A Randomized, Multicenter, Open-Label, Phase III Trial Comparing Trastuzumab Plus Pertuzumab Plus a Taxane Following Anthracyclines Versus Trastuzumab Emtansine Plus Pertuzumab Following Anthracyclines as Adjuvant Therapy in Patients With Operable HER2-Positive Primary Breast Cancer
Overview
- Phase
- Phase 3
- Intervention
- Trastuzumab
- Conditions
- Breast Cancer
- Sponsor
- Hoffmann-La Roche
- Enrollment
- 1846
- Locations
- 295
- Primary Endpoint
- Invasive Disease-Free Survival (IDFS) in the Node-Positive Subpopulation
- Status
- Completed
- Last Updated
- 3 years ago
Overview
Brief Summary
This two-arm, randomized, open-label, multicenter study will evaluate the efficacy and safety of trastuzumab emtansine in combination with pertuzumab versus trastuzumab in combination with pertuzumab and a taxane as adjuvant therapy in participants with human epidermal growth (HER) factor 2 (HER2)-positive primary invasive breast cancer. Following surgery and anthracycline-based chemotherapy, participants will receive either trastuzumab emtansine at a dose of 3.6 milligrams per kilogram (mg/kg) and pertuzumab at a dose of 420 milligrams (mg) intravenously (IV) every 3 weeks (q3w) or trastuzumab at a dose of 6 mg/kg and pertuzumab at a dose of 420 mg IV q3w in combination with a taxane.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to (\</=) 1
- •Non-metastatic histologically confirmed primary invasive breast carcinoma that was operable
- •HER2-positive breast cancer
- •Known hormone receptor status of the primary tumor
- •Adequately excised: participants must have undergone either breast-conserving surgery or mastectomy/nipple- or skin-sparing mastectomy
- •Pathological tumor-node-metastasis staging (Union for International Cancer Control-American Joint Committee on Cancer \[UICC/AJCC\] 7th edition): eligible participants must have either:
- •Node-positive disease (pN more than or equal to \[\>/=\] 1), any tumor size except T0, and any hormonal receptor status; or Node-negative disease (pN0) with pathologic tumor size \>2.0 centimeters by standard local assessment and negative for estrogen receptor (ER) and progesterone receptor (PR) determined by a central pathology laboratory
- •Participants with synchronous bilateral invasive disease are eligible only if both lesions are HER2-positive
- •No more than 9 weeks (63 days) may elapse between definitive breast surgery (or the last surgery if additional resection required for breast cancer) and randomization
- •Baseline left ventricular ejection fraction (LVEF) \>/=55% measured by echocardiogram (ECHO; preferred) or multiple-gated acquisition (MUGA) scans
Exclusion Criteria
- •History of any prior (ipsilateral and/or contralateral) invasive breast carcinoma
- •History of non-breast malignancies within the 5 years prior to randomization, except for carcinoma in situ (CIS) of the cervix, CIS of the colon, melanoma in situ, and basal cell and squamous cell carcinomas of the skin
- •Any clinical T4 tumor as defined by tumor-node-metastasis classification in UICC/AJCC 7th edition, including inflammatory breast cancer
- •For the currently diagnosed breast cancer, any previous systemic anti-cancer treatment (for example, neoadjuvant or adjuvant), including but not limited to, chemotherapy, anti-HER2 therapy (for example, trastuzumab, trastuzumab emtansine, pertuzumab, lapatinib, neratinib, or other tyrosine kinase inhibitors), hormonal therapy, OR anti-cancer radiation therapy (RT) (intra-operative radiotherapy as a boost at the time of primary surgery is acceptable)
- •Previous therapy with anthracyclines, taxanes, or HER2-targeted therapy for any malignancy
- •History of DCIS and/or lobular CIS (LCIS) that was treated with any form of systemic chemotherapy, hormonal therapy, or RT to the ipsilateral breast where invasive cancer subsequently developed. Participants who had their DCIS/LCIS treated with surgery only and/or contralateral DCIS treated with radiation are allowed to enter the study
- •Participants with contraindication to RT while adjuvant RT is clinically indicated
- •Concurrent anti-cancer treatment in another investigational trial
- •Cardiopulmonary dysfunction as defined by protocol: angina pectoris requiring anti-anginal medication, serious cardiac arrhythmia not controlled by adequate medication, severe conduction abnormality, or clinically significant valvular disease, significant symptoms (Grade \>/=2) relating to left ventricular dysfunction, cardiac arrhythmia, or cardiac ischemia, myocardial infarction within 12 months prior to randomization, uncontrolled hypertension, evidence of transmural infarction on electrocardiogram (ECG), requirement for oxygen therapy
- •Other concurrent serious diseases that may interfere with planned treatment, including severe pulmonary conditions/illness, uncontrolled infections, uncontrolled diabetes, or known infection with HIV
Arms & Interventions
Anthracycline Followed by Trastuzumab, Pertuzumab, and Taxane
Trastuzumab and pertuzumab will be administered concurrently for up to a total duration of 1 year (up to 18 cycles \[1 Cycle = 21 days\]) with the taxane (docetaxel or paclitaxel) component of chemotherapy following anthracycline \[5 fluorouracil, epirubicin, and cyclophosphamide (FEC) or epirubicin and cyclophosphamide (EC) or doxorubicin and cyclophosphamide (AC)\] based chemotherapy.
Intervention: Trastuzumab
Anthracycline Followed by Trastuzumab, Pertuzumab, and Taxane
Trastuzumab and pertuzumab will be administered concurrently for up to a total duration of 1 year (up to 18 cycles \[1 Cycle = 21 days\]) with the taxane (docetaxel or paclitaxel) component of chemotherapy following anthracycline \[5 fluorouracil, epirubicin, and cyclophosphamide (FEC) or epirubicin and cyclophosphamide (EC) or doxorubicin and cyclophosphamide (AC)\] based chemotherapy.
Intervention: Pertuzumab
Anthracycline Followed by Trastuzumab, Pertuzumab, and Taxane
Trastuzumab and pertuzumab will be administered concurrently for up to a total duration of 1 year (up to 18 cycles \[1 Cycle = 21 days\]) with the taxane (docetaxel or paclitaxel) component of chemotherapy following anthracycline \[5 fluorouracil, epirubicin, and cyclophosphamide (FEC) or epirubicin and cyclophosphamide (EC) or doxorubicin and cyclophosphamide (AC)\] based chemotherapy.
Intervention: Paclitaxel
Anthracycline Followed by Trastuzumab Emtansine and Pertuzumab
Trastuzumab emtansine and pertuzumab will continue for up to a total duration of 1 year (up to 18 cycles \[1 Cycle = 21 days\]) following anthracycline \[5 fluorouracil, epirubicin, and cyclophosphamide (FEC) or epirubicin and cyclophosphamide (EC) or doxorubicin and cyclophosphamide (AC)\] based chemotherapy.
Intervention: Trastuzumab Emtansine
Anthracycline Followed by Trastuzumab, Pertuzumab, and Taxane
Trastuzumab and pertuzumab will be administered concurrently for up to a total duration of 1 year (up to 18 cycles \[1 Cycle = 21 days\]) with the taxane (docetaxel or paclitaxel) component of chemotherapy following anthracycline \[5 fluorouracil, epirubicin, and cyclophosphamide (FEC) or epirubicin and cyclophosphamide (EC) or doxorubicin and cyclophosphamide (AC)\] based chemotherapy.
Intervention: Epirubicin
Anthracycline Followed by Trastuzumab, Pertuzumab, and Taxane
Trastuzumab and pertuzumab will be administered concurrently for up to a total duration of 1 year (up to 18 cycles \[1 Cycle = 21 days\]) with the taxane (docetaxel or paclitaxel) component of chemotherapy following anthracycline \[5 fluorouracil, epirubicin, and cyclophosphamide (FEC) or epirubicin and cyclophosphamide (EC) or doxorubicin and cyclophosphamide (AC)\] based chemotherapy.
Intervention: Doxorubicin
Anthracycline Followed by Trastuzumab, Pertuzumab, and Taxane
Trastuzumab and pertuzumab will be administered concurrently for up to a total duration of 1 year (up to 18 cycles \[1 Cycle = 21 days\]) with the taxane (docetaxel or paclitaxel) component of chemotherapy following anthracycline \[5 fluorouracil, epirubicin, and cyclophosphamide (FEC) or epirubicin and cyclophosphamide (EC) or doxorubicin and cyclophosphamide (AC)\] based chemotherapy.
Intervention: Docetaxel
Anthracycline Followed by Trastuzumab, Pertuzumab, and Taxane
Trastuzumab and pertuzumab will be administered concurrently for up to a total duration of 1 year (up to 18 cycles \[1 Cycle = 21 days\]) with the taxane (docetaxel or paclitaxel) component of chemotherapy following anthracycline \[5 fluorouracil, epirubicin, and cyclophosphamide (FEC) or epirubicin and cyclophosphamide (EC) or doxorubicin and cyclophosphamide (AC)\] based chemotherapy.
Intervention: Cyclophosphamide
Anthracycline Followed by Trastuzumab, Pertuzumab, and Taxane
Trastuzumab and pertuzumab will be administered concurrently for up to a total duration of 1 year (up to 18 cycles \[1 Cycle = 21 days\]) with the taxane (docetaxel or paclitaxel) component of chemotherapy following anthracycline \[5 fluorouracil, epirubicin, and cyclophosphamide (FEC) or epirubicin and cyclophosphamide (EC) or doxorubicin and cyclophosphamide (AC)\] based chemotherapy.
Intervention: 5-Fluorouracil
Anthracycline Followed by Trastuzumab Emtansine and Pertuzumab
Trastuzumab emtansine and pertuzumab will continue for up to a total duration of 1 year (up to 18 cycles \[1 Cycle = 21 days\]) following anthracycline \[5 fluorouracil, epirubicin, and cyclophosphamide (FEC) or epirubicin and cyclophosphamide (EC) or doxorubicin and cyclophosphamide (AC)\] based chemotherapy.
Intervention: Epirubicin
Anthracycline Followed by Trastuzumab Emtansine and Pertuzumab
Trastuzumab emtansine and pertuzumab will continue for up to a total duration of 1 year (up to 18 cycles \[1 Cycle = 21 days\]) following anthracycline \[5 fluorouracil, epirubicin, and cyclophosphamide (FEC) or epirubicin and cyclophosphamide (EC) or doxorubicin and cyclophosphamide (AC)\] based chemotherapy.
Intervention: Doxorubicin
Anthracycline Followed by Trastuzumab Emtansine and Pertuzumab
Trastuzumab emtansine and pertuzumab will continue for up to a total duration of 1 year (up to 18 cycles \[1 Cycle = 21 days\]) following anthracycline \[5 fluorouracil, epirubicin, and cyclophosphamide (FEC) or epirubicin and cyclophosphamide (EC) or doxorubicin and cyclophosphamide (AC)\] based chemotherapy.
Intervention: Cyclophosphamide
Anthracycline Followed by Trastuzumab Emtansine and Pertuzumab
Trastuzumab emtansine and pertuzumab will continue for up to a total duration of 1 year (up to 18 cycles \[1 Cycle = 21 days\]) following anthracycline \[5 fluorouracil, epirubicin, and cyclophosphamide (FEC) or epirubicin and cyclophosphamide (EC) or doxorubicin and cyclophosphamide (AC)\] based chemotherapy.
Intervention: 5-Fluorouracil
Outcomes
Primary Outcomes
Invasive Disease-Free Survival (IDFS) in the Node-Positive Subpopulation
Time Frame: Last participant randomized to data cut-off date of 27 November 2019 (approximately 70 months). The 3 year IDFS event-free rate was assessed based on the data collected for each participant considering the cut-off date mentioned above.
IDFS event was defined as the time from randomization until the date of first occurrence of one of the following: Ipsilateral invasive breast tumor recurrence (an invasive breast cancer \[bc\] involving the same breast parenchyma as the original primary lesion); Ipsilateral local-regional invasive bc recurrence (an invasive bc in the axilla, regional lymph nodes, chest wall, and/or skin of the ipsilateral breast); Contralateral or ipsilateral second primary invasive bc; Distant recurrence (evidence of bc in any anatomic site \[other than the three sites mentioned above\]) that has either been histologically confirmed or clinically/radiographically diagnosed as recurrent invasive bc; Death attributable to any cause, including bc, non-bc, or unknown cause. 3-year IDFS event-free rate per randomized treatment arms in the ITT population was estimated using the Kaplan-Meier method and estimated the probability of a participant being event-free after 3 years after randomization.
Invasive Disease-Free Survival (IDFS) in the Overall Population
Time Frame: First participant randomized up to approximately 7.5 years
IDFS event was defined as the time from randomization until the date of first occurrence of one of the following: Ipsilateral invasive breast tumor recurrence (an invasive breast cancer \[bc\] involving the same breast parenchyma as the original primary lesion); Ipsilateral local-regional invasive bc recurrence (an invasive bc in the axilla, regional lymph nodes, chest wall, and/or skin of the ipsilateral breast); Contralateral or ipsilateral second primary invasive bc; Distant recurrence (evidence of bc in any anatomic site \[other than the three sites mentioned above\]) that has either been histologically confirmed or clinically/radiographically diagnosed as recurrent invasive bc; Death attributable to any cause, including bc, non-bc, or unknown cause. 3-year IDFS event-free rate per randomized treatment arms in the ITT population were estimated using the Kaplan-Meier method and estimated the probability of a patient being event-free after 3 years after randomization.
Secondary Outcomes
- Overall Survival (OS)(First participant randomized up to approximately 7.5 years)
- IDFS Plus Second Primary Non-Breast Cancer(Baseline up to approximately 70 months)
- Disease-Free Survival (DFS)(Baseline up to approximately 70 months)
- Distant Recurrence-Free Interval (DRFI)(Baseline up to approximately 70 months)
- Percentage of Participants With Adverse Events(From randomization to approximately 7.5 years)
- Percentage of Participants With Decrease in Left Ventricular Ejection Fraction (LVEF) From Baseline Over Time(First participant randomized up to approximately 7.5 years.)
- European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Score(Baseline, Cycles 1, 2, 3, 4, 5, 9, 14, End of Treatment, Follow-up Month 6, Follow-up Month 12, Follow-up Month 18)
- EORTC Quality of Life Questionnaire-Breast Cancer 23 (QLQ-BR23) Score(Baseline, Cycles 1, 2, 3, 4, 5, 9, 14, End of Treatment, Follow-up Month 6, Follow-up Month 12, Follow-up Month 18)
- Time to Clinically Meaningful Deterioration in the Global Health Status/ Quality of Life and Functional (Physical, Role, and Cognitive) Subscales of the QLQ-C30 From First HER2-Targeted Treatment(From start of HER-2 targeted treatment up to 18 months after treatment discontinuation. The median time to clinically meaningful deterioration was assessed based on the data collection described above.)