Neoplasms, Breast
Conditions
Keywords
ErbB2 positive, human epidermal growth factor receptor 2 positive (Her2+), metastatic breast cancer, Fluorescence in situ hybridization (FISH) positive, Stage IV
Brief summary
This was a randomized, double-blind, placebo-controlled, multicenter, Phase III study to evaluate and compare the efficacy and safety of Lapatinib + Paclitaxel versus Placebo + Paclitaxel in men and women with ErbB2 amplified metastatic (Stage IV) breast cancer who had not received prior therapy for metastatic disease.
Detailed description
Subjects were randomized to receive either Lapatinib (1500 mg once daily) + Paclitaxel (80 mg/m2 IV weekly for 3 weeks every 4 weeks) or Placebo (once daily) + Paclitaxel (80 mg/m2 IV weekly for 3 weeks every 4 weeks). Subjects who progressed while on study and were on the placebo+paclitaxel arm were permitted to enter an extension phase of open label monotherapy therapy with lapatinib or open label combination therapy with lapatinib+paclitaxel and followed for response, progression and survival. Based on the positive results in the primary analysis, Protocol Amendment 02 (dated 09 May 2011) discontinued further entry into the lapatinib monotherapy extension phase, and ongoing subjects taking placebo were permitted to replace it with open label lapatinib therapy (with or without continued paclitaxel therapy). Following the primary Overall Survival (OS) analysis and subsequent implementation of Protocol Amendment 03, subjects who were still receiving active treatment entered the Long-term follow-up (LTFU) phase of the study. Reporting requirements in the LTFU phase were limited to Adverse events of special interest (AESI), Serious adverse events (SAEs) and pregnancy, and the subjects continued to receive treatment until the occurrence of unacceptable toxicity or disease progression (as determined by the investigator) or permanent withdrawal from treatment for any reason. Subjects who were no longer receiving active treatment were withdrawn from the study.
Interventions
1500 mg oral daily continuously
Paclitaxel 80 mg/m2 every 3 weeks, 4th week rest for minimum 6 months
DRUGPlacebo
Paclitaxel Matching Placebo
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Signed informed consent; * Male or female ≥18 years; * Histologically confirmed invasive breast cancer with stage IV disease; If the disease is restricted to a solitary lesion, its neoplastic nature should be confirmed by cytology or histology. * Documented amplification of ErbB2 by fluorescence in situ hybridization (FISH) in primary or metastatic tumor tissue by the central laboratory for randomization into the study; * If a taxane was administered in the neoadjuvant or adjuvant setting, progression must have occurred \>12 months after completion of this treatment and the patient recovered from all associated toxicities; * Measurable lesion(s) according to RECIST (Response Evaluation Criteria in Solid Tumors); * Radiotherapy as palliative treatment for painful metastatic disease is permitted but must have been stopped within 2 weeks prior to initiation of any investigational treatment. All subjects must have recovered from all radiotherapy related toxicities prior to initiation of any investigational treatment. The site of radiotherapy must not be used as a site of measurable disease; * Bisphosphonate therapy for bone metastases and is allowed; however, treatment must be initiated prior to the first dose of investigational treatment. Prophylactic use of bisphosphonates in subjects without bone disease is not permitted, except for the treatment of osteoporosis; * For those patients whose disease is ER+ and/or PR+ the following criteria should be met: Patients with visceral disease that requires chemotherapy (eg., patients with liver or lung metastases) Rapidly progressing or life threatening disease, as determined by the investigator Patients who received hormonal therapy and are no longer benefiting from this therapy and the hormonal treatment must have been stopped before the first dose of investigational treatment; * Cardiac ejection fraction within institutional range of normal as measured by echocardiogram. MUGA scans will be accepted in cases where an echocardiogram cannot be performed or is inconclusive; * ECOG Performance Status of 0 to 1; * Life expectancy of ≥ 12 weeks; * Able to swallow and retain oral medication; * Archived tumor tissue available for testing; * Women and men with potential to have children must be willing to practice acceptable methods of birth control during the study; * Willing to complete all screening assessments as outlined in the protocol; * Adequate organ function as defined in Table 1 Baseline Laboratory Values;
Exclusion criteria
* Pregnant or lactating females at anytime during the study * Subjects with only non-measurable metastatic sites of disease per RECIST, (e.g. bone metastases, pleural effusion, or ascites, etc. (Refer to Section 5.3 Efficacy for list sites considered to be non-measurable disease.); * Received prior chemotherapy, immunotherapy, biologic therapy, or anti-ErbB1/ErbB2 therapy for metastatic disease. * Prior therapy with an ErbB1 and/or ErbB2 inhibitor, other than trastuzumab in the adjuvant setting. If trastuzumab was administered in the adjuvant setting, then \> 12 months must have elapsed since completion of trastuzumab therapy; * Planned concurrent anti-cancer therapy (chemotherapy, radiation therapy, immunotherapy, biologic therapy, hormonal therapy) while taking investigational treatment; * Unresolved or unstable, serious toxicity from prior administration of another investigational drug and/or of prior cancer treatment; * Peripheral neuropathy of Grade 2 or greater; * Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel. Subjects with ulcerative colitis are also excluded; * History of other malignancy. However, subjects who have been disease-free for 5 years, or subjects with a history of completely resected non-melanoma skin cancer or successfully treated in situ carcinoma, are eligible; * Concurrent disease or condition that would make the subject inappropriate for study participation, or any serious medical disorder that would interfere with the subject's safety; * Uncontrolled infection; * Dementia, altered mental status, or any psychiatric condition that would prohibit the understanding or rendering of informed consent; * Known history of uncontrolled or symptomatic angina, arrhythmias, or congestive heart failure; * Known history or clinical evidence of central nervous system (CNS) metastases or leptomeningeal carcinomatosis; * Concurrent treatment with prohibited medications, including herbal remedies and Chinese traditional medicines; * Concurrent treatment with an investigational agent or participation in another clinical trial involving investigational agents; * Used an investigational drug within 30 days or 5 half-lives, whichever is longer, preceding the first dose of investigational treatment; * Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to paclitaxel or lapatinib or their excipients.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) at 53 Months | From date of randomization until date of death from any cause, assessed up to 53 months (Primary OS analysis cut-off date = 18-Jun-2010) | Overall Survival (OS) was defined as the interval of time (in months) between the date of randomization and the date of death due to any cause. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) by Investigator Assessment | From date of randomization until date of progression or date of death from any cause, whichever comes first, assessed up to 190 months (Final analysis cut-off date = 23-Nov-2021) | Progression-free survival (PFS) during the randomized phase was defined as the interval of time (in months) between the date of randomization and the earlier of date of disease progression (radiological or clinical assessment of symptomatic progression), or date of death due to any cause. |
| Overall Response Rate (ORR) by Investigator Assessment | From date of randomization until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to 190 months (Final analysis cut-off date = 23-Nov-2021) | Overall response rate (ORR) during the randomized phase was evaluated per Response Evaluation Criteria in Solid Tumors (RECIST v1.1) and defined as the percentage of subjects achieving either a Complete Response (CR) or a Partial Response (PR). Participants with unknown or missing responses were treated as non-responders. |
| Clinical Benefit Rate (CBR) | From date of randomization until date of progression or date of death from any cause, whichever comes first, assessed up to 53 months (Primary analysis cut-off date = 18-Jun-2010) | Clinical benefit rate (CBR) was defined as the percentage of subjects with evidence of CR or PR or stable disease (neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease \[at least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of \>=1 new lesions\], taking as reference the smallest sum LD since treatment start) of \>=24 weeks, based on confirmed responses from the investigator assessment of best overall response during the randomized phase. |
| Duration of Response (DOR) | From date of confirmed CR or PR until date of progression or date of death from any cause, whichever comes first, assessed up to 190 months (Final analysis cut-off date = 23-Nov-2021) | For subjects who show CR or PR, duration of response (DOR) was defined to be the time from first documented evidence of PR or CR until the first documented sign of disease progression (radiological or clinical assessment of symptomatic progression) or death due to any cause, if sooner during the randomized phase. |
| Number of Participants With a CR or PR at Weeks 8, 12, 16, 24, 32, 40, 48, 56, 64, and 72 | Weeks 8, 12, 16, 24, 32, 40, 48, 56, 64, and 72 | The original outcome measure to be analyzed was Time to response (TTR) during the randomized phase defined as the time from randomization until first documented evidence of PR or CR (whichever status was recorded first); however, data were presented as the number of participants with a response at each nominal visit. Responses were based on the investigator's assessment, and only participants with a confirmed CR or PR were included in this analysis. |
| Overall Survival (OS) at 190 Months | From date of randomization until date of death from any cause, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) | Overall Survival (OS) was defined as the interval of time (in months) between the date of randomization and the date of death due to any cause. |
| Number of Participants With Tumors Evaluable for PTEN | Baseline | Phosphatidylinositol 3-kinase (PI3K) pathway deregulation (that is PIK3CA mutations and/or phosphatase and tensin homolog (PTEN) loss) was studied to evaluate the predictive and prognostic value of PIK3CA mutations and/or PTEN low in HER2-positive patients receiving first-line treatment with paclitaxel alone or in combination with lapatinib. Immunohistochemistry (IHC) staining in an analytically validated assay was used in the assessment of PTEN protein expression on tumor tissue. Staining intensity was allocated a score of 0, 1+, 2+ or 3+. Tumors scored IHC 0 were considered as exhibiting an absence of PTEN expression whereas those scored ICH 1+, 2+ or 3+ were considered as exhibiting any PTEN expression, being 3+ the highest expression. |
| Predictive Effect of PIK3CA Mutations Status on Overall Response Rate (ORR) | From date of randomization until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to 53 months (Primary OS analysis cut-off date = 18-Jun-2010) | ORR was evaluated per RECIST v1.1 and defined as the percentage of subjects achieving either CR or PR. Phosphatidylinositol 3-kinase (PI3K) pathway deregulation (that is PIK3CA mutations and/or phosphatase and tensin homolog (PTEN) loss) was studied to evaluate the predictive and prognostic value of PIK3CA mutations and/or PTEN low in HER2-positive patients receiving first-line treatment with paclitaxel alone or in combination with lapatinib. A PIK3CA mutation test kit was used to assess mutation status on genomic deoxyribonucleic acid (DNA) isolated from tumor tissue. |
| Predictive Effect of PTEN Low on Overall Response Rate (ORR) | From date of randomization until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to 53 months (Primary OS analysis cut-off date = 18-Jun-2010) | ORR was evaluated per RECIST v1.1 and defined as the percentage of subjects achieving either CR or PR. Phosphatidylinositol 3-kinase (PI3K) pathway deregulation (that is PIK3CA mutations and/or phosphatase and tensin homolog (PTEN) loss) was studied to evaluate the predictive and prognostic value of PIK3CA mutations and/or PTEN low in HER2-positive patients receiving first-line treatment with paclitaxel alone or in combination with lapatinib. Immunohistochemistry (IHC) staining in an analytically validated assay was used in the assessment of PTEN protein expression on tumor tissue. Staining intensity was allocated a score of 0, 1+, 2+ or 3+. Tumors scored IHC 0 were considered as exhibiting an absence of PTEN expression whereas those scored ICH 1+, 2+ or 3+ were considered as exhibiting any PTEN expression, being 3+ the highest expression. Tumors scored IHC 0/1+ were considered PTEN low. |
| Predictive Effect of PIK3CA Mutations Status on Clinical Benefit Rate (CBR) | From date of randomization until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to 53 months (Primary OS analysis cut-off date = 18-Jun-2010) | CBR was evaluated per RECIST v1.1 and defined as the percentage of subjects achieving CR or PR or stable disease. Phosphatidylinositol 3-kinase (PI3K) pathway deregulation (that is PIK3CA mutations and/or phosphatase and tensin homolog (PTEN) loss) was studied to evaluate the predictive and prognostic value of PIK3CA mutations and/or PTEN low in HER2-positive patients receiving first-line treatment with paclitaxel alone or in combination with lapatinib. A PIK3CA mutation test kit was used to assess mutation status on genomic deoxyribonucleic acid (DNA) isolated from tumor tissue. |
| Predictive Effect of PTEN Low on Clinical Benefit Rate (CBR) | From date of randomization until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to 53 months (Primary OS analysis cut-off date = 18-Jun-2010) | CBR was evaluated per RECIST v1.1 and defined as the percentage of subjects achieving CR or PR or stable disease. Phosphatidylinositol 3-kinase (PI3K) pathway deregulation (that is PIK3CA mutations and/or phosphatase and tensin homolog (PTEN) loss) was studied to evaluate the predictive and prognostic value of PIK3CA mutations and/or PTEN low in HER2-positive patients receiving first-line treatment with paclitaxel alone or in combination with lapatinib. Immunohistochemistry (IHC) staining in an analytically validated assay was used in the assessment of PTEN protein expression on tumor tissue. Staining intensity was allocated a score of 0, 1+, 2+ or 3+. Tumors scored IHC 0 were considered as exhibiting an absence of PTEN expression whereas those scored ICH 1+, 2+ or 3+ were considered as exhibiting any PTEN expression, being 3+ the highest expression. Tumors scored IHC 0/1+ were considered PTEN low. |
| Number of Tumors Evaluable for PIK3CA Mutations | Baseline | Phosphatidylinositol 3-kinase (PI3K) pathway deregulation (that is PIK3CA mutations and/or phosphatase and tensin homolog (PTEN) loss) was studied to evaluate the predictive and prognostic value of PIK3CA mutations and/or PTEN low in HER2-positive patients receiving first-line treatment with paclitaxel alone or in combination with lapatinib. A PIK3CA mutation test kit was used to assess mutation status on genomic deoxyribonucleic acid (DNA) isolated from tumor tissue. |
Countries
Brazil, China, Hong Kong, Pakistan, Peru, Russia, Thailand, Ukraine
Participant flow
Recruitment details
This study was conducted in 43 centers in eight participating countries: Brazil (7), China (20), Hong Kong (3), Pakistan (3), Peru (1), Russian Federation (6), Thailand (2) and Ukraine (1).
Participants by arm
| Arm | Count |
|---|---|
| Lapatinib 1500 mg + Paclitaxel Lapatinib 1500 milligrams (mg) administered once daily plus paclitaxel 80 mg/meters squared (m\^2) administered intravenously (IV) weekly for 3 weeks every 4 weeks | 222 |
| Placebo + Paclitaxel Matching placebo administered once daily plus paclitaxel 80 mg/m\^2 administered IV weekly for 3 weeks every 4 weeks | 222 |
| Total | 444 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Open Label Phase | Adverse Event | 0 | 0 | 1 | 0 |
| Open Label Phase | Disease progression | 0 | 0 | 18 | 0 |
| Open Label Phase | Lost to Follow-up | 0 | 0 | 16 | 2 |
| Open Label Phase | Physician Decision | 0 | 0 | 1 | 0 |
| Open Label Phase | Reason for withdrawal unspecified | 0 | 0 | 5 | 0 |
| Open Label Phase | Relocation of patient | 0 | 0 | 1 | 0 |
| Open Label Phase | Withdrawal by Subject | 0 | 0 | 3 | 2 |
| Randomized Phase | Adverse Event | 0 | 2 | 0 | 0 |
| Randomized Phase | Disease progression | 36 | 27 | 0 | 0 |
| Randomized Phase | Lost to Follow-up | 34 | 27 | 0 | 0 |
| Randomized Phase | Other reasons as defined per protocol | 4 | 3 | 0 | 0 |
| Randomized Phase | Physician Decision | 1 | 1 | 0 | 0 |
| Randomized Phase | Reason for withdrawal unspecified | 4 | 5 | 0 | 0 |
| Randomized Phase | Study closed/terminated | 1 | 1 | 0 | 0 |
| Randomized Phase | Treatment ongoing | 1 | 0 | 0 | 0 |
| Randomized Phase | Withdrawal by Subject | 8 | 7 | 0 | 0 |
Baseline characteristics
| Characteristic | Lapatinib 1500 mg + Paclitaxel | Placebo + Paclitaxel | Total |
|---|---|---|---|
| Age, Continuous | 49.1 Years STANDARD_DEVIATION 10.74 | 49.3 Years STANDARD_DEVIATION 9.75 | 49.2 Years STANDARD_DEVIATION 10.25 |
| Mean Time of Disease-Free Interval | 27.51 months STANDARD_DEVIATION 27.481 | 29.04 months STANDARD_DEVIATION 34.522 | 28.27 months STANDARD_DEVIATION 31.174 |
| Number of participants with any visceral metastatic disease and with only non-visceral disease Non-visceral | 35 Participants | 36 Participants | 71 Participants |
| Number of participants with any visceral metastatic disease and with only non-visceral disease Visceral | 187 Participants | 186 Participants | 373 Participants |
| Number of Participants with the Indicated Eastern Cooperative Oncology Group Performance Status 0, Fully Active | 103 Participants | 113 Participants | 216 Participants |
| Number of Participants with the Indicated Eastern Cooperative Oncology Group Performance Status 1, Ambulatory, Restricted Strenuous Activity | 119 Participants | 109 Participants | 228 Participants |
| Number of Participants with the Indicated Hormone Receptor Status ER+ and/or PgR+ or Unknown | 111 Participants | 113 Participants | 224 Participants |
| Number of Participants with the Indicated Hormone Receptor Status ER- and PgR- | 111 Participants | 109 Participants | 220 Participants |
| Number of Participants with the Indicated Number of Metastatic Sites Greater than or equal to 3 | 131 Participants | 115 Participants | 246 Participants |
| Number of Participants with the Indicated Number of Metastatic Sites Less than 3 | 91 Participants | 107 Participants | 198 Participants |
| Number of Participants with the Indicated Stage of Disease at Initial Diagnosis Stage III | 75 Participants | 68 Participants | 143 Participants |
| Number of Participants with the Indicated Stage of Disease at Initial Diagnosis Stage I to II | 107 Participants | 119 Participants | 226 Participants |
| Number of Participants with the Indicated Stage of Disease at Initial Diagnosis Stage IV | 30 Participants | 24 Participants | 54 Participants |
| Number of Participants with the Indicated Stage of Disease at Initial Diagnosis Unknown | 10 Participants | 11 Participants | 21 Participants |
| Race/Ethnicity, Customized Asian | 192 Participants | 192 Participants | 384 Participants |
| Race/Ethnicity, Customized Hispanic | 21 Participants | 16 Participants | 37 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 9 Participants | 13 Participants | 22 Participants |
| Sex: Female, Male Female | 222 Participants | 217 Participants | 439 Participants |
| Sex: Female, Male Male | 0 Participants | 5 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 10 / 222 | 15 / 221 | 2 / 149 | 0 / 4 |
| other Total, other adverse events | 219 / 222 | 206 / 221 | 86 / 149 | 3 / 4 |
| serious Total, serious adverse events | 67 / 222 | 30 / 221 | 8 / 149 | 0 / 4 |
Outcome results
Primary
Overall Survival (OS) at 53 Months
Overall Survival (OS) was defined as the interval of time (in months) between the date of randomization and the date of death due to any cause.
Time frame: From date of randomization until date of death from any cause, assessed up to 53 months (Primary OS analysis cut-off date = 18-Jun-2010)
Population: Intent-to-Treat (ITT) Population. The ITT population was comprised of all randomized subjects and was based on the treatment to which the subject was randomized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lapatinib 1500 mg + Paclitaxel | Overall Survival (OS) at 53 Months | 27.8 months |
| Placebo + Paclitaxel | Overall Survival (OS) at 53 Months | 20.5 months |
Comparison: Primary OS analysis cut-off date = 18-Jun-2010p-value: 0.006295% CI: [0.58, 0.94]Log Rank
Secondary
Clinical Benefit Rate (CBR)
Clinical benefit rate (CBR) was defined as the percentage of subjects with evidence of CR or PR or stable disease (neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease \[at least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of \>=1 new lesions\], taking as reference the smallest sum LD since treatment start) of \>=24 weeks, based on confirmed responses from the investigator assessment of best overall response during the randomized phase.
Time frame: From date of randomization until date of progression or date of death from any cause, whichever comes first, assessed up to 53 months (Primary analysis cut-off date = 18-Jun-2010)
Population: Intent-to-Treat (ITT) Population. The ITT population was comprised of all randomized subjects and was based on the treatment to which the subject was randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lapatinib 1500 mg + Paclitaxel | Clinical Benefit Rate (CBR) | 75 Percentage of Participants |
| Placebo + Paclitaxel | Clinical Benefit Rate (CBR) | 56 Percentage of Participants |
95% CI: [1.54, 3.58]
Secondary
Duration of Response (DOR)
For subjects who show CR or PR, duration of response (DOR) was defined to be the time from first documented evidence of PR or CR until the first documented sign of disease progression (radiological or clinical assessment of symptomatic progression) or death due to any cause, if sooner during the randomized phase.
Time frame: From date of confirmed CR or PR until date of progression or date of death from any cause, whichever comes first, assessed up to 190 months (Final analysis cut-off date = 23-Nov-2021)
Population: Subset of participants in the Intent-to-Treat (ITT) Population with a confirmed CR or PR
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lapatinib 1500 mg + Paclitaxel | Duration of Response (DOR) | 9.3 months |
| Placebo + Paclitaxel | Duration of Response (DOR) | 5.8 months |
Secondary
Number of Participants With a CR or PR at Weeks 8, 12, 16, 24, 32, 40, 48, 56, 64, and 72
The original outcome measure to be analyzed was Time to response (TTR) during the randomized phase defined as the time from randomization until first documented evidence of PR or CR (whichever status was recorded first); however, data were presented as the number of participants with a response at each nominal visit. Responses were based on the investigator's assessment, and only participants with a confirmed CR or PR were included in this analysis.
Time frame: Weeks 8, 12, 16, 24, 32, 40, 48, 56, 64, and 72
Population: Participants in the Intent-to-Treat (ITT) Population with a confirmed CR or PR
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Lapatinib 1500 mg + Paclitaxel | Number of Participants With a CR or PR at Weeks 8, 12, 16, 24, 32, 40, 48, 56, 64, and 72 | Week 8 | 94 Participants |
| Lapatinib 1500 mg + Paclitaxel | Number of Participants With a CR or PR at Weeks 8, 12, 16, 24, 32, 40, 48, 56, 64, and 72 | Week 12 | 40 Participants |
| Lapatinib 1500 mg + Paclitaxel | Number of Participants With a CR or PR at Weeks 8, 12, 16, 24, 32, 40, 48, 56, 64, and 72 | Week 16 | 6 Participants |
| Lapatinib 1500 mg + Paclitaxel | Number of Participants With a CR or PR at Weeks 8, 12, 16, 24, 32, 40, 48, 56, 64, and 72 | Week 24 | 7 Participants |
| Lapatinib 1500 mg + Paclitaxel | Number of Participants With a CR or PR at Weeks 8, 12, 16, 24, 32, 40, 48, 56, 64, and 72 | Week 32 | 3 Participants |
| Lapatinib 1500 mg + Paclitaxel | Number of Participants With a CR or PR at Weeks 8, 12, 16, 24, 32, 40, 48, 56, 64, and 72 | Week 40 | 0 Participants |
| Lapatinib 1500 mg + Paclitaxel | Number of Participants With a CR or PR at Weeks 8, 12, 16, 24, 32, 40, 48, 56, 64, and 72 | Week 48 | 1 Participants |
| Lapatinib 1500 mg + Paclitaxel | Number of Participants With a CR or PR at Weeks 8, 12, 16, 24, 32, 40, 48, 56, 64, and 72 | Week 56 | 1 Participants |
| Lapatinib 1500 mg + Paclitaxel | Number of Participants With a CR or PR at Weeks 8, 12, 16, 24, 32, 40, 48, 56, 64, and 72 | Week 64 | 1 Participants |
| Lapatinib 1500 mg + Paclitaxel | Number of Participants With a CR or PR at Weeks 8, 12, 16, 24, 32, 40, 48, 56, 64, and 72 | Week 72 | 1 Participants |
| Placebo + Paclitaxel | Number of Participants With a CR or PR at Weeks 8, 12, 16, 24, 32, 40, 48, 56, 64, and 72 | Week 56 | 0 Participants |
| Placebo + Paclitaxel | Number of Participants With a CR or PR at Weeks 8, 12, 16, 24, 32, 40, 48, 56, 64, and 72 | Week 8 | 61 Participants |
| Placebo + Paclitaxel | Number of Participants With a CR or PR at Weeks 8, 12, 16, 24, 32, 40, 48, 56, 64, and 72 | Week 40 | 0 Participants |
| Placebo + Paclitaxel | Number of Participants With a CR or PR at Weeks 8, 12, 16, 24, 32, 40, 48, 56, 64, and 72 | Week 12 | 28 Participants |
| Placebo + Paclitaxel | Number of Participants With a CR or PR at Weeks 8, 12, 16, 24, 32, 40, 48, 56, 64, and 72 | Week 72 | 0 Participants |
| Placebo + Paclitaxel | Number of Participants With a CR or PR at Weeks 8, 12, 16, 24, 32, 40, 48, 56, 64, and 72 | Week 16 | 11 Participants |
| Placebo + Paclitaxel | Number of Participants With a CR or PR at Weeks 8, 12, 16, 24, 32, 40, 48, 56, 64, and 72 | Week 48 | 0 Participants |
| Placebo + Paclitaxel | Number of Participants With a CR or PR at Weeks 8, 12, 16, 24, 32, 40, 48, 56, 64, and 72 | Week 24 | 8 Participants |
| Placebo + Paclitaxel | Number of Participants With a CR or PR at Weeks 8, 12, 16, 24, 32, 40, 48, 56, 64, and 72 | Week 64 | 0 Participants |
| Placebo + Paclitaxel | Number of Participants With a CR or PR at Weeks 8, 12, 16, 24, 32, 40, 48, 56, 64, and 72 | Week 32 | 2 Participants |
Secondary
Number of Participants With Tumors Evaluable for PTEN
Phosphatidylinositol 3-kinase (PI3K) pathway deregulation (that is PIK3CA mutations and/or phosphatase and tensin homolog (PTEN) loss) was studied to evaluate the predictive and prognostic value of PIK3CA mutations and/or PTEN low in HER2-positive patients receiving first-line treatment with paclitaxel alone or in combination with lapatinib. Immunohistochemistry (IHC) staining in an analytically validated assay was used in the assessment of PTEN protein expression on tumor tissue. Staining intensity was allocated a score of 0, 1+, 2+ or 3+. Tumors scored IHC 0 were considered as exhibiting an absence of PTEN expression whereas those scored ICH 1+, 2+ or 3+ were considered as exhibiting any PTEN expression, being 3+ the highest expression.
Time frame: Baseline
Population: Participants in the Intent-to-Treat (ITT) Population with tumors evaluable for PTEN
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Lapatinib 1500 mg + Paclitaxel | Number of Participants With Tumors Evaluable for PTEN | PTEN IHC 0 | 28 Participants |
| Lapatinib 1500 mg + Paclitaxel | Number of Participants With Tumors Evaluable for PTEN | PTEN IHC 1+ | 76 Participants |
| Lapatinib 1500 mg + Paclitaxel | Number of Participants With Tumors Evaluable for PTEN | PTEN IHC 2+/3+ | 76 Participants |
| Placebo + Paclitaxel | Number of Participants With Tumors Evaluable for PTEN | PTEN IHC 0 | 21 Participants |
| Placebo + Paclitaxel | Number of Participants With Tumors Evaluable for PTEN | PTEN IHC 1+ | 80 Participants |
| Placebo + Paclitaxel | Number of Participants With Tumors Evaluable for PTEN | PTEN IHC 2+/3+ | 74 Participants |
Secondary
Number of Tumors Evaluable for PIK3CA Mutations
Phosphatidylinositol 3-kinase (PI3K) pathway deregulation (that is PIK3CA mutations and/or phosphatase and tensin homolog (PTEN) loss) was studied to evaluate the predictive and prognostic value of PIK3CA mutations and/or PTEN low in HER2-positive patients receiving first-line treatment with paclitaxel alone or in combination with lapatinib. A PIK3CA mutation test kit was used to assess mutation status on genomic deoxyribonucleic acid (DNA) isolated from tumor tissue.
Time frame: Baseline
Population: Participants in the Intent-to-Treat (ITT) Population with tumors evaluable for PIK3CA mutations
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Lapatinib 1500 mg + Paclitaxel | Number of Tumors Evaluable for PIK3CA Mutations | PIK3CA mutation | 29 Participants |
| Lapatinib 1500 mg + Paclitaxel | Number of Tumors Evaluable for PIK3CA Mutations | PIK3CA wild-type | 58 Participants |
| Lapatinib 1500 mg + Paclitaxel | Number of Tumors Evaluable for PIK3CA Mutations | PIK3CA indeterminate | 17 Participants |
| Placebo + Paclitaxel | Number of Tumors Evaluable for PIK3CA Mutations | PIK3CA mutation | 36 Participants |
| Placebo + Paclitaxel | Number of Tumors Evaluable for PIK3CA Mutations | PIK3CA wild-type | 48 Participants |
| Placebo + Paclitaxel | Number of Tumors Evaluable for PIK3CA Mutations | PIK3CA indeterminate | 22 Participants |
Secondary
Overall Response Rate (ORR) by Investigator Assessment
Overall response rate (ORR) during the randomized phase was evaluated per Response Evaluation Criteria in Solid Tumors (RECIST v1.1) and defined as the percentage of subjects achieving either a Complete Response (CR) or a Partial Response (PR). Participants with unknown or missing responses were treated as non-responders.
Time frame: From date of randomization until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to 190 months (Final analysis cut-off date = 23-Nov-2021)
Population: Intent-to-Treat (ITT) Population. The ITT population was comprised of all randomized subjects and was based on the treatment to which the subject was randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lapatinib 1500 mg + Paclitaxel | Overall Response Rate (ORR) by Investigator Assessment | 69 Percentage of Participants |
| Placebo + Paclitaxel | Overall Response Rate (ORR) by Investigator Assessment | 50 Percentage of Participants |
95% CI: [1.54, 3.47]
Secondary
Overall Survival (OS) at 190 Months
Overall Survival (OS) was defined as the interval of time (in months) between the date of randomization and the date of death due to any cause.
Time frame: From date of randomization until date of death from any cause, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021)
Population: Intent-to-Treat (ITT) Population. The ITT population was comprised of all randomized subjects and was based on the treatment to which the subject was randomized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lapatinib 1500 mg + Paclitaxel | Overall Survival (OS) at 190 Months | 27.6 months |
| Placebo + Paclitaxel | Overall Survival (OS) at 190 Months | 20.3 months |
Comparison: Final OS analysis cut-0ff date = 23-Nov-202195% CI: [0.64, 0.98]
Secondary
Predictive Effect of PIK3CA Mutations Status on Clinical Benefit Rate (CBR)
CBR was evaluated per RECIST v1.1 and defined as the percentage of subjects achieving CR or PR or stable disease. Phosphatidylinositol 3-kinase (PI3K) pathway deregulation (that is PIK3CA mutations and/or phosphatase and tensin homolog (PTEN) loss) was studied to evaluate the predictive and prognostic value of PIK3CA mutations and/or PTEN low in HER2-positive patients receiving first-line treatment with paclitaxel alone or in combination with lapatinib. A PIK3CA mutation test kit was used to assess mutation status on genomic deoxyribonucleic acid (DNA) isolated from tumor tissue.
Time frame: From date of randomization until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to 53 months (Primary OS analysis cut-off date = 18-Jun-2010)
Population: Participants in the Intent-to-Treat (ITT) Population with tumors evaluable for PIK3CA mutations (PIK3CA mutation and PIK3CA wild type)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Lapatinib 1500 mg + Paclitaxel | Predictive Effect of PIK3CA Mutations Status on Clinical Benefit Rate (CBR) | PIK3CA mutation | 69 percentage of participants |
| Lapatinib 1500 mg + Paclitaxel | Predictive Effect of PIK3CA Mutations Status on Clinical Benefit Rate (CBR) | PIK3CA wild-type | 84 percentage of participants |
| Placebo + Paclitaxel | Predictive Effect of PIK3CA Mutations Status on Clinical Benefit Rate (CBR) | PIK3CA mutation | 56 percentage of participants |
| Placebo + Paclitaxel | Predictive Effect of PIK3CA Mutations Status on Clinical Benefit Rate (CBR) | PIK3CA wild-type | 65 percentage of participants |
Secondary
Predictive Effect of PIK3CA Mutations Status on Overall Response Rate (ORR)
ORR was evaluated per RECIST v1.1 and defined as the percentage of subjects achieving either CR or PR. Phosphatidylinositol 3-kinase (PI3K) pathway deregulation (that is PIK3CA mutations and/or phosphatase and tensin homolog (PTEN) loss) was studied to evaluate the predictive and prognostic value of PIK3CA mutations and/or PTEN low in HER2-positive patients receiving first-line treatment with paclitaxel alone or in combination with lapatinib. A PIK3CA mutation test kit was used to assess mutation status on genomic deoxyribonucleic acid (DNA) isolated from tumor tissue.
Time frame: From date of randomization until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to 53 months (Primary OS analysis cut-off date = 18-Jun-2010)
Population: Participants in the Intent-to-Treat (ITT) Population with tumors evaluable for PIK3CA mutations (PIK3CA mutation and PIK3CA wild type)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Lapatinib 1500 mg + Paclitaxel | Predictive Effect of PIK3CA Mutations Status on Overall Response Rate (ORR) | PIK3CA mutation | 62 percentage of participants |
| Lapatinib 1500 mg + Paclitaxel | Predictive Effect of PIK3CA Mutations Status on Overall Response Rate (ORR) | PIK3CA wild-type | 80 percentage of participants |
| Placebo + Paclitaxel | Predictive Effect of PIK3CA Mutations Status on Overall Response Rate (ORR) | PIK3CA mutation | 50 percentage of participants |
| Placebo + Paclitaxel | Predictive Effect of PIK3CA Mutations Status on Overall Response Rate (ORR) | PIK3CA wild-type | 59 percentage of participants |
Comparison: Participants with PIK3CA wild-type95% CI: [1.07, 7.57]
Secondary
Predictive Effect of PTEN Low on Clinical Benefit Rate (CBR)
CBR was evaluated per RECIST v1.1 and defined as the percentage of subjects achieving CR or PR or stable disease. Phosphatidylinositol 3-kinase (PI3K) pathway deregulation (that is PIK3CA mutations and/or phosphatase and tensin homolog (PTEN) loss) was studied to evaluate the predictive and prognostic value of PIK3CA mutations and/or PTEN low in HER2-positive patients receiving first-line treatment with paclitaxel alone or in combination with lapatinib. Immunohistochemistry (IHC) staining in an analytically validated assay was used in the assessment of PTEN protein expression on tumor tissue. Staining intensity was allocated a score of 0, 1+, 2+ or 3+. Tumors scored IHC 0 were considered as exhibiting an absence of PTEN expression whereas those scored ICH 1+, 2+ or 3+ were considered as exhibiting any PTEN expression, being 3+ the highest expression. Tumors scored IHC 0/1+ were considered PTEN low.
Time frame: From date of randomization until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to 53 months (Primary OS analysis cut-off date = 18-Jun-2010)
Population: Participants in the Intent-to-Treat (ITT) Population with PTEN low and without PTEN low
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Lapatinib 1500 mg + Paclitaxel | Predictive Effect of PTEN Low on Clinical Benefit Rate (CBR) | PTEN low | 82 percentage of participants |
| Lapatinib 1500 mg + Paclitaxel | Predictive Effect of PTEN Low on Clinical Benefit Rate (CBR) | Without PTEN low | 80 percentage of participants |
| Placebo + Paclitaxel | Predictive Effect of PTEN Low on Clinical Benefit Rate (CBR) | PTEN low | 59 percentage of participants |
| Placebo + Paclitaxel | Predictive Effect of PTEN Low on Clinical Benefit Rate (CBR) | Without PTEN low | 61 percentage of participants |
Comparison: Participants with PTEN low95% CI: [1.58, 6.49]
Comparison: Participants without PTEN low95% CI: [1.13, 5.66]
Secondary
Predictive Effect of PTEN Low on Overall Response Rate (ORR)
ORR was evaluated per RECIST v1.1 and defined as the percentage of subjects achieving either CR or PR. Phosphatidylinositol 3-kinase (PI3K) pathway deregulation (that is PIK3CA mutations and/or phosphatase and tensin homolog (PTEN) loss) was studied to evaluate the predictive and prognostic value of PIK3CA mutations and/or PTEN low in HER2-positive patients receiving first-line treatment with paclitaxel alone or in combination with lapatinib. Immunohistochemistry (IHC) staining in an analytically validated assay was used in the assessment of PTEN protein expression on tumor tissue. Staining intensity was allocated a score of 0, 1+, 2+ or 3+. Tumors scored IHC 0 were considered as exhibiting an absence of PTEN expression whereas those scored ICH 1+, 2+ or 3+ were considered as exhibiting any PTEN expression, being 3+ the highest expression. Tumors scored IHC 0/1+ were considered PTEN low.
Time frame: From date of randomization until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to 53 months (Primary OS analysis cut-off date = 18-Jun-2010)
Population: Participants in the Intent-to-Treat (ITT) Population with PTEN low and without PTEN low
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Lapatinib 1500 mg + Paclitaxel | Predictive Effect of PTEN Low on Overall Response Rate (ORR) | PTEN low | 73 percentage of participants |
| Lapatinib 1500 mg + Paclitaxel | Predictive Effect of PTEN Low on Overall Response Rate (ORR) | Without PTEN low | 76 percentage of participants |
| Placebo + Paclitaxel | Predictive Effect of PTEN Low on Overall Response Rate (ORR) | PTEN low | 53 percentage of participants |
| Placebo + Paclitaxel | Predictive Effect of PTEN Low on Overall Response Rate (ORR) | Without PTEN low | 58 percentage of participants |
Comparison: Participants with PTEN low95% CI: [1.28, 4.63]
Comparison: Participants without PTEN low95% CI: [1.04, 4.82]
Secondary
Progression-free Survival (PFS) by Investigator Assessment
Progression-free survival (PFS) during the randomized phase was defined as the interval of time (in months) between the date of randomization and the earlier of date of disease progression (radiological or clinical assessment of symptomatic progression), or date of death due to any cause.
Time frame: From date of randomization until date of progression or date of death from any cause, whichever comes first, assessed up to 190 months (Final analysis cut-off date = 23-Nov-2021)
Population: Intent-to-Treat (ITT) Population. The ITT population was comprised of all randomized subjects and was based on the treatment to which the subject was randomized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lapatinib 1500 mg + Paclitaxel | Progression-free Survival (PFS) by Investigator Assessment | 9.7 months |
| Placebo + Paclitaxel | Progression-free Survival (PFS) by Investigator Assessment | 6.5 months |
95% CI: [0.44, 0.66]