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A Study of Neratinib Plus Capecitabine Versus Lapatinib Plus Capecitabine in Patients With HER2+ Metastatic Breast Cancer Who Have Received Two or More Prior HER2 Directed Regimens in the Metastatic Setting (NALA)

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ClinicalTrials.gov Identifier: NCT01808573
Recruitment Status : Completed
First Posted : March 11, 2013
Results First Posted : December 11, 2019
Last Update Posted : June 11, 2021
Sponsor:
Information provided by (Responsible Party):
Puma Biotechnology, Inc.

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition HER2+ Metastatic Breast Cancer (MBC)
Interventions Drug: neratinib
Drug: capecitabine
Drug: lapatinib
Enrollment 621
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Neratinib Plus Capecitabine Lapatinib Plus Capecitabine
Hide Arm/Group Description neratinib 240 mg orally, once daily with food, continuously in 21 day cycles, and capecitabine 1500 mg/m^2 daily in 2 evenly divided doses, orally with water within 30 minutes after a meal, taken on days 1 to 14 of each 21 day cycle. lapatinib 1250 mg orally, once daily, continuously in 21 day cycles, and capecitabine 2000 mg/m^2 daily in 2 evenly divided doses, orally with water within 30 minutes after a meal, taken on days 1 to 14 of each 21 day cycle.
Period Title: Overall Study
Started 307 314
Received Treatment 303 311
Completed 0 0
Not Completed 307 314
Reason Not Completed
Death             212             240
Withdrawal by Subject             12             10
Lost to Follow-up             3             0
Discontinuation of study by sponsor             79             64
Randomized in Error             1             0
Arm/Group Title Neratinib Plus Capecitabine Lapatinib Plus Capecitabine Total
Hide Arm/Group Description neratinib 240 mg orally, once daily with food, continuously in 21 day cycles, and capecitabine 1500 mg/m^2 daily in 2 evenly divided doses, orally with water within 30 minutes after a meal, taken on days 1 to 14 of each 21 day cycle. lapatinib 1250 mg orally, once daily, continuously in 21 day cycles, and capecitabine 2000 mg/m^2 daily in 2 evenly divided doses, orally with water within 30 minutes after a meal, taken on days 1 to 14 of each 21 day cycle. Total of all reporting groups
Overall Number of Baseline Participants 307 314 621
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 307 participants 314 participants 621 participants
55.04  (11.37) 54.32  (11.36) 54.67  (11.36)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 307 participants 314 participants 621 participants
Female
307
 100.0%
311
  99.0%
618
  99.5%
Male
0
   0.0%
3
   1.0%
3
   0.5%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 307 participants 314 participants 621 participants
Hispanic or Latino
40
  13.0%
42
  13.4%
82
  13.2%
Not Hispanic or Latino
256
  83.4%
259
  82.5%
515
  82.9%
Unknown or Not Reported
11
   3.6%
13
   4.1%
24
   3.9%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Race Number Analyzed 307 participants 314 participants 621 participants
Asian
109
  35.5%
105
  33.4%
214
  34.5%
Black or African American
9
   2.9%
15
   4.8%
24
   3.9%
Native Hawaiian or Other Pacific Islander
1
   0.3%
1
   0.3%
2
   0.3%
White
178
  58.0%
177
  56.4%
355
  57.2%
Other
7
   2.3%
10
   3.2%
17
   2.7%
Unknown/Missing
3
   1.0%
6
   1.9%
9
   1.4%
Previous HER2 Regimens  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 307 participants 314 participants 621 participants
2
215
  70.0%
215
  68.5%
430
  69.2%
>=3
92
  30.0%
99
  31.5%
191
  30.8%
Disease Location  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 307 participants 314 participants 621 participants
Non Visceral
60
  19.5%
61
  19.4%
121
  19.5%
Visceral
247
  80.5%
253
  80.6%
500
  80.5%
Hormone Receptor Status  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 307 participants 314 participants 621 participants
Negative
126
  41.0%
128
  40.8%
254
  40.9%
Positive
181
  59.0%
186
  59.2%
367
  59.1%
Geographic Region  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 307 participants 314 participants 621 participants
Europe
121
  39.4%
123
  39.2%
244
  39.3%
North America
59
  19.2%
65
  20.7%
124
  20.0%
Rest of World
127
  41.4%
126
  40.1%
253
  40.7%
1.Primary Outcome
Title Centrally Assessed Progression Free Survival
Hide Description Progression Free Survival (PFS), Measured in Months, for Randomized Subjects of the Central Assessment. The time interval from the date of randomization until the first date on which recurrence, progression (per Response Evaluation Criteria in Solid Tumors Criteria (RECIST) v1.1), or death due to any cause, is documented. For subjects without recurrence, progression or death, it is censored at the last valid tumor assessment. Progression is defined using Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.1), as 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. Here, the time to event was reported as the restricted mean survival time. The restricted mean survival time was defined as the area under the curve of the survival function up to 24 months.
Time Frame From randomization date to recurrence, progression or death, assessed up to 38 months. The result is based on primary analysis data cut.
Hide Outcome Measure Data
Hide Analysis Population Description
Randomized ITT Population
Arm/Group Title Neratinib Plus Capecitabine Lapatinib Plus Capecitabine
Hide Arm/Group Description:
neratinib 240 mg orally, once daily with food, continuously in 21 day cycles, and capecitabine 1500 mg/m^2 daily in 2 evenly divided doses, orally with water within 30 minutes after a meal, taken on days 1 to 14 of each 21 day cycle.
lapatinib 1250 mg orally, once daily, continuously in 21 day cycles, and capecitabine 2000 mg/m^2 daily in 2 evenly divided doses, orally with water within 30 minutes after a meal, taken on days 1 to 14 of each 21 day cycle.
Overall Number of Participants Analyzed 307 314
Mean (95% Confidence Interval)
Unit of Measure: months
8.8
(7.8 to 9.8)
6.6
(5.9 to 7.4)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Neratinib Plus Capecitabine, Lapatinib Plus Capecitabine
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0059
Comments [Not Specified]
Method Log Rank
Comments Stratified by hormone receptor status, number of prior HER2-directed regimens in the metastatic setting, and visceral disease vs. non-visceral.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.762
Confidence Interval (2-Sided) 95%
0.626 to 0.926
Estimation Comments Lapatinib Plus Capecitabine is the reference. Stratified by hormone receptor status, number of prior HER2-directed regimens in the metastatic setting, and visceral disease vs. non-visceral.
2.Primary Outcome
Title Overall Survival
Hide Description Overall survival (OS) is defined as the time from randomization to death due to any cause, censored at the last date known alive on or prior to the data cutoff employed for the analysis, whichever was earlier. Here, the time to event was reported as the restricted mean survival time. The restricted mean survival time was defined as the area under the curve of the survival function up to 48 months.
Time Frame From randomization date to death, assessed up to 59 months.The result is based on primary analysis data cut.
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Neratinib Plus Capecitabine Lapatinib Plus Capecitabine
Hide Arm/Group Description:
neratinib 240 mg orally, once daily with food, continuously in 21 day cycles, and capecitabine 1500 mg/m^2 daily in 2 evenly divided doses, orally with water within 30 minutes after a meal, taken on days 1 to 14 of each 21 day cycle.
lapatinib 1250 mg orally, once daily, continuously in 21 day cycles, and capecitabine 2000 mg/m^2 daily in 2 evenly divided doses, orally with water within 30 minutes after a meal, taken on days 1 to 14 of each 21 day cycle.
Overall Number of Participants Analyzed 307 314
Mean (95% Confidence Interval)
Unit of Measure: months
24.0
(22.1 to 25.9)
22.2
(20.4 to 24.0)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Neratinib Plus Capecitabine, Lapatinib Plus Capecitabine
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2086
Comments [Not Specified]
Method Log Rank
Comments Stratified by hormone receptor status, number of prior HER2-directed regimens in the metastatic setting, and visceral disease vs. non-visceral.
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.881
Confidence Interval (2-Sided) 95%
0.723 to 1.073
Estimation Comments Lapatinib plus Capecitabine is the reference. Stratified by hormone receptor status, number of prior HER2-directed regimens in the metastatic setting, and visceral disease vs. non-visceral.
3.Secondary Outcome
Title Intervention for Symptomatic Metastatic Central Nervous System Disease
Hide Description Intervention for symptomatic metastatic central nervous system disease is defined as the time from randomization to the first start date of an intervention for symptomatic metastatic CNS disease. Subjects that do not have an intervention for symptomatic metastatic CNS and do not die will be censored at the last date known alive on or prior to the data cutoff. Deaths are treated as competing events. Percentage of participants with intervention for CNS, estimated by cumulative incidence methods. Cumulative incidence methods are the standard way to estimate incidence of an endpoint in the presence of competing risks and censoring.
Time Frame From randomization date to first intervention for symptomatic metastatic CNS disease, assessed up to 59 months.The result is based on primary analysis data cut.
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Neratinib Plus Capecitabine Lapatinib Plus Capecitabine
Hide Arm/Group Description:
neratinib 240 mg orally, once daily with food, continuously in 21 day cycles, and capecitabine 1500 mg/m^2 daily in 2 evenly divided doses, orally with water within 30 minutes after a meal, taken on days 1 to 14 of each 21 day cycle.
lapatinib 1250 mg orally, once daily, continuously in 21 day cycles, and capecitabine 2000 mg/m^2 daily in 2 evenly divided doses, orally with water within 30 minutes after a meal, taken on days 1 to 14 of each 21 day cycle.
Overall Number of Participants Analyzed 307 314
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
22.76
(15.48 to 30.91)
29.19
(22.54 to 36.14)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Neratinib Plus Capecitabine, Lapatinib Plus Capecitabine
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.043
Comments [Not Specified]
Method Gray's test
Comments Stratified by hormone receptor status, number of prior HER2-directed regimens in the metastatic setting and visceral disease vs. non-visceral disease.
4.Secondary Outcome
Title Objective Response Rate (ORR) - Central Assessment (ITT Population With Measurable Disease at Screening)
Hide Description Objective response rate is defined as the percentage of participants demonstrating an objective response during the study. Objective response includes confirmed complete responses (CR) and partial responses (PR) as defined in the RECIST criteria included in the study protocol. The ORR is for Central Assessment for subjects that had measurable disease at screening. Per Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
Time Frame From randomization date to first confirmed Complete or Partial Response, whichever came earlier, up to 42 months.The result is based on primary analysis data cut.
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Neratinib Plus Capecitabine Lapatinib Plus Capecitabine
Hide Arm/Group Description:
neratinib 240 mg orally, once daily with food, continuously in 21 day cycles, and capecitabine 1500 mg/m^2 daily in 2 evenly divided doses, orally with water within 30 minutes after a meal, taken on days 1 to 14 of each 21 day cycle.
lapatinib 1250 mg orally, once daily, continuously in 21 day cycles, and capecitabine 2000 mg/m^2 daily in 2 evenly divided doses, orally with water within 30 minutes after a meal, taken on days 1 to 14 of each 21 day cycle.
Overall Number of Participants Analyzed 256 270
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
32.8
(27.1 to 38.9)
26.7
(21.5 to 32.4)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Neratinib Plus Capecitabine, Lapatinib Plus Capecitabine
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1201
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments Stratified by hormone receptor status, number of prior HER2-directed regimens in the metastatic setting and visceral disease vs. non-visceral.
5.Secondary Outcome
Title Clinical Benefit Rate (CBR) - Central Assessment (ITT Population With Measurable Disease at Screening)
Hide Description Clinical benefit rate is the percentage of participants who achieve overall tumor response (confirmed CR or PR) or stable disease (SD) lasting for at least 24 weeks from randomization. The CBR was for Central Assessment for subjects who had Measurable Disease at Screening.
Time Frame From randomization date to either first confirmed CR or PR or Stable Disease, whichever came earlier, up to 42 months.The result is based on primary analysis data cut.
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Neratinib Plus Capecitabine Lapatinib Plus Capecitabine
Hide Arm/Group Description:
neratinib 240 mg orally, once daily with food, continuously in 21 day cycles, and capecitabine 1500 mg/m^2 daily in 2 evenly divided doses, orally with water within 30 minutes after a meal, taken on days 1 to 14 of each 21 day cycle.
lapatinib 1250 mg orally, once daily, continuously in 21 day cycles, and capecitabine 2000 mg/m^2 daily in 2 evenly divided doses, orally with water within 30 minutes after a meal, taken on days 1 to 14 of each 21 day cycle.
Overall Number of Participants Analyzed 256 270
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
44.5
(38.3 to 50.8)
35.6
(29.8 to 41.6)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Neratinib Plus Capecitabine, Lapatinib Plus Capecitabine
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0328
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments Stratified by hormone receptor status, number of prior HER2-directed regimens in the metastatic setting and visceral disease vs. non-visceral.
6.Secondary Outcome
Title Duration of Response (DOR) - Central Assessment (Population That Had a Response With Measurable Disease at Screening)
Hide Description

The Duration of Response (DOR) is for Central Assessment for the Population that Had a Response with Measurable Disease at Screening.

Duration of response is measured from the time at which measurement criteria are first met for CR or PR (whichever status is recorded first) until the first date of recurrence or progressive disease (PD) or death is objectively documented, taking as a reference for PD the smallest measurements recorded since enrollment, per RECIST v1.1. This value is censored at the last valid tumor assessment if PD or death has not been documented.

Time Frame From start date of response after randomization to first PD, up to 33 months.The result is based on primary analysis data cut.
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Neratinib Plus Capecitabine Lapatinib Plus Capecitabine
Hide Arm/Group Description:
neratinib 240 mg orally, once daily with food, continuously in 21 day cycles, and capecitabine 1500 mg/m^2 daily in 2 evenly divided doses, orally with water within 30 minutes after a meal, taken on days 1 to 14 of each 21 day cycle.
lapatinib 1250 mg orally, once daily, continuously in 21 day cycles, and capecitabine 2000 mg/m^2 daily in 2 evenly divided doses, orally with water within 30 minutes after a meal, taken on days 1 to 14 of each 21 day cycle.
Overall Number of Participants Analyzed 84 72
Median (95% Confidence Interval)
Unit of Measure: months
8.54
(5.62 to 11.17)
5.55
(4.21 to 6.41)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Neratinib Plus Capecitabine, Lapatinib Plus Capecitabine
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0004
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.495
Confidence Interval (2-Sided) 95%
0.332 to 0.736
Estimation Comments Lapatinib Plus Capecitabine is the reference.
7.Secondary Outcome
Title Percentage of Participants With Treatment-Emergent Adverse Events (Adverse Events and Serious Adverse Events)
Hide Description Adverse Events to be measured are Treatment-Emergent and Serious AEs that occurred on or after first dose of investigational product and up to 28 days after the last dose
Time Frame From first dose through last dose + 28 days, up to 41 months. The result is based on final data cut.
Hide Outcome Measure Data
Hide Analysis Population Description
Safety population: Participants receiving at least 1 dose of investigational product.
Arm/Group Title Neratinib Plus Capecitabine Lapatinib Plus Capecitabine
Hide Arm/Group Description:
neratinib 240 mg orally, once daily with food, continuously in 21 day cycles, and capecitabine 1500 mg/m^2 daily in 2 evenly divided doses, orally with water within 30 minutes after a meal, taken on days 1 to 14 of each 21 day cycle.
lapatinib 1250 mg orally, once daily, continuously in 21 day cycles, and capecitabine 2000 mg/m^2 daily in 2 evenly divided doses, orally with water within 30 minutes after a meal, taken on days 1 to 14 of each 21 day cycle.
Overall Number of Participants Analyzed 303 311
Measure Type: Number
Unit of Measure: percentage of participants
All Treatment-Emergent Adverse Events 99.7 99.4
Serious Treatment-Emergent Adverse Events 34.0 29.9
Time Frame From time of first dose, through 28 days after last dose, assessed up to 41 months.
Adverse Event Reporting Description

Safety population: Participants receiving at least 1 dose of investigational product.

All-Cause Mortality was monitored/assessed for all randomized participants. Serious and Other Adverse Events were monitored/assessed only in the safety population

For All-Cause Mortality and Serious/Other Adverse Events, the result is based on final data cut.

 
Arm/Group Title Neratinib Plus Capecitabine Lapatinib Plus Capecitabine
Hide Arm/Group Description neratinib 240 mg orally, once daily with food, continuously in 21 day cycles, and capecitabine 1500 mg/m^2 daily in 2 evenly divided doses, orally with water within 30 minutes after a meal, taken on days 1 to 14 of each 21 day cycle. lapatinib 1250 mg orally, once daily, continuously in 21 day cycles, and capecitabine 2000 mg/m^2 daily in 2 evenly divided doses, orally with water within 30 minutes after a meal, taken on days 1 to 14 of each 21 day cycle.
All-Cause Mortality
Neratinib Plus Capecitabine Lapatinib Plus Capecitabine
Affected / at Risk (%) Affected / at Risk (%)
Total   219/307 (71.34%)   243/314 (77.39%) 
Hide Serious Adverse Events
Neratinib Plus Capecitabine Lapatinib Plus Capecitabine
Affected / at Risk (%) Affected / at Risk (%)
Total   103/303 (33.99%)   93/311 (29.90%) 
Blood and lymphatic system disorders     
Anaemia  1  1/303 (0.33%)  2/311 (0.64%) 
Febrile neutropenia  1  1/303 (0.33%)  3/311 (0.96%) 
Neutropenia  1  1/303 (0.33%)  0/311 (0.00%) 
Cardiac disorders     
Acute myocardial infarction  1  0/303 (0.00%)  1/311 (0.32%) 
Atrial fibrillation  1  1/303 (0.33%)  0/311 (0.00%) 
Cardiac arrest  1  0/303 (0.00%)  1/311 (0.32%) 
Cardiac tamponade  1  1/303 (0.33%)  1/311 (0.32%) 
Cardiomyopathy  1  1/303 (0.33%)  0/311 (0.00%) 
Palpitations  1  2/303 (0.66%)  0/311 (0.00%) 
Pericardial effusion  1  1/303 (0.33%)  1/311 (0.32%) 
Tachycardia  1  0/303 (0.00%)  1/311 (0.32%) 
Ear and labyrinth disorders     
Vertigo  1  1/303 (0.33%)  0/311 (0.00%) 
Eye disorders     
Chorioretinopathy  1  1/303 (0.33%)  0/311 (0.00%) 
Gastrointestinal disorders     
Abdominal distension  1  0/303 (0.00%)  1/311 (0.32%) 
Abdominal pain  1  1/303 (0.33%)  5/311 (1.61%) 
Abdominal pain upper  1  2/303 (0.66%)  0/311 (0.00%) 
Ascites  1  0/303 (0.00%)  2/311 (0.64%) 
Constipation  1  3/303 (0.99%)  1/311 (0.32%) 
Diarrhoea  1  22/303 (7.26%)  13/311 (4.18%) 
Gastric ulcer  1  2/303 (0.66%)  1/311 (0.32%) 
Gastritis  1  0/303 (0.00%)  1/311 (0.32%) 
Gastrointestinal haemorrhage  1  1/303 (0.33%)  0/311 (0.00%) 
Nausea  1  7/303 (2.31%)  6/311 (1.93%) 
Pancreatitis  1  2/303 (0.66%)  0/311 (0.00%) 
Pancreatitis acute  1  1/303 (0.33%)  0/311 (0.00%) 
Stomatitis  1  1/303 (0.33%)  1/311 (0.32%) 
Varices oesophageal  1  1/303 (0.33%)  0/311 (0.00%) 
Vomiting  1  9/303 (2.97%)  6/311 (1.93%) 
General disorders     
Abasia  1  0/303 (0.00%)  1/311 (0.32%) 
Asthenia  1  1/303 (0.33%)  2/311 (0.64%) 
Chest pain  1  1/303 (0.33%)  0/311 (0.00%) 
Fatigue  1  2/303 (0.66%)  0/311 (0.00%) 
General physical health deterioration  1  1/303 (0.33%)  2/311 (0.64%) 
Malaise  1  0/303 (0.00%)  1/311 (0.32%) 
Multiple organ dysfunction syndrome  1  1/303 (0.33%)  0/311 (0.00%) 
Non-cardiac chest pain  1  1/303 (0.33%)  2/311 (0.64%) 
Oedema  1  1/303 (0.33%)  0/311 (0.00%) 
Pyrexia  1  3/303 (0.99%)  0/311 (0.00%) 
Suprapubic pain  1  0/303 (0.00%)  1/311 (0.32%) 
Hepatobiliary disorders     
Bile duct obstruction  1  1/303 (0.33%)  0/311 (0.00%) 
Hepatic failure  1  1/303 (0.33%)  1/311 (0.32%) 
Hepatic mass  1  1/303 (0.33%)  0/311 (0.00%) 
Hepatitis fulminant  1  0/303 (0.00%)  1/311 (0.32%) 
Jaundice  1  0/303 (0.00%)  2/311 (0.64%) 
Jaundice cholestatic  1  1/303 (0.33%)  1/311 (0.32%) 
Immune system disorders     
Hypersensitivity  1  1/303 (0.33%)  0/311 (0.00%) 
Infections and infestations     
Abdominal infection  1  1/303 (0.33%)  0/311 (0.00%) 
Atypical pneumonia  1  1/303 (0.33%)  0/311 (0.00%) 
Bacteraemia  1  1/303 (0.33%)  1/311 (0.32%) 
Catheter site infection  1  0/303 (0.00%)  1/311 (0.32%) 
Cellulitis  1  4/303 (1.32%)  5/311 (1.61%) 
Enterocolitis infectious  1  0/303 (0.00%)  1/311 (0.32%) 
Epiglottitis  1  1/303 (0.33%)  0/311 (0.00%) 
Erysipelas  1  0/303 (0.00%)  1/311 (0.32%) 
Gastroenteritis  1  1/303 (0.33%)  0/311 (0.00%) 
Influenza  1  0/303 (0.00%)  2/311 (0.64%) 
Lung infection  1  2/303 (0.66%)  0/311 (0.00%) 
Paronychia  1  1/303 (0.33%)  0/311 (0.00%) 
Pneumonia  1  6/303 (1.98%)  5/311 (1.61%) 
Pneumonia bacterial  1  1/303 (0.33%)  0/311 (0.00%) 
Respiratory tract infection  1  1/303 (0.33%)  1/311 (0.32%) 
Sepsis  1  1/303 (0.33%)  4/311 (1.29%) 
Septic shock  1  0/303 (0.00%)  1/311 (0.32%) 
Soft tissue infection  1  0/303 (0.00%)  1/311 (0.32%) 
Streptococcal sepsis  1  1/303 (0.33%)  0/311 (0.00%) 
Tooth infection  1  0/303 (0.00%)  1/311 (0.32%) 
Upper respiratory tract infection  1  2/303 (0.66%)  0/311 (0.00%) 
Urinary tract infection  1  3/303 (0.99%)  1/311 (0.32%) 
Urosepsis  1  0/303 (0.00%)  1/311 (0.32%) 
Viral upper respiratory tract infection  1  0/303 (0.00%)  1/311 (0.32%) 
Wound infection  1  0/303 (0.00%)  1/311 (0.32%) 
Injury, poisoning and procedural complications     
Fall  1  2/303 (0.66%)  2/311 (0.64%) 
Femur fracture  1  1/303 (0.33%)  1/311 (0.32%) 
Fracture  1  0/303 (0.00%)  1/311 (0.32%) 
Head injury  1  1/303 (0.33%)  0/311 (0.00%) 
Hip fracture  1  1/303 (0.33%)  0/311 (0.00%) 
Humerus fracture  1  2/303 (0.66%)  0/311 (0.00%) 
Seroma  1  1/303 (0.33%)  0/311 (0.00%) 
Investigations     
Blood bilirubin increased  1  0/303 (0.00%)  3/311 (0.96%) 
Blood potassium increased  1  0/303 (0.00%)  1/311 (0.32%) 
Liver function test increased  1  0/303 (0.00%)  1/311 (0.32%) 
Weight decreased  1  2/303 (0.66%)  0/311 (0.00%) 
Metabolism and nutrition disorders     
Decreased appetite  1  1/303 (0.33%)  0/311 (0.00%) 
Dehydration  1  4/303 (1.32%)  5/311 (1.61%) 
Hypercalcaemia  1  1/303 (0.33%)  0/311 (0.00%) 
Hypokalaemia  1  2/303 (0.66%)  4/311 (1.29%) 
Hyponatraemia  1  0/303 (0.00%)  1/311 (0.32%) 
Hypophosphataemia  1  0/303 (0.00%)  2/311 (0.64%) 
Musculoskeletal and connective tissue disorders     
Back pain  1  1/303 (0.33%)  2/311 (0.64%) 
Bone pain  1  0/303 (0.00%)  1/311 (0.32%) 
Muscular weakness  1  0/303 (0.00%)  1/311 (0.32%) 
Musculoskeletal pain  1  0/303 (0.00%)  1/311 (0.32%) 
Osteonecrosis of jaw  1  0/303 (0.00%)  1/311 (0.32%) 
Pain in extremity  1  1/303 (0.33%)  4/311 (1.29%) 
Pathological fracture  1  0/303 (0.00%)  1/311 (0.32%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Brain neoplasm  1  0/303 (0.00%)  1/311 (0.32%) 
Endometrial cancer  1  1/303 (0.33%)  0/311 (0.00%) 
Intracranial tumour haemorrhage  1  0/303 (0.00%)  1/311 (0.32%) 
Malignant pleural effusion  1  1/303 (0.33%)  1/311 (0.32%) 
Metastases to bone  1  1/303 (0.33%)  0/311 (0.00%) 
Metastases to central nervous system  1  6/303 (1.98%)  2/311 (0.64%) 
Papillary thyroid cancer  1  1/303 (0.33%)  0/311 (0.00%) 
Pericarditis malignant  1  0/303 (0.00%)  1/311 (0.32%) 
Tumour compression  1  1/303 (0.33%)  0/311 (0.00%) 
Tumour haemorrhage  1  2/303 (0.66%)  2/311 (0.64%) 
Tumour pain  1  0/303 (0.00%)  1/311 (0.32%) 
Nervous system disorders     
Amnesia  1  0/303 (0.00%)  1/311 (0.32%) 
Aphasia  1  0/303 (0.00%)  2/311 (0.64%) 
Ataxia  1  0/303 (0.00%)  1/311 (0.32%) 
Brain oedema  1  0/303 (0.00%)  2/311 (0.64%) 
Cerebellar syndrome  1  1/303 (0.33%)  0/311 (0.00%) 
Cerebral haematoma  1  1/303 (0.33%)  0/311 (0.00%) 
Cerebral infarction  1  0/303 (0.00%)  1/311 (0.32%) 
Cerebrovascular accident  1  1/303 (0.33%)  0/311 (0.00%) 
Dizziness  1  1/303 (0.33%)  2/311 (0.64%) 
Haemorrhage intracranial  1  0/303 (0.00%)  1/311 (0.32%) 
Headache  1  1/303 (0.33%)  6/311 (1.93%) 
Hemiparesis  1  1/303 (0.33%)  1/311 (0.32%) 
Hypoaesthesia  1  0/303 (0.00%)  1/311 (0.32%) 
Intracranial pressure increased  1  2/303 (0.66%)  0/311 (0.00%) 
Lethargy  1  1/303 (0.33%)  1/311 (0.32%) 
Nerve root compression  1  1/303 (0.33%)  0/311 (0.00%) 
Neurological decompensation  1  0/303 (0.00%)  1/311 (0.32%) 
Neuropathy peripheral  1  1/303 (0.33%)  0/311 (0.00%) 
Paraparesis  1  1/303 (0.33%)  0/311 (0.00%) 
Presyncope  1  1/303 (0.33%)  0/311 (0.00%) 
Seizure  1  4/303 (1.32%)  3/311 (0.96%) 
Spinal cord oedema  1  1/303 (0.33%)  0/311 (0.00%) 
Subarachnoid haemorrhage  1  0/303 (0.00%)  1/311 (0.32%) 
Syncope  1  1/303 (0.33%)  0/311 (0.00%) 
Tonic convulsion  1  0/303 (0.00%)  1/311 (0.32%) 
Psychiatric disorders     
Confusional state  1  1/303 (0.33%)  1/311 (0.32%) 
Delirium  1  0/303 (0.00%)  1/311 (0.32%) 
Disorientation  1  1/303 (0.33%)  0/311 (0.00%) 
Mental status changes  1  0/303 (0.00%)  1/311 (0.32%) 
Renal and urinary disorders     
Acute kidney injury  1  7/303 (2.31%)  1/311 (0.32%) 
Hydronephrosis  1  0/303 (0.00%)  1/311 (0.32%) 
Renal failure  1  1/303 (0.33%)  0/311 (0.00%) 
Reproductive system and breast disorders     
Vaginal haemorrhage  1  1/303 (0.33%)  0/311 (0.00%) 
Respiratory, thoracic and mediastinal disorders     
Acute respiratory failure  1  0/303 (0.00%)  1/311 (0.32%) 
Atelectasis  1  1/303 (0.33%)  0/311 (0.00%) 
Dyspnoea  1  2/303 (0.66%)  3/311 (0.96%) 
Dyspnoea exertional  1  1/303 (0.33%)  0/311 (0.00%) 
Haemoptysis  1  0/303 (0.00%)  2/311 (0.64%) 
Hypoxia  1  0/303 (0.00%)  1/311 (0.32%) 
Pleural effusion  1  10/303 (3.30%)  11/311 (3.54%) 
Pneumonia aspiration  1  0/303 (0.00%)  1/311 (0.32%) 
Pneumothorax  1  0/303 (0.00%)  1/311 (0.32%) 
Pulmonary embolism  1  2/303 (0.66%)  7/311 (2.25%) 
Respiratory failure  1  1/303 (0.33%)  0/311 (0.00%) 
Skin and subcutaneous tissue disorders     
Palmar-plantar erythrodysaesthesia syndrome  1  1/303 (0.33%)  1/311 (0.32%) 
Skin necrosis  1  0/303 (0.00%)  1/311 (0.32%) 
Vascular disorders     
Hypotension  1  0/303 (0.00%)  2/311 (0.64%) 
Shock  1  0/303 (0.00%)  1/311 (0.32%) 
Vena cava thrombosis  1  0/303 (0.00%)  1/311 (0.32%) 
1
Term from vocabulary, MedDRA 20.0
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Neratinib Plus Capecitabine Lapatinib Plus Capecitabine
Affected / at Risk (%) Affected / at Risk (%)
Total   301/303 (99.34%)   309/311 (99.36%) 
Blood and lymphatic system disorders     
Anaemia  1  45/303 (14.85%)  50/311 (16.08%) 
Neutropenia  1  23/303 (7.59%)  16/311 (5.14%) 
Gastrointestinal disorders     
Abdominal distension  1  25/303 (8.25%)  9/311 (2.89%) 
Abdominal pain  1  37/303 (12.21%)  42/311 (13.50%) 
Abdominal pain upper  1  18/303 (5.94%)  28/311 (9.00%) 
Constipation  1  95/303 (31.35%)  40/311 (12.86%) 
Diarrhoea  1  248/303 (81.85%)  205/311 (65.92%) 
Dry mouth  1  15/303 (4.95%)  18/311 (5.79%) 
Dyspepsia  1  20/303 (6.60%)  29/311 (9.32%) 
Nausea  1  161/303 (53.14%)  130/311 (41.80%) 
Stomatitis  1  63/303 (20.79%)  83/311 (26.69%) 
Vomiting  1  138/303 (45.54%)  95/311 (30.55%) 
General disorders     
Asthenia  1  36/303 (11.88%)  34/311 (10.93%) 
Fatigue  1  102/303 (33.66%)  97/311 (31.19%) 
Oedema peripheral  1  16/303 (5.28%)  21/311 (6.75%) 
Pyrexia  1  32/303 (10.56%)  32/311 (10.29%) 
Infections and infestations     
Paronychia  1  35/303 (11.55%)  49/311 (15.76%) 
Upper respiratory tract infection  1  26/303 (8.58%)  14/311 (4.50%) 
Urinary tract infection  1  27/303 (8.91%)  12/311 (3.86%) 
Viral upper respiratory tract infection  1  20/303 (6.60%)  23/311 (7.40%) 
Investigations     
Alanine aminotransferase increased  1  27/303 (8.91%)  22/311 (7.07%) 
Aspartate aminotransferase increased  1  29/303 (9.57%)  28/311 (9.00%) 
Blood bilirubin increased  1  18/303 (5.94%)  34/311 (10.93%) 
Weight decreased  1  60/303 (19.80%)  41/311 (13.18%) 
Metabolism and nutrition disorders     
Decreased appetite  1  107/303 (35.31%)  67/311 (21.54%) 
Dehydration  1  14/303 (4.62%)  16/311 (5.14%) 
Hypokalaemia  1  35/303 (11.55%)  41/311 (13.18%) 
Musculoskeletal and connective tissue disorders     
Arthralgia  1  29/303 (9.57%)  20/311 (6.43%) 
Back pain  1  30/303 (9.90%)  22/311 (7.07%) 
Musculoskeletal pain  1  19/303 (6.27%)  14/311 (4.50%) 
Pain in extremity  1  25/303 (8.25%)  21/311 (6.75%) 
Nervous system disorders     
Dizziness  1  43/303 (14.19%)  30/311 (9.65%) 
Dysgeusia  1  17/303 (5.61%)  13/311 (4.18%) 
Headache  1  32/303 (10.56%)  50/311 (16.08%) 
Psychiatric disorders     
Insomnia  1  20/303 (6.60%)  23/311 (7.40%) 
Respiratory, thoracic and mediastinal disorders     
Cough  1  41/303 (13.53%)  34/311 (10.93%) 
Dyspnoea  1  19/303 (6.27%)  26/311 (8.36%) 
Epistaxis  1  13/303 (4.29%)  20/311 (6.43%) 
Skin and subcutaneous tissue disorders     
Dermatitis acneiform  1  13/303 (4.29%)  23/311 (7.40%) 
Dry skin  1  20/303 (6.60%)  15/311 (4.82%) 
Palmar-plantar erythrodysaesthesia syndrome  1  139/303 (45.87%)  175/311 (56.27%) 
Pruritus  1  26/303 (8.58%)  25/311 (8.04%) 
Rash  1  31/303 (10.23%)  69/311 (22.19%) 
Skin fissures  1  9/303 (2.97%)  19/311 (6.11%) 
Skin hyperpigmentation  1  7/303 (2.31%)  17/311 (5.47%) 
1
Term from vocabulary, MedDRA 20.0
Indicates events were collected by systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT 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.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Senior Director, Clinical Operations
Organization: Puma Biotechnology, Inc.
Phone: 424-248-6500
EMail: clinicaltrials@pumabiotechnology.com
Layout table for additonal information
Responsible Party: Puma Biotechnology, Inc.
ClinicalTrials.gov Identifier: NCT01808573    
Other Study ID Numbers: PUMA-NER-1301
2012-004492-38 ( EudraCT Number )
UTN U1111-1161-1603 ( Other Identifier: WHO )
First Submitted: March 4, 2013
First Posted: March 11, 2013
Results First Submitted: September 27, 2019
Results First Posted: December 11, 2019
Last Update Posted: June 11, 2021