Trial Outcomes & Findings for Pazopanib Plus Lapatinib Compared To Lapatinib Alone In Subjects With Advanced Or Metastatic Breast Cancer (NCT NCT00347919)

Last Updated: 2016-02-25

Results Overview

The percentage of participants with progressive disease (PD) 12 weeks after randomization was measured. Per Response Evaluation Criteria In Solid Tumors (RECIST), a response of PD is defined as a \>=20% increase in target lesions. Participants were also classified as having PD if their response at Week 12 was unknown or missing. Response was determined by an independent radiologist and by an investigator.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

189 participants

Primary outcome timeframe

Week 12

Results posted on

2016-02-25

Participant Flow

Participants (par.) were enrolled into two cohorts. Cohort 1: Par. were randomized 1:1 to lapatinib 1500 mg or lapatinib 1000 mg/pazopanib 400 mg. Cohort 2: After enrollment was complete for Cohort 1, par. were enrolled to lapatinib 1500 mg/pazopanib 800 mg. All par. who received study drug are accounted for in the Participant Flow module.

Female par. with \>=18 years of age with histologically confirmed invasive breast cancer were enrolled in the study. Total 189 par. (Cohort 1, combination n = 76, lapatinib n = 73; Cohort 2, n = 40) received study drug.

Participant milestones

Participant milestones
Measure	Cohort 1: Lapatinib 1500 mg Lapatinib 1500 milligrams (mg) administered orally once a day	Cohort 1: Lapatinib 1000 mg/Pazopanib 400 mg Lapatinib 1000 mg and Pazopanib 400 mg administered orally once a day	Cohort 2: Lapatinib 1500 mg/Pazopanib 800 mg Lapatinib 1500 mg and Pazopanib 800 mg administered orally once a day
Overall Study STARTED	73	76	40
Overall Study COMPLETED	2	0	2
Overall Study NOT COMPLETED	71	76	38

Reasons for withdrawal

Reasons for withdrawal
Measure	Cohort 1: Lapatinib 1500 mg Lapatinib 1500 milligrams (mg) administered orally once a day	Cohort 1: Lapatinib 1000 mg/Pazopanib 400 mg Lapatinib 1000 mg and Pazopanib 400 mg administered orally once a day	Cohort 2: Lapatinib 1500 mg/Pazopanib 800 mg Lapatinib 1500 mg and Pazopanib 800 mg administered orally once a day
Overall Study Lost to Follow-up	11	13	0
Overall Study Withdrawal by Subject	6	8	0
Overall Study Physician Decision	1	1	0
Overall Study Sponsor terminated study	15	10	16
Overall Study Death	35	42	19
Overall Study Par. Started Other Treatment	1	1	1
Overall Study Missing	2	1	2

Baseline Characteristics

Pazopanib Plus Lapatinib Compared To Lapatinib Alone In Subjects With Advanced Or Metastatic Breast Cancer

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Cohort 1: Lapatinib 1500 mg n=72 Participants Lapatinib 1500 milligrams (mg) administered orally once a day	Cohort 1: Lapatinib 1000 mg/Pazopanib 400 mg n=69 Participants Lapatinib 1000 mg and Pazopanib 400 mg administered orally once a day	Cohort 2: Lapatinib 1500 mg/Pazopanib 800 mg n=36 Participants Lapatinib 1500 mg and Pazopanib 800 mg administered orally once a day	Total n=177 Participants Total of all reporting groups
Age, Continuous	53.5 years STANDARD_DEVIATION 11.20 • n=5 Participants	52.1 years STANDARD_DEVIATION 12.76 • n=7 Participants	54.1 years STANDARD_DEVIATION 12.93 • n=5 Participants	52.8 years STANDARD_DEVIATION 11.97 • n=4 Participants
Sex: Female, Male Female	72 Participants n=5 Participants	69 Participants n=7 Participants	36 Participants n=5 Participants	177 Participants n=4 Participants
Sex: Female, Male Male	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race/Ethnicity, Customized African American/African Heritage	0 participants n=5 Participants	1 participants n=7 Participants	0 participants n=5 Participants	1 participants n=4 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	20 participants n=5 Participants	18 participants n=7 Participants	0 participants n=5 Participants	38 participants n=4 Participants
Race/Ethnicity, Customized Asian	33 participants n=5 Participants	30 participants n=7 Participants	3 participants n=5 Participants	66 participants n=4 Participants
Race/Ethnicity, Customized White	19 participants n=5 Participants	18 participants n=7 Participants	32 participants n=5 Participants	69 participants n=4 Participants
Race/Ethnicity, Customized Other	0 participants n=5 Participants	1 participants n=7 Participants	0 participants n=5 Participants	1 participants n=4 Participants
Race/Ethnicity, Customized Unknown	0 participants n=5 Participants	1 participants n=7 Participants	1 participants n=5 Participants	2 participants n=4 Participants
Child-Bearing Potential Post-Menopausal	49 participants n=5 Participants	46 participants n=7 Participants	22 participants n=5 Participants	117 participants n=4 Participants
Child-Bearing Potential Sterile (of child-bearing age)	3 participants n=5 Participants	2 participants n=7 Participants	5 participants n=5 Participants	10 participants n=4 Participants
Child-Bearing Potential Potentially able to bear children	20 participants n=5 Participants	21 participants n=7 Participants	9 participants n=5 Participants	50 participants n=4 Participants

PRIMARY outcome

Timeframe: Week 12

Population: Cohort 1: Modified Intent-to-Treat (ITT) Population (all randomized, centrally confirmed, ErbB2 FISH-positive participants).

Outcome measures

Outcome measures
Measure	Cohort 1: Lapatinib 1500 mg n=72 Participants Lapatinib 1500 milligrams (mg) administered orally once a day	Cohort 1: Lapatinib 1000 mg/Pazopanib 400 mg n=69 Participants Lapatinib 1000 mg and Pazopanib 400 mg administered orally once a day	Cohort 2: Lapatinib 1500 mg/Pazopanib 800 mg Lapatinib 1500 mg and Pazopanib 800 mg administered orally once a day
Percentage of Participants With Progressive Disease at Week 12 in Cohort 1 Independently Evaluated	38.9 percentage of participants	36.2 percentage of participants	—
Percentage of Participants With Progressive Disease at Week 12 in Cohort 1 Investigator Evaluated	43.1 percentage of participants	37.7 percentage of participants	—

SECONDARY outcome

Timeframe: Randomization until death due to any cause (up to 106.43 weeks)

Population: MITT Population

Overall survival (OS) is defined as the time from randomization until death due to any cause. Participants who are alive as of the date of last contact are censored. There was insufficient follow-up to adequately assess OS for Cohort 2. Median OS cannot be presented for the lapatinib arm because the upper bound of the 95% confidence interval is undefined due to insufficient follow-up.

Outcome measures

Outcome measures
Measure	Cohort 1: Lapatinib 1500 mg Lapatinib 1500 milligrams (mg) administered orally once a day	Cohort 1: Lapatinib 1000 mg/Pazopanib 400 mg n=69 Participants Lapatinib 1000 mg and Pazopanib 400 mg administered orally once a day	Cohort 2: Lapatinib 1500 mg/Pazopanib 800 mg Lapatinib 1500 mg and Pazopanib 800 mg administered orally once a day
Overall Survival for Cohort 1	—	91.0 weeks Interval 69.4 to 91.0	—

SECONDARY outcome

Timeframe: Week 12

Population: MITT Population

The percentage of participants achieving either a complete (CR) or partial (PR) tumor response per Response Evaluation Criteria in Solid Tumors (RECIST) is presented. CR, all detectable tumor has disappeared; PR, a \>=30% decrease in the sum of the longest dimensions of the target lesions taking as a reference the baseline sum; Progressive disease (PD), a \>=20% increase in target lesions; Stable Disease, small changes that do not meet previously given criteria. IRC, independent review committee. Participants with an unknown or missing response were treated as non-responders.

Outcome measures

Outcome measures
Measure	Cohort 1: Lapatinib 1500 mg n=72 Participants Lapatinib 1500 milligrams (mg) administered orally once a day	Cohort 1: Lapatinib 1000 mg/Pazopanib 400 mg n=69 Participants Lapatinib 1000 mg and Pazopanib 400 mg administered orally once a day	Cohort 2: Lapatinib 1500 mg/Pazopanib 800 mg n=36 Participants Lapatinib 1500 mg and Pazopanib 800 mg administered orally once a day
Response at Week 12 for Cohort 1 and Cohort 2 Complete response, IRC evaluated	0 percentage of participants	0 percentage of participants	0 percentage of participants
Response at Week 12 for Cohort 1 and Cohort 2 Partial response, Investigator evaluated	26 percentage of participants	45 percentage of participants	50 percentage of participants
Response at Week 12 for Cohort 1 and Cohort 2 Complete response, Investigator evaluated	1 percentage of participants	0 percentage of participants	0 percentage of participants
Response at Week 12 for Cohort 1 and Cohort 2 Partial response, IRC evaluated	22 percentage of participants	36 percentage of participants	33 percentage of participants
Response at Week 12 for Cohort 1 and Cohort 2 Stable disease, IRC evaluated	39 percentage of participants	28 percentage of participants	31 percentage of participants
Response at Week 12 for Cohort 1 and Cohort 2 Stable disease, Investigator evaluated	29 percentage of participants	17 percentage of participants	14 percentage of participants
Response at Week 12 for Cohort 1 and Cohort 2 Progressive disease, IRC evaluated	17 percentage of participants	20 percentage of participants	8 percentage of participants
Response at Week 12 for Cohort 1 and Cohort 2 Progressive disease, Investigator evaluated	38 percentage of participants	20 percentage of participants	11 percentage of participants
Response at Week 12 for Cohort 1 and Cohort 2 Unknown/missing, IRC evaluated	22 percentage of participants	15 percentage of participants	28 percentage of participants
Response at Week 12 for Cohort 1 and Cohort 2 Unknown/missing, Investigator	6 percentage of participants	17 percentage of participants	25 percentage of participants

SECONDARY outcome

Timeframe: Time from first documented evidence of complete or partial response until the first documented sign of disease progression or death due to any cause (up to 106.71 weeks)

Population: MITT Population

Duration of response is defined as the length of time from the time from the first observation of response until progression of disease or death. Duration of response depends on two things: (1) when response is counted as starting; (2) when response is counted as ending.There were insufficient data to adequately assess duration of response for Cohort 2. IRC, independent review committee. For participants who do not progress or die, duration of response was censored at the date of last adequate assessment.

Outcome measures

Outcome measures
Measure	Cohort 1: Lapatinib 1500 mg n=72 Participants Lapatinib 1500 milligrams (mg) administered orally once a day	Cohort 1: Lapatinib 1000 mg/Pazopanib 400 mg n=69 Participants Lapatinib 1000 mg and Pazopanib 400 mg administered orally once a day	Cohort 2: Lapatinib 1500 mg/Pazopanib 800 mg Lapatinib 1500 mg and Pazopanib 800 mg administered orally once a day
Duration of Response in Cohort 1	27.1 weeks Interval 24.3 to 27.7	24.3 weeks Interval 12.3 to 24.3	—

SECONDARY outcome

Timeframe: The time from randomization to the time of first documented evidence of complete or partial response (up to 81.14 weeks for Cohort 1 and 44.29 weeks for Cohort 2)

Population: MITT Population

Time to response is defined as the time from randomization to the time of first documented evidence of a complete (CR) or partial response (PR). The time to response will depend on when the response is counted as starting. Per RECIST: CR, all detectable tumor has disappeared; PR, a \>=30% decrease in the sum of the target dimensions of the target lesions taking as a reference the baseline sum.

Outcome measures

Outcome measures
Measure	Cohort 1: Lapatinib 1500 mg n=72 Participants Lapatinib 1500 milligrams (mg) administered orally once a day	Cohort 1: Lapatinib 1000 mg/Pazopanib 400 mg n=69 Participants Lapatinib 1000 mg and Pazopanib 400 mg administered orally once a day	Cohort 2: Lapatinib 1500 mg/Pazopanib 800 mg n=36 Participants Lapatinib 1500 mg and Pazopanib 800 mg administered orally once a day
Time to Response (Complete or Partial Response) in Cohort 1 and Cohort 2 IRC Evaluated	8.1 weeks Interval 7.9 to 11.4	8.3 weeks Interval 8.0 to 11.9	8.3 weeks Interval 7.4 to 8.7
Time to Response (Complete or Partial Response) in Cohort 1 and Cohort 2 Investigator Evaluated	8.0 weeks Interval 7.9 to 8.1	8.1 weeks Interval 8.0 to 8.4	8.0 weeks Interval 7.3 to 8.6

SECONDARY outcome

Timeframe: Week 12

Population: Cohort 2 MITT Population

The percentage of participants with progressive disease (PD) 12 weeks after randomization was measured. Participants were classified as having PD if their response at Week 12 was unknown or missing. Per Response Evaluation Criteria In Solid Tumors (RECIST), PD is defined as a \>=20% increase in target lesions. IRC, independent review committee.

Outcome measures

Outcome measures
Measure	Cohort 1: Lapatinib 1500 mg n=36 Participants Lapatinib 1500 milligrams (mg) administered orally once a day	Cohort 1: Lapatinib 1000 mg/Pazopanib 400 mg Lapatinib 1000 mg and Pazopanib 400 mg administered orally once a day	Cohort 2: Lapatinib 1500 mg/Pazopanib 800 mg Lapatinib 1500 mg and Pazopanib 800 mg administered orally once a day
Percentage of Participants With Progressive Disease at Week 12 PD+Missing+Unknown, Investigator Evaluated	36 percentage of participants	—	—
Percentage of Participants With Progressive Disease at Week 12 PD+Missing+Unknown, IRC evaluated	36 percentage of participants	—	—

Adverse Events

Cohort 1: Lapatinib 1500 mg

Serious events: 10 serious events

Other events: 63 other events

Deaths: 0 deaths

Cohort 1: Lapatinib 1000 mg/Pazopanib 400 mg

Serious events: 18 serious events

Other events: 71 other events

Deaths: 0 deaths

Cohort 2: Lapatinib 1500 mg/Pazopanib 800 mg

Serious events: 13 serious events

Other events: 39 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

GSK Response Center

GlaxoSmithKline

Phone: 866-435-7343

Results disclosure agreements

Principal investigator is a sponsor employee GSK agreements may vary with individual investigators, but will not prohibit any investigator from publishing. GSK supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.
Publication restrictions are in place

Restriction type: OTHER

Measure	Cohort 1: Lapatinib 1500 mg n=73 participants at risk Lapatinib 1500 milligrams (mg) administered orally once a day	Cohort 1: Lapatinib 1000 mg/Pazopanib 400 mg n=76 participants at risk Lapatinib 1000 mg and Pazopanib 400 mg administered orally once a day	Cohort 2: Lapatinib 1500 mg/Pazopanib 800 mg n=40 participants at risk Lapatinib 1500 mg and Pazopanib 800 mg administered orally once a day
Blood and lymphatic system disorders Anaemia	0.00% 0/73 • Study Entry until 28 days after the last dose.	2.6% 2/76 • Number of events 2 • Study Entry until 28 days after the last dose.	0.00% 0/40 • Study Entry until 28 days after the last dose.
Blood and lymphatic system disorders Febrile neutropenia	0.00% 0/73 • Study Entry until 28 days after the last dose.	0.00% 0/76 • Study Entry until 28 days after the last dose.	2.5% 1/40 • Number of events 1 • Study Entry until 28 days after the last dose.
Blood and lymphatic system disorders Thrombocytopenia	0.00% 0/73 • Study Entry until 28 days after the last dose.	0.00% 0/76 • Study Entry until 28 days after the last dose.	2.5% 1/40 • Number of events 1 • Study Entry until 28 days after the last dose.
Cardiac disorders Left ventricular dysfunction	0.00% 0/73 • Study Entry until 28 days after the last dose.	2.6% 2/76 • Number of events 2 • Study Entry until 28 days after the last dose.	0.00% 0/40 • Study Entry until 28 days after the last dose.
Gastrointestinal disorders Diarrhoea	2.7% 2/73 • Number of events 2 • Study Entry until 28 days after the last dose.	1.3% 1/76 • Number of events 1 • Study Entry until 28 days after the last dose.	7.5% 3/40 • Number of events 3 • Study Entry until 28 days after the last dose.
Gastrointestinal disorders Oesophagitis	0.00% 0/73 • Study Entry until 28 days after the last dose.	1.3% 1/76 • Number of events 1 • Study Entry until 28 days after the last dose.	0.00% 0/40 • Study Entry until 28 days after the last dose.
Gastrointestinal disorders Vomiting	1.4% 1/73 • Number of events 1 • Study Entry until 28 days after the last dose.	0.00% 0/76 • Study Entry until 28 days after the last dose.	0.00% 0/40 • Study Entry until 28 days after the last dose.
Gastrointestinal disorders Abdominal pain upper	0.00% 0/73 • Study Entry until 28 days after the last dose.	0.00% 0/76 • Study Entry until 28 days after the last dose.	2.5% 1/40 • Number of events 1 • Study Entry until 28 days after the last dose.
Gastrointestinal disorders Colitis	0.00% 0/73 • Study Entry until 28 days after the last dose.	0.00% 0/76 • Study Entry until 28 days after the last dose.	2.5% 1/40 • Number of events 1 • Study Entry until 28 days after the last dose.
General disorders Fatigue	0.00% 0/73 • Study Entry until 28 days after the last dose.	1.3% 1/76 • Number of events 1 • Study Entry until 28 days after the last dose.	0.00% 0/40 • Study Entry until 28 days after the last dose.
General disorders Pyrexia	0.00% 0/73 • Study Entry until 28 days after the last dose.	1.3% 1/76 • Number of events 1 • Study Entry until 28 days after the last dose.	10.0% 4/40 • Number of events 4 • Study Entry until 28 days after the last dose.
Hepatobiliary disorders Cholecystitis	0.00% 0/73 • Study Entry until 28 days after the last dose.	0.00% 0/76 • Study Entry until 28 days after the last dose.	2.5% 1/40 • Number of events 1 • Study Entry until 28 days after the last dose.
Hepatobiliary disorders Hepatic failure	1.4% 1/73 • Number of events 1 • Study Entry until 28 days after the last dose.	0.00% 0/76 • Study Entry until 28 days after the last dose.	0.00% 0/40 • Study Entry until 28 days after the last dose.
Immune system disorders Hypersensitivity	0.00% 0/73 • Study Entry until 28 days after the last dose.	1.3% 1/76 • Number of events 1 • Study Entry until 28 days after the last dose.	0.00% 0/40 • Study Entry until 28 days after the last dose.
Infections and infestations Gastroenteritis	1.4% 1/73 • Number of events 1 • Study Entry until 28 days after the last dose.	1.3% 1/76 • Number of events 1 • Study Entry until 28 days after the last dose.	0.00% 0/40 • Study Entry until 28 days after the last dose.
Infections and infestations Cellulitis	0.00% 0/73 • Study Entry until 28 days after the last dose.	0.00% 0/76 • Study Entry until 28 days after the last dose.	2.5% 1/40 • Number of events 1 • Study Entry until 28 days after the last dose.
Injury, poisoning and procedural complications Femoral neck fracture	1.4% 1/73 • Number of events 1 • Study Entry until 28 days after the last dose.	0.00% 0/76 • Study Entry until 28 days after the last dose.	0.00% 0/40 • Study Entry until 28 days after the last dose.
Injury, poisoning and procedural complications Upper limb fracture	0.00% 0/73 • Study Entry until 28 days after the last dose.	0.00% 0/76 • Study Entry until 28 days after the last dose.	2.5% 1/40 • Number of events 1 • Study Entry until 28 days after the last dose.
Investigations Ejection fraction decreased	0.00% 0/73 • Study Entry until 28 days after the last dose.	3.9% 3/76 • Number of events 3 • Study Entry until 28 days after the last dose.	5.0% 2/40 • Number of events 3 • Study Entry until 28 days after the last dose.
Investigations Alanine aminotransferase increased	0.00% 0/73 • Study Entry until 28 days after the last dose.	0.00% 0/76 • Study Entry until 28 days after the last dose.	2.5% 1/40 • Number of events 1 • Study Entry until 28 days after the last dose.
Investigations Aspartate aminotransferase increased	0.00% 0/73 • Study Entry until 28 days after the last dose.	0.00% 0/76 • Study Entry until 28 days after the last dose.	2.5% 1/40 • Number of events 1 • Study Entry until 28 days after the last dose.
Investigations Hepatic enzyme increased	0.00% 0/73 • Study Entry until 28 days after the last dose.	0.00% 0/76 • Study Entry until 28 days after the last dose.	7.5% 3/40 • Number of events 3 • Study Entry until 28 days after the last dose.
Metabolism and nutrition disorders Dehydration	4.1% 3/73 • Number of events 3 • Study Entry until 28 days after the last dose.	0.00% 0/76 • Study Entry until 28 days after the last dose.	2.5% 1/40 • Number of events 1 • Study Entry until 28 days after the last dose.
Metabolism and nutrition disorders Hyponatraemia	0.00% 0/73 • Study Entry until 28 days after the last dose.	1.3% 1/76 • Number of events 1 • Study Entry until 28 days after the last dose.	2.5% 1/40 • Number of events 1 • Study Entry until 28 days after the last dose.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastases to central nervous system	0.00% 0/73 • Study Entry until 28 days after the last dose.	0.00% 0/76 • Study Entry until 28 days after the last dose.	2.5% 1/40 • Number of events 1 • Study Entry until 28 days after the last dose.
Nervous system disorders Somnolence	1.4% 1/73 • Number of events 1 • Study Entry until 28 days after the last dose.	0.00% 0/76 • Study Entry until 28 days after the last dose.	0.00% 0/40 • Study Entry until 28 days after the last dose.
Nervous system disorders Dizziness	0.00% 0/73 • Study Entry until 28 days after the last dose.	0.00% 0/76 • Study Entry until 28 days after the last dose.	2.5% 1/40 • Number of events 1 • Study Entry until 28 days after the last dose.
Respiratory, thoracic and mediastinal disorders Dyspnoea	2.7% 2/73 • Number of events 2 • Study Entry until 28 days after the last dose.	1.3% 1/76 • Number of events 1 • Study Entry until 28 days after the last dose.	0.00% 0/40 • Study Entry until 28 days after the last dose.
Respiratory, thoracic and mediastinal disorders Epistaxis	1.4% 1/73 • Number of events 1 • Study Entry until 28 days after the last dose.	0.00% 0/76 • Study Entry until 28 days after the last dose.	0.00% 0/40 • Study Entry until 28 days after the last dose.
Respiratory, thoracic and mediastinal disorders Pleural effusion	1.4% 1/73 • Number of events 1 • Study Entry until 28 days after the last dose.	2.6% 2/76 • Number of events 2 • Study Entry until 28 days after the last dose.	0.00% 0/40 • Study Entry until 28 days after the last dose.
Respiratory, thoracic and mediastinal disorders Pneumothorax	0.00% 0/73 • Study Entry until 28 days after the last dose.	1.3% 1/76 • Number of events 1 • Study Entry until 28 days after the last dose.	0.00% 0/40 • Study Entry until 28 days after the last dose.
Renal and urinary disorders Hydronephrosis	0.00% 0/73 • Study Entry until 28 days after the last dose.	0.00% 0/76 • Study Entry until 28 days after the last dose.	2.5% 1/40 • Number of events 1 • Study Entry until 28 days after the last dose.
Vascular disorders Hypertension	0.00% 0/73 • Study Entry until 28 days after the last dose.	1.3% 1/76 • Number of events 1 • Study Entry until 28 days after the last dose.	0.00% 0/40 • Study Entry until 28 days after the last dose.
Vascular disorders Embolism	0.00% 0/73 • Study Entry until 28 days after the last dose.	1.3% 1/76 • Number of events 1 • Study Entry until 28 days after the last dose.	0.00% 0/40 • Study Entry until 28 days after the last dose.