LUX-Breast 2; Afatinib in HER2 (Human Epidermal Growth Factor Receptor)-Treatment Failures

• Sponsor: Boehringer Ingelheim (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01271725
• Collaborator: (none)
• Enrollment: 74
• Locations: 27
• Arms: 3
• Actual Duration (Months): 69.7
• Patients Per Site: 2.7
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

The general aim of this study is to investigate the efficacy and safety of afatinib (BIBW 2992) alone and in combination with weekly paclitaxel or weekly vinorelbine (in patients who progress on afatinib monotherapy within this trial) as treatment in patients with HER2-overexpressing, metastatic breast cancer, who failed HER2-targeted treatment in the neoadjuvant or adjuvant setting

Condition or Disease	Intervention/Treatment	Phase
Breast Neoplasms	Drug: Vinorelbine 25 mg/m2 weekly; Drug: Afatinib 40mg once daily (OD); Drug: Paclitaxel 80 mg/m2 weekly	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 74 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: LUX-Breast 2; An Open Label, Phase II Trial of Afatinib (BIBW 2992) in Patients With Metastatic HER2-overexpressing Breast Cancer Failing HER2-targeted Treatment in the Neoadjuvant and/or Adjuvant Treatment Setting
• Actual Study Start Date: May 24, 2011
• Actual Primary Completion Date: Mar 13, 2017
• Actual Study Completion Date: Mar 13, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Afatinib 40mg once daily (OD) Patient to receive afatinib monotherapy at a dose of 40 mg/d until progression of their disease	Drug: Afatinib 40mg once daily (OD); Patient to receive afatinib monotherapy at a dose of 40 mg/d until progression of their disease
Experimental: Paclitaxel 80 mg/m2 weekly Patients to additionally receive paclitaxel at a dose of 80 mg/m2 weekly on disease progression on afatinib monotherapy	Drug: Paclitaxel 80 mg/m2 weekly; Patients to additionally receive paclitaxel at a dose of 80 mg/m2 weekly on disease progression on afatinib monotherapy
Experimental: Vinorelbine 25 mg/m2 weekly Patients to additionally receive vinorelbine at a dose of 25 mg/m2 weekly on disease progression on afatinib monotherapy	Drug: Vinorelbine 25 mg/m2 weekly; Patients to additionally receive vinorelbine at a dose of 25 mg/m2 weekly on disease progression on afatinib monotherapy

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With Objective Response (OR) Assessed by Response Evaluation Criteria in Solid Tumours Version (RECIST) 1.1 [From the initial dose of study drug until 28 days after end of the treatment period, up to 1562 days]

   Objective response according to RECIST v1.1. Best overall response of confirmed complete response (CR) or confirmed partial response (PR) recorded since first administration of trial medication and until the earliest of disease progression, death or start of next treatment in each part separately. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by Magnetic resonance imaging (MRI): Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Objective Response (OR) = CR + PR. Percentage of participants with OR along with exact 95% Confidence Interval by Clopper and Pearson is presented.

Secondary Outcome Measures

1. Best Overall Response According to RECIST v1.1 (With Confirmation) [From the initial dose of study drug until 28 days after end of the treatment period, up to 1562 days]

   Best overall response was assessed according to RECIST version 1.1 and was calculated relative to the baseline of each respective part .Percentage of participants with best overall response along with exact 95% Confidence Interval by Clopper and Pearson is presented. Best overall response was defined as the best response recorded at any time from the first administration of drug to the End of Treatment (EOT). As Per RECIST v1.1 for target lesions and assessed by Magnetic resonance imaging (MRI): Complete Response (CR), disappearance of all target lesions; Partial Response (PR), at least 30% decrease in the sum of the longest diameter of target lesions; progression, at least 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; Stable Disease (SD), neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for disease progression.

2. Best Overall Response According to RECIST v1.1 (Regardless of Confirmation) [From the initial dose of study drug until 28 days after end of the treatment period, up to 1562 days]

   Best overall response was assessed according to RECIST version 1.1 and was calculated relative to the baseline of each respective part (without clinical disease assessment) .Percentage of participants with best overall response along with exact 95% Confidence Interval by Clopper and Pearson is presented. Best overall response was defined as the best response recorded at any time from the first administration of drug to the End of Treatment (EOT). As Per RECIST v1.1 for target lesions and assessed by Magnetic resonance imaging (MRI): Complete Response (CR), disappearance of all target lesions; Partial Response (PR), at least 30% decrease in the sum of the longest diameter of target lesions; progression, at least 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; Stable Disease (SD), neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for disease progression.

3. Progression Free Survival (PFS) [From drug start date in monotherapy to 1st disease progression and drug start date in combination therapy to 2nd disease progression]

   Progression Free Survival is defined as the time from the drug start date to the date of 1st disease progression or death for monotherapy and 2nd disease progression or death from the drug start date of the combination therapy for combination therapy'. Median is calculated from the Kaplan-Meier curve.

4. Duration of Objective Response According to RECIST v1.1 [From the first objective response to the time of progression or death, up to 1562 days]

   Duration of objective response, defined as the time from first objective response to the time of progression or death. (regardless of confirmation). As Per RECIST v1.1 for target lesions and assessed by Magnetic resonance imaging (MRI): Complete Response (CR), disappearance of all target lesions; Partial Response (PR), at least 30% decrease in the sum of the longest diameter of target lesions; progression, at least 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; Stable Disease (SD), neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for disease progression.

5. Percentage of Patients With Highest Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 Grade of 3 or Higher [From the initial dose of study drug until 28 days after end of the treatment period, up to 1562 days]

   Percentage of patients with highest common terminology criteria for adverse events (CTCAE) version 3.0 Grade of 3 or higher.

6. Change From Baseline to End of Treatment in Systolic Blood Pressure (SBP) [Baseline and End of treatment period, up to 1562 days]

   Change from baseline to end of treatment in systolic blood pressure (SBP).

7. Change From Baseline to End of Treatment in Diastolic Blood Pressure (DBP) [Baseline and End of treatment period, up to 1562 days]

   Change from baseline to end of treatment in diastolic blood pressure (DBP).

8. Number of Patient With Possibly Clinically Significant (PCS) Laboratory Values [From the initial dose of study drug until 28 days after end of the treatment period, up to 1562 days]

   Number of patient with possibly clinically significant (PCS) laboratory values by functional group (haematology, differentials, coagulation, electrolytes, enzymes, and substrates). Acronyms Used: Prothrombin time-International normalized ratio (PT-INR), Alanine aminotransferase/Glutamic pyruvic transaminase (ALT/GPT) Serum glutamic pyruvic transaminase (SGPT), Aspartate aminotransferase/Glutamic-oxaloacetic transaminase (AST/GOT) Serum glutamic-oxaloacetic transaminase (SGOT)

Eligibility Criteria

Criteria

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

Inclusion criteria:

1. Female patients >=18 years with proven diagnosis of HER2-overexpressing, histologically confirmed breast cancer

2. Stage IV metastatic disease

3. At least one measurable lesion according to RECIST 1.1 (Response Evaluation Criteria for Solid Tumours version 1.1). Skin, bone and brain lesions are considered non-target lesions

4. Must have failed or progressed on either trastuzumab or lapatinib or trastuzumab and lapatinib treatment in the neoadjuvant and/or adjuvant setting

Exclusion criteria:

1. Prior first line therapy for metastatic breast cancer

2. Known pre-existing interstitial lung disease

3. Active brain metastases

4. History or presence of clinically relevant cardiovascular abnormalities such as uncontrolled hypertension, congestive heart failure NYHA classification of 3, unstable angina or poorly controlled arrhythmia. Myocardial infarction within 6 months prior to trial treatment.

5. Cardiac left ventricular function with resting ejection fraction of less than 50%.

6. Prior treatment with Epidermal Growth Factor Receptor (EGFR)/HER2-targeted small molecules or antibodies other than trastuzumab and lapatinib in the neoadjuvant or adjuvant setting

7. Prior treatment with paclitaxel in the past 12 months

8. Must not have received prior vinorelbine treatment - Further exclusion criteria apply

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Queen Mary Hospital	Hong Kong		Hong Kong
2	Prince of Wales Hospital	Shatin		Hong Kong
3	Sujan Surgical Cancer Hospital	Amravati		India	444606
4	Tata Memorial Hospital	Maharashtra		India	400 012
5	Curie Manavata Cancer Centre	Maharashtra		India	422 004
6	Central India Cancer Research Institute	Nagpur		India	440010
7	Ruby Hall Clinic	Pune		India	411001
8	Regional Cancer Center	Thiruvananthapuram		India	695 011
9	University Clinical Center, Gdansk	Gdansk		Poland	80-211
10	St.Auton.Heal.Inst."Rep.Clin.Onc.Disp.of MoH of Rep. Tatarstan"	Kazan		Russian Federation	420029
11	Clinical Oncology Dispensary No. 1, Dept. Chemotherapy	Krasnodar		Russian Federation	350040
12	N.A. Semashko Central Clinical Hospital, Moscow	Moscow		Russian Federation	129128
13	SBIH of Stavropol territory "Pyatigorsk Oncol. Dispensary"	Pyatigorsk		Russian Federation	357502
14	SBIH "Samara Regional Clinical Oncol. Dispensary", Samara	Samara		Russian Federation	443 031
15	GUZ "Oncological Dispesary #2"	Sochi		Russian Federation	354057
16	Stavropol Regional Clin. Oncology Dispensary Dept. Oncology	Stavropol		Russian Federation	355 047
17	Yaroslavl Regional Clinical Oncology Hosp. Dept.Chemotherapy	Yaroslavl		Russian Federation	150 040
18	China Medical University Hospital	Taichung		Taiwan	404
19	Taichung Veterans General Hospital	Taichung		Taiwan	40705
20	National Taiwan University Hospital	Taipei		Taiwan	100
21	Mackay Memorial Hospital	Taipei		Taiwan	10449
22	Koo Foundation Sun Yet-Sen Cancer Center	Taipei		Taiwan	112
23	Taipe Veterans General Hospital	Taipei		Taiwan	112
24	North Devon District Hospital	Barnstaple		United Kingdom	EX31 4JB
25	Royal Bournemouth and Christchurch Hospital	Bournemouth		United Kingdom	BH7 7DW
26	Royal Devon and Exeter Hospital	Exeter		United Kingdom	EX2 5DW
27	Charing Cross Hospital	London		United Kingdom	W6 8RF

Sponsors and Collaborators

• Boehringer Ingelheim

Investigators

• Study Chair: Boehringer Ingelheim, Boehringer Ingelheim

Study Documents (Full-Text)

• Statistical Analysis Plan - Oct 20, 2014
• Study Protocol - Jun 27, 2013

More Information

Additional Information:

• Related Info

Publications

None provided.

• Responsible Party: Boehringer Ingelheim
• ClinicalTrials.gov Identifier: NCT01271725
• Other Study ID Numbers: 1200.98; 2010-021945-29
• First Posted: Jan 7, 2011
• Last Update Posted: Jun 17, 2019
• Last Verified: Mar 1, 2019

• Additional relevant MeSH terms: Breast Neoplasms; Paclitaxel; Vinorelbine; Afatinib

Study Results

Participant Flow

Recruitment Details	An open-label, multinational, phase-II trial of Afatinib (BIBW 2992) in patients with metastatic human epidermal growth factor receptor (HER2) - overexpressing breast cancer failing HER2 - targeted treatment in the neoadjuvant and/or adjuvant treatment setting
Pre-assignment Detail	All subjects were screened for eligibility. It was not planned to compare efficacy of the combination therapies "Afatinib and Paclitaxel or Afatinib and Vinorelbine" as the study was stopped prematurely and the patient number in both treatment groups is not significant. However, for safety reporting both combination therapy are reported separately

Arm/Group Title	Afatinib Monotherapy	Afatinib and Paclitaxel or Vinorelbine Combination Therapy
Arm/Group Description	Patient received Afatinib monotherapy orally once daily at a dose of 40 milligram (mg) film-coated tablets until progression of their disease, unacceptable adverse events or other reason necessitating withdrawal. Patients could have dose reduced if 40 mg was not tolerated.	Patient received Afatinib monotherapy orally once daily at a dose of 40 mg film-coated tablets until progression of their disease, unacceptable adverse events or other reason necessitating withdrawal (Patients could have dose reduced if 40 mg was not tolerated) and 80 mg/square meter (m2) Paclitaxel concentrate for intravenous infusion or 25 mg/m2 Vinorelbine concentrate for intravenous infusion once weekly starting after treatment failure on afatinib monotherapy
Period Title: Part A
STARTED	74	0
COMPLETED	39	0
NOT COMPLETED	35	0
Period Title: Part A
STARTED	0	39
COMPLETED	0	27
NOT COMPLETED	0	12

Baseline Characteristics

Arm/Group Title	Afatinib Monotherapy
Arm/Group Description	Patient received Afatinib monotherapy orally once daily at a dose of 40 milligram (mg) film-coated tablets until progression of their disease, unacceptable adverse events or other reason necessitating withdrawal. Patients could have dose reduced if 40 mg was not tolerated.
Overall Participants	74
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	51.3 (10.6)
Sex: Female, Male (Count of Participants)
Female	74 100%
Male	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	47 63.5%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	27 36.5%
More than one race	0 0%
Unknown or Not Reported	0 0%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Objective Response (OR) Assessed by Response Evaluation Criteria in Solid Tumours Version (RECIST) 1.1
Description	Objective response according to RECIST v1.1. Best overall response of confirmed complete response (CR) or confirmed partial response (PR) recorded since first administration of trial medication and until the earliest of disease progression, death or start of next treatment in each part separately. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by Magnetic resonance imaging (MRI): Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Objective Response (OR) = CR + PR. Percentage of participants with OR along with exact 95% Confidence Interval by Clopper and Pearson is presented.
Time Frame	From the initial dose of study drug until 28 days after end of the treatment period, up to 1562 days

Outcome Measure Data

Analysis Population Description

The treated set for monotherapy comprised all patients who received at least 1 dose of afatinib. Treated set for combination therapy comprised all patients who received at least 1 dose of each of afatinib and paclitaxel or of afatinib and vinorelbine. It was not planned to compare between the two types of combination therapies hence arm is combined

Arm/Group Title	Afatinib Monotherapy	Afatinib and Paclitaxel or Vinorelbine Combination Therapy
Arm/Group Description	Patient received Afatinib monotherapy orally once daily at a dose of 40 milligram (mg) film-coated tablets until progression of their disease, unacceptable adverse events or other reason necessitating withdrawal. Patients could have dose reduced if 40 mg was not tolerated.	Patient received Afatinib monotherapy orally once daily at a dose of 40 mg film-coated tablets until progression of their disease, unacceptable adverse events or other reason necessitating withdrawal (Patients could have dose reduced if 40 mg was not tolerated) and 80 mg/square meter (m2) Paclitaxel concentrate for intravenous infusion or 25 mg/m2 Vinorelbine concentrate for intravenous infusion once weekly starting after treatment failure on afatinib monotherapy
Measure Participants	74	39
Number (95% Confidence Interval) [Percentage of participants]	18 24.3%	31 NaN

2. Secondary Outcome

Title	Best Overall Response According to RECIST v1.1 (With Confirmation)
Description	Best overall response was assessed according to RECIST version 1.1 and was calculated relative to the baseline of each respective part .Percentage of participants with best overall response along with exact 95% Confidence Interval by Clopper and Pearson is presented. Best overall response was defined as the best response recorded at any time from the first administration of drug to the End of Treatment (EOT). As Per RECIST v1.1 for target lesions and assessed by Magnetic resonance imaging (MRI): Complete Response (CR), disappearance of all target lesions; Partial Response (PR), at least 30% decrease in the sum of the longest diameter of target lesions; progression, at least 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; Stable Disease (SD), neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for disease progression.
Time Frame	From the initial dose of study drug until 28 days after end of the treatment period, up to 1562 days

Outcome Measure Data

Analysis Population Description

The treated set for monotherapy comprised all patients who received at least 1 dose of afatinib. Treated set for combination therapy comprised all patients who received at least 1 dose of each of afatinib and paclitaxel or of afatinib and vinorelbine. It was not planned to compare between the two types of combination therapies hence arm is combined

Arm/Group Title	Afatinib Monotherapy	Afatinib and Paclitaxel or Vinorelbine Combination Therapy
Arm/Group Description	Patient received Afatinib monotherapy orally once daily at a dose of 40 milligram (mg) film-coated tablets until progression of their disease, unacceptable adverse events or other reason necessitating withdrawal. Patients could have dose reduced if 40 mg was not tolerated.	Patient received Afatinib monotherapy orally once daily at a dose of 40 mg film-coated tablets until progression of their disease, unacceptable adverse events or other reason necessitating withdrawal (Patients could have dose reduced if 40 mg was not tolerated) and 80 mg/square meter (m2) Paclitaxel concentrate for intravenous infusion or 25 mg/m2 Vinorelbine concentrate for intravenous infusion once weekly starting after treatment failure on afatinib monotherapy
Measure Participants	74	39
Complete response (CR)	1 1.4%	0 NaN
Partial response (PR)	16 21.6%	31 NaN
Stable disease (SD)	45 60.8%	46 NaN
Progressive disease	28 37.8%	10 NaN
Not evaluable	9 12.2%	13 NaN

3. Secondary Outcome

Title	Best Overall Response According to RECIST v1.1 (Regardless of Confirmation)
Description	Best overall response was assessed according to RECIST version 1.1 and was calculated relative to the baseline of each respective part (without clinical disease assessment) .Percentage of participants with best overall response along with exact 95% Confidence Interval by Clopper and Pearson is presented. Best overall response was defined as the best response recorded at any time from the first administration of drug to the End of Treatment (EOT). As Per RECIST v1.1 for target lesions and assessed by Magnetic resonance imaging (MRI): Complete Response (CR), disappearance of all target lesions; Partial Response (PR), at least 30% decrease in the sum of the longest diameter of target lesions; progression, at least 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; Stable Disease (SD), neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for disease progression.
Time Frame	From the initial dose of study drug until 28 days after end of the treatment period, up to 1562 days

Outcome Measure Data

Analysis Population Description

The treated set for monotherapy comprised all patients who received at least 1 dose of afatinib. Treated set for combination therapy comprised all patients who received at least 1 dose of each of afatinib and paclitaxel or of afatinib and vinorelbine. It was not planned to compare between the two types of combination therapies hence arm is combined

Arm/Group Title	Afatinib Monotherapy	Afatinib and Paclitaxel or Vinorelbine Combination Therapy
Arm/Group Description	Patient received Afatinib monotherapy orally once daily at a dose of 40 milligram (mg) film-coated tablets until progression of their disease, unacceptable adverse events or other reason necessitating withdrawal. Patients could have dose reduced if 40 mg was not tolerated.	Patient received Afatinib monotherapy orally once daily at a dose of 40 mg film-coated tablets until progression of their disease, unacceptable adverse events or other reason necessitating withdrawal (Patients could have dose reduced if 40 mg was not tolerated) and 80 mg/square meter (m2) Paclitaxel concentrate for intravenous infusion or 25 mg/m2 Vinorelbine concentrate for intravenous infusion once weekly starting after treatment failure on afatinib monotherapy
Measure Participants	74	39
Complete response (CR)	1 1.4%	0 NaN
Partial response (PR)	19 25.7%	44 NaN
Stable disease (SD)	42 56.8%	33 NaN
Progressive disease	28 37.8%	10 NaN
Not evaluable	9 12.2%	13 NaN

4. Secondary Outcome

Title	Progression Free Survival (PFS)
Description	Progression Free Survival is defined as the time from the drug start date to the date of 1st disease progression or death for monotherapy and 2nd disease progression or death from the drug start date of the combination therapy for combination therapy'. Median is calculated from the Kaplan-Meier curve.
Time Frame	From drug start date in monotherapy to 1st disease progression and drug start date in combination therapy to 2nd disease progression

Outcome Measure Data

Analysis Population Description

The treated set for monotherapy comprised all patients who received at least 1 dose of afatinib. Treated set for combination therapy comprised all patients who received at least 1 dose of each of afatinib and paclitaxel or of afatinib and vinorelbine. It was not planned to compare between the two types of combination therapies hence arm is combined

Arm/Group Title	Afatinib Monotherapy	Afatinib and Paclitaxel or Vinorelbine Combination Therapy
Arm/Group Description	Patient received Afatinib monotherapy orally once daily at a dose of 40 milligram (mg) film-coated tablets until progression of their disease, unacceptable adverse events or other reason necessitating withdrawal. Patients could have dose reduced if 40 mg was not tolerated.	Patient received Afatinib monotherapy orally once daily at a dose of 40 mg film-coated tablets until progression of their disease, unacceptable adverse events or other reason necessitating withdrawal (Patients could have dose reduced if 40 mg was not tolerated) and 80 mg/square meter (m2) Paclitaxel concentrate for intravenous infusion or 25 mg/m2 Vinorelbine concentrate for intravenous infusion once weekly starting after treatment failure on afatinib monotherapy
Measure Participants	74	39
Median (95% Confidence Interval) [Days]	86.0	135.0

5. Secondary Outcome

Title	Duration of Objective Response According to RECIST v1.1
Description	Duration of objective response, defined as the time from first objective response to the time of progression or death. (regardless of confirmation). As Per RECIST v1.1 for target lesions and assessed by Magnetic resonance imaging (MRI): Complete Response (CR), disappearance of all target lesions; Partial Response (PR), at least 30% decrease in the sum of the longest diameter of target lesions; progression, at least 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; Stable Disease (SD), neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for disease progression.
Time Frame	From the first objective response to the time of progression or death, up to 1562 days

Outcome Measure Data

Analysis Population Description

The treated set for monotherapy comprised all patients who received at least 1 dose of afatinib. Treated set for combination therapy comprised all patients who received at least 1 dose of each of afatinib and paclitaxel or of afatinib and vinorelbine. It was not planned to compare between the two types of combination therapies hence arm is combined

Arm/Group Title	Afatinib Monotherapy	Afatinib and Paclitaxel or Vinorelbine Combination Therapy
Arm/Group Description	Patient received Afatinib monotherapy orally once daily at a dose of 40 milligram (mg) film-coated tablets until progression of their disease, unacceptable adverse events or other reason necessitating withdrawal. Patients could have dose reduced if 40 mg was not tolerated.	Patient received Afatinib monotherapy orally once daily at a dose of 40 mg film-coated tablets until progression of their disease, unacceptable adverse events or other reason necessitating withdrawal (Patients could have dose reduced if 40 mg was not tolerated) and 80 mg/square meter (m2) Paclitaxel concentrate for intravenous infusion or 25 mg/m2 Vinorelbine concentrate for intravenous infusion once weekly starting after treatment failure on afatinib monotherapy
Measure Participants	74	39
Median (95% Confidence Interval) [Days]	168.5	125.0

6. Secondary Outcome

Title	Percentage of Patients With Highest Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 Grade of 3 or Higher
Description	Percentage of patients with highest common terminology criteria for adverse events (CTCAE) version 3.0 Grade of 3 or higher.
Time Frame	From the initial dose of study drug until 28 days after end of the treatment period, up to 1562 days

Outcome Measure Data

Analysis Population Description

The treated set for monotherapy comprised all patients who received at least 1 dose of afatinib. The treated set for combination therapy comprised all patients who received at least 1 dose of each of afatinib and paclitaxel, or of afatinib and vinorelbine.

Arm/Group Title	Afatinib Monotherapy	Afatinib and Vinorelbine Combination Therapy	Afatinib and Paclitaxel Combination Therapy
Arm/Group Description	Patient received Afatinib monotherapy orally once daily at a dose of 40 milligram (mg) film-coated tablets until progression of their disease, unacceptable adverse events or other reason necessitating withdrawal. Patients could have dose reduced if 40 mg was not tolerated.	Patient received Afatinib monotherapy orally once daily at a dose of 40 mg film-coated tablets until progression of their disease, unacceptable adverse events or other reason necessitating withdrawal (Patients could have dose reduced if 40 mg was not tolerated) and 25 mg/m2 Vinorelbine concentrate for intravenous infusion once weekly starting after treatment failure on afatinib monotherapy	Patient received Afatinib monotherapy orally once daily at a dose of 40 mg film-coated tablets until progression of their disease, unacceptable adverse events or other reason necessitating withdrawal (Patients could have dose reduced if 40 mg was not tolerated) and 80 mg/square meter (m2) Paclitaxel concentrate for intravenous infusion once weekly starting after treatment failure on afatinib monotherapy
Measure Participants	74	13	26
Number [Percentage of participants]	43 58.1%	62 NaN	65 NaN

7. Secondary Outcome

Title	Change From Baseline to End of Treatment in Systolic Blood Pressure (SBP)
Description	Change from baseline to end of treatment in systolic blood pressure (SBP).
Time Frame	Baseline and End of treatment period, up to 1562 days

Outcome Measure Data

Analysis Population Description

The treated set for monotherapy comprised all patients who received at least 1 dose of afatinib. The treated set for combination therapy comprised all patients who received at least 1 dose of each of afatinib and paclitaxel, or of afatinib and vinorelbine.

Arm/Group Title	Afatinib Monotherapy	Afatinib and Vinorelbine Combination Therapy	Afatinib and Paclitaxel Combination Therapy
Arm/Group Description	Patient received Afatinib monotherapy orally once daily at a dose of 40 milligram (mg) film-coated tablets until progression of their disease, unacceptable adverse events or other reason necessitating withdrawal. Patients could have dose reduced if 40 mg was not tolerated.	Patient received Afatinib monotherapy orally once daily at a dose of 40 mg film-coated tablets until progression of their disease, unacceptable adverse events or other reason necessitating withdrawal (Patients could have dose reduced if 40 mg was not tolerated) and 25 mg/m2 Vinorelbine concentrate for intravenous infusion once weekly starting after treatment failure on afatinib monotherapy	Patient received Afatinib monotherapy orally once daily at a dose of 40 mg film-coated tablets until progression of their disease, unacceptable adverse events or other reason necessitating withdrawal (Patients could have dose reduced if 40 mg was not tolerated) and 80 mg/square meter (m2) Paclitaxel concentrate for intravenous infusion once weekly starting after treatment failure on afatinib monotherapy
Measure Participants	74	13	26
Mean (Standard Deviation) [Millimeter of mercury (mmHg)]	-1.2 (17.9)	-1.0 (15.1)	-3.7 (12.1)

8. Secondary Outcome

Title	Change From Baseline to End of Treatment in Diastolic Blood Pressure (DBP)
Description	Change from baseline to end of treatment in diastolic blood pressure (DBP).
Time Frame	Baseline and End of treatment period, up to 1562 days

Outcome Measure Data

Analysis Population Description

The treated set for monotherapy comprised all patients who received at least 1 dose of afatinib. The treated set for combination therapy comprised all patients who received at least 1 dose of each of afatinib and paclitaxel, or of afatinib and vinorelbine.

Arm/Group Title	Afatinib Monotherapy	Afatinib and Vinorelbine Combination Therapy	Afatinib and Paclitaxel Combination Therapy
Arm/Group Description	Patient received Afatinib monotherapy orally once daily at a dose of 40 milligram (mg) film-coated tablets until progression of their disease, unacceptable adverse events or other reason necessitating withdrawal. Patients could have dose reduced if 40 mg was not tolerated.	Patient received Afatinib monotherapy orally once daily at a dose of 40 mg film-coated tablets until progression of their disease, unacceptable adverse events or other reason necessitating withdrawal (Patients could have dose reduced if 40 mg was not tolerated) and 25 mg/m2 Vinorelbine concentrate for intravenous infusion once weekly starting after treatment failure on afatinib monotherapy	Patient received Afatinib monotherapy orally once daily at a dose of 40 mg film-coated tablets until progression of their disease, unacceptable adverse events or other reason necessitating withdrawal (Patients could have dose reduced if 40 mg was not tolerated) and 80 mg/square meter (m2) Paclitaxel concentrate for intravenous infusion once weekly starting after treatment failure on afatinib monotherapy
Measure Participants	74	13	26
Mean (Standard Deviation) [Millimeter of mercury (mmHg)]	-1.8 (12.0)	1.9 (10.7)	-1.6 (10.0)

9. Secondary Outcome

Title	Number of Patient With Possibly Clinically Significant (PCS) Laboratory Values
Description	Number of patient with possibly clinically significant (PCS) laboratory values by functional group (haematology, differentials, coagulation, electrolytes, enzymes, and substrates). Acronyms Used: Prothrombin time-International normalized ratio (PT-INR), Alanine aminotransferase/Glutamic pyruvic transaminase (ALT/GPT) Serum glutamic pyruvic transaminase (SGPT), Aspartate aminotransferase/Glutamic-oxaloacetic transaminase (AST/GOT) Serum glutamic-oxaloacetic transaminase (SGOT)
Time Frame	From the initial dose of study drug until 28 days after end of the treatment period, up to 1562 days

Outcome Measure Data

Analysis Population Description

The treated set for monotherapy comprised all patients who received at least 1 dose of afatinib. Number Analyzed are the patients with no possible clinically significant abnormality at baseline. Treated set for combination therapy comprised all patients who received at least 1 dose of each of afatinib and paclitaxel, or of afatinib and vinorelbine.

Arm/Group Title	Afatinib Monotherapy	Afatinib and Vinorelbine Combination Therapy	Afatinib and Paclitaxel Combination Therapy
Arm/Group Description	Patient received Afatinib monotherapy orally once daily at a dose of 40 milligram (mg) film-coated tablets until progression of their disease, unacceptable adverse events or other reason necessitating withdrawal. Patients could have dose reduced if 40 mg was not tolerated.	Patient received Afatinib monotherapy orally once daily at a dose of 40 mg film-coated tablets until progression of their disease, unacceptable adverse events or other reason necessitating withdrawal (Patients could have dose reduced if 40 mg was not tolerated) and 25 mg/m2 Vinorelbine concentrate for intravenous infusion once weekly starting after treatment failure on afatinib monotherapy	Patient received Afatinib monotherapy orally once daily at a dose of 40 mg film-coated tablets until progression of their disease, unacceptable adverse events or other reason necessitating withdrawal (Patients could have dose reduced if 40 mg was not tolerated) and 80 mg/square meter (m2) Paclitaxel concentrate for intravenous infusion once weekly starting after treatment failure on afatinib monotherapy
Measure Participants	74	13	26
Haematology - Haemoglobin (low)	9 12.2%	5 NaN	17 NaN
Haematology - White blood cell count (low)	5 6.8%	9 NaN	13 NaN
Haematology - Platelets (low)	2 2.7%	0 NaN	1 NaN
Differentials, automatic - Neutrophils (low)	1 1.4%	10 NaN	12 NaN
Coagulation - PT-INR (high)	1 1.4%	0 NaN	0 NaN
Electrolytes - Potassium (low)	3 4.1%	0 NaN	3 NaN
Electrolytes - Potassium (high)	2 2.7%	0 NaN	0 NaN
Electrolytes - Magnesium (low)	0 0%	0 NaN	1 NaN
Enzymes - AST/GOT SGOT (high)	8 10.8%	0 NaN	2 NaN
Enzymes - ALT/GPT SGPT (high)	6 8.1%	3 NaN	4 NaN
Enzymes - Alkaline phosphatase (high)	6 8.1%	1 NaN	2 NaN
Substrates - Creatinine (high)	0 0%	0 NaN	1 NaN
Substrates - Bilirubin, total (high)	2 2.7%	1 NaN	0 NaN

Adverse Events

Time Frame	From the initial dose of study drug until 28 days after end of the treatment period, up to 1562 days
Adverse Event Reporting Description	Safety analyses were performed for monotherapy and combination therapy separately using the respective treated sets.The treated set for monotherapy comprised all patients who received at least 1 dose of afatinib. The treated set for combination therapy comprised all patients who received at least 1 dose of each of afatinib and paclitaxel, or of afatinib and vinorelbine.
Arm/Group Title	Afatinib Monotherapy		Afatinib and Vinorelbine Combination Therapy		Afatinib and Paclitaxel Combination Therapy
Arm/Group Description	Patient received Afatinib monotherapy orally once daily at a dose of 40 milligram (mg) film-coated tablets until progression of their disease, unacceptable adverse events or other reason necessitating withdrawal. Patients could have dose reduced if 40 mg was not tolerated.		Patient received Afatinib monotherapy orally once daily at a dose of 40 mg film-coated tablets until progression of their disease, unacceptable adverse events or other reason necessitating withdrawal (Patients could have dose reduced if 40 mg was not tolerated) and 25 mg/m2 Vinorelbine concentrate for intravenous infusion once weekly starting after treatment failure on afatinib monotherapy		Patient received Afatinib monotherapy orally once daily at a dose of 40 mg film-coated tablets until progression of their disease, unacceptable adverse events or other reason necessitating withdrawal (Patients could have dose reduced if 40 mg was not tolerated) and 80 mg/square meter (m2) Paclitaxel concentrate for intravenous infusion once weekly starting after treatment failure on afatinib monotherapy
All Cause Mortality
	Afatinib Monotherapy		Afatinib and Vinorelbine Combination Therapy		Afatinib and Paclitaxel Combination Therapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/74 (8.1%)		1/13 (7.7%)		5/26 (19.2%)
Serious Adverse Events
	Afatinib Monotherapy		Afatinib and Vinorelbine Combination Therapy		Afatinib and Paclitaxel Combination Therapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	18/74 (24.3%)		5/13 (38.5%)		10/26 (38.5%)
Blood and lymphatic system disorders
Anaemia	0/74 (0%)		1/13 (7.7%)		0/26 (0%)
Febrile neutropenia	0/74 (0%)		1/13 (7.7%)		0/26 (0%)
Cardiac disorders
Cardio-respiratory arrest	1/74 (1.4%)		0/13 (0%)		0/26 (0%)
Gastrointestinal disorders
Abdominal pain	2/74 (2.7%)		2/13 (15.4%)		1/26 (3.8%)
Diarrhoea	3/74 (4.1%)		0/13 (0%)		1/26 (3.8%)
Nausea	0/74 (0%)		0/13 (0%)		2/26 (7.7%)
Vomiting	2/74 (2.7%)		1/13 (7.7%)		1/26 (3.8%)
General disorders
Asthenia	3/74 (4.1%)		1/13 (7.7%)		0/26 (0%)
Chest pain	1/74 (1.4%)		0/13 (0%)		1/26 (3.8%)
Pain	0/74 (0%)		1/13 (7.7%)		0/26 (0%)
Pyrexia	0/74 (0%)		2/13 (15.4%)		1/26 (3.8%)
Hepatobiliary disorders
Hepatic function abnormal	1/74 (1.4%)		0/13 (0%)		0/26 (0%)
Infections and infestations
Diarrhoea infectious	1/74 (1.4%)		0/13 (0%)		0/26 (0%)
Herpes zoster	1/74 (1.4%)		0/13 (0%)		0/26 (0%)
Liver abscess	0/74 (0%)		1/13 (7.7%)		0/26 (0%)
Pneumonia	1/74 (1.4%)		0/13 (0%)		0/26 (0%)
Upper respiratory tract infection	1/74 (1.4%)		0/13 (0%)		0/26 (0%)
Urinary tract infection	0/74 (0%)		0/13 (0%)		1/26 (3.8%)
Urosepsis	1/74 (1.4%)		0/13 (0%)		0/26 (0%)
Investigations
Blood creatinine increased	0/74 (0%)		0/13 (0%)		1/26 (3.8%)
Metabolism and nutrition disorders
Decreased appetite	2/74 (2.7%)		0/13 (0%)		0/26 (0%)
Musculoskeletal and connective tissue disorders
Back pain	0/74 (0%)		1/13 (7.7%)		0/26 (0%)
Pathological fracture	0/74 (0%)		0/13 (0%)		1/26 (3.8%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast cancer metastatic	0/74 (0%)		0/13 (0%)		1/26 (3.8%)
Malignant neoplasm progression	0/74 (0%)		1/13 (7.7%)		1/26 (3.8%)
Metastases to central nervous system	2/74 (2.7%)		0/13 (0%)		1/26 (3.8%)
Neoplasm progression	4/74 (5.4%)		0/13 (0%)		2/26 (7.7%)
Nervous system disorders
Brain oedema	0/74 (0%)		0/13 (0%)		1/26 (3.8%)
Dizziness	0/74 (0%)		0/13 (0%)		1/26 (3.8%)
Neuralgia	1/74 (1.4%)		0/13 (0%)		0/26 (0%)
Seizure	1/74 (1.4%)		0/13 (0%)		0/26 (0%)
Product Issues
Device leakage	1/74 (1.4%)		0/13 (0%)		0/26 (0%)
Device occlusion	1/74 (1.4%)		0/13 (0%)		0/26 (0%)
Renal and urinary disorders
Azotaemia	0/74 (0%)		0/13 (0%)		1/26 (3.8%)
Renal failure	1/74 (1.4%)		0/13 (0%)		1/26 (3.8%)
Urinary tract obstruction	1/74 (1.4%)		0/13 (0%)		0/26 (0%)
Respiratory, thoracic and mediastinal disorders
Dysphonia	1/74 (1.4%)		0/13 (0%)		0/26 (0%)
Dyspnoea	3/74 (4.1%)		2/13 (15.4%)		0/26 (0%)
Interstitial lung disease	1/74 (1.4%)		0/13 (0%)		0/26 (0%)
Pleural effusion	1/74 (1.4%)		0/13 (0%)		0/26 (0%)
Respiratory arrest	0/74 (0%)		1/13 (7.7%)		0/26 (0%)
Respiratory distress	1/74 (1.4%)		0/13 (0%)		0/26 (0%)
Respiratory failure	0/74 (0%)		0/13 (0%)		1/26 (3.8%)
Vascular disorders
Hypotension	1/74 (1.4%)		0/13 (0%)		0/26 (0%)
Other (Not Including Serious) Adverse Events
	Afatinib Monotherapy		Afatinib and Vinorelbine Combination Therapy		Afatinib and Paclitaxel Combination Therapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	67/74 (90.5%)		13/13 (100%)		23/26 (88.5%)
Blood and lymphatic system disorders
Anaemia	7/74 (9.5%)		4/13 (30.8%)		13/26 (50%)
Leukopenia	1/74 (1.4%)		4/13 (30.8%)		5/26 (19.2%)
Neutropenia	1/74 (1.4%)		9/13 (69.2%)		9/26 (34.6%)
Thrombocytopenia	2/74 (2.7%)		1/13 (7.7%)		1/26 (3.8%)
Ear and labyrinth disorders
Vertigo	0/74 (0%)		0/13 (0%)		2/26 (7.7%)
Eye disorders
Dry eye	3/74 (4.1%)		1/13 (7.7%)		1/26 (3.8%)
Gastrointestinal disorders
Abdominal pain	5/74 (6.8%)		0/13 (0%)		1/26 (3.8%)
Abdominal pain upper	1/74 (1.4%)		0/13 (0%)		3/26 (11.5%)
Anal inflammation	0/74 (0%)		1/13 (7.7%)		0/26 (0%)
Constipation	0/74 (0%)		0/13 (0%)		3/26 (11.5%)
Diarrhoea	50/74 (67.6%)		3/13 (23.1%)		9/26 (34.6%)
Haemorrhoids	3/74 (4.1%)		1/13 (7.7%)		2/26 (7.7%)
Mouth ulceration	8/74 (10.8%)		2/13 (15.4%)		2/26 (7.7%)
Nausea	9/74 (12.2%)		1/13 (7.7%)		4/26 (15.4%)
Stomatitis	3/74 (4.1%)		1/13 (7.7%)		0/26 (0%)
Vomiting	6/74 (8.1%)		2/13 (15.4%)		4/26 (15.4%)
General disorders
Asthenia	5/74 (6.8%)		2/13 (15.4%)		7/26 (26.9%)
Fatigue	7/74 (9.5%)		0/13 (0%)		5/26 (19.2%)
Mucosal inflammation	15/74 (20.3%)		0/13 (0%)		1/26 (3.8%)
Oedema	0/74 (0%)		1/13 (7.7%)		0/26 (0%)
Oedema peripheral	1/74 (1.4%)		0/13 (0%)		2/26 (7.7%)
Pain	0/74 (0%)		1/13 (7.7%)		1/26 (3.8%)
Pyrexia	4/74 (5.4%)		1/13 (7.7%)		2/26 (7.7%)
Ulcer	0/74 (0%)		1/13 (7.7%)		0/26 (0%)
Infections and infestations
Bronchitis	0/74 (0%)		1/13 (7.7%)		0/26 (0%)
Escherichia urinary tract infection	0/74 (0%)		1/13 (7.7%)		0/26 (0%)
Folliculitis	4/74 (5.4%)		0/13 (0%)		0/26 (0%)
Gastroenteritis	0/74 (0%)		1/13 (7.7%)		0/26 (0%)
Nasopharyngitis	1/74 (1.4%)		0/13 (0%)		2/26 (7.7%)
Paronychia	9/74 (12.2%)		2/13 (15.4%)		1/26 (3.8%)
Periodontitis	0/74 (0%)		1/13 (7.7%)		0/26 (0%)
Pulpitis dental	0/74 (0%)		1/13 (7.7%)		0/26 (0%)
Respiratory tract infection	0/74 (0%)		0/13 (0%)		2/26 (7.7%)
Upper respiratory tract infection	4/74 (5.4%)		0/13 (0%)		1/26 (3.8%)
Urinary tract infection	3/74 (4.1%)		0/13 (0%)		3/26 (11.5%)
Viral infection	0/74 (0%)		0/13 (0%)		2/26 (7.7%)
Injury, poisoning and procedural complications
Wound	0/74 (0%)		1/13 (7.7%)		0/26 (0%)
Wound secretion	0/74 (0%)		1/13 (7.7%)		0/26 (0%)
Investigations
Alanine aminotransferase	0/74 (0%)		1/13 (7.7%)		0/26 (0%)
Alanine aminotransferase increased	5/74 (6.8%)		0/13 (0%)		4/26 (15.4%)
Aspartate aminotransferase	0/74 (0%)		1/13 (7.7%)		0/26 (0%)
Aspartate aminotransferase increased	3/74 (4.1%)		1/13 (7.7%)		3/26 (11.5%)
Blood alkaline phosphatase increased	4/74 (5.4%)		0/13 (0%)		0/26 (0%)
Blood glucose decreased	0/74 (0%)		1/13 (7.7%)		0/26 (0%)
Blood lactate dehydrogenase increased	2/74 (2.7%)		0/13 (0%)		2/26 (7.7%)
Blood uric acid increased	2/74 (2.7%)		0/13 (0%)		2/26 (7.7%)
Neutrophil count decreased	0/74 (0%)		2/13 (15.4%)		1/26 (3.8%)
Weight decreased	10/74 (13.5%)		1/13 (7.7%)		4/26 (15.4%)
Metabolism and nutrition disorders
Decreased appetite	5/74 (6.8%)		0/13 (0%)		4/26 (15.4%)
Hypocalcaemia	2/74 (2.7%)		0/13 (0%)		2/26 (7.7%)
Hypokalaemia	3/74 (4.1%)		0/13 (0%)		2/26 (7.7%)
Musculoskeletal and connective tissue disorders
Arthralgia	2/74 (2.7%)		0/13 (0%)		2/26 (7.7%)
Back pain	2/74 (2.7%)		2/13 (15.4%)		0/26 (0%)
Musculoskeletal pain	5/74 (6.8%)		0/13 (0%)		1/26 (3.8%)
Pain in extremity	0/74 (0%)		1/13 (7.7%)		1/26 (3.8%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasm progression	6/74 (8.1%)		0/13 (0%)		1/26 (3.8%)
Nervous system disorders
Dizziness	3/74 (4.1%)		1/13 (7.7%)		1/26 (3.8%)
Headache	7/74 (9.5%)		1/13 (7.7%)		2/26 (7.7%)
Hypoaesthesia	3/74 (4.1%)		1/13 (7.7%)		3/26 (11.5%)
Neuropathy peripheral	0/74 (0%)		0/13 (0%)		3/26 (11.5%)
Peripheral sensory neuropathy	0/74 (0%)		0/13 (0%)		4/26 (15.4%)
Psychiatric disorders
Insomnia	1/74 (1.4%)		0/13 (0%)		3/26 (11.5%)
Renal and urinary disorders
Dysuria	0/74 (0%)		1/13 (7.7%)		0/26 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	8/74 (10.8%)		0/13 (0%)		3/26 (11.5%)
Dyspnoea	8/74 (10.8%)		0/13 (0%)		2/26 (7.7%)
Epistaxis	6/74 (8.1%)		0/13 (0%)		2/26 (7.7%)
Oropharyngeal pain	3/74 (4.1%)		0/13 (0%)		2/26 (7.7%)
Rhinorrhoea	4/74 (5.4%)		0/13 (0%)		0/26 (0%)
Skin and subcutaneous tissue disorders
Acne	5/74 (6.8%)		0/13 (0%)		0/26 (0%)
Alopecia	2/74 (2.7%)		1/13 (7.7%)		10/26 (38.5%)
Dermatitis	5/74 (6.8%)		2/13 (15.4%)		1/26 (3.8%)
Eczema	4/74 (5.4%)		1/13 (7.7%)		1/26 (3.8%)
Eczema asteatotic	1/74 (1.4%)		1/13 (7.7%)		0/26 (0%)
Nail bed inflammation	0/74 (0%)		1/13 (7.7%)		0/26 (0%)
Palmar-plantar erythrodysaesthesia syndrome	13/74 (17.6%)		1/13 (7.7%)		3/26 (11.5%)
Pruritus	5/74 (6.8%)		0/13 (0%)		2/26 (7.7%)
Rash	37/74 (50%)		3/13 (23.1%)		4/26 (15.4%)
Rash pruritic	0/74 (0%)		1/13 (7.7%)		2/26 (7.7%)
Skin hyperpigmentation	2/74 (2.7%)		0/13 (0%)		2/26 (7.7%)
Vascular disorders
Phlebitis	0/74 (0%)		2/13 (15.4%)		0/26 (0%)

Limitations/Caveats

Enrollment of patients into the afatinib and vinorelbine combination option was stopped prematurely following a benefit-risk analysis in other trial. Any patients who were already benefiting from this combination were allowed to continue.

More Information

Certain Agreements

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

Boehringer Ingelheim (BI) acknowledges that investigators have the right to publish the study results. Investigators shall provide BI with a copy of any publication or presentation for review prior to any submission. Such review will be done with regard to proprietary information, information related to patentable inventions, medical, scientific, and statistical accuracy within 60 days. BI may request a delay of the publication in order to protect BI's intellectual property rights.