A Study to Evaluate the Efficacy and Safety of Trastuzumab Emtansine in Combination With Atezolizumab or Atezolizumab-Placebo in Participants With Human Epidermal Growth Factor-2 (HER2) Positive Locally Advanced or Metastatic Breast Cancer (BC) Who Received Prior Trastuzumab and Taxane Based Therapy (KATE2)

A Randomized, Multicenter, Double-Blind, Placebo-Controlled Phase II Study of the Efficacy and Safety of Trastuzumab Emtansine in Combination With Atezolizumab or Atezolizumab-Placebo in Patients With HER2-Positive Locally Advanced or Metastatic Breast Cancer Who Have Received Prior Trastuzumab and Taxane Based Therapy

This Phase II, double-blind, randomized, placebo-controlled multicenter study will investigate the efficacy and safety of trastuzumab emtansine in combination with atezolizumab or atezolizumab-placebo in participants with HER2-positive locally advanced or metastatic BC who have received prior trastuzumab and taxane based therapy, either alone or in combination, and/or who have progressed within 6 months after completing adjuvant therapy.

Study Overview

• Status: Completed
• Conditions: Metastatic Breast Cancer
• Intervention / Treatment: Other: Placebo; Drug: Atezolizumab; Drug: Trastuzumab emtansine

• Study Type: Interventional
• Enrollment (Actual): 202
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Kogarah, New South Wales, Australia, 2217
      • St George Hospital; Cancer Care Centre
    • Waratah, New South Wales, Australia, 2298
      • Calvary Mater Newcastle
  • Queensland
    • Woolloongabba, Queensland, Australia, 4102
      • Princess Alexandra Hospital Woolloongabba; Clinical Hematology and Medical Oncology
  • Victoria
    • East Melbourne, Victoria, Australia, 3002
      • Peter MacCallum Cancer Center
    • Frankston, Victoria, Australia, 3199
      • Peninsula and South Eastern Haematology and Oncology Group
    • St Albans, Victoria, Australia, 3021
      • Sunshine Hospital
  • Western Australia
    • Subiaco, Western Australia, Australia, 6008
      • St John of God Hospital; Bendat Cancer Centre
• Canada
  • Ontario
    • Oshawa, Ontario, Canada, L1G 2B9
      • Lakeridge Health Oshawa; Oncology
    • Ottawa, Ontario, Canada, K1H 8L6
      • The Ottawa Hospital Cancer Centre; Oncology
    • Toronto, Ontario, Canada, M4N 3M5
      • Sunnybrook Odette Cancer Centre
  • Quebec
    • Montreal, Quebec, Canada, H4A 3J1
      • McGill University; Glen Site; Oncology
    • Montreal, Quebec, Canada, H3T 1E2
      • McGill University; Sir Mortimer B Davis Jewish General Hospital; Oncology
    • Quebec City, Quebec, Canada, G1S 4L8
      • Hopital du Saint Sacrement
• Germany
  • Berlin, Germany, 14169
    • Studienzentrum Berlin City
  • Berlin, Germany, 13125
    • HELIOS Klinikum Berlin-Buch; Klinik für Gynäkologie und Geburtshilfe
  • Essen, Germany, 45136
    • Klinikum Essen-Mitte Ev. Huyssens-Stiftung / Knappschafts GmbH; Klinik für Senologie / Brustzentrum
  • Freiburg, Germany, 79110
    • Praxis für Interdisziplinäre Onkologie und Hämatologie GbR
  • Heidelberg, Germany, 69120
    • Nationales Centrum für Tumorerkrankungen (NCT) ; Gyn. Onk. Frauenklinik; Uniklinikum Heidelberg
  • Koblenz, Germany, 56068
    • Institut für Versorgungsforschung in der Onkologie GbR Koblenz
• Italy
  • Campania
    • Napoli, Campania, Italy, 80131
      • IRCCS Istituto Nazionale Tumori Fondazione Pascale; Oncologia Medica A
  • Emilia-Romagna
    • Bologna, Emilia-Romagna, Italy, 40138
      • A.O.U Policlinico S. Orsola Malpighi di Bologna U.O di Medicina Interna Borghi - Pad.2
    • Parma, Emilia-Romagna, Italy, 43100
      • Ospedale Regionale Di Parma; Divisione Di Oncologia Medica
  • Friuli-Venezia Giulia
    • Aviano, Friuli-Venezia Giulia, Italy, 33081
      • Centro Di Riferimento Oncologico; SOC Oncologia Medica C
  • Sicilia
    • Catania, Sicilia, Italy, 95126
      • Centro Catanese Di Oncologia; Oncologia Medica
  • Toscana
    • Prato, Toscana, Italy, 59100
      • Ospedale Santo Stefano, Azienda USL Centro Prato
• Korea, Republic of
  • Goyang-si, Korea, Republic of, 10408
    • National Cancer Center
  • Seoul, Korea, Republic of, 03080
    • Seoul National University Hospital
  • Seoul, Korea, Republic of, 03722
    • Severance Hospital, Yonsei University Health System
  • Seoul, Korea, Republic of, 05505
    • Asan Medical Center
  • Seoul, Korea, Republic of, (0)6351
    • Samsung Medical Center
• Spain
  • Barcelona, Spain, 08035
    • Hospital Univ Vall d'Hebron; Servicio de Oncologia
  • La Coruña, Spain, 15006
    • Complejo Hospitalario Universitario A Coruña (CHUAC, Materno Infantil), Oncología
  • Madrid, Spain, 28034
    • Hospital Ramon y Cajal; Servicio de Oncologia
  • Valencia, Spain, 46010
    • Hospital Clinico Universitario de Valencia; Servicio de Onco-hematologia
  • Valencia, Spain, 46015
    • Hospital Arnau de Vilanova (Valencia) Servicio de Oncologia
  • Cordoba
    • Córdoba, Cordoba, Spain, 14004
      • Hospital Universitario Reina Sofia; Servicio de Oncologia
• Taiwan
  • Changhua, Taiwan, 500
    • Changhua Christian Hospital; Dept of Surgery
  • Kaohsiung, Taiwan, 807
    • Kaohsiung Medical Uni Chung-Ho Hospital; Dept of Surgery
  • Taichung, Taiwan, 404
    • China Medical University Hospital; Surgery
  • Tainan, Taiwan, 736
    • Chi-Mei Medical Center
  • Taipei, Taiwan, 00112
    • VETERANS GENERAL HOSPITAL; Department of General Surgery
  • Taipei, Taiwan, 100
    • National Taiwan Uni Hospital; General Surgery
  • Taipei City, Taiwan, 11259
    • Koo Foundation Sun Yat-Sen Cancer Center; Hemato-Oncology
  • Taoyuan, Taiwan, 333
    • Chang Gung Memorial Hospital - Linkou
• United Kingdom
  • Bath, United Kingdom, BA1 3NG
    • Royal United Hospital; Oncology Department
  • Glasgow, United Kingdom, G12 0YN
    • Beatson West of Scotland Cancer Centre
  • London, United Kingdom, NW3 2QG
    • Royal Free Hospital; Dept of Oncology
  • London, United Kingdom, SW3 6JJ
    • Royal Marsden Hosp NHS Fnd; Breast Unit
  • Manchester, United Kingdom, M20 4QL
    • Christie Hospital; Breast Cancer Research Office
  • Nottingham, United Kingdom, NG5 1PB
    • Nottingham City Hospital
  • Sheffield, United Kingdom, S10 2SJ
    • Weston Park Hospital; Cancer Clinical Trials Centre
  • Sutton, United Kingdom, SM2 5PT
    • Royal Marsden Hosp NHS Fnd; Medicine - Breast Unit
  • Swansea, United Kingdom, SA2 8QA
    • Singleton Hospital; Pharmacy
• United States
  • California
    • Orange, California, United States, 92868
      • Breastlink Med Group Inc
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado
  • District of Columbia
    • Washington, District of Columbia, United States, 20007
      • MedStar Georgetown University Hospital (Lombardi Comprehensive Cancer Center)
  • Florida
    • Fort Myers, Florida, United States, 33916
      • SCRI Florida Cancer Specialists South
    • Saint Petersburg, Florida, United States, 33719
      • Florida Cancer Specialists; Saint Petersburg
  • Georgia
    • Atlanta, Georgia, United States, 30342
      • Northside Hospital
  • Maryland
    • Baltimore, Maryland, United States, 21231
      • Johns Hopkins Univ Med Center
  • New Mexico
    • Farmington, New Mexico, United States, 87401
      • San Juan Oncology Associates
  • New York
    • New York, New York, United States, 10016
      • Laura and ISAAC Perlmutter Cancer Center at NYU Langone.
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Ohio State Uni Medical Center
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • Magee Womens Hospital
    • York, Pennsylvania, United States, 17403
      • Cancer Care Associates of York
  • Tennessee
    • Chattanooga, Tennessee, United States, 37404
      • SCRI Tennessee Oncology Chattanooga
    • Nashville, Tennessee, United States, 37203
      • Tennessee Oncology; Sarah Cannon Research Institute
  • Washington
    • Seattle, Washington, United States, 98195
      • University of Washington

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Archival tumor samples must be obtained from primary and/or metastatic sites
• Able to submit tumor tissue that is evaluable for programmed death- ligand 1 (PD-L1) expression
• HER-2 positive BC as defined by an immunohistochemistry score of 3 or gene amplified by in-situ hybridization as defined by a ratio of greater than or equal to (>=) 2.0 for the number of HER2 gene copies to the number of chromosome 17 copies
• Histologically or cytologically confirmed invasive BC: incurable, unresectable, locally advanced BC previously treated with multimodality therapy or metastatic BC
• Prior treatment for BC in the: adjuvant; unresectable locally advanced; or metastatic settings; which must include both, a taxane and trastuzumab (alone or in combination with another agent)
• Progression must have occurred during or after most recent treatment for locally advanced/metastatic BC or within 6 months after completing adjuvant therapy
• Participants must have measurable disease that is evaluable as per RECIST v1.1
• Eastern Cooperative Oncology Group Performance Status of 0 or 1
• Negative serum pregnancy test within 7 days of enrollment for pre-menopausal women and for women less than 12 months after the onset of menopause
• Use of highly effective method of contraception as defined by the protocol

Exclusion Criteria:

• Prior treatment with trastuzumab emtansine, cluster of differentiation 137 agonists, anti-programmed death-1, or anti-PD-L1 therapeutic antibody or pathway-targeting agents
• Receipt of any anti-cancer drug/biologic or investigational treatment within 21 days prior to Cycle 1 Day 1 except hormone therapy, which can be given up to 7 days prior to Cycle 1 Day 1; recovery of treatment related toxicity consistent with other eligibility criteria
• Radiation therapy within 2 weeks prior to Cycle 1, Day 1
• History of exposure to the cumulative doses of anthracyclines
• History of other malignancy within the previous 5 years, except for appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, Stage I uterine cancer, or participants who have undergone potentially curative therapy with no evidence of disease and are deemed by the treating physician to be at low risk for recurrence
• Cardiopulmonary dysfunction, symptomatic pleural effusion, pericardial effusion, or ascites
• Participants with severe infection within 4 weeks prior to randomization, including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia
• Current severe, uncontrolled systemic disease
• Major surgical procedure or significant traumatic injury within 28 days prior to randomization or anticipation of the need for major surgery during the course of study treatment
• Clinically significant history of liver disease, including cirrhosis, current alcohol abuse, autoimmune hepatic disorders, sclerosis cholangitis or active infection with human immunodeficiency virus, hepatitis B virus, or hepatitis C virus
• Need for current chronic corticosteroid therapy (>=10 mg of prednisone per day or an equivalent dose of other anti-inflammatory corticosteroids)
• Spinal cord compression not definitively treated with surgery and/or radiation, or previously diagnosed and treated spinal cord compression without evidence that disease has been clinically stable for greater than (>) 2 weeks prior to randomization
• Participants with known central nervous system disease
• Leptomeningeal disease
• History of autoimmune disease
• Prior allogeneic stem cell or solid organ transplantation
• Active tuberculosis
• Receipt of a live, attenuated vaccine within 4 weeks prior to randomization or anticipation that such a live, attenuated vaccine will be required during the study
• Treatment with systemic immunostimulatory agents within 4 weeks or five half-lives of the drug (whichever is shorter) prior to randomization
• Treatment with systemic corticosteroids or other systemic immunosuppressive medications within 2 weeks prior to randomization, or anticipated requirement for systemic immunosuppressive medications during the trial
• Participants who are breastfeeding, or intending to become pregnant during the study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Trastuzumab Emtansine + Atezolizumab; Atezolizumab 1200 milligrams (mg) intravenous (IV) infusion or matching Placebo followed by trastuzumab emtansine 3.6 milligrams per kilogram (mg/kg) IV infusion on Day 1 Cycle 1 and thereafter on Day 1 of each 21-day cycle until disease progression, unmanageable toxicity, or study termination by the Sponsor (approximately 29 months)	Other: Placebo; Placebo matched to atezolizumab; Drug: Atezolizumab; Atezolizumab 1200 mg IV infusion; Other Names: Tecentriq, RO5541267, MPDL3280A; Drug: Trastuzumab emtansine; Trastuzumab emtansine 3.6 mg/kg IV infusion; Other Names: Kadcyla®, T-DM1, RO5304020
Active Comparator: Trastuzumab Emtansine + Placebo; Placebo matched to atezolizumab followed by trastuzumab emtansine 3.6 mg/kg IV infusion on Day 1 Cycle 1 and thereafter on Day 1 of each 21-day cycle until disease progression, unmanageable toxicity, or study termination by the sponsor (approximately 29 months)	Other: Placebo; Placebo matched to atezolizumab; Drug: Trastuzumab emtansine; Trastuzumab emtansine 3.6 mg/kg IV infusion; Other Names: Kadcyla®, T-DM1, RO5304020

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-Free Survival (PFS) as Determined by Investigator's Tumor Assessment Using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 (v1.1)	PFS was defined as the time from randomization to the first occurrence of disease progression or death from any cause, whichever occurred first, on the basis of investigator assessments. Progression was defined as at least a 20% increase in the sum of diameters of target lesions with an absolute increase of at least 5 millimeter (mm) or the appearance of one or more new lesions.	Baseline up to approximately 15 months
Percentage of Participants With Adverse Events	An adverse event is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events.	Baseline up to study completion, approximately 40 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival (OS)	OS was defined as the time from randomization to death from any cause.	Baseline up to study completion or death, whichever occurs first, approximately 40 months
Percentage of Participants With Objective Response (OR) as Determined by Investigator's Tumor Assessment Using RECIST v1.1	An OR was defined as a complete or partial response determined on 2 consecutive occasions ≥ 4 weeks apart using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Complete response was defined as the disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must be < 10 mm on the short axis. Partial response was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum. Participants who had no post-baseline tumor assessment were counted as non-responders.	Baseline up to approximately 15 months
Duration of OR as Determined by Investigator's Tumor Assessment Using RECIST v1.1	Duration of OR was defined as the time from the first tumor assessment that was judged to indicate that the patient had an objective response to the time of first documented disease progression using RECIST v1.1 per investigator assessment or death from any cause, whichever occurred first.	Baseline up to approximately 15 months
Maximum Serum Concentration (Cmax) of Trastuzumab Emtansine	Average post infusion Trastuzumab Emtansine concentration	Pre-infusion (0 hour [h]), 30 minutes (min) after end of infusion (EOI) (over 90 min) on Day 1 Cycles 1 and 4; pre-infusion (0 h) on Day 1 Cycle 2 (each cycle = 21 days); at any time during study treatment/early discontinuation visit (approx. 40 months)
Cmax of Deacetyl Mercapto 1-Oxopropyl Maytansine (DM1)	Average post infusion Deacetyl Mercapto 1-Oxopropyl Maytansine concentration of trastuzumab emtansine infusion	Pre-infusion (0 h) on Day 1 Cycle 1 and 30 min after EOI (over 90 min) on Day 1 Cycles 1 and 4 (each cycle = 21 days)
Cmax of Total Trastuzumab		Pre-infusion (0 h), 30 min after EOI (over 90 min) on Day 1 Cycles 1 and 4; pre-infusion (0 h) on Day 1 Cycle 2 (each cycle = 21 days)
Cmax of Atezolizumab	Average post infusion atezolizumab concentration	Pre-infusion (0 h), 30 min after EOI (over 60 min) on Day 1 Cycles 1 and 4; pre-infusion (0 h) on Day 1 Cycles 2, 3, 8, and every 8 cycles thereafter (each cycle=21 days) up to 120 days after treatment completion/early discontinuation (approx. 40 months)
Percentage of Participants With Anti-therapeutic Antibodies (ATAs) to Atezolizumab	ATAs are antibodies that inactivate the therapeutic effects of Atezolizumab. Patients are considered to be ATA positive if they are ATA negative at baseline but develop an ATA response following study drug administration (treatment-induced ATA response), or if they are ATA positive at baseline and the titer of one or more post-baseline samples is at least 4-fold greater (i.e., ≥ 0.60 titer units) than the titer of the baseline sample (treatment-enhanced ATA response).	Pre-infusion (0 h) on Day 1 Cycles 1, 2, 3, 4, 8, and every 8 cycles thereafter (each cycle = 21 days) up to 120 days after treatment completion or early discontinuation (approximately 40 months)
Percentage of Participants With ATAs to Trastuzumab Emtansine	ATAs are antibodies that inactivate the therapeutic effects of Trastuzumab Emtansine. Patients are considered to be ATA positive if they are ATA negative at baseline but develop an ATA response following study drug administration (treatment-induced ATA response), or if they are ATA positive at baseline and the titer of one or more post-baseline samples is at least 4-fold greater (i.e., ≥ 0.60 titer units) than the titer of the baseline sample (treatment-enhanced ATA response).	Pre-infusion (0 h) on Day 1 Cycles 1 and 4 (each cycle = 21 days); and at any time during study treatment/early discontinuation visit (approximately 40 months)

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche

Publications and helpful links

General Publications

• Emens LA, Esteva FJ, Beresford M, Saura C, De Laurentiis M, Kim SB, Im SA, Wang Y, Salgado R, Mani A, Shah J, Lambertini C, Liu H, de Haas SL, Patre M, Loi S. Trastuzumab emtansine plus atezolizumab versus trastuzumab emtansine plus placebo in previously treated, HER2-positive advanced breast cancer (KATE2): a phase 2, multicentre, randomised, double-blind trial. Lancet Oncol. 2020 Oct;21(10):1283-1295. doi: 10.1016/S1470-2045(20)30465-4.

Study record dates

Study Major Dates

• Study Start (Actual): September 26, 2016
• Primary Completion (Actual): December 11, 2017
• Study Completion (Actual): February 6, 2020

Study Registration Dates

• First Submitted: September 21, 2016
• First Submitted That Met QC Criteria: October 4, 2016
• First Posted (Estimate): October 5, 2016

Study Record Updates

• Last Update Posted (Actual): February 17, 2021
• Last Update Submitted That Met QC Criteria: January 28, 2021
• Last Verified: January 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Antineoplastic Agents, Immunological; Trastuzumab; Maytansine; Atezolizumab; Ado-Trastuzumab Emtansine
• Other Study ID Numbers: WO30085; 2015-004189-27 (EudraCT Number)