Trial Outcomes & Findings for Letrozole In Combination With Lapatinib In Neoadjuvant Treatment Of Early Breast Cancer (NCT NCT00422903)

NCT ID: NCT00422903

Last Updated: 2016-05-12

Results Overview

cOR is defined as the documented evidence of complete response (CR) and partial response (PR) as assessed by ultrasound examination using Response Evaluation Criteria In Solid Tumors (RECIST). CR is defined as the disappearance of all target lesions (TLs) and non-TLs and the appearance of no new lesions (NLs). PR for TLs is defined as a \>=30% decrease in the sum of the longest diameter (LD) of TLs, taking as a reference the Baseline sum LD. For non-TLs, it is defined as the persistence of \>=1 non-TL and no new TLs or non-TLs.

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 92 participants
• Primary outcome timeframe: From Baseline (Day 1) up to 6 months, evaluated every 12 weeks
• Results posted on: 2016-05-12

Participant Flow

Participant milestones

Measure	Letrozole + Placebo Letrozole tablets in the dose of 2.5 milligrams (mg) plus matching placebo were administered orally once daily for 6 months prior to surgery.	Letrozole + Lapatinib Letrozole tablets in the dose of 2.5 mg plus lapatinib ditosylate monohydrate tablets in the dose of 1500 mg were administered orally once daily for 6 months prior to surgery.
Overall Study STARTED	49	43
Overall Study COMPLETED	45	38
Overall Study NOT COMPLETED	4	5

Reasons for withdrawal

Measure	Letrozole + Placebo Letrozole tablets in the dose of 2.5 milligrams (mg) plus matching placebo were administered orally once daily for 6 months prior to surgery.	Letrozole + Lapatinib Letrozole tablets in the dose of 2.5 mg plus lapatinib ditosylate monohydrate tablets in the dose of 1500 mg were administered orally once daily for 6 months prior to surgery.
Overall Study Disease Progression	3	1
Overall Study Adverse Event	0	2
Overall Study Informed Consent Withdrawn	1	2

Baseline Characteristics

Letrozole In Combination With Lapatinib In Neoadjuvant Treatment Of Early Breast Cancer

Baseline characteristics by cohort

Measure	Letrozole + Placebo n=49 Participants Letrozole tablets in the dose of 2.5 milligrams (mg) plus matching placebo were administered orally once daily for 6 months prior to surgery.	Letrozole + Lapatinib n=43 Participants Letrozole tablets in the dose of 2.5 mg plus lapatinib ditosylate monohydrate tablets in the dose of 1500 mg were administered orally once daily for 6 months prior to surgery	Total n=92 Participants Total of all reporting groups
Age, Continuous	70 Years n=5 Participants	70 Years n=7 Participants	70 Years n=5 Participants
Sex: Female, Male Female	49 Participants n=5 Participants	43 Participants n=7 Participants	92 Participants n=5 Participants
Sex: Female, Male Male	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants

PRIMARY outcome

Timeframe: From Baseline (Day 1) up to 6 months, evaluated every 12 weeks

Population: Intent-to-Treat (ITT) Population: all participants who entered the study and received at least one dose of letrozole. Three participants withdrew consent and were not included in the efficacy analysis.

cOR is defined as the documented evidence of complete response (CR) and partial response (PR) as assessed by ultrasound examination using Response Evaluation Criteria In Solid Tumors (RECIST). CR is defined as the disappearance of all target lesions (TLs) and non-TLs and the appearance of no new lesions (NLs). PR for TLs is defined as a >=30% decrease in the sum of the longest diameter (LD) of TLs, taking as a reference the Baseline sum LD. For non-TLs, it is defined as the persistence of >=1 non-TL and no new TLs or non-TLs.

Outcome measures

Measure	Letrozole + Placebo n=48 Participants Letrozole tablets in the dose of 2.5 milligrams (mg) plus matching placebo were administered orally once daily for 6 months prior to surgery.	Letrozole + Lapatinib n=41 Participants Letrozole tablets in the dose of 2.5 mg plus lapatinib ditosylate monohydrate tablets in the dose of 1500 mg were administered orally once daily for 6 months prior to surgery.
Percentage of Participants With Clinical Objective Response (cOR) in the Breast, Evaluated by an Independent Radiological Evaluation Monitoring Committee CR	2 percentage of participants	12 percentage of participants
Percentage of Participants With Clinical Objective Response (cOR) in the Breast, Evaluated by an Independent Radiological Evaluation Monitoring Committee PR	58 percentage of participants	54 percentage of participants

PRIMARY outcome

Timeframe: From Baseline (Day 1) up to 6 months, evaluated every 12 weeks

Population: ITT Population. Three participants withdrew consent and were not included in the efficacy analysis.

Complete clinical response=nodule not detectable; all ultrasound abnormalities detected at diagnosis have disappeared. Partial clinical response=the tumor's longest diameter (LD) is reduced by 50% or more; ultrasound characteristics of the tumor persist. Minimal response=the tumor's LD is reduced by 25%-49%. Stable disease=the tumor's LD is decreased by less than 25% and is increased by no more than 25% from the starting value. Progressive disease=the tumor's LD is increased by more than 25% from the starting value. Participants who were not evaluable did not have data available.

Outcome measures

Measure	Letrozole + Placebo n=48 Participants Letrozole tablets in the dose of 2.5 milligrams (mg) plus matching placebo were administered orally once daily for 6 months prior to surgery.	Letrozole + Lapatinib n=41 Participants Letrozole tablets in the dose of 2.5 mg plus lapatinib ditosylate monohydrate tablets in the dose of 1500 mg were administered orally once daily for 6 months prior to surgery.
Percentage of Participants With Various Responses in the Breast, Evaluated Using Per Protocol Criteria Not Evaluable	2 percentage of participants	7 percentage of participants
Percentage of Participants With Various Responses in the Breast, Evaluated Using Per Protocol Criteria Complete Response	2 percentage of participants	12 percentage of participants
Percentage of Participants With Various Responses in the Breast, Evaluated Using Per Protocol Criteria Partial Response	27 percentage of participants	34 percentage of participants
Percentage of Participants With Various Responses in the Breast, Evaluated Using Per Protocol Criteria Minimal Response	40 percentage of participants	24 percentage of participants
Percentage of Participants With Various Responses in the Breast, Evaluated Using Per Protocol Criteria Stable Disease	33 percentage of participants	20 percentage of participants
Percentage of Participants With Various Responses in the Breast, Evaluated Using Per Protocol Criteria Progressive Disease	6 percentage of participants	2 percentage of participants

SECONDARY outcome

Timeframe: At the point of definitive surgery (up to 6 months after Baseline)

Population: ITT Population

pCR is defined as the complete absence of infiltrating tumor cells (TCs) in the breast and lymph nodes. Miller and Payne criteria: Grade 1, no change/some alteration to individual malignant cells, but no reduction in overall cellularity; Grade 2, up to a 30% loss in TCs; Grade 3, between an estimated 30% and 90% reduction in TCs; Grade 4, more than a 90% reduction in TCs, only small cluster/dispersed cells remaining; Grade 5, no malignant identifiable cells; carcinoma in the milk ducts may be present. Grades 1 and 2 = No response; Grades 3 and 4= PR; Grade 5 = CR.

Outcome measures

Measure	Letrozole + Placebo n=49 Participants Letrozole tablets in the dose of 2.5 milligrams (mg) plus matching placebo were administered orally once daily for 6 months prior to surgery.	Letrozole + Lapatinib n=43 Participants Letrozole tablets in the dose of 2.5 mg plus lapatinib ditosylate monohydrate tablets in the dose of 1500 mg were administered orally once daily for 6 months prior to surgery.
Percentage of Participants With Pathological Complete Response (pCR) in the Breast and Axillary Nodes, Evaluated Using Miller and Payne Criteria	0 Percentage of participants Interval 0.0 to 7.3	0 Percentage of participants Interval 0.0 to 8.2

SECONDARY outcome

Timeframe: At the point of definitive surgery (up to 6 months after Baseline)

Population: ITT Population. Only those participants contributing data were analyzed.

Tumors were categorized as follows: T0, no evidence of primary tumor, but carcinoma of the milk ducts, accumulation of abnormal cells in the breast lobules, or Paget disease (cancer condition that appears like a skin disease involving the breast nipple) with no associated tumor mass; T1, tumor was <=2 centimeters (cm) across; T2, tumor was >2 cm but <5 cm across; T3, tumor was >5 cm across; T4, tumor of any size growing into the chest wall or skin, including inflammatory breast cancer.

Outcome measures

Measure	Letrozole + Placebo n=47 Participants Letrozole tablets in the dose of 2.5 milligrams (mg) plus matching placebo were administered orally once daily for 6 months prior to surgery.	Letrozole + Lapatinib n=42 Participants Letrozole tablets in the dose of 2.5 mg plus lapatinib ditosylate monohydrate tablets in the dose of 1500 mg were administered orally once daily for 6 months prior to surgery.
Number of Participants With Breast Tumors Per Pathological Stage at Surgery T0	1 participants	0 participants
Number of Participants With Breast Tumors Per Pathological Stage at Surgery T1	20 participants	26 participants
Number of Participants With Breast Tumors Per Pathological Stage at Surgery T2	24 participants	12 participants
Number of Participants With Breast Tumors Per Pathological Stage at Surgery T3	2 participants	2 participants
Number of Participants With Breast Tumors Per Pathological Stage at Surgery T4	0 participants	2 participants

SECONDARY outcome

Timeframe: At the point of definitive surgery (up to 6 months after Baseline)

Population: ITT Population. Only those participants contributing data were analyzed.

The nodal status of cancer indicates the involvement of lymph nodes in the participant with cancer. N0 indicates no involvement of lymph nodes, and N+ indicates involvement of lymph nodes.

Outcome measures

Measure	Letrozole + Placebo n=47 Participants Letrozole tablets in the dose of 2.5 milligrams (mg) plus matching placebo were administered orally once daily for 6 months prior to surgery.	Letrozole + Lapatinib n=42 Participants Letrozole tablets in the dose of 2.5 mg plus lapatinib ditosylate monohydrate tablets in the dose of 1500 mg were administered orally once daily for 6 months prior to surgery.
Number of Participants With the Indicated Nodal Status at Surgery N0	19 participants	21 participants
Number of Participants With the Indicated Nodal Status at Surgery N+	28 participants	21 participants

SECONDARY outcome

Timeframe: At the point of definitive surgery (up to 6 months after Baseline 1)

Population: ITT Population. Only those participants contributing data were analyzed.

Mastectomy is the medical term for the surgical removal of one or both breasts. Breast-conserving surgery (BCS) involves removing only the affected part of the breast tissue during surgery, as opposed to removal of the entire breast.

Outcome measures

Measure	Letrozole + Placebo n=49 Participants Letrozole tablets in the dose of 2.5 milligrams (mg) plus matching placebo were administered orally once daily for 6 months prior to surgery.	Letrozole + Lapatinib n=43 Participants Letrozole tablets in the dose of 2.5 mg plus lapatinib ditosylate monohydrate tablets in the dose of 1500 mg were administered orally once daily for 6 months prior to surgery.
Number of Participants With the Indicated Type of Surgery Mastectomy	13 participants	15 participants
Number of Participants With the Indicated Type of Surgery BCS	34 participants	27 participants
Number of Participants With the Indicated Type of Surgery Not done	2 participants	1 participants

SECONDARY outcome

Timeframe: At the point of definitive surgery (up to 6 months after Baseline)

Population: ITT Population. Only those participants contributing data were analyzed.

The percentage of participants who were planned to undergo a mastectomy at baseline but later underwent BCS was measured.

Outcome measures

Measure	Letrozole + Placebo n=49 Participants Letrozole tablets in the dose of 2.5 milligrams (mg) plus matching placebo were administered orally once daily for 6 months prior to surgery.	Letrozole + Lapatinib n=43 Participants Letrozole tablets in the dose of 2.5 mg plus lapatinib ditosylate monohydrate tablets in the dose of 1500 mg were administered orally once daily for 6 months prior to surgery.
Percentage of Participants With Conversion From Planned Mastectomy at Baseline to BCS at Surgery	56 percentage of participants	46 percentage of participants

SECONDARY outcome

Timeframe: From Baseline (Day 1) up to 6 months (until definitive surgery)

Population: ITT Population. Only those participants contributing data were analyzed.

Toxicity was measured in grades (severity of the AE) as per National Cancer Institute Common Toxicity Criteria for Adverse Event (NCI CTCAE) version (v) 3.0. The CTCAE v3.0 displays Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1, mild; Grade 2, moderate; Grade 3, severe; Grade 4, life-threatening/disabling; Grade 5, death related to the AE. Mucositis is the painful inflammation and ulceration of the mucous membranes lining the digestive tract, and hypertension is high blood pressure.

Outcome measures

Measure	Letrozole + Placebo n=49 Participants Letrozole tablets in the dose of 2.5 milligrams (mg) plus matching placebo were administered orally once daily for 6 months prior to surgery.	Letrozole + Lapatinib n=43 Participants Letrozole tablets in the dose of 2.5 mg plus lapatinib ditosylate monohydrate tablets in the dose of 1500 mg were administered orally once daily for 6 months prior to surgery.
Number of Participants With the Indicated Adverse Events With a Classification of >=Grade 2 Musculoskeletal pain	4 participants	2 participants
Number of Participants With the Indicated Adverse Events With a Classification of >=Grade 2 Diarrhea	2 participants	10 participants
Number of Participants With the Indicated Adverse Events With a Classification of >=Grade 2 Mucositis	0 participants	8 participants
Number of Participants With the Indicated Adverse Events With a Classification of >=Grade 2 Liver toxicity	1 participants	4 participants
Number of Participants With the Indicated Adverse Events With a Classification of >=Grade 2 Skin disorders	1 participants	18 participants
Number of Participants With the Indicated Adverse Events With a Classification of >=Grade 2 Hypertension	1 participants	2 participants

SECONDARY outcome

Timeframe: Baseline (Day 1), after 12 weeks, and after 24 weeks

Population: ITT Population. Only those participants contributing data were analyzed.

Cardiac safety was evaluated as any signs or symptoms of deterioration in LVEF. LVEF is the measurement of how much blood is being pumped out of the left ventricle of the heart (the main pumping chamber) with each contraction. LVEF was evaluated using NCI CTCAE.

Outcome measures

Measure	Letrozole + Placebo n=49 Participants Letrozole tablets in the dose of 2.5 milligrams (mg) plus matching placebo were administered orally once daily for 6 months prior to surgery.	Letrozole + Lapatinib n=43 Participants Letrozole tablets in the dose of 2.5 mg plus lapatinib ditosylate monohydrate tablets in the dose of 1500 mg were administered orally once daily for 6 months prior to surgery.
Mean Left Ventricular Ejection Fraction (LVEF) Baseline	61 Percent volume Interval 50.0 to 78.0	61 Percent volume Interval 54.0 to 76.0
Mean Left Ventricular Ejection Fraction (LVEF) After 12 weeks	62 Percent volume Interval 50.0 to 76.0	60 Percent volume Interval 52.0 to 75.0
Mean Left Ventricular Ejection Fraction (LVEF) After 24 weeks	61 Percent volume Interval 50.0 to 84.0	59 Percent volume Interval 50.0 to 75.0

SECONDARY outcome

Timeframe: From Baseline (Day 1) up to study withdrawal (approx. 66 months)

Population: ITT Population. Only those participants contributing data were analyzed.

Time to treatment failure is calculated as the interval between the date of randomization and the occurrence of local tumor progression (including ipsilateral [on the same side] and controlateral breast tumor progression), distant tumor progression, permanent treatment discontinuation (either for the experimental or conventional treatment arm), or death for any cause.

Outcome measures

Measure	Letrozole + Placebo n=13 Participants Letrozole tablets in the dose of 2.5 milligrams (mg) plus matching placebo were administered orally once daily for 6 months prior to surgery.	Letrozole + Lapatinib n=6 Participants Letrozole tablets in the dose of 2.5 mg plus lapatinib ditosylate monohydrate tablets in the dose of 1500 mg were administered orally once daily for 6 months prior to surgery.
Time to Treatment Failure From the Start of the Primary Therapy	32.2 Months Interval 6.3 to 38.5	22.2 Months The confidence limits for the median value are not estimable because there are no time points that satisfy the condition using the method of Klein and Moeschberger (1997).

Adverse Events

Letrozole + Placebo

Serious events: 1 serious events

Other events: 20 other events

Deaths: 0 deaths

Letrozole + Lapatinib

Serious events: 3 serious events

Other events: 36 other events

Deaths: 0 deaths

Serious adverse events

Measure	Letrozole + Placebo n=49 participants at risk Letrozole tablets in the dose of 2.5 milligrams (mg) plus matching placebo were administered orally once daily for 6 months prior to surgery.	Letrozole + Lapatinib n=43 participants at risk Letrozole tablets in the dose of 2.5 mg plus lapatinib ditosylate monohydrate tablets in the dose of 1500 mg were administered orally once daily for 6 months prior to surgery.
Cardiac disorders Myocardial infarction	2.0% 1/49	0.00% 0/43
Cardiac disorders Cardiac failure	0.00% 0/49	2.3% 1/43
Hepatobiliary disorders Sphincter of Oddi dysfunction	0.00% 0/49	2.3% 1/43
Injury, poisoning and procedural complications Overdose	0.00% 0/49	2.3% 1/43
Nervous system disorders Spinal cord compression	0.00% 0/49	2.3% 1/43

Other adverse events

Measure	Letrozole + Placebo n=49 participants at risk Letrozole tablets in the dose of 2.5 milligrams (mg) plus matching placebo were administered orally once daily for 6 months prior to surgery.	Letrozole + Lapatinib n=43 participants at risk Letrozole tablets in the dose of 2.5 mg plus lapatinib ditosylate monohydrate tablets in the dose of 1500 mg were administered orally once daily for 6 months prior to surgery.
General disorders Astenia/Fatigue	12.2% 6/49	16.3% 7/43
Skin and subcutaneous tissue disorders Dermatology/Skin	0.00% 0/49	58.1% 25/43
Gastrointestinal disorders Diarrhea	10.2% 5/49	60.5% 26/43
Gastrointestinal disorders Dyspepsia	10.2% 5/49	11.6% 5/43
Investigations LFT transaminases	0.00% 0/49	18.6% 8/43
Injury, poisoning and procedural complications Mucositis	0.00% 0/49	16.3% 7/43
Musculoskeletal and connective tissue disorders Musculoskeletal pain	18.4% 9/49	14.0% 6/43
Skin and subcutaneous tissue disorders Nail changes	0.00% 0/49	11.6% 5/43
Gastrointestinal disorders Nausea	12.2% 6/49	0.00% 0/43

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