A Study of Trastuzumab Emtansine Versus Trastuzumab as Adjuvant Therapy in Patients With HER2-Positive Breast Cancer Who Have Residual Tumor in the Breast or Axillary Lymph Nodes Following Preoperative Therapy (KATHERINE)

Hoffmann-La Roche1,486 enrolled

Overview

This 2-arm, randomized, open-label study will evaluate the efficacy and safety of trastuzumab emtansine versus trastuzumab as adjuvant therapy in patients with HER2-positive breast cancer who have residual tumor present in the breast or axillary lymph nodes following preoperative therapy. Eligible patients will be randomized to receive either trastuzumab emtansine 3.6 mg/kg or trastuzumab 6 mg/kg intravenously every 3 weeks for 14 cycles. Radiotherapy and/or hormone therapy will be given in addition if indicated.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

1,486

Conditions

Breast Cancer

Interventions

trastuzumab

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Adult patient, \>/= 18 years of age * HER2-positive breast cancer * Histologically confirmed invasive breast carcinoma * Clinical stage T1-4/N0-3/M0 at presentation (patients with T1a/bN0 tumors will not be eligible) * Completion of preoperative systemic chemotherapy and HER2-directed treatment consisting of at least 6 cycles of chemotherapy with a total duration of at least 16 weeks, including at least 9 weeks of trastuzumab and at least 9 weeks of taxane-based therapy * Adequate excision: surgical removal of all clinically evident disease in the breast and lymph nodes as specified in protocol * Pathological evidence of residual invasive carcinoma in the breast or axillary lymph nodes following completion of preoperative therapy * An interval of no more than 12 weeks between the date of surgery and the date of randomization * Known hormone-receptor status * Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 * Adequate hematologic, renal and liver function * Screening Left ventricular ejection fraction (LVEF) \>/= 50% on echocardiogram (ECHO) or multiple-gated acquisition (MUGA) after receiving neoadjuvant chemotherapy and no decrease in LVEF by more than 15% absolute points from the pre-chemotherapy LVEF. Or, if pre-chemotherapy LVEF was not assessed, the screening LVEF must be \>/= 55% after completion of neoadjuvant chemotherapy. * For women who are not postmenopausal or surgically sterile: agreement to remain abstinent or use single or combined contraceptive methods that result in a failure rate of \< 1% per year during the treatment period and for at least 7 months after the last dose of study drug * Documentation of hepatitis B virus and hepatitis C virus serology is required Exclusion Criteria: * Stage IV (metastatic) breast cancer * History of any prior (ipsi- or contralateral breast cancer except lobular carcinoma in situ * Evidence of clinically evident gross residual or recurrent disease following preoperative therapy and surgery * Progressive disease during preoperative systemic therapy * Treatment with any anti-cancer investigational drug within 28 days prior to commencing study treatment * History of other malignancy within the last 5 years except for appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, Stage I uterine cancer, or other non-breast malignancies with a similar outcome to those mentioned above * Patients for whom radiotherapy would be recommended for breast cancer treatment but for whom it is contraindicated because of medical reasons * Current NCI CTCAE (Version 4.0) Grade \>/= 2 peripheral neuropathy * History of exposure to the following cumulative doses of anthracyclines: Doxorubicin \> 240 mg/m2; Epirubicin or Liposomal Doxorubicin-Hydrochloride (Myocet®) \> 480 mg/m2; For other anthracyclines, exposure equivalent to doxorubicin \> 240 mg/m2 * Cardiopulmonary dysfunction as defined by protocol * Prior treatment with trastuzumab emtansine * Current severe, uncontrolled systemic disease * Pregnant or lactating women * Any known active liver disease, e.g. due to HBV, HCV, autoimmune hepatic disorders, or sclerosing cholangitis * Concurrent serious uncontrolled infections requiring treatment or known infection with HIV * History of intolerance, including Grade 3 to 4 infusion reaction or hypersensitivity to trastuzumab or murine proteins or any components of the product

Locations (268)

Providence Alaska Medical Center

Anchorage, Alaska, United States

Todd Cancer Institute at Long Beach Memorial Medical Center

Long Beach, California, United States

Chao Family Comprehensive Cancer Center

Orange, California, United States

Stanford University Medical Center

Palo Alto, California, United States

Kaiser Permanente - San Diego

San Diego, California, United States

Outcomes

Primary Outcomes

Invasive Disease-free Survival (IDFS) Rate at 3 Years

IDFS event was defined as the first occurrence of any one of the following events: ipsilateral invasive breast tumor recurrence (i.e., an invasive breast cancer involving the same breast parenchyma as the original primary lesion); ipsilateral local-regional invasive breast cancer recurrence (i.e., an invasive breast cancer in the axilla, regional lymph nodes, chest wall and/or skin of the ipsilateral breast); distant recurrence (i.e., evidence of breast cancer in any anatomic site-other than the 2 above-mentioned sites - that has either been histologically confirmed or clinically diagnosed as recurrent invasive breast cancer); contralateral invasive breast cancer; death attributable to any cause including breast cancer, non-breast cancer or unknown cause . 3-year IDFS rate in ITT population was estimated using Kaplan Meier (KM) method and the percentage of participants who were event-free 3 years after randomization was estimated.

Time frame: At Year 3

Secondary Outcomes

IDFS Including Second Primary Non-breast Cancer (SPNBC) Rate at 3 Years

IDFS including SPNBC was defined the same way as IDFS but including second primary non breast invasive cancer as an event (with the exception of non-melanoma skin cancers and carcinoma in situ \[CIS\] of any site). IDFS event was defined as outlined in the description for IDFS rate outcome measure (OM) number 1. 3-year IDFS including SPNBC rate in the ITT population was estimated using KM method, and the percentage of participants who were event-free 3 years after randomization was estimated.

Time frame: At Year 3

IDFS Including SPNBC Rate at 7 Years

IDFS including SPNBC was defined the same way as IDFS but including second primary non breast invasive cancer as an event (with the exception of non-melanoma skin cancers and CIS of any site). IDFS event was defined as outlined in the description for IDFS rate OM number 1. 7-year IDFS including SPNBC rate in the ITT population was estimated using KM method, and the percentage of participants who were event-free 7 years after randomization was estimated.

Time frame: At Year 7

IDFS Including SPNBC Rate at 8 Years

IDFS including SPNBC was defined the same way as IDFS but including second primary non breast invasive cancer as an event (with the exception of non-melanoma skin cancers and CIS of any site). IDFS event was defined as outlined in the description for IDFS rate OM number 1. 8-year IDFS including SPNBC rate in the ITT population was estimated using KM method, and the percentage of participants who were event-free 8 years after randomization was estimated.

Time frame: At Year 8

Disease-free Survival (DFS) Rate at 3 Years

DFS was defined as the time between randomization and the date of the first occurrence of an IDFS event including SPNBC event or contralateral or ipsilateral ductal carcinoma in situ (DCIS). IDFS event was defined as outlined in the description for IDFS rate OM number 1. 3-year DFS rate in the ITT population was estimated using KM method, and the percentage of participants who were event-free 3 years after randomization was estimated.

Time frame: At Year 3

DFS Rate at 7 Years

DFS was defined as the time between randomization and the date of the first occurrence of an IDFS event including SPNBC event or contralateral or ipsilateral DCIS. IDFS event was defined as outlined in the description for IDFS rate OM number 1. 7-year DFS rate in the ITT population was estimated using KM method, and the percentage of participants who were event-free 7 years after randomization was estimated.

Time frame: At Year 7

DFS Rate at 8 Years

DFS was defined as the time between randomization and the date of the first occurrence of an IDFS event including SPNBC event or contralateral or ipsilateral DCIS. IDFS event was defined as outlined in the description for IDFS rate OM number 1. 8-year DFS rate in the ITT population was estimated using KM method, and the percentage of participants who were event-free 8 years after randomization was estimated.

Time frame: At Year 8

Overall Survival (OS) Rate at 5 Years

OS was defined as the time from randomization to death due to any cause. 5-year OS event-free rate in the ITT population was estimated using KM method, and the percentage of participants who were event-free 5 years after randomization was estimated.

Time frame: At Year 5

OS Rate at 7 Years

OS was defined as the time from randomization to death due to any cause. 7-year OS event-free rate in the ITT population was estimated using KM method, and the percentage of participants who were event-free 7 years after randomization was estimated.

Time frame: At Year 7

OS Rate at 8 Years

OS was defined as the time from randomization to death due to any cause. 8-year OS event-free rate in the ITT population was estimated using KM method, and the percentage of participants who were event-free 8 years after randomization was estimated.

Time frame: At Year 8

Distant Recurrence-free Interval (DRFI) Rate at 3 Years

DRFI was defined as the time between randomization and the date of distant breast cancer recurrence. 3-year DRFI event-free rate in the ITT population was estimated using KM method, and the percentage of participants who were event-free 3 years after randomization was estimated.

Time frame: At Year 3

DRFI Rate at 7 Years

DRFI was defined as the time between randomization and the date of distant breast cancer recurrence. 7-year DRFI event-free rate in the ITT population was estimated using KM method, and the percentage of participants who were event-free 7 years after randomization was estimated.

Time frame: At Year 7

DRFI Rate at 8 Years

DRFI was defined as the time between randomization and the date of distant breast cancer recurrence. 8-year DRFI event-free rate in the ITT population was estimated using KM method, and the percentage of participants who were event-free 8 years after randomization was estimated.

Time frame: At Year 8

Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)

AE=any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product, regardless of causal attribution. AE can therefore be any unfavorable \& unintended sign (including abnormal laboratory finding), symptom/disease temporally associated with use of a medicinal product, whether or not considered related to medicinal product. SAE=any AE that met any given criteria: fatal (i.e. AE causes/leads to death); life-threatening (i.e. AE, in view of investigator, placed the participant at immediate risk of death); required/prolonged inpatient hospitalization; resulted in persistent or significant disability/incapacity (i.e. AE results in substantial disruption of participant's ability to conduct normal life functions); congenital anomaly/birth defect in a neonate/infant born to a mother exposed to study drug; significant medical event in investigator's judgment. Percentages have been rounded off.

Time frame: From signing of informed consent till end of follow up (up to approximately 131 months)

Percentage of Participants With Cardiac Events as Adjudicated by the Cardiac Review Committee

Cardiac events were defined as death from cardiac cause or severe congestive heart failure (New York Heart Association \[NYHA\] Class III or IV) with a decrease in left ventricular ejection fraction (LVEF) of 10 percentage points or more from baseline to an LVEF of \< 50%. Other cardiac-related events (e.g., any symptomatic congestive heart failure \[CHF\] associated with a 10% drop in LVEF to \< 50%; asymptomatic declines in LVEF requiring dose delay) were summarized as adjudicated by the Cardiac Review Committee. Percentages have been rounded off.

Time frame: Up to approximately 126 months

Percentage of Participants With Hepatotoxicity Events as Adjudicated by the Hepatic Review Committee

Hepatotoxicity events were summarized by treatment arm. Hepatotoxicity events were assessed using liver function laboratory test (LFT) results which included the analysis of baseline and post-baseline levels of alanine transaminase (ALT), aspartate aminotransferase (AST), total bilirubin (TBILI), and alkaline phosphatase (ALK). Hepatic events, as adjudicated by the Hepatic Review Committee, are summarized. Percentages have been rounded off.

Time frame: Up to approximately 64 months

Number of Participants Who Discontinued Treatment Due to AEs

Time frame: Up to approximately 9.6 months

Number of Participants With AEs and SAEs Leading to Death

An AE was any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product, regardless of causal attribution. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. A SAE was any AE that met any of the following criteria: fatal (i.e., the AE actually causes or leads to death); life-threatening (i.e., the AE, in the view of the investigator, placed the participant at immediate risk of death); required or prolonged inpatient hospitalization; resulted in persistent or significant disability/incapacity (i.e., the AE results in substantial disruption of the participant's ability to conduct normal life functions); congenital anomaly/birth defect in a neonate/infant born to a mother exposed to study drug; significant medical event in the investigator's judgment.

Time frame: From signing of informed consent till end of follow up (up to approximately 131 months)

Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire - Core 30 (QLQ-C30)

The EORTC QLQ-C30 consists of 30 questions which assess five functional domains (physical, role, cognitive, emotional, and social), a global health status/quality of life (GHS/QoL) scale, three symptom scales (fatigue, pain, nausea, and vomiting), five single items (dyspnea, appetite loss, sleep disturbance, constipation, and diarrhea), and a perceived financial impact of the disease item. Most questions used a 4-point scale (1= Not at all to 4 = Very much; 2 questions used a 7-point scale \[1 = very poor to 7 = Excellent\]). Obtained scores are linearly transformed to a score range of 0-100, whereby higher scores indicate greater functioning, greater quality of life, or a greater degree of symptoms. A positive change from baseline indicates improvement.

Time frame: Baseline, Cycles 5 &11, Follow-up (FU) Month 6, FU Month 12 (1 cycle = 21 days)

Change From Baseline in EORTC Quality of Life Questionnaire - Breast Cancer (QLQ-BR23)

EORTC-QLQ-BR23 is a 23-item breast cancer-specific companion module to the EORTC-QLQ-C30 and consists of four functional scales (body image, sexual enjoyment, sexual functioning, future perspective \[FP\]) and four symptom scales (systemic side effects \[SE\], upset by hair loss, arm symptoms, breast symptoms). Questions used 4-point scale (1=not at all, 2=a little, 3=quite a bit, 4=very much). Obtained scores are linearly transformed to a score range of 0-100. High score for functional scale indicated high/better level of functioning/healthy functioning. Higher scores for symptom scales represent higher levels of symptoms/problems. For functional scales, positive change from baseline indicated deterioration in QOL and negative change from baseline indicated an improvement in QOL. For symptom scales, positive change from baseline indicated an improvement in QOL and negative change from baseline indicated a deterioration in QOL.

Time frame: Baseline, Cycles 5 &11, Follow-up (FU) Month 6, FU Month 12 (1 cycle = 21 days)

Serum Concentrations of Trastuzumab Emtansine

Time frame: Pre-infusion on Cycles 1, 2, 4 and 5; 15-30 minutes and 2 hours post-infusion on Cycles 1 and 4; treatment discontinuation/completion visit (up to approximately 64 months) (1 cycle = 21 days)

Plasma Concentrations of Deacetyl Mercapto 1-Oxopropyl Maytansine (DM1)

Concentration of DM1 in plasma was measured through the samples obtained from participants randomized to the trastuzumab emtansine arm. DM1 is an ant-microtubule agent derived from maytansine. In transtuzumab entansine, DM1 is linked to the antibody transtuzumab thus helping the drug to specifically target the HER 2- positive cancer cells.

Time frame: Pre-infusion, 15-30 minutes and 2 hour post-infusion on Cycles 1 and 4 (1 cycle = 21 days)

Serum Concentrations of Trastuzumab

Time frame: Pre-infusion and 15-30 minutes post-infusion on Cycles 1 and 4; Treatment completion/discontinuation visit (up to approximately 64 months) (1 cycle = 21 days)

Serum Concentrations of Total Trastuzumab

Total trastuzumab is the sum of conjugated and unconjugated trastuzumab. Blood and serum samples were obtained from participants randomized to the trastuzumab arm.

Time frame: Pre-infusion on Day 1 of Cycles 1, 2, 4, and 5; 15-30 minutes and 2 hours post-infusion on Day 1 of Cycles 1 and 4 (1 cycle = 21 days)

Median Duration of Trastuzumab Emtansine Exposure

Treatment duration was defined as the time between the first and the last infusion of trastuzumab emtansine.

Time frame: Up to 12 months

Number of Participants With Positive Anti-drug Antibodies (ADAs) to Trastuzumab Emtansine

ADA-positive participants after drug administration were determined for participants exposed to trastuzumab emtansine. For determining post-baseline incidence, participants were considered to be ADA-positive if they were ADA-negative or had missing data at baseline but developed an ADA response following study drug exposure, or if they were ADA-positive at baseline and the titer of 1 or more post-baseline samples was at least 0.60 titer units (t.u.) greater than the baseline titer result. The total number of participants who developed ADAs to trastuzumab emtansine was determined by summing the ADA-positive participants across all timepoints.

Time frame: Baseline (Day1 of Cycle1) and Post Baseline (Day 1 of Cycle 4 up to 3-4 months after last dose of the drug [up to approximately 13.6 months])

Number of Participants With Positive ADAs to Trastuzumab

ADA-positive participants after drug administration were determined for participants exposed to trastuzumab. For determining post-baseline incidence, participants were considered to be ADA-positive if they were ADA-negative or had missing data at baseline but developed an ADA response following study drug exposure, or if they were ADA-positive at baseline and the titer of 1 or more post-baseline samples was at least 0.60 t.u. greater than the baseline titer result. The total number of participants who developed ADAs to trastuzumab was determined by summing the ADA-positive participants across all timepoints.

Time frame: Baseline (Day1 of Cycle1) and Post Baseline (Day 1 of Cycle 4 up to 3-4 months after last dose of the drug [up to approximately 13.6 months])