CLAP016B2301

Novartis Pharma AG

Novartis Campus, Basel, Switzerland,

Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.com

Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.com

No

No

No

Final

01 Jul 2021

No

Yes

01 Jul 2021

No

The primary objective was to compare disease-free survival (DFS) in patients with Human Epidermal Growth Factor Receptor 2 (HER2) overexpressing and/or amplified breast cancer randomized to trastuzumab for one year (Trastuzumab arm) versus lapatinib for one year (Lapatinib arm; this arm was discontinued prior to the primary analysis due to futility) versus weekly trastuzumab (12 or 18 weeks, according to assigned design) followed by a six-week washout period followed by lapatinib (28 or 34 weeks, according to assigned design; Trastuzumab followed by Lapatinib arm) versus trastuzumab in combination with lapatinib for one year (Lapatinib plus Trastuzumab arm).

The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.

16 May 2007

No

Yes

Argentina: 64

Australia: 181

Austria: 5

Belgium: 231

Brazil: 98

Bulgaria: 26

Canada: 42

Chile: 108

China: 441

Czechia: 116

Denmark: 187

Estonia: 4

France: 410

Germany: 1375

Greece: 56

Hong Kong: 56

Hungary: 134

India: 201

Ireland: 52

Israel: 47

Italy: 371

Japan: 142

Korea, Republic of: 353

Mexico: 31

Netherlands: 87

New Zealand: 41

Norway: 40

Pakistan: 204

Peru: 143

Philippines: 150

Poland: 176

Romania: 105

Russian Federation: 324

Singapore: 25

Slovakia: 53

Slovenia: 20

South Africa: 168

Spain: 267

Switzerland: 56

Taiwan: 374

Thailand: 172

Ukraine: 85

United Kingdom: 243

United States: 917

8381

3715

0

0

0

0

0

0

7526

855

0

Overall Study (overall period)

Randomised - controlled

Yes

Lapatinib plus Trastuzumab

Tablet, Injection

Oral use, Intravenous use

Design 1: Oral lapatinib 1000 mg daily concurrent with trastuzumab 8 mg/kg IV loading dose followed by 6mg/kg IV every 3 weeks (52 weeks total). Design 2: Trastuzumab (4mg/kg loading dose followed by 2mg/kg IV weekly) concurrent with oral lapatinib 750 mg daily and either paclitaxel 80mg/m2 IV weekly for 12 weeks OR docetaxel 75mg/m2 every 21 days for 4 cycles (12 weeks). After completion of chemotherapy, the dose of lapatinib will be increased to 1000mg daily concurrently with trastuzumab every 3 weeks (6mg/kg without loading dose) for an additional 40 weeks (52 weeks total). Design 2B: Docetaxel 75mg/m2 and carboplatin AUC 6 every 3 weeks for 6 cycles (18 weeks) administered concurrently with oral lapatinib 750mg plus weekly trastuzumab (4mg/kg IV loading dose followed by 2mg/kg IV. After the completion of chemotherapy, trastuzumab will be administered every 3 weeks (6mg/kg without loading dose) concurrent with lapatinib 1000mg daily for an additional 40 weeks (52 weeks total).

Trastuzumab followed by Lapatinib

Tablet, Injection

Oral use, Intravenous use

Design 1: Trastuzumab (4mg/kg IV loading dose followed by 2mg/kg IV weekly) for 12 weeks followed by a 6 week treatment-free interval followed by oral lapatinib 1500mg daily for 34 weeks (52 weeks total). Design 2: Trastuzumab (4mg/kg IV loading dose followed by 2mg/kg IV weekly) for 12 weeks administered concomitantly and either paclitaxel 80mg/m2 IV weekly for 12 weeks OR docetaxel 75mg/m2 every 21 days for 4 cycles; followed by a 6 week treatment-free interval followed by oral lapatinib 1500mg daily for 34 weeks (52 weeks total). Design 2B: Docetaxel 75mg/m2 and carboplatin AUC 6 every 3 weeks for 6 cycles (18 weeks) administered concomitantly with trastuzumab (4mg/kg IV loading dose followed by 2mg/kg IV weekly) followed by a 6 week treatment-free interval followed by oral lapatinib 1500 mg daily for 28 weeks (52 weeks total).

Lapatinib

Tablet, Injection

Oral use, Intravenous use

Design 1: Lapatinib 1500mg oral daily for a total of 52 weeks. Design 2: Either paclitaxel 80mg/m2 IV weekly for 12 weeks OR docetaxel 75mg/m2 IV every 3 weeks for 4 cycles administered concomitantly with oral lapatinib at 750mg daily. After completion of chemotherapy, oral lapatinib administered at 1500mg daily for an additional 40 weeks (52 weeks total). Design 2B: Docetaxel 75mg/m2 and carboplatin AUC 6 every 3 weeks for 6 cycles (18 weeks) administered concomitantly with oral lapatinib at 750mg daily. After completion of chemotherapy, the dose of lapatinib will be increased to 1500mg oral daily for an additional 40 weeks (52 weeks total).

Trastuzumab

Injection

Intravenous use

Design 1: Trastuzumab 8mg/kg IV loading dose followed by 6mg/kg IV every 3 weeks for a total of 52 weeks. Design 2: Either paclitaxel 80mg/m2 IV weekly for 12 weeks OR docetaxel 75mg/m2 IV every 3 weeks for 4 cycles administered concomitantly with trastuzumab 4mg/kg IV loading dose followed by 2mg/kg IV weekly. After completion of chemotherapy, trastuzumab administered every 3 weeks (6mg/kg IV without loading dose) for an additional 40 weeks (52 weeks total). Design 2B: Docetaxel 75mg/m2 and carboplatin AUC 6 every 3 weeks for 6 cycles (18 weeks) administered concomitantly with trastuzumab 4mg/kg IV loading dose followed by 2mg/kg IV weekly. After completion of chemotherapy, trastuzumab (6mg/kg without loading dose) every 3 weeks for an additional 40 weeks (52 weeks total).

Lapatinib plus Trastuzumab

Trastuzumab followed by Lapatinib

Lapatinib

Trastuzumab

Lapatinib plus Trastuzumab

Trastuzumab followed by Lapatinib

Lapatinib

Trastuzumab

Disease-Free Survival (DFS) was defined as the interval between randomization and the date of first occurrence of disease recurrence (local, regional or distant), a contralateral invasive breast cancer, a second primary cancer or death without recurrence. Only deaths occurring in participants whose clinical follow-up was ongoing at the time of death and who had no recurrence, contralateral breast cancer (CBC) or second primary malignancy (SPM) reported prior to death were considered as death without recurrence. DFS was estimated using the Kaplan Meier method. The percentile data values presented here indicate the percentage (95, 90, 85, 80 and 75 percent) of participants who had disease free survival for the indicated years.

Primary

From randomization until the date of the first occurrence of disease recurrence, a contralateral invasive breast cancer, a second primary cancer, or death from any cause (median follow-up of 4.5 years)

Stratification was by chemotherapy timing, hormone receptor status, and axillary lymph node status.

Lapatinib plus Trastuzumab v Trastuzumab

4190

Pre-specified

0.84

2-sided

Stratification was by chemotherapy timing, hormone receptor status, and axillary lymph node status.

Trastuzumab followed by Lapatinib v Trastuzumab

4188

Pre-specified

0.96

2-sided

Disease-Free Survival (DFS) was defined as the interval between randomization and the date of first occurrence of disease recurrence (local, regional or distant), a contralateral invasive breast cancer, a second primary cancer or death without recurrence. Only deaths occurring in participants whose clinical follow-up was ongoing at the time of death and who had no recurrence, contralateral breast cancer (CBC) or second primary malignancy (SPM) reported prior to death were considered as death without recurrence. DFS was estimated using the Kaplan Meier method. The percentile data values presented here indicate the percentage (95, 90, 85 and 80 percent) of participants who had disease free survival for the indicated years.

Secondary

From randomization until the date of the first occurrence of disease recurrence, a contralateral invasive breast cancer, a second primary cancer, or death from any cause, assessed up to approximately 10 years

Trastuzumab followed by Lapatinib v Trastuzumab

4188

Pre-specified

0.914

2-sided

Lapatinib plus Trastuzumab v Trastuzumab

4190

Pre-specified

0.887

2-sided

Overall Survival (OS) was defined as the time from randomization until death due to any cause. Participants who had not died were censored at the last date they were known to be alive, or date of withdrawal of consent. OS was calculated in years as (date of death minus the date of randomization +1) divided by 365.25. The percentile data values presented here indicate the percentage (99, 98, 97, 96, 95 and 90 percent) of participants who survived for the indicated years.

Secondary

From randomization until death due to any cause (median follow-up of 4.5 years)

Stratification was by chemotherapy timing, hormone receptor status, and axillary lymph node status.

Lapatinib plus Trastuzumab v Trastuzumab

4190

Pre-specified

0.8

2-sided

Stratification was by chemotherapy timing, hormone receptor status, and axillary lymph node status.

Trastuzumab followed by Lapatinib v Trastuzumab

4188

Pre-specified

0.91

2-sided

Overall Survival (OS) was defined as the time from randomization until death due to any cause. Participants who had not died were censored at the last date they were known to be alive, or date of withdrawal of consent. OS was calculated in years as (date of death minus the date of randomization +1) divided by 365.25. The percentile data values presented here indicate the percentage (99, 98, 95 and 90 percent) of participants who survived for the indicated years.

Secondary

From randomization until death due to any cause, assessed up to approximately 10 years

Lapatinib plus Trastuzumab v Trastuzumab

4190

Pre-specified

0.853

2-sided

Trastuzumab followed by Lapatinib v Trastuzumab

4188

Pre-specified

0.863

2-sided

Time to Recurrence (TTR) was defined as the the time from randomization to breast cancer recurrence, ignoring second primary cancers (including contralateral breast cancers and non-breast second malignancies) and counting deaths without recurrence as a competing risk.

Secondary

From randomization until the date of the first occurrence of a disease recurrence, assessed up to approximately 10 years

Lapatinib plus Trastuzumab v Trastuzumab

4190

Pre-specified

0.811

2-sided

Trastuzumab followed by Lapatinib v Trastuzumab

4188

Pre-specified

0.93

2-sided

Time to Distant Recurrence (TTDR) was defined as the the time from randomization to first distant breast cancer recurrence, ignoring locoregional recurrences and second primary cancers, (including contralateral breast cancers and non-breast second malignancies ) and counting deaths without recurrence as a competing risk.

Secondary

From randomization until the date of the first occurrence of distant recurrence, assessed up to approximately 10 years

Lapatinib plus Trastuzumab v Trastuzumab

4190

Pre-specified

0.852

2-sided

Trastuzumab followed by Lapatinib v Trastuzumab

4188

Pre-specified

0.968

2-sided

Time to Central Nervous System (CNS) recurrence was defined as the time from randomization to first CNS recurrence. Both brain metastasis and meningitis carcinomatosa were considered.

Secondary

From randomization until the first central nervous system recurrence, assessed up to approximately 10 years

Lapatinib plus Trastuzumab v Trastuzumab

4190

Pre-specified

0.986

2-sided

Trastuzumab followed by Lapatinib v Trastuzumab

4188

Pre-specified

0.98

2-sided

The cumulative incidence of brain metastases as the first site of breast cancer recurrence among treatment arms was assessed using a hierarchy of primary type and location of first DFS event in cases where more than one event was identified simultaneously. Because diagnostic procedures for different types of recurrence could not be performed on exactly the same day, any diagnoses noted within a two month (60 day) period of the first reported event was considered as identified simultaneously for purposes of defining the type of the first event and the date of event was be regarded as the earliest of the relevant events.

Secondary

From randomization until the date of the first occurrence of a disease recurrence, assessed up to approximately 10 years

On-treatment deaths were collected from the start of treatment up to 30 days after study drug discontinuation, for a maximum duration of 56 weeks. Post-treatment deaths were collected after the on-treatment period (starting at day 31 after last dose of study treatment), up to 10 years.

Post-hoc

Up to 56 weeks (on-treatment deaths), up to 10 years (all deaths)

Adverse events were collected from First Patient First Treatment (FPFT) up to 30 days after study drug discontinuation, for a maximum duration of 56 weeks.

Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.

24.1

Lapatinib plus Trastuzumab

Lapatinib

Trastuzumab

Trastuzumab followed by Lapatinib