud Hospital	Saint Cloud	Minnesota	United States	56303
9	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
10	New Hampshire Oncology Hematology PA-Hooksett	Hooksett	New Hampshire	United States	03106
11	Hematology Oncology Associates of Central New York-East Syracuse	East Syracuse	New York	United States	13057
12	State University of New York Upstate Medical University	Syracuse	New York	United States	13210
13	UNC Lineberger Comprehensive Cancer Center	Chapel Hill	North Carolina	United States	27599
14	Duke University Medical Center	Durham	North Carolina	United States	27710
15	Sanford Broadway Medical Center	Fargo	North Dakota	United States	58122
16	Ohio State University Comprehensive Cancer Center	Columbus	Ohio	United States	43210
17	Upstate Carolina CCOP	Spartanburg	South Carolina	United States	29303
18	Rapid City Regional Hospital	Rapid City	South Dakota	United States	57701
19	Saint Vincent Hospital Cancer Center Green Bay	Green Bay	Wisconsin	United States	54301

Sponsors and Collaborators

• Academic and Community Cancer Research United
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Thomas E Stinchcombe, Academic and Community Cancer Research United

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jul 26, 2019

More Information

Publications

None provided.

• Responsible Party: Academic and Community Cancer Research United
• ClinicalTrials.gov Identifier: NCT01532089
• Other Study ID Numbers: RC1126; NCI-2012-00053; 11-006881; RC1126; P30CA015083
• First Posted: Feb 14, 2012
• Last Update Posted: Oct 6, 2020
• Last Verified: Jul 1, 2020

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Additional relevant MeSH terms: Carcinoma, Non-Small-Cell Lung; Bevacizumab; Antineoplastic Agents, Immunological; Erlotinib Hydrochloride; Endothelial Growth Factors; Antibodies; Immunoglobulins; Antibodies, Monoclonal; Immunoglobulin G

Study Results

Participant Flow

Arm/Group Title	Arm A (Erlotinib Hydrochloride)	Arm B (Erlotinib Hydrochloride, Bevacizumab)
Arm/Group Description	Patients receive 150 mg erlotinib hydrochloride PO QD on days 1-21.	Patients receive 150 mg erlotinib hydrochloride as in Arm A and 15 mg/kg bevacizumab IV over 30-90 minutes on day 1.
Period Title: Overall Study
STARTED	45	43
COMPLETED	45	43
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Arm A (Erlotinib Hydrochloride)	Arm B (Erlotinib Hydrochloride, Bevacizumab)	Total
Arm/Group Description	Patients receive 150 mg erlotinib hydrochloride PO QD on days 1-21.	Patients receive 150 mg erlotinib hydrochloride as in Arm A and 15 mg/kg bevacizumab IV over 30-90 minutes on day 1.	Total of all reporting groups
Overall Participants	45	43	88
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	63	65	63.5
Sex: Female, Male (Count of Participants)
Female	31 68.9%	31 72.1%	62 70.5%
Male	14 31.1%	12 27.9%	26 29.5%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	2 4.4%	1 2.3%	3 3.4%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	3 6.7%	5 11.6%	8 9.1%
White	39 86.7%	36 83.7%	75 85.2%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	1 2.2%	1 2.3%	2 2.3%
ECOG Performance Status (Count of Participants)
0	19 42.2%	24 55.8%	43 48.9%
1	26 57.8%	19 44.2%	45 51.1%
EGFR exon mutation (Count of Participants)
Exon 19 deletion	30 66.7%	29 67.4%	59 67%
Exon 21 L858R mutation	15 33.3%	14 32.6%	29 33%

Outcome Measures

1. Primary Outcome

Title	Progression Free Survival (PFS)
Description	Progression free survival (PFS) is defined as the time from the date of randomization to the date of disease progression or death resulting from any cause, whichever comes first. Progression is defined according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 as at least a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. The median and 95% confidence intervals are estimated using the Kaplan-Meier estimator.
Time Frame	Time from randomization to disease progression and death of any cause, whichever comes first, assessed up to 6 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm A (Erlotinib Hydrochloride)	Arm B (Erlotinib Hydrochloride, Bevacizumab)
Arm/Group Description	Patients receive 150 mg erlotinib hydrochloride PO QD on days 1-21.	Patients receive 150 mg erlotinib hydrochloride as in Arm A and 15 mg/kg bevacizumab IV over 30-90 minutes on day 1.
Measure Participants	45	43
Median (95% Confidence Interval) [months]	13.5	17.9

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A (Erlotinib Hydrochloride), Arm B (Erlotinib Hydrochloride, Bevacizumab)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.39
	Comments
	Method	Log Rank
	Comments	Comparisons of PFS between arms were conducted using a stratified log-rank test.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.81
	Confidence Interval	(2-Sided) 95%; 0.50 to 1.31
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Overall Survival
Description	Overall survival time is defined as the time from randomization to death due to any cause. The median and 95% confidence intervals are estimated using the Kaplan-Meier estimator.
Time Frame	Time from randomization to death of any causes, assessed up to 6 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm A (Erlotinib Hydrochloride)	Arm B (Erlotinib Hydrochloride, Bevacizumab)
Arm/Group Description	Patients receive 150 mg erlotinib hydrochloride PO QD on days 1-21.	Patients receive 150 mg erlotinib hydrochloride as in Arm A and 15 mg/kg bevacizumab IV over 30-90 minutes on day 1.
Measure Participants	45	43
Median (95% Confidence Interval) [months]	50.6	32.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A (Erlotinib Hydrochloride), Arm B (Erlotinib Hydrochloride, Bevacizumab)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.33
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.41
	Confidence Interval	(2-Sided) 95%; 0.71 to 2.81
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Response Rate (Complete or Partial) to Each Treatment, Evaluated Using the New International Criteria Proposed by the Revised Response Evaluation Criteria in Solid Tumors Guidelines (Version 1.1)
Description	The response rate (percentage) is the percent of patients whose best response was Complete Response (CR) or Partial Response (PR) as defined by RECIST 1.1 criteria. Percentage of successes will be estimated by 100 times the number of successes divided by the total number of evaluable patients. (CR: Disappearance of all evidence of disease, PR: Regression of measurable disease and no new sites).
Time Frame	Up to 6 years

Outcome Measure Data

Analysis Population Description

Patients with tumor response data available were included in this analysis.

Arm/Group Title	Arm A (Erlotinib Hydrochloride)	Arm B (Erlotinib Hydrochloride, Bevacizumab)
Arm/Group Description	Patients receive 150 mg erlotinib hydrochloride PO QD on days 1-21.	Patients receive 150 mg erlotinib hydrochloride as in Arm A and 15 mg/kg bevacizumab IV over 30-90 minutes on day 1.
Measure Participants	42	43
Number (95% Confidence Interval) [percentage of patients]	83	81

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A (Erlotinib Hydrochloride), Arm B (Erlotinib Hydrochloride, Bevacizumab)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.81
	Comments
	Method	Chi-squared
	Comments

4. Secondary Outcome

Title	Progression Free Survival of Patients With Different Mutation Types (Exon Deletion 19 Versus Exon 21 L858R)
Description	Progression free survival (PFS) is defined as the time from the date of randomization to the date of disease progression or death resulting from any cause, whichever comes first. Progression is defined according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 as at least a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. The median and 95% confidence intervals are estimated using the Kaplan-Meier estimator by mutation type.
Time Frame	From the date of randomization to the date of disease progression or death of any cause, whichever comes first, assessed up to 6 years

Outcome Measure Data

Analysis Population Description

This analysis includes all patients with EGFR exon mutation data available and primary endpoint data available.

Arm/Group Title	Exon 19 Deletion	Exon 21 L858R
Arm/Group Description	Patients with exon 19 deletion EGFR exon mutation.	Patients with exon 21 L858R EGFR exon mutation.
Measure Participants	59	29
Median (95% Confidence Interval) [months]	17.9	12.6

5. Secondary Outcome

Title	Number of Patients Experiencing Toxicity
Description	The number of patients experiencing toxicity defined as grade 3 or higher adverse events (using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0) considered at least possibly related to treatment is reported below.
Time Frame	Up to 42 days after treatment discontinuation

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm A (Erlotinib Hydrochloride)	Arm B (Erlotinib Hydrochloride, Bevacizumab)
Arm/Group Description	Patients receive 150 mg erlotinib hydrochloride PO QD on days 1-21.	Patients receive 150 mg erlotinib hydrochloride as in Arm A and 15 mg/kg bevacizumab IV over 30-90 minutes on day 1.
Measure Participants	45	43
Count of Participants [Participants]	13 28.9%	31 72.1%

6. Other Pre-specified Outcome

Title	EGFR Mutations Detected in Plasma Deoxyribonucleic Acid (DNA)
Description	Agreement of EGFR mutations detected in plasma DNA with those detected in tumor DNA will be evaluated.
Time Frame	Up to 6 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

7. Other Pre-specified Outcome

Title	EGFR Mutations Detected in Tumor Deoxyribonucleic Acid (DNA)
Description	Agreement of EGFR mutations detected in plasma DNA with those detected in tumor DNA will be evaluated.
Time Frame	Up to 6 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

8. Other Pre-specified Outcome

Title	Prevalence of EGFR T790M Resistance Mutations From Pretreatment > Tumor Biopsies Using More Sensitive Mutation Detection Methods
Description	Tested using Cox proportional hazard model after adjusting for treatment effect. The robustness of treatment effect in different subgroups will be examined in a Forest plot.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

9. Other Pre-specified Outcome

Title	EGFR T790M Mutations
Description	Detected from pre-treatment tumor specimen using allele specific quantitative polymerase chain reaction (PCR). The PFS of patients with EGFR T790M mutations will be estimated and the survival difference will be tested using Cox proportional hazard model after adjusting for treatment effect. The robustness of treatment effect in different subgroups will be examined in a Forest plot.
Time Frame	Up to 6 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

10. Other Pre-specified Outcome

Title	Predictive Value of Plasma VEGF-A Levels on Progression Free Survival in Patients Treated With Erlotinib Hydrochloride Alone or in Combination With Bevacizumab
Description	Evaluated using time-dependent receiver operating characteristic curve and area under curve.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	Up to 42 days after treatment discontinuation
Arm/Group Title	Arm A (Erlotinib Hydrochloride)		Arm B (Erlotinib Hydrochloride, Bevacizumab)
Arm/Group Description	Patients receive 150 mg erlotinib hydrochloride PO QD on days 1-21.		Patients receive 150 mg erlotinib hydrochloride as in Arm A and 15 mg/kg bevacizumab IV over 30-90 minutes on day 1.
All Cause Mortality
	Arm A (Erlotinib Hydrochloride)		Arm B (Erlotinib Hydrochloride, Bevacizumab)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	23/45 (51.1%)		27/43 (62.8%)
Serious Adverse Events
	Arm A (Erlotinib Hydrochloride)		Arm B (Erlotinib Hydrochloride, Bevacizumab)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	12/45 (26.7%)		17/43 (39.5%)
Cardiac disorders
Acute coronary syndrome	0/45 (0%)	0	1/43 (2.3%)	1
Chest pain - cardiac	1/45 (2.2%)	1	1/43 (2.3%)	1
Gastrointestinal disorders
Abdominal pain	1/45 (2.2%)	1	1/43 (2.3%)	1
Anal hemorrhage	0/45 (0%)	0	1/43 (2.3%)	1
Diarrhea	2/45 (4.4%)	2	1/43 (2.3%)	1
General disorders
Sudden death NOS	1/45 (2.2%)	1	0/43 (0%)	0
Infections and infestations
Kidney infection	0/45 (0%)	0	1/43 (2.3%)	1
Lung infection	2/45 (4.4%)	3	0/43 (0%)	0
Nail infection	0/45 (0%)	0	1/43 (2.3%)	1
Rash pustular	0/45 (0%)	0	1/43 (2.3%)	1
Injury, poisoning and procedural complications
Fall	0/45 (0%)	0	1/43 (2.3%)	1
Investigations
Alanine aminotransferase increased	1/45 (2.2%)	2	0/43 (0%)	0
Aspartate aminotransferase increased	1/45 (2.2%)	2	0/43 (0%)	0
Blood bilirubin increased	1/45 (2.2%)	1	1/43 (2.3%)	1
Cardiac troponin I increased	1/45 (2.2%)	1	0/43 (0%)	0
Metabolism and nutrition disorders
Dehydration	0/45 (0%)	0	2/43 (4.7%)	2
Hyponatremia	0/45 (0%)	0	1/43 (2.3%)	1
Nervous system disorders
Cognitive disturbance	1/45 (2.2%)	1	0/43 (0%)	0
Dizziness	1/45 (2.2%)	1	0/43 (0%)	0
Syncope	0/45 (0%)	0	1/43 (2.3%)	1
Psychiatric disorders
Confusion	0/45 (0%)	0	1/43 (2.3%)	1
Renal and urinary disorders
Proteinuria	0/45 (0%)	0	1/43 (2.3%)	1
Urinary retention	1/45 (2.2%)	1	0/43 (0%)	0
Respiratory, thoracic and mediastinal disorders
Bronchopulmonary hemorrhage	0/45 (0%)	0	1/43 (2.3%)	2
Dyspnea	0/45 (0%)	0	1/43 (2.3%)	1
Pleural effusion	0/45 (0%)	0	1/43 (2.3%)	1
Skin and subcutaneous tissue disorders
Erythema multiforme	0/45 (0%)	0	1/43 (2.3%)	1
Pain of skin	0/45 (0%)	0	1/43 (2.3%)	1
Rash acneiform	1/45 (2.2%)	1	3/43 (7%)	3
Vascular disorders
Hypertension	4/45 (8.9%)	4	2/43 (4.7%)	3
Thromboembolic event	2/45 (4.4%)	2	1/43 (2.3%)	2
Other (Not Including Serious) Adverse Events
	Arm A (Erlotinib Hydrochloride)		Arm B (Erlotinib Hydrochloride, Bevacizumab)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	43/45 (95.6%)		43/43 (100%)
Blood and lymphatic system disorders
Anemia	2/45 (4.4%)	5	0/43 (0%)	0
Blood and lymph sys disorders - Oth Spec	2/45 (4.4%)	3	1/43 (2.3%)	1
Leukocytosis	1/45 (2.2%)	1	2/43 (4.7%)	5
Cardiac disorders
Acute coronary syndrome	1/45 (2.2%)	1	0/43 (0%)	0
Cardiac disorders - Other, specify	1/45 (2.2%)	4	0/43 (0%)	0
Left ventricular systolic dysfunction	1/45 (2.2%)	1	0/43 (0%)	0
Ear and labyrinth disorders
Ear and labyrinth disorders - Oth spec	0/45 (0%)	0	2/43 (4.7%)	2
Hearing impaired	0/45 (0%)	0	1/43 (2.3%)	29
Tinnitus	1/45 (2.2%)	1	0/43 (0%)	0
Vertigo	1/45 (2.2%)	1	0/43 (0%)	0
Eye disorders
Cataract	1/45 (2.2%)	1	0/43 (0%)	0
Dry eye	1/45 (2.2%)	1	1/43 (2.3%)	1
Eye disorders - Other, specify	2/45 (4.4%)	3	2/43 (4.7%)	5
Periorbital edema	1/45 (2.2%)	1	1/43 (2.3%)	2
Watering eyes	1/45 (2.2%)	7	0/43 (0%)	0
Gastrointestinal disorders
Abdominal pain	0/45 (0%)	0	4/43 (9.3%)	5
Anal hemorrhage	3/45 (6.7%)	16	3/43 (7%)	24
Ascites	1/45 (2.2%)	1	0/43 (0%)	0
Cheilitis	1/45 (2.2%)	3	0/43 (0%)	0
Colitis	0/45 (0%)	0	1/43 (2.3%)	1
Diarrhea	37/45 (82.2%)	606	38/43 (88.4%)	528
Dyspepsia	1/45 (2.2%)	4	1/43 (2.3%)	3
Gastroesophageal reflux disease	0/45 (0%)	0	2/43 (4.7%)	45
Gastrointestinal disorders - Oth spec	0/45 (0%)	0	1/43 (2.3%)	1
Gastrointestinal pain	1/45 (2.2%)	1	0/43 (0%)	0
Mucositis oral	2/45 (4.4%)	2	3/43 (7%)	4
Nausea	3/45 (6.7%)	10	5/43 (11.6%)	9
Oral hemorrhage	2/45 (4.4%)	28	5/43 (11.6%)	9
Rectal hemorrhage	2/45 (4.4%)	2	2/43 (4.7%)	28
Stomach pain	0/45 (0%)	0	1/43 (2.3%)	5
Vomiting	2/45 (4.4%)	2	1/43 (2.3%)	1
General disorders
Edema limbs	1/45 (2.2%)	1	1/43 (2.3%)	2
Fatigue	10/45 (22.2%)	44	14/43 (32.6%)	39
Fever	1/45 (2.2%)	1	0/43 (0%)	0
Gen disord and admin site conds-Oth spec	1/45 (2.2%)	11	0/43 (0%)	0
Malaise	0/45 (0%)	0	2/43 (4.7%)	5
Pain	2/45 (4.4%)	3	1/43 (2.3%)	1
Hepatobiliary disorders
Hepatic hemorrhage	1/45 (2.2%)	1	0/43 (0%)	0
Immune system disorders
Allergic reaction	2/45 (4.4%)	2	0/43 (0%)	0
Infections and infestations
Anorectal infection	0/45 (0%)	0	1/43 (2.3%)	2
Bronchial infection	0/45 (0%)	0	1/43 (2.3%)	3
Conjunctivitis	1/45 (2.2%)	1	0/43 (0%)	0
Gum infection	0/45 (0%)	0	1/43 (2.3%)	1
Infections and infestations - Oth spec	1/45 (2.2%)	1	0/43 (0%)	0
Lip infection	0/45 (0%)	0	1/43 (2.3%)	1
Lung infection	0/45 (0%)	0	3/43 (7%)	3
Nail infection	2/45 (4.4%)	5	1/43 (2.3%)	23
Papulopustular rash	0/45 (0%)	0	1/43 (2.3%)	5
Paronychia	6/45 (13.3%)	37	3/43 (7%)	10
Sinusitis	1/45 (2.2%)	1	0/43 (0%)	0
Skin infection	2/45 (4.4%)	3	1/43 (2.3%)	2
Urinary tract infection	3/45 (6.7%)	4	3/43 (7%)	3
Injury, poisoning and procedural complications
Bruising	0/45 (0%)	0	1/43 (2.3%)	3
Investigations
Activated partial throm time prolonged	1/45 (2.2%)	9	0/43 (0%)	0
Alanine aminotransferase increased	2/45 (4.4%)	4	2/43 (4.7%)	2
Alkaline phosphatase increased	1/45 (2.2%)	1	0/43 (0%)	0
Aspartate aminotransferase increased	1/45 (2.2%)	1	0/43 (0%)	0
Blood bilirubin increased	8/45 (17.8%)	19	1/43 (2.3%)	4
Cardiac troponin I increased	1/45 (2.2%)	21	0/43 (0%)	0
Creatinine increased	2/45 (4.4%)	2	2/43 (4.7%)	6
Lymphocyte count decreased	5/45 (11.1%)	33	1/43 (2.3%)	1
Lymphocyte count increased	1/45 (2.2%)	1	0/43 (0%)	0
Weight gain	0/45 (0%)	0	1/43 (2.3%)	1
Weight loss	4/45 (8.9%)	19	6/43 (14%)	33
Metabolism and nutrition disorders
Anorexia	4/45 (8.9%)	24	7/43 (16.3%)	14
Dehydration	3/45 (6.7%)	4	1/43 (2.3%)	1
Glucose intolerance	0/45 (0%)	0	1/43 (2.3%)	20
Hyperglycemia	0/45 (0%)	0	2/43 (4.7%)	11
Hyperkalemia	0/45 (0%)	0	1/43 (2.3%)	2
Hypocalcemia	1/45 (2.2%)	1	0/43 (0%)	0
Hypokalemia	1/45 (2.2%)	2	1/43 (2.3%)	1
Hyponatremia	1/45 (2.2%)	1	3/43 (7%)	10
Hypophosphatemia	2/45 (4.4%)	4	2/43 (4.7%)	13
Musculoskeletal and connective tissue disorders
Arthralgia	1/45 (2.2%)	2	0/43 (0%)	0
Back pain	2/45 (4.4%)	3	0/43 (0%)	0
Buttock pain	1/45 (2.2%)	2	0/43 (0%)	0
Flank pain	1/45 (2.2%)	2	0/43 (0%)	0
Generalized muscle weakness	0/45 (0%)	0	2/43 (4.7%)	3
Musculoskeletal, conn tissue - Oth spec	1/45 (2.2%)	3	1/43 (2.3%)	1
Myalgia	1/45 (2.2%)	8	1/43 (2.3%)	1
Pain in extremity	2/45 (4.4%)	2	1/43 (2.3%)	4
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, mal, uncpec - Oth spec	1/45 (2.2%)	2	0/43 (0%)	0
Nervous system disorders
Cerebrospinal fluid leakage	0/45 (0%)	0	1/43 (2.3%)	1
Concentration impairment	0/45 (0%)	0	1/43 (2.3%)	1
Dizziness	0/45 (0%)	0	1/43 (2.3%)	1
Dysgeusia	2/45 (4.4%)	7	3/43 (7%)	23
Encephalopathy	0/45 (0%)	0	1/43 (2.3%)	1
Headache	3/45 (6.7%)	3	1/43 (2.3%)	1
Memory impairment	1/45 (2.2%)	1	0/43 (0%)	0
Nervous system disorders - Oth spec	0/45 (0%)	0	1/43 (2.3%)	1
Neuralgia	0/45 (0%)	0	1/43 (2.3%)	2
Peripheral motor neuropathy	1/45 (2.2%)	3	0/43 (0%)	0
Peripheral sensory neuropathy	0/45 (0%)	0	2/43 (4.7%)	3
Presyncope	1/45 (2.2%)	1	0/43 (0%)	0
Syncope	0/45 (0%)	0	1/43 (2.3%)	1
Transient ischemic attacks	0/45 (0%)	0	2/43 (4.7%)	2
Psychiatric disorders
Anxiety	0/45 (0%)	0	2/43 (4.7%)	2
Confusion	1/45 (2.2%)	1	0/43 (0%)	0
Delirium	0/45 (0%)	0	1/43 (2.3%)	1
Depression	1/45 (2.2%)	1	1/43 (2.3%)	6
Insomnia	4/45 (8.9%)	19	0/43 (0%)	0
Renal and urinary disorders
Chronic kidney disease	1/45 (2.2%)	1	1/43 (2.3%)	4
Hematuria	15/45 (33.3%)	102	12/43 (27.9%)	79
Proteinuria	15/45 (33.3%)	106	24/43 (55.8%)	218
Reproductive system and breast disorders
Vaginal hemorrhage	0/45 (0%)	0	1/43 (2.3%)	4
Respiratory, thoracic and mediastinal disorders
Bronchopulmonary hemorrhage	3/45 (6.7%)	3	1/43 (2.3%)	12
Cough	2/45 (4.4%)	3	0/43 (0%)	0
Dyspnea	2/45 (4.4%)	8	5/43 (11.6%)	6
Epistaxis	0/45 (0%)	0	1/43 (2.3%)	1
Nasal congestion	0/45 (0%)	0	2/43 (4.7%)	2
Pleural effusion	1/45 (2.2%)	1	2/43 (4.7%)	2
Pneumonitis	0/45 (0%)	0	1/43 (2.3%)	6
Pulmonary edema	0/45 (0%)	0	1/43 (2.3%)	1
Resp, thoracic, mediastinal - Oth spec	0/45 (0%)	0	3/43 (7%)	34
Skin and subcutaneous tissue disorders
Alopecia	4/45 (8.9%)	11	3/43 (7%)	54
Bullous dermatitis	0/45 (0%)	0	1/43 (2.3%)	5
Dry skin	6/45 (13.3%)	34	6/43 (14%)	74
Erythema multiforme	1/45 (2.2%)	3	0/43 (0%)	0
Nail loss	1/45 (2.2%)	2	0/43 (0%)	0
Pain of skin	0/45 (0%)	0	2/43 (4.7%)	3
Palmar-plantar erythrodysesthesia syndrm	0/45 (0%)	0	1/43 (2.3%)	1
Photosensitivity	1/45 (2.2%)	1	0/43 (0%)	0
Pruritus	0/45 (0%)	0	2/43 (4.7%)	17
Rash acneiform	40/45 (88.9%)	586	42/43 (97.7%)	732
Rash maculo-papular	3/45 (6.7%)	7	3/43 (7%)	11
Skin and subcut tissue disord - Oth spec	2/45 (4.4%)	2	2/43 (4.7%)	2
Surgical and medical procedures
Surgical and medical proced - Oth spec	0/45 (0%)	0	2/43 (4.7%)	2
Vascular disorders
Hypertension	23/45 (51.1%)	413	36/43 (83.7%)	617
Hypotension	1/45 (2.2%)	2	0/43 (0%)	0
Phlebitis	1/45 (2.2%)	1	0/43 (0%)	0
Thromboembolic event	1/45 (2.2%)	1	2/43 (4.7%)	42

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.