Breast Cancer
Conditions
Brief summary
This 4 arm study will evaluate the efficacy and safety of 4 neoadjuvant treatment regimens in female patients with locally advanced, inflammatory or early stage HER2 positive breast cancer. Before surgery, patients will be randomized to one of 4 treatment arms, to receive 4 cycles of a)Herceptin + docetaxel b)Herceptin + docetaxel + pertuzumab c)Herceptin + pertuzumab or 4)pertuzumab + docetaxel. Pertuzumab will be administered at a loading dose of 840mg iv, then 420mg iv 3-weekly, Herceptin at a loading dose of 8mg/kg iv then 6mg/kg 3-weekly, and docetaxel at a dose of 75mg/m2 escalating to 100mg/m2 3-weekly. During the entire pre- and post-surgery period all patients will receive adequate chemotherapy as per standard of care, as well as any surgery and/or radiotherapy as required. The anticipated time on study treatment is 3-12 months, and the target sample size is 100-500 individuals.
Interventions
DRUGHerceptin
8mg/kg iv loading dose, followed by 6mg/kg iv 3-weekly
DRUGDocetaxel
75mg/m2 iv escalating to 100mg/m2 iv 3-weekly
DRUGPertuzumab
840mg iv loading dose, followed by 420mg iv 3-weekly
Sponsors
Hoffmann-La Roche
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* female patients, \>=18 years of age; * locally advanced, inflammatory or early stage invasive breast cancer; * HER2 positive (HER2+++ by IHC or FISH/CISH+).
Exclusion criteria
* metastatic disease (Stage IV) or bilateral breast cancer; * previous anticancer therapy or radiotherapy for any malignancy; * other malignancy, other than cancer in situ of the cervix, or basal cell cancer; * insulin-dependent diabetes; * clinically relevant cardiovascular disease.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Achieving Pathological Complete Response (pCR) | Approximately 4 months from randomization following surgery or early withdrawal, whichever occurred first (Surgery was performed within 2 weeks after Cycle 4) | pCR was defined as an absence of invasive neoplastic cells at microscopic examination of the tumor remnants after surgery following primary systemic therapy. Participants with invalid/missing pCR assessments were defined as non-responders |
| Percentage of Participants Achieving pCR by Breast Cancer Type | Approximately 4 months from randomization following surgery or early withdrawal, whichever occurred first (Surgery was performed within 2 weeks after Cycle 4) | pCR was defined as an absence of invasive neoplastic cells at microscopic examination of the tumor remnants after surgery following primary systemic therapy. Based on the type of breast cancer participants were categorized as those with 1. Operable breast cancer, 2. Inflammatory breast cancer and 3. Locally advanced breast cancer. Participants with invalid/missing pCR assessments were defined as non-responders. |
| Percentage of Participants Achieving pCR by Hormone Receptor Status | Approximately 4 months from randomization following surgery or early withdrawal, whichever occurred first (Surgery was performed within 2 weeks after Cycle 4) | pCR was defined as an absence of invasive neoplastic cells at microscopic examination of the tumor remnants after surgery following primary systemic therapy. Participants were classified as Estrogen and/or Progesterone positive (+ve), Estrogen and/or Progesterone negative (-ve) or receptor status unknown. Participants with invalid/missing pCR assessments were defined as non-responders. |
| Percentage of Participants Achieving pCR by Lymph Node Status | Approximately 4 months from randomization following surgery or early withdrawal, whichever occurred first (Surgery was performed within 2 weeks after Cycle 4) | pCR was defined as an absence of invasive neoplastic cells at microscopic examination of the tumor remnants after surgery following primary systemic therapy. Lymph node status was defined as either negative lymph node at surgery or positive lymph node at surgery. Participants with invalid/missing pCR assessments were defined as non-responders. |
| Percentage of Participants Achieving pCR by Presence or Absence of Residual Intraductal Carcinoma (DCIS) / Intalobular Carcinoma (LCIS) | Approximately 4 months from randomization following surgery or early withdrawal, whichever occurred first (Surgery was performed within 2 weeks after Cycle 4) | pCR was defined as an absence of invasive neoplastic cells at microscopic examination of the tumor remnants after surgery following primary systemic therapy. Participants with invalid/missing pCR assessments were defined as non-responders. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Achieving Clinical Response During Neo-Adjuvant Period by Clinical Examination | Baseline up to Cycle 4 (assessed at Baseline, Day 1 of Cycles 1-4 Pre-Surgery) Up to approximately 24 months | Tumor assessments were made based on the RECIST criteria - version 1.0 The clinical response at each cycle up to the last assessment prior to surgery was derived for: i) the primary breast lesion; (ii) across secondary breast lesions, (iii) across all breast lesions (iv) across axillary nodes (v) across supraclavicular nodes and (vi) across all nodes (vii) across all lesions (overall) using the following algorithm: CR: if measurement of '0' is noted at a given cycle as compared to baseline measurement which is \>0 at screening or cycle 1 day 1; PR: if measurement is at least a 30% decreased compared to baseline levels . (Reference= baseline size or sum of sizes). Clinical Responders are participants who have achieved CR or PR during the Neo-adjuvant treatment. Primary breast tumor clinical response is based on primary breast tumor assessment. Overall response is derived based on the sum total of breast tumors and all nodes examined. |
| Time to Clinical Response During Neo-Adjuvant Treatment Period | Baseline up to Cycle 4 (assessed at Baseline, Day 1 of Cycles 1-4 Pre-Surgery) Up to approximately 24 months | Time to clinical response was defined as the time from the date of first dose received to the date of assessment of clinical response. Time to Clinical response was determined by Kaplan-Meier estimates. Tumor assessments were made based on the RECIST criteria - version 1.0. The clinical response at each cycle up to the last assessment prior to surgery was derived for: i) the primary breast lesion; (ii) across secondary breast lesions, (iii) across all breast lesions (iv) across axillary nodes (v) across supraclavicular nodes and (vi) across all nodes (vii) across all lesions (overall) using the following algorithm: CR: if measurement of '0' is noted at a given cycle as compared to baseline measurement which is \>0 at screening or cycle 1 day 1; PR: if measurement is at least a 30% decreased compared to baseline levels . (Reference= baseline size or sum of sizes). Clinical Responders are participants who have achieved CR or PR during the Neo-adjuvant treatment. |
| Percentage of Participants With Progressive Disease During Neo-Adjuvant Treatment Period | Baseline up to Cycle 4 (assessed at Baseline, Day 1 of Cycles 1-4 Pre-Surgery) Up to approximately 24 months | Tumor assessments were made based upon the Response Evaluation Criteria in Solid Tumors (RECIST) criteria - version 1.0. The clinical response at each cycle up to the last assessment prior to surgery was derived for: i) the primary breast lesion; (ii) across secondary breast lesions, (iii) across all breast lesions (iv) across axillary nodes (v) across supraclavicular nodes and (vi) across all nodes (vii) across all lesions (overall) using the following algorithm: PD: if lesion is at least a 20 % increased from measurements at baseline. Percentage of participants along with 95% Confidence Interval (CI) for one sample binomial using Pearson-Clopper method were reported. Missing investigator assessments were considered as no progressive disease. |
| Percentage of Participants Achieving Best Primary Tumor Response (Complete Response [CR], Partial Response [PR], Stable Disease [SD] or Disease Progression [PD]) During Neo-Adjuvant Treatment by X-Ray/Mammography | Baseline up to Cycle 4 (assessed at, Baseline and Day 1 of Cycles 1-4 Pre-Surgery) Up to approximately 24 months | Tumor assessments were made based upon the Response Evaluation Criteria in Solid Tumors (RECIST) criteria - version 1.0. The clinical response at each cycle up to the last assessment prior to surgery was derived for primary breast tumor using the following algorithm: CR: if measurement of '0' is noted at a given cycle as compared to baseline measurement which is greater than (\>)0 at screening or cycle 1 Day 1; PR: if measurement is at least a 30 percent (%) decreased compared to baseline levels . (Reference= baseline size or sum of sizes); SD: if measurement at a given cycle is not sufficient shrinkage to qualify for neither PR nor sufficient increase to qualify for PD compared to baseline levels. PD: if lesion is at least a 20 % increase from measurements at baseline. |
| Percentage of Participants Who Were Progression Free and Disease Free | Randomization up to a maximum of 329 weeks | Disease-free survival (DFS) was defined as the time from first date of no disease to first documentation of PD or death. Participants without progression after surgery were considered Disease Free. Any evidence of contralateral disease in-situ was not considered as PD. Participants who were withdrawn from the study without documented progression and for whom evaluations were made, were censored at date of last assessment when participant was known to be disease-free. Progression-free survival (PFS) was defined as time from date of randomization to first documentation of PD or death. Any evidence of contralateral disease in-situ was not considered as PD. Participants who were withdrawn from study without documented progression and for whom evaluations were made, were censored at date of last assessment when the participant was known to be free from progressive disease. Participants without post baseline assessments but known to be alive were censored at the time of randomization. |
| Progression Free and Disease Free Survival | Randomization up to a maximum of 329 weeks | DFS was defined as the time from the first date of no disease (date of surgery) to the first documentation of PD or death. Participants without progression after surgery were considered Disease Free. Any evidence of contralateral disease in-situ was not considered as PD. PFS was defined as the time from the date of randomization to the first documentation of PD or death. Any evidence of contralateral disease in-situ was not considered as PD. DFS and PFS were determined using Kaplan-Meier estimates. |
| Percentage of Participants Achieving Breast Conserving Surgery For Whom Mastectomy Was Planned | Surgery (Within 2 weeks after Cycle 4) Up to approximately 24 months | Breast Conserving Surgery (BCS) was defined as quadrantectomy, lumpectomy, no surgery, sentinel node biopsy, axillary surgical resection or other method of avoiding mastectomy. |
| Percentage of Participants Achieving Best Overall Response (CR, PR, SD or PD) During Neo-Adjuvant Period by X-Ray/Mammography | Baseline up to Cycle 4 (assessed at Baseline, Day 1 of Cycles 1-4 Pre-Surgery) Up to approximately 24 months | Tumor assessments were made based on the RECIST criteria - version 1.0 The overall response at each cycle up to the last assessment prior to surgery was derived for: i) the primary breast lesion; (ii) across secondary breast lesions, (iii) across all breast lesions (iv) across axillary nodes (v) across supraclavicular nodes and (vi) across all nodes (vii) across all lesions (overall) using the following algorithm: CR: if measurement of '0' is noted at a given cycle as compared to baseline measurement which is \>0 at screening or cycle 1 day 1; PR: if measurement is at least a 30% decreased compared to baseline levels . (Reference= baseline size or sum of sizes); SD: if measurement at a given cycle is not sufficient shrinkage to qualify for neither PR nor sufficient increase to qualify for PD compared to baseline levels. PD: if lesion is at least a 20 % increase from measurements at baseline. Overall response is derived based on the sum total of breast tumors and all nodes examined. |
| Percentage of Participants Achieving Best Primary Breast Tumor Response (CR, PR, SD or PD) During Neo-Adjuvant Period by Clinical Examination | Baseline up to Cycle 4 (assessed at Baseline, Day 1 of Cycles 1-4 Pre-Surgery) Up to approximately 24 months | Tumor assessments were made based on the RECIST criteria - version 1.0 The clinical response at each cycle up to the last assessment prior to surgery was derived for primary breast tumor using the following algorithm: CR: if measurement of '0' is noted at a given cycle as compared to baseline measurement which is \>0 at screening or cycle 1 day 1; PR: if measurement is at least a 30% decreased compared to baseline levels . (Reference= baseline size or sum of sizes); SD: if measurement at a given cycle is not sufficient shrinkage to qualify for neither PR nor sufficient increase to qualify for PD compared to baseline levels. PD: if lesion is at least a 20 % increase from measurements at baseline. Overall response is derived based on the sum total of breast tumors and all nodes examined. |
| Percentage of Participants Achieving Best Overall Response (CR, PR, SD or PD) During the Neo-Adjuvant Period by Clinical Examination | Baseline up to Cycle 4 (assessed at Baseline, Day 1 of Cycles 1-4 Pre-Surgery) Up to approximately 24 months | Tumor assessments were made based on the RECIST criteria - version 1.0 The clinical response at each cycle up to the last assessment prior to surgery was derived for: i) the primary breast lesion; (ii) across secondary breast lesions, (iii) across all breast lesions (iv) across axillary nodes (v) across supraclavicular nodes and (vi) across all nodes (vii) across all lesions (overall) using the following algorithm: CR: if measurement of '0' is noted at a given cycle as compared to baseline measurement which is \>0 at screening or cycle 1 day 1; PR: if measurement is at least a 30% decreased compared to baseline levels . (Reference= baseline size or sum of sizes); SD: if measurement at a given cycle is not sufficient shrinkage to qualify for neither PR nor sufficient increase to qualify for PD compared to baseline levels. PD: if lesion is at least a 20 % increase from measurements at baseline. Overall response is derived based on the sum total of breast tumors and all nodes examined. |
| Percentage of Participants Achieving Clinical Response During Neo-Adjuvant Period by X-Ray/Mammography | Baseline up to Cycle 4 (assessed at Baseline, Day 1 of Cycles 1-4 Pre-Surgery) Up to approximately 24 months | Clinical response was determined based on tumor measurements by sponsor in combination with tumor response assessment by investigator. Tumor assessments were made based on the RECIST criteria - version 1.0 The clinical response at each cycle up to the last assessment prior to surgery was derived for: i) the primary breast lesion; (ii) across secondary breast lesions, (iii) across all breast lesions (iv) across axillary nodes (v) across supraclavicular nodes and (vi) across all nodes (vii) across all lesions (overall) using the following algorithm: CR: if measurement of '0' is noted at a given cycle as compared to baseline measurement which is \>0 at screening or cycle 1 day 1; PR: if measurement is at least a 30% decreased compared to baseline levels . (Reference= baseline size or sum of sizes). Clinical Responders are participants who have achieved CR or PR during the Neo-adjuvant treatment. Overall response is derived based on the sum total of breast tumors and all nodes examined. |
Countries
Australia, Austria, Brazil, Canada, Israel, Italy, Mexico, Peru, Poland, Russia, South Korea, Spain, Sweden, Switzerland, Taiwan, Thailand, Turkey (Türkiye), United Kingdom
Participant flow
Recruitment details
A total of 107, 107, 107, and 96 participants (total 417) were randomized to Arms Trastuzumab plus (+) Docetaxel (T+ D) , Trastuzumab+Pertuzumab+Docetaxel (T+Ptz+D), Trastuzumab+Pertuzumab (T+Ptz), and Pertuzumab+Docetaxel (Ptz+D), respectively and were included in intent-to-treat population (as randomized).
Pre-assignment details
3 participants did not receive correct treatment, as randomized, and 1 (in Arm Trastuzumab + Docetaxel) did not receive any treatment. Safety population (as treated) included 107, 107, 108, and 94 participants in Arms 'T+D', 'T+Ptz+D', 'T+Ptz', and 'Ptz+D', respectively. Participant flow was available for As Treated participants.
Participants by arm
| Arm | Count |
|---|---|
| Trastuzumab+Docetaxel Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg on Day 1 of Cycles 2-4 and docetaxel IV infusion at a starting dose of 75 mg/m\^2 on Day 1 of Cycle 1 followed by 100 mg/m\^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred.
Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 17. | 107 |
| Trastuzumab+Pertuzumab+Docetaxel Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg and pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg trastuzumab and 420 mg pertuzumab on Day 1 of Cycles 2-4. Docetaxel IV infusion was administered at a starting dose of 75 mg/m\^2 on Day 1 of Cycle 1 followed by 100 mg/m\^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred.
Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 17. | 107 |
| Trastuzumab+Pertuzumab Neoadjuvant (Pre-Operative) Treatment: Participants received trastuzumab IV infusion at a loading dose of 8 mg/kg and pertuzumab IV infusion at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 6 mg/kg trastuzumab and 420 mg pertuzumab on Day 1 of Cycles 2-4.
Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by docetaxel 75 mg/m\^2 IV on Day 1 of Cycle 5 followed by docetaxel 100 mg/m\^2 for three cycles (Cycles 6-8) if no dose-limiting toxicity occurred. For Cycles 9 to 11, participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles. Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 12 until Cycle 17. | 107 |
| Pertuzumab+Docetaxel Neoadjuvant (Pre-Operative) Treatment: Participants received pertuzumab IV at a loading dose of 840 mg on Day 1 of Cycle 1 (21-day cycle) followed by a maintenance dose of 420 mg on Day 1 of Cycles 2-4. Docetaxel IV infusion was administered at a starting dose of 75 mg/m\^2 on Day 1 of Cycle 1 followed by 100 mg/m\^2 on Day 1 of Cycles 2-4, if no dose limiting toxicity occurred.
Adjuvant (2-Week Post-Operative) Treatment: Participants received trastuzumab 6 mg/kg IV followed by FEC on Day 1 and every 3 weeks thereafter for three cycles (Cycles 5-7). Trastuzumab 6 mg/kg IV was continued every 3 weeks from Cycle 8 to Cycle 21. | 96 |
| Total | 417 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Adjuvant Treatment Period | Adverse Event | 0 | 3 | 2 | 2 |
| Adjuvant Treatment Period | Disease Progression | 3 | 3 | 0 | 7 |
| Adjuvant Treatment Period | Lost to Follow-up | 1 | 0 | 1 | 0 |
| Adjuvant Treatment Period | Refused Treatment | 1 | 1 | 1 | 5 |
| Adjuvant Treatment Period | Unknown Reason | 0 | 1 | 0 | 0 |
| Follow-Up Period | Death | 4 | 2 | 2 | 6 |
| Follow-Up Period | Disease Progression | 6 | 5 | 9 | 9 |
| Follow-Up Period | Lost to Follow-up | 3 | 3 | 3 | 1 |
| Follow-Up Period | Refused Treatment | 6 | 2 | 0 | 2 |
| Follow-Up Period | Unspecified Reason | 2 | 5 | 6 | 8 |
| Follow-Up Period | Violation of Selection Criteria at Entry | 0 | 2 | 0 | 1 |
| Neo-Adjuvant Treatment Period | Adverse Event | 0 | 0 | 2 | 2 |
| Neo-Adjuvant Treatment Period | Death | 0 | 1 | 0 | 0 |
| Neo-Adjuvant Treatment Period | Disease Progression | 0 | 1 | 7 | 2 |
| Neo-Adjuvant Treatment Period | Lost to Follow-up | 1 | 0 | 0 | 0 |
| Neo-Adjuvant Treatment Period | Protocol Violation | 1 | 2 | 1 | 1 |
| Neo-Adjuvant Treatment Period | Refused Treatment | 1 | 1 | 4 | 1 |
| Neo-Adjuvant Treatment Period | Unknown Reason | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Trastuzumab+Docetaxel | Trastuzumab+Pertuzumab+Docetaxel | Trastuzumab+Pertuzumab | Pertuzumab+Docetaxel | Total |
|---|---|---|---|---|---|
| Age, Continuous | 50.9 years STANDARD_DEVIATION 8.94 | 49.6 years STANDARD_DEVIATION 10.05 | 49.7 years STANDARD_DEVIATION 10.67 | 48.9 years STANDARD_DEVIATION 10.5 | 49.8 years STANDARD_DEVIATION 10.04 |
| Sex: Female, Male Female | 107 Participants | 107 Participants | 107 Participants | 96 Participants | 417 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 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 | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 107 / 107 | 105 / 107 | 101 / 108 | 94 / 94 |
| serious Total, serious adverse events | 21 / 107 | 22 / 107 | 19 / 108 | 21 / 94 |
Outcome results
Primary
Percentage of Participants Achieving Pathological Complete Response (pCR)
pCR was defined as an absence of invasive neoplastic cells at microscopic examination of the tumor remnants after surgery following primary systemic therapy. Participants with invalid/missing pCR assessments were defined as non-responders
Time frame: Approximately 4 months from randomization following surgery or early withdrawal, whichever occurred first (Surgery was performed within 2 weeks after Cycle 4)
Population: ITT Population; Analysis was performed according to initial randomization.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Trastuzumab+Docetaxel | Percentage of Participants Achieving Pathological Complete Response (pCR) | 29.0 percentage of participants |
| Trastuzumab+Pertuzumab+Docetaxel | Percentage of Participants Achieving Pathological Complete Response (pCR) | 45.8 percentage of participants |
| Trastuzumab+Pertuzumab | Percentage of Participants Achieving Pathological Complete Response (pCR) | 16.8 percentage of participants |
| Pertuzumab+Docetaxel | Percentage of Participants Achieving Pathological Complete Response (pCR) | 24.0 percentage of participants |
p-value: 0.009495% CI: [3.5, 30.1]Cochran-Mantel-Haenszel
p-value: 0.0141Cochran-Mantel-Haenszel
p-value: 0.019895% CI: [-23.8, -0.5]Cochran-Mantel-Haenszel
p-value: 0.0198Cochran-Mantel-Haenszel
p-value: 0.00195% CI: [-35.1, -8.5]Cochran-Mantel-Haenszel
p-value: 0.003Cochran-Mantel-Haenszel
Primary
Percentage of Participants Achieving pCR by Breast Cancer Type
pCR was defined as an absence of invasive neoplastic cells at microscopic examination of the tumor remnants after surgery following primary systemic therapy. Based on the type of breast cancer participants were categorized as those with 1. Operable breast cancer, 2. Inflammatory breast cancer and 3. Locally advanced breast cancer. Participants with invalid/missing pCR assessments were defined as non-responders.
Time frame: Approximately 4 months from randomization following surgery or early withdrawal, whichever occurred first (Surgery was performed within 2 weeks after Cycle 4)
Population: ITT Population; Analysis was performed according to initial randomization. Number (n) equal (=) number of participants included in the specified type of breast cancer.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Trastuzumab+Docetaxel | Percentage of Participants Achieving pCR by Breast Cancer Type | Operable Breast Cancer (n=64,65,65,60) | 23.4 percentage of participants |
| Trastuzumab+Docetaxel | Percentage of Participants Achieving pCR by Breast Cancer Type | Locally Advance Breast Cancer (36,32,35,31) | 41.7 percentage of participants |
| Trastuzumab+Docetaxel | Percentage of Participants Achieving pCR by Breast Cancer Type | Inflammatory Breast Cancer (n=7,10,7,5) | 14.3 percentage of participants |
| Trastuzumab+Pertuzumab+Docetaxel | Percentage of Participants Achieving pCR by Breast Cancer Type | Operable Breast Cancer (n=64,65,65,60) | 47.7 percentage of participants |
| Trastuzumab+Pertuzumab+Docetaxel | Percentage of Participants Achieving pCR by Breast Cancer Type | Locally Advance Breast Cancer (36,32,35,31) | 43.8 percentage of participants |
| Trastuzumab+Pertuzumab+Docetaxel | Percentage of Participants Achieving pCR by Breast Cancer Type | Inflammatory Breast Cancer (n=7,10,7,5) | 40.0 percentage of participants |
| Trastuzumab+Pertuzumab | Percentage of Participants Achieving pCR by Breast Cancer Type | Inflammatory Breast Cancer (n=7,10,7,5) | 28.6 percentage of participants |
| Trastuzumab+Pertuzumab | Percentage of Participants Achieving pCR by Breast Cancer Type | Operable Breast Cancer (n=64,65,65,60) | 16.9 percentage of participants |
| Trastuzumab+Pertuzumab | Percentage of Participants Achieving pCR by Breast Cancer Type | Locally Advance Breast Cancer (36,32,35,31) | 14.3 percentage of participants |
| Pertuzumab+Docetaxel | Percentage of Participants Achieving pCR by Breast Cancer Type | Operable Breast Cancer (n=64,65,65,60) | 26.7 percentage of participants |
| Pertuzumab+Docetaxel | Percentage of Participants Achieving pCR by Breast Cancer Type | Locally Advance Breast Cancer (36,32,35,31) | 16.1 percentage of participants |
| Pertuzumab+Docetaxel | Percentage of Participants Achieving pCR by Breast Cancer Type | Inflammatory Breast Cancer (n=7,10,7,5) | 40.0 percentage of participants |
Primary
Percentage of Participants Achieving pCR by Hormone Receptor Status
pCR was defined as an absence of invasive neoplastic cells at microscopic examination of the tumor remnants after surgery following primary systemic therapy. Participants were classified as Estrogen and/or Progesterone positive (+ve), Estrogen and/or Progesterone negative (-ve) or receptor status unknown. Participants with invalid/missing pCR assessments were defined as non-responders.
Time frame: Approximately 4 months from randomization following surgery or early withdrawal, whichever occurred first (Surgery was performed within 2 weeks after Cycle 4)
Population: ITT Population; Analysis was performed according to initial randomization. n = number of participants included in the specified hormone receptor status.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Trastuzumab+Docetaxel | Percentage of Participants Achieving pCR by Hormone Receptor Status | Estrogen and/or Progesterone +ve (n=50,50,51,46) | 20.0 percentage of participants |
| Trastuzumab+Docetaxel | Percentage of Participants Achieving pCR by Hormone Receptor Status | Receptor Status Unknown (0,0,1,0) | NA percentage of participants |
| Trastuzumab+Docetaxel | Percentage of Participants Achieving pCR by Hormone Receptor Status | Estrogen and/or Progesterone -ve (n=57,57,55,50) | 36.8 percentage of participants |
| Trastuzumab+Pertuzumab+Docetaxel | Percentage of Participants Achieving pCR by Hormone Receptor Status | Estrogen and/or Progesterone +ve (n=50,50,51,46) | 26.0 percentage of participants |
| Trastuzumab+Pertuzumab+Docetaxel | Percentage of Participants Achieving pCR by Hormone Receptor Status | Receptor Status Unknown (0,0,1,0) | NA percentage of participants |
| Trastuzumab+Pertuzumab+Docetaxel | Percentage of Participants Achieving pCR by Hormone Receptor Status | Estrogen and/or Progesterone -ve (n=57,57,55,50) | 63.2 percentage of participants |
| Trastuzumab+Pertuzumab | Percentage of Participants Achieving pCR by Hormone Receptor Status | Estrogen and/or Progesterone -ve (n=57,57,55,50) | 27.3 percentage of participants |
| Trastuzumab+Pertuzumab | Percentage of Participants Achieving pCR by Hormone Receptor Status | Estrogen and/or Progesterone +ve (n=50,50,51,46) | 5.9 percentage of participants |
| Trastuzumab+Pertuzumab | Percentage of Participants Achieving pCR by Hormone Receptor Status | Receptor Status Unknown (0,0,1,0) | 0.0 percentage of participants |
| Pertuzumab+Docetaxel | Percentage of Participants Achieving pCR by Hormone Receptor Status | Estrogen and/or Progesterone +ve (n=50,50,51,46) | 17.4 percentage of participants |
| Pertuzumab+Docetaxel | Percentage of Participants Achieving pCR by Hormone Receptor Status | Receptor Status Unknown (0,0,1,0) | NA percentage of participants |
| Pertuzumab+Docetaxel | Percentage of Participants Achieving pCR by Hormone Receptor Status | Estrogen and/or Progesterone -ve (n=57,57,55,50) | 30.0 percentage of participants |
Primary
Percentage of Participants Achieving pCR by Lymph Node Status
pCR was defined as an absence of invasive neoplastic cells at microscopic examination of the tumor remnants after surgery following primary systemic therapy. Lymph node status was defined as either negative lymph node at surgery or positive lymph node at surgery. Participants with invalid/missing pCR assessments were defined as non-responders.
Time frame: Approximately 4 months from randomization following surgery or early withdrawal, whichever occurred first (Surgery was performed within 2 weeks after Cycle 4)
Population: ITT Population; Analysis was performed according to initial randomization.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Trastuzumab+Docetaxel | Percentage of Participants Achieving pCR by Lymph Node Status | pCR achieved and Negative Lymph Nodes at Surgery | 21.5 percentage of participants |
| Trastuzumab+Docetaxel | Percentage of Participants Achieving pCR by Lymph Node Status | pCR achieved and Positive Lymph Nodes at Surgery | 7.5 percentage of participants |
| Trastuzumab+Pertuzumab+Docetaxel | Percentage of Participants Achieving pCR by Lymph Node Status | pCR achieved and Positive Lymph Nodes at Surgery | 6.5 percentage of participants |
| Trastuzumab+Pertuzumab+Docetaxel | Percentage of Participants Achieving pCR by Lymph Node Status | pCR achieved and Negative Lymph Nodes at Surgery | 39.3 percentage of participants |
| Trastuzumab+Pertuzumab | Percentage of Participants Achieving pCR by Lymph Node Status | pCR achieved and Negative Lymph Nodes at Surgery | 11.2 percentage of participants |
| Trastuzumab+Pertuzumab | Percentage of Participants Achieving pCR by Lymph Node Status | pCR achieved and Positive Lymph Nodes at Surgery | 5.6 percentage of participants |
| Pertuzumab+Docetaxel | Percentage of Participants Achieving pCR by Lymph Node Status | pCR achieved and Negative Lymph Nodes at Surgery | 17.7 percentage of participants |
| Pertuzumab+Docetaxel | Percentage of Participants Achieving pCR by Lymph Node Status | pCR achieved and Positive Lymph Nodes at Surgery | 6.3 percentage of participants |
Primary
Percentage of Participants Achieving pCR by Presence or Absence of Residual Intraductal Carcinoma (DCIS) / Intalobular Carcinoma (LCIS)
pCR was defined as an absence of invasive neoplastic cells at microscopic examination of the tumor remnants after surgery following primary systemic therapy. Participants with invalid/missing pCR assessments were defined as non-responders.
Time frame: Approximately 4 months from randomization following surgery or early withdrawal, whichever occurred first (Surgery was performed within 2 weeks after Cycle 4)
Population: ITT Population; Analysis was performed according to initial randomization.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Trastuzumab+Docetaxel | Percentage of Participants Achieving pCR by Presence or Absence of Residual Intraductal Carcinoma (DCIS) / Intalobular Carcinoma (LCIS) | pCR Achieved and No residual DCIS/LCIS at Surgery | 16.8 percentage of participants |
| Trastuzumab+Docetaxel | Percentage of Participants Achieving pCR by Presence or Absence of Residual Intraductal Carcinoma (DCIS) / Intalobular Carcinoma (LCIS) | pCR Achieved and Residual DCIS/LCIS at Surgery | 12.1 percentage of participants |
| Trastuzumab+Pertuzumab+Docetaxel | Percentage of Participants Achieving pCR by Presence or Absence of Residual Intraductal Carcinoma (DCIS) / Intalobular Carcinoma (LCIS) | pCR Achieved and Residual DCIS/LCIS at Surgery | 9.3 percentage of participants |
| Trastuzumab+Pertuzumab+Docetaxel | Percentage of Participants Achieving pCR by Presence or Absence of Residual Intraductal Carcinoma (DCIS) / Intalobular Carcinoma (LCIS) | pCR Achieved and No residual DCIS/LCIS at Surgery | 36.4 percentage of participants |
| Trastuzumab+Pertuzumab | Percentage of Participants Achieving pCR by Presence or Absence of Residual Intraductal Carcinoma (DCIS) / Intalobular Carcinoma (LCIS) | pCR Achieved and No residual DCIS/LCIS at Surgery | 9.3 percentage of participants |
| Trastuzumab+Pertuzumab | Percentage of Participants Achieving pCR by Presence or Absence of Residual Intraductal Carcinoma (DCIS) / Intalobular Carcinoma (LCIS) | pCR Achieved and Residual DCIS/LCIS at Surgery | 7.5 percentage of participants |
| Pertuzumab+Docetaxel | Percentage of Participants Achieving pCR by Presence or Absence of Residual Intraductal Carcinoma (DCIS) / Intalobular Carcinoma (LCIS) | pCR Achieved and No residual DCIS/LCIS at Surgery | 17.7 percentage of participants |
| Pertuzumab+Docetaxel | Percentage of Participants Achieving pCR by Presence or Absence of Residual Intraductal Carcinoma (DCIS) / Intalobular Carcinoma (LCIS) | pCR Achieved and Residual DCIS/LCIS at Surgery | 6.3 percentage of participants |
Secondary
Percentage of Participants Achieving Best Overall Response (CR, PR, SD or PD) During Neo-Adjuvant Period by X-Ray/Mammography
Tumor assessments were made based on the RECIST criteria - version 1.0 The overall response at each cycle up to the last assessment prior to surgery was derived for: i) the primary breast lesion; (ii) across secondary breast lesions, (iii) across all breast lesions (iv) across axillary nodes (v) across supraclavicular nodes and (vi) across all nodes (vii) across all lesions (overall) using the following algorithm: CR: if measurement of '0' is noted at a given cycle as compared to baseline measurement which is \>0 at screening or cycle 1 day 1; PR: if measurement is at least a 30% decreased compared to baseline levels . (Reference= baseline size or sum of sizes); SD: if measurement at a given cycle is not sufficient shrinkage to qualify for neither PR nor sufficient increase to qualify for PD compared to baseline levels. PD: if lesion is at least a 20 % increase from measurements at baseline. Overall response is derived based on the sum total of breast tumors and all nodes examined.
Time frame: Baseline up to Cycle 4 (assessed at Baseline, Day 1 of Cycles 1-4 Pre-Surgery) Up to approximately 24 months
Population: ITT Population; Analysis was performed according to initial randomization. Number of participants analyzed = participants evaluable for this outcome.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Trastuzumab+Docetaxel | Percentage of Participants Achieving Best Overall Response (CR, PR, SD or PD) During Neo-Adjuvant Period by X-Ray/Mammography | CR | 18.3 percentage of participants |
| Trastuzumab+Docetaxel | Percentage of Participants Achieving Best Overall Response (CR, PR, SD or PD) During Neo-Adjuvant Period by X-Ray/Mammography | PR | 49.3 percentage of participants |
| Trastuzumab+Docetaxel | Percentage of Participants Achieving Best Overall Response (CR, PR, SD or PD) During Neo-Adjuvant Period by X-Ray/Mammography | SD | 31.0 percentage of participants |
| Trastuzumab+Docetaxel | Percentage of Participants Achieving Best Overall Response (CR, PR, SD or PD) During Neo-Adjuvant Period by X-Ray/Mammography | PD | 1.4 percentage of participants |
| Trastuzumab+Pertuzumab+Docetaxel | Percentage of Participants Achieving Best Overall Response (CR, PR, SD or PD) During Neo-Adjuvant Period by X-Ray/Mammography | PR | 49.1 percentage of participants |
| Trastuzumab+Pertuzumab+Docetaxel | Percentage of Participants Achieving Best Overall Response (CR, PR, SD or PD) During Neo-Adjuvant Period by X-Ray/Mammography | SD | 30.2 percentage of participants |
| Trastuzumab+Pertuzumab+Docetaxel | Percentage of Participants Achieving Best Overall Response (CR, PR, SD or PD) During Neo-Adjuvant Period by X-Ray/Mammography | PD | 1.9 percentage of participants |
| Trastuzumab+Pertuzumab+Docetaxel | Percentage of Participants Achieving Best Overall Response (CR, PR, SD or PD) During Neo-Adjuvant Period by X-Ray/Mammography | CR | 18.9 percentage of participants |
| Trastuzumab+Pertuzumab | Percentage of Participants Achieving Best Overall Response (CR, PR, SD or PD) During Neo-Adjuvant Period by X-Ray/Mammography | SD | 45.5 percentage of participants |
| Trastuzumab+Pertuzumab | Percentage of Participants Achieving Best Overall Response (CR, PR, SD or PD) During Neo-Adjuvant Period by X-Ray/Mammography | PR | 34.5 percentage of participants |
| Trastuzumab+Pertuzumab | Percentage of Participants Achieving Best Overall Response (CR, PR, SD or PD) During Neo-Adjuvant Period by X-Ray/Mammography | PD | 7.3 percentage of participants |
| Trastuzumab+Pertuzumab | Percentage of Participants Achieving Best Overall Response (CR, PR, SD or PD) During Neo-Adjuvant Period by X-Ray/Mammography | CR | 12.7 percentage of participants |
| Pertuzumab+Docetaxel | Percentage of Participants Achieving Best Overall Response (CR, PR, SD or PD) During Neo-Adjuvant Period by X-Ray/Mammography | PD | 0.0 percentage of participants |
| Pertuzumab+Docetaxel | Percentage of Participants Achieving Best Overall Response (CR, PR, SD or PD) During Neo-Adjuvant Period by X-Ray/Mammography | PR | 46.5 percentage of participants |
| Pertuzumab+Docetaxel | Percentage of Participants Achieving Best Overall Response (CR, PR, SD or PD) During Neo-Adjuvant Period by X-Ray/Mammography | CR | 18.6 percentage of participants |
| Pertuzumab+Docetaxel | Percentage of Participants Achieving Best Overall Response (CR, PR, SD or PD) During Neo-Adjuvant Period by X-Ray/Mammography | SD | 34.9 percentage of participants |
Secondary
Percentage of Participants Achieving Best Overall Response (CR, PR, SD or PD) During the Neo-Adjuvant Period by Clinical Examination
Tumor assessments were made based on the RECIST criteria - version 1.0 The clinical response at each cycle up to the last assessment prior to surgery was derived for: i) the primary breast lesion; (ii) across secondary breast lesions, (iii) across all breast lesions (iv) across axillary nodes (v) across supraclavicular nodes and (vi) across all nodes (vii) across all lesions (overall) using the following algorithm: CR: if measurement of '0' is noted at a given cycle as compared to baseline measurement which is \>0 at screening or cycle 1 day 1; PR: if measurement is at least a 30% decreased compared to baseline levels . (Reference= baseline size or sum of sizes); SD: if measurement at a given cycle is not sufficient shrinkage to qualify for neither PR nor sufficient increase to qualify for PD compared to baseline levels. PD: if lesion is at least a 20 % increase from measurements at baseline. Overall response is derived based on the sum total of breast tumors and all nodes examined.
Time frame: Baseline up to Cycle 4 (assessed at Baseline, Day 1 of Cycles 1-4 Pre-Surgery) Up to approximately 24 months
Population: ITT Population; Analysis was performed according to initial randomization. Number of participants analyzed = participants evaluable for this outcome.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Trastuzumab+Docetaxel | Percentage of Participants Achieving Best Overall Response (CR, PR, SD or PD) During the Neo-Adjuvant Period by Clinical Examination | CR | 21.6 percentage of participants |
| Trastuzumab+Docetaxel | Percentage of Participants Achieving Best Overall Response (CR, PR, SD or PD) During the Neo-Adjuvant Period by Clinical Examination | PR | 59.8 percentage of participants |
| Trastuzumab+Docetaxel | Percentage of Participants Achieving Best Overall Response (CR, PR, SD or PD) During the Neo-Adjuvant Period by Clinical Examination | SD | 17.5 percentage of participants |
| Trastuzumab+Docetaxel | Percentage of Participants Achieving Best Overall Response (CR, PR, SD or PD) During the Neo-Adjuvant Period by Clinical Examination | PD | 1.0 percentage of participants |
| Trastuzumab+Pertuzumab+Docetaxel | Percentage of Participants Achieving Best Overall Response (CR, PR, SD or PD) During the Neo-Adjuvant Period by Clinical Examination | PR | 63.0 percentage of participants |
| Trastuzumab+Pertuzumab+Docetaxel | Percentage of Participants Achieving Best Overall Response (CR, PR, SD or PD) During the Neo-Adjuvant Period by Clinical Examination | SD | 12.0 percentage of participants |
| Trastuzumab+Pertuzumab+Docetaxel | Percentage of Participants Achieving Best Overall Response (CR, PR, SD or PD) During the Neo-Adjuvant Period by Clinical Examination | PD | 0.0 percentage of participants |
| Trastuzumab+Pertuzumab+Docetaxel | Percentage of Participants Achieving Best Overall Response (CR, PR, SD or PD) During the Neo-Adjuvant Period by Clinical Examination | CR | 25.0 percentage of participants |
| Trastuzumab+Pertuzumab | Percentage of Participants Achieving Best Overall Response (CR, PR, SD or PD) During the Neo-Adjuvant Period by Clinical Examination | SD | 31.6 percentage of participants |
| Trastuzumab+Pertuzumab | Percentage of Participants Achieving Best Overall Response (CR, PR, SD or PD) During the Neo-Adjuvant Period by Clinical Examination | PR | 55.1 percentage of participants |
| Trastuzumab+Pertuzumab | Percentage of Participants Achieving Best Overall Response (CR, PR, SD or PD) During the Neo-Adjuvant Period by Clinical Examination | PD | 2.0 percentage of participants |
| Trastuzumab+Pertuzumab | Percentage of Participants Achieving Best Overall Response (CR, PR, SD or PD) During the Neo-Adjuvant Period by Clinical Examination | CR | 11.2 percentage of participants |
| Pertuzumab+Docetaxel | Percentage of Participants Achieving Best Overall Response (CR, PR, SD or PD) During the Neo-Adjuvant Period by Clinical Examination | PD | 0.0 percentage of participants |
| Pertuzumab+Docetaxel | Percentage of Participants Achieving Best Overall Response (CR, PR, SD or PD) During the Neo-Adjuvant Period by Clinical Examination | PR | 58.0 percentage of participants |
| Pertuzumab+Docetaxel | Percentage of Participants Achieving Best Overall Response (CR, PR, SD or PD) During the Neo-Adjuvant Period by Clinical Examination | CR | 15.9 percentage of participants |
| Pertuzumab+Docetaxel | Percentage of Participants Achieving Best Overall Response (CR, PR, SD or PD) During the Neo-Adjuvant Period by Clinical Examination | SD | 26.1 percentage of participants |
Secondary
Percentage of Participants Achieving Best Primary Breast Tumor Response (CR, PR, SD or PD) During Neo-Adjuvant Period by Clinical Examination
Tumor assessments were made based on the RECIST criteria - version 1.0 The clinical response at each cycle up to the last assessment prior to surgery was derived for primary breast tumor using the following algorithm: CR: if measurement of '0' is noted at a given cycle as compared to baseline measurement which is \>0 at screening or cycle 1 day 1; PR: if measurement is at least a 30% decreased compared to baseline levels . (Reference= baseline size or sum of sizes); SD: if measurement at a given cycle is not sufficient shrinkage to qualify for neither PR nor sufficient increase to qualify for PD compared to baseline levels. PD: if lesion is at least a 20 % increase from measurements at baseline. Overall response is derived based on the sum total of breast tumors and all nodes examined.
Time frame: Baseline up to Cycle 4 (assessed at Baseline, Day 1 of Cycles 1-4 Pre-Surgery) Up to approximately 24 months
Population: ITT Population; Analysis was performed according to initial randomization. Number of participants analyzed = participants evaluable for this outcome.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Trastuzumab+Docetaxel | Percentage of Participants Achieving Best Primary Breast Tumor Response (CR, PR, SD or PD) During Neo-Adjuvant Period by Clinical Examination | CR | 23.2 percentage of participants |
| Trastuzumab+Docetaxel | Percentage of Participants Achieving Best Primary Breast Tumor Response (CR, PR, SD or PD) During Neo-Adjuvant Period by Clinical Examination | PR | 56.6 percentage of participants |
| Trastuzumab+Docetaxel | Percentage of Participants Achieving Best Primary Breast Tumor Response (CR, PR, SD or PD) During Neo-Adjuvant Period by Clinical Examination | SD | 20.2 percentage of participants |
| Trastuzumab+Docetaxel | Percentage of Participants Achieving Best Primary Breast Tumor Response (CR, PR, SD or PD) During Neo-Adjuvant Period by Clinical Examination | PD | 0.0 percentage of participants |
| Trastuzumab+Pertuzumab+Docetaxel | Percentage of Participants Achieving Best Primary Breast Tumor Response (CR, PR, SD or PD) During Neo-Adjuvant Period by Clinical Examination | PR | 57.4 percentage of participants |
| Trastuzumab+Pertuzumab+Docetaxel | Percentage of Participants Achieving Best Primary Breast Tumor Response (CR, PR, SD or PD) During Neo-Adjuvant Period by Clinical Examination | SD | 11.9 percentage of participants |
| Trastuzumab+Pertuzumab+Docetaxel | Percentage of Participants Achieving Best Primary Breast Tumor Response (CR, PR, SD or PD) During Neo-Adjuvant Period by Clinical Examination | PD | 0.0 percentage of participants |
| Trastuzumab+Pertuzumab+Docetaxel | Percentage of Participants Achieving Best Primary Breast Tumor Response (CR, PR, SD or PD) During Neo-Adjuvant Period by Clinical Examination | CR | 30.7 percentage of participants |
| Trastuzumab+Pertuzumab | Percentage of Participants Achieving Best Primary Breast Tumor Response (CR, PR, SD or PD) During Neo-Adjuvant Period by Clinical Examination | SD | 30.4 percentage of participants |
| Trastuzumab+Pertuzumab | Percentage of Participants Achieving Best Primary Breast Tumor Response (CR, PR, SD or PD) During Neo-Adjuvant Period by Clinical Examination | PR | 51.0 percentage of participants |
| Trastuzumab+Pertuzumab | Percentage of Participants Achieving Best Primary Breast Tumor Response (CR, PR, SD or PD) During Neo-Adjuvant Period by Clinical Examination | PD | 2.0 percentage of participants |
| Trastuzumab+Pertuzumab | Percentage of Participants Achieving Best Primary Breast Tumor Response (CR, PR, SD or PD) During Neo-Adjuvant Period by Clinical Examination | CR | 16.7 percentage of participants |
| Pertuzumab+Docetaxel | Percentage of Participants Achieving Best Primary Breast Tumor Response (CR, PR, SD or PD) During Neo-Adjuvant Period by Clinical Examination | PD | 0.0 percentage of participants |
| Pertuzumab+Docetaxel | Percentage of Participants Achieving Best Primary Breast Tumor Response (CR, PR, SD or PD) During Neo-Adjuvant Period by Clinical Examination | PR | 50.5 percentage of participants |
| Pertuzumab+Docetaxel | Percentage of Participants Achieving Best Primary Breast Tumor Response (CR, PR, SD or PD) During Neo-Adjuvant Period by Clinical Examination | CR | 20.9 percentage of participants |
| Pertuzumab+Docetaxel | Percentage of Participants Achieving Best Primary Breast Tumor Response (CR, PR, SD or PD) During Neo-Adjuvant Period by Clinical Examination | SD | 28.6 percentage of participants |
Secondary
Percentage of Participants Achieving Best Primary Tumor Response (Complete Response [CR], Partial Response [PR], Stable Disease [SD] or Disease Progression [PD]) During Neo-Adjuvant Treatment by X-Ray/Mammography
Tumor assessments were made based upon the Response Evaluation Criteria in Solid Tumors (RECIST) criteria - version 1.0. The clinical response at each cycle up to the last assessment prior to surgery was derived for primary breast tumor using the following algorithm: CR: if measurement of '0' is noted at a given cycle as compared to baseline measurement which is greater than (\>)0 at screening or cycle 1 Day 1; PR: if measurement is at least a 30 percent (%) decreased compared to baseline levels . (Reference= baseline size or sum of sizes); SD: if measurement at a given cycle is not sufficient shrinkage to qualify for neither PR nor sufficient increase to qualify for PD compared to baseline levels. PD: if lesion is at least a 20 % increase from measurements at baseline.
Time frame: Baseline up to Cycle 4 (assessed at, Baseline and Day 1 of Cycles 1-4 Pre-Surgery) Up to approximately 24 months
Population: ITT Population; Analysis was performed according to initial randomization. Number of participants analyzed = participants evaluable for this outcome.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Trastuzumab+Docetaxel | Percentage of Participants Achieving Best Primary Tumor Response (Complete Response [CR], Partial Response [PR], Stable Disease [SD] or Disease Progression [PD]) During Neo-Adjuvant Treatment by X-Ray/Mammography | CR | 18.3 percentage of participants |
| Trastuzumab+Docetaxel | Percentage of Participants Achieving Best Primary Tumor Response (Complete Response [CR], Partial Response [PR], Stable Disease [SD] or Disease Progression [PD]) During Neo-Adjuvant Treatment by X-Ray/Mammography | PR | 49.3 percentage of participants |
| Trastuzumab+Docetaxel | Percentage of Participants Achieving Best Primary Tumor Response (Complete Response [CR], Partial Response [PR], Stable Disease [SD] or Disease Progression [PD]) During Neo-Adjuvant Treatment by X-Ray/Mammography | SD | 31.0 percentage of participants |
| Trastuzumab+Docetaxel | Percentage of Participants Achieving Best Primary Tumor Response (Complete Response [CR], Partial Response [PR], Stable Disease [SD] or Disease Progression [PD]) During Neo-Adjuvant Treatment by X-Ray/Mammography | PD | 1.4 percentage of participants |
| Trastuzumab+Pertuzumab+Docetaxel | Percentage of Participants Achieving Best Primary Tumor Response (Complete Response [CR], Partial Response [PR], Stable Disease [SD] or Disease Progression [PD]) During Neo-Adjuvant Treatment by X-Ray/Mammography | PR | 46.6 percentage of participants |
| Trastuzumab+Pertuzumab+Docetaxel | Percentage of Participants Achieving Best Primary Tumor Response (Complete Response [CR], Partial Response [PR], Stable Disease [SD] or Disease Progression [PD]) During Neo-Adjuvant Treatment by X-Ray/Mammography | SD | 32.8 percentage of participants |
| Trastuzumab+Pertuzumab+Docetaxel | Percentage of Participants Achieving Best Primary Tumor Response (Complete Response [CR], Partial Response [PR], Stable Disease [SD] or Disease Progression [PD]) During Neo-Adjuvant Treatment by X-Ray/Mammography | PD | 1.7 percentage of participants |
| Trastuzumab+Pertuzumab+Docetaxel | Percentage of Participants Achieving Best Primary Tumor Response (Complete Response [CR], Partial Response [PR], Stable Disease [SD] or Disease Progression [PD]) During Neo-Adjuvant Treatment by X-Ray/Mammography | CR | 19.0 percentage of participants |
| Trastuzumab+Pertuzumab | Percentage of Participants Achieving Best Primary Tumor Response (Complete Response [CR], Partial Response [PR], Stable Disease [SD] or Disease Progression [PD]) During Neo-Adjuvant Treatment by X-Ray/Mammography | SD | 44.3 percentage of participants |
| Trastuzumab+Pertuzumab | Percentage of Participants Achieving Best Primary Tumor Response (Complete Response [CR], Partial Response [PR], Stable Disease [SD] or Disease Progression [PD]) During Neo-Adjuvant Treatment by X-Ray/Mammography | PR | 36.1 percentage of participants |
| Trastuzumab+Pertuzumab | Percentage of Participants Achieving Best Primary Tumor Response (Complete Response [CR], Partial Response [PR], Stable Disease [SD] or Disease Progression [PD]) During Neo-Adjuvant Treatment by X-Ray/Mammography | PD | 6.6 percentage of participants |
| Trastuzumab+Pertuzumab | Percentage of Participants Achieving Best Primary Tumor Response (Complete Response [CR], Partial Response [PR], Stable Disease [SD] or Disease Progression [PD]) During Neo-Adjuvant Treatment by X-Ray/Mammography | CR | 13.1 percentage of participants |
| Pertuzumab+Docetaxel | Percentage of Participants Achieving Best Primary Tumor Response (Complete Response [CR], Partial Response [PR], Stable Disease [SD] or Disease Progression [PD]) During Neo-Adjuvant Treatment by X-Ray/Mammography | PD | 0.0 percentage of participants |
| Pertuzumab+Docetaxel | Percentage of Participants Achieving Best Primary Tumor Response (Complete Response [CR], Partial Response [PR], Stable Disease [SD] or Disease Progression [PD]) During Neo-Adjuvant Treatment by X-Ray/Mammography | PR | 46.8 percentage of participants |
| Pertuzumab+Docetaxel | Percentage of Participants Achieving Best Primary Tumor Response (Complete Response [CR], Partial Response [PR], Stable Disease [SD] or Disease Progression [PD]) During Neo-Adjuvant Treatment by X-Ray/Mammography | CR | 19.1 percentage of participants |
| Pertuzumab+Docetaxel | Percentage of Participants Achieving Best Primary Tumor Response (Complete Response [CR], Partial Response [PR], Stable Disease [SD] or Disease Progression [PD]) During Neo-Adjuvant Treatment by X-Ray/Mammography | SD | 34.0 percentage of participants |
Secondary
Percentage of Participants Achieving Breast Conserving Surgery For Whom Mastectomy Was Planned
Breast Conserving Surgery (BCS) was defined as quadrantectomy, lumpectomy, no surgery, sentinel node biopsy, axillary surgical resection or other method of avoiding mastectomy.
Time frame: Surgery (Within 2 weeks after Cycle 4) Up to approximately 24 months
Population: ITT Population; Analysis was performed according to initial randomization. Number of participants analyzed = participants evaluable for this outcome.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Trastuzumab+Docetaxel | Percentage of Participants Achieving Breast Conserving Surgery For Whom Mastectomy Was Planned | 22.6 percentage of participants |
| Trastuzumab+Pertuzumab+Docetaxel | Percentage of Participants Achieving Breast Conserving Surgery For Whom Mastectomy Was Planned | 23.2 percentage of participants |
| Trastuzumab+Pertuzumab | Percentage of Participants Achieving Breast Conserving Surgery For Whom Mastectomy Was Planned | 18.0 percentage of participants |
| Pertuzumab+Docetaxel | Percentage of Participants Achieving Breast Conserving Surgery For Whom Mastectomy Was Planned | 31.7 percentage of participants |
Secondary
Percentage of Participants Achieving Clinical Response During Neo-Adjuvant Period by Clinical Examination
Tumor assessments were made based on the RECIST criteria - version 1.0 The clinical response at each cycle up to the last assessment prior to surgery was derived for: i) the primary breast lesion; (ii) across secondary breast lesions, (iii) across all breast lesions (iv) across axillary nodes (v) across supraclavicular nodes and (vi) across all nodes (vii) across all lesions (overall) using the following algorithm: CR: if measurement of '0' is noted at a given cycle as compared to baseline measurement which is \>0 at screening or cycle 1 day 1; PR: if measurement is at least a 30% decreased compared to baseline levels . (Reference= baseline size or sum of sizes). Clinical Responders are participants who have achieved CR or PR during the Neo-adjuvant treatment. Primary breast tumor clinical response is based on primary breast tumor assessment. Overall response is derived based on the sum total of breast tumors and all nodes examined.
Time frame: Baseline up to Cycle 4 (assessed at Baseline, Day 1 of Cycles 1-4 Pre-Surgery) Up to approximately 24 months
Population: ITT Population; Analysis was performed according to initial randomization. Number of participants analyzed = participants evaluable for this outcome and n = number participants analyzed in the specified category.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Trastuzumab+Docetaxel | Percentage of Participants Achieving Clinical Response During Neo-Adjuvant Period by Clinical Examination | Primary Breast Tumor (n=99,101,102,91) | 79.8 percentage of participants |
| Trastuzumab+Docetaxel | Percentage of Participants Achieving Clinical Response During Neo-Adjuvant Period by Clinical Examination | Overall Response (n=97,100,98,88) | 81.4 percentage of participants |
| Trastuzumab+Pertuzumab+Docetaxel | Percentage of Participants Achieving Clinical Response During Neo-Adjuvant Period by Clinical Examination | Overall Response (n=97,100,98,88) | 88.0 percentage of participants |
| Trastuzumab+Pertuzumab+Docetaxel | Percentage of Participants Achieving Clinical Response During Neo-Adjuvant Period by Clinical Examination | Primary Breast Tumor (n=99,101,102,91) | 88.1 percentage of participants |
| Trastuzumab+Pertuzumab | Percentage of Participants Achieving Clinical Response During Neo-Adjuvant Period by Clinical Examination | Primary Breast Tumor (n=99,101,102,91) | 67.6 percentage of participants |
| Trastuzumab+Pertuzumab | Percentage of Participants Achieving Clinical Response During Neo-Adjuvant Period by Clinical Examination | Overall Response (n=97,100,98,88) | 66.3 percentage of participants |
| Pertuzumab+Docetaxel | Percentage of Participants Achieving Clinical Response During Neo-Adjuvant Period by Clinical Examination | Primary Breast Tumor (n=99,101,102,91) | 71.4 percentage of participants |
| Pertuzumab+Docetaxel | Percentage of Participants Achieving Clinical Response During Neo-Adjuvant Period by Clinical Examination | Overall Response (n=97,100,98,88) | 73.9 percentage of participants |
Secondary
Percentage of Participants Achieving Clinical Response During Neo-Adjuvant Period by X-Ray/Mammography
Clinical response was determined based on tumor measurements by sponsor in combination with tumor response assessment by investigator. Tumor assessments were made based on the RECIST criteria - version 1.0 The clinical response at each cycle up to the last assessment prior to surgery was derived for: i) the primary breast lesion; (ii) across secondary breast lesions, (iii) across all breast lesions (iv) across axillary nodes (v) across supraclavicular nodes and (vi) across all nodes (vii) across all lesions (overall) using the following algorithm: CR: if measurement of '0' is noted at a given cycle as compared to baseline measurement which is \>0 at screening or cycle 1 day 1; PR: if measurement is at least a 30% decreased compared to baseline levels . (Reference= baseline size or sum of sizes). Clinical Responders are participants who have achieved CR or PR during the Neo-adjuvant treatment. Overall response is derived based on the sum total of breast tumors and all nodes examined.
Time frame: Baseline up to Cycle 4 (assessed at Baseline, Day 1 of Cycles 1-4 Pre-Surgery) Up to approximately 24 months
Population: ITT Population; Analysis was performed according to initial randomization. Number of participants analyzed = participants evaluable for this outcome and n = number participants analyzed in the specified category.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Trastuzumab+Docetaxel | Percentage of Participants Achieving Clinical Response During Neo-Adjuvant Period by X-Ray/Mammography | Primary Breast Tumor (n=71,58,61,47) | 67.6 percentage of participants |
| Trastuzumab+Docetaxel | Percentage of Participants Achieving Clinical Response During Neo-Adjuvant Period by X-Ray/Mammography | Overall Response (n=71,53,55,43) | 67.6 percentage of participants |
| Trastuzumab+Pertuzumab+Docetaxel | Percentage of Participants Achieving Clinical Response During Neo-Adjuvant Period by X-Ray/Mammography | Overall Response (n=71,53,55,43) | 67.9 percentage of participants |
| Trastuzumab+Pertuzumab+Docetaxel | Percentage of Participants Achieving Clinical Response During Neo-Adjuvant Period by X-Ray/Mammography | Primary Breast Tumor (n=71,58,61,47) | 65.5 percentage of participants |
| Trastuzumab+Pertuzumab | Percentage of Participants Achieving Clinical Response During Neo-Adjuvant Period by X-Ray/Mammography | Primary Breast Tumor (n=71,58,61,47) | 49.2 percentage of participants |
| Trastuzumab+Pertuzumab | Percentage of Participants Achieving Clinical Response During Neo-Adjuvant Period by X-Ray/Mammography | Overall Response (n=71,53,55,43) | 47.3 percentage of participants |
| Pertuzumab+Docetaxel | Percentage of Participants Achieving Clinical Response During Neo-Adjuvant Period by X-Ray/Mammography | Primary Breast Tumor (n=71,58,61,47) | 66.0 percentage of participants |
| Pertuzumab+Docetaxel | Percentage of Participants Achieving Clinical Response During Neo-Adjuvant Period by X-Ray/Mammography | Overall Response (n=71,53,55,43) | 65.1 percentage of participants |
Secondary
Percentage of Participants Who Were Progression Free and Disease Free
Disease-free survival (DFS) was defined as the time from first date of no disease to first documentation of PD or death. Participants without progression after surgery were considered Disease Free. Any evidence of contralateral disease in-situ was not considered as PD. Participants who were withdrawn from the study without documented progression and for whom evaluations were made, were censored at date of last assessment when participant was known to be disease-free. Progression-free survival (PFS) was defined as time from date of randomization to first documentation of PD or death. Any evidence of contralateral disease in-situ was not considered as PD. Participants who were withdrawn from study without documented progression and for whom evaluations were made, were censored at date of last assessment when the participant was known to be free from progressive disease. Participants without post baseline assessments but known to be alive were censored at the time of randomization.
Time frame: Randomization up to a maximum of 329 weeks
Population: ITT Population; Analysis was performed according to initial randomization.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Trastuzumab+Docetaxel | Percentage of Participants Who Were Progression Free and Disease Free | Progression Free | 82.2 percentage of participants |
| Trastuzumab+Docetaxel | Percentage of Participants Who Were Progression Free and Disease Free | Disease Free | 82.5 percentage of participants |
| Trastuzumab+Pertuzumab+Docetaxel | Percentage of Participants Who Were Progression Free and Disease Free | Disease Free | 85.1 percentage of participants |
| Trastuzumab+Pertuzumab+Docetaxel | Percentage of Participants Who Were Progression Free and Disease Free | Progression Free | 84.1 percentage of participants |
| Trastuzumab+Pertuzumab | Percentage of Participants Who Were Progression Free and Disease Free | Progression Free | 74.8 percentage of participants |
| Trastuzumab+Pertuzumab | Percentage of Participants Who Were Progression Free and Disease Free | Disease Free | 80.2 percentage of participants |
| Pertuzumab+Docetaxel | Percentage of Participants Who Were Progression Free and Disease Free | Progression Free | 75.0 percentage of participants |
| Pertuzumab+Docetaxel | Percentage of Participants Who Were Progression Free and Disease Free | Disease Free | 76.1 percentage of participants |
Secondary
Percentage of Participants With Progressive Disease During Neo-Adjuvant Treatment Period
Tumor assessments were made based upon the Response Evaluation Criteria in Solid Tumors (RECIST) criteria - version 1.0. The clinical response at each cycle up to the last assessment prior to surgery was derived for: i) the primary breast lesion; (ii) across secondary breast lesions, (iii) across all breast lesions (iv) across axillary nodes (v) across supraclavicular nodes and (vi) across all nodes (vii) across all lesions (overall) using the following algorithm: PD: if lesion is at least a 20 % increased from measurements at baseline. Percentage of participants along with 95% Confidence Interval (CI) for one sample binomial using Pearson-Clopper method were reported. Missing investigator assessments were considered as no progressive disease.
Time frame: Baseline up to Cycle 4 (assessed at Baseline, Day 1 of Cycles 1-4 Pre-Surgery) Up to approximately 24 months
Population: ITT Population; Analysis was performed according to initial randomization.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Trastuzumab+Docetaxel | Percentage of Participants With Progressive Disease During Neo-Adjuvant Treatment Period | 0.0 percentage of participants |
| Trastuzumab+Pertuzumab+Docetaxel | Percentage of Participants With Progressive Disease During Neo-Adjuvant Treatment Period | 0.9 percentage of participants |
| Trastuzumab+Pertuzumab | Percentage of Participants With Progressive Disease During Neo-Adjuvant Treatment Period | 7.5 percentage of participants |
| Pertuzumab+Docetaxel | Percentage of Participants With Progressive Disease During Neo-Adjuvant Treatment Period | 2.1 percentage of participants |
Secondary
Progression Free and Disease Free Survival
DFS was defined as the time from the first date of no disease (date of surgery) to the first documentation of PD or death. Participants without progression after surgery were considered Disease Free. Any evidence of contralateral disease in-situ was not considered as PD. PFS was defined as the time from the date of randomization to the first documentation of PD or death. Any evidence of contralateral disease in-situ was not considered as PD. DFS and PFS were determined using Kaplan-Meier estimates.
Time frame: Randomization up to a maximum of 329 weeks
Population: ITT Population; Analysis was performed according to initial randomization.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Trastuzumab+Docetaxel | Progression Free and Disease Free Survival | PFS | NA percentage of participants |
| Trastuzumab+Docetaxel | Progression Free and Disease Free Survival | DFS | NA percentage of participants |
| Trastuzumab+Pertuzumab+Docetaxel | Progression Free and Disease Free Survival | DFS | 67.2 percentage of participants |
| Trastuzumab+Pertuzumab+Docetaxel | Progression Free and Disease Free Survival | PFS | 71.0 percentage of participants |
| Trastuzumab+Pertuzumab | Progression Free and Disease Free Survival | PFS | NA percentage of participants |
| Trastuzumab+Pertuzumab | Progression Free and Disease Free Survival | DFS | NA percentage of participants |
| Pertuzumab+Docetaxel | Progression Free and Disease Free Survival | PFS | NA percentage of participants |
| Pertuzumab+Docetaxel | Progression Free and Disease Free Survival | DFS | NA percentage of participants |
Comparison: PFSp-value: 0.298395% CI: [0.34, 1.4]Cochran-Mantel-Haenszel
Comparison: PFSp-value: 0.472295% CI: [0.68, 2.3]Cochran-Mantel-Haenszel
Comparison: PFSp-value: 0.026895% CI: [1.07, 3.93]Cochran-Mantel-Haenszel
Comparison: DFSp-value: 0.180595% CI: [0.28, 1.27]Cochran-Mantel-Haenszel
Comparison: DFSp-value: 0.590195% CI: [0.42, 1.64]Cochran-Mantel-Haenszel
Comparison: DFSp-value: 0.02595% CI: [1.08, 4.32]Cochran-Mantel-Haenszel
Secondary
Time to Clinical Response During Neo-Adjuvant Treatment Period
Time to clinical response was defined as the time from the date of first dose received to the date of assessment of clinical response. Time to Clinical response was determined by Kaplan-Meier estimates. Tumor assessments were made based on the RECIST criteria - version 1.0. The clinical response at each cycle up to the last assessment prior to surgery was derived for: i) the primary breast lesion; (ii) across secondary breast lesions, (iii) across all breast lesions (iv) across axillary nodes (v) across supraclavicular nodes and (vi) across all nodes (vii) across all lesions (overall) using the following algorithm: CR: if measurement of '0' is noted at a given cycle as compared to baseline measurement which is \>0 at screening or cycle 1 day 1; PR: if measurement is at least a 30% decreased compared to baseline levels . (Reference= baseline size or sum of sizes). Clinical Responders are participants who have achieved CR or PR during the Neo-adjuvant treatment.
Time frame: Baseline up to Cycle 4 (assessed at Baseline, Day 1 of Cycles 1-4 Pre-Surgery) Up to approximately 24 months
Population: ITT Population; Analysis was performed according to initial randomization. Number of participants analyzed = participants evaluable for this outcome.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Trastuzumab+Docetaxel | Time to Clinical Response During Neo-Adjuvant Treatment Period | 6.3 months |
| Trastuzumab+Pertuzumab+Docetaxel | Time to Clinical Response During Neo-Adjuvant Treatment Period | 6.3 months |
| Trastuzumab+Pertuzumab | Time to Clinical Response During Neo-Adjuvant Treatment Period | 6.9 months |
| Pertuzumab+Docetaxel | Time to Clinical Response During Neo-Adjuvant Treatment Period | 7.3 months |