Trastuzumab Duocarmazine in Pretreated Human Epidermal Growth Factor Receptor 2–Positive Advanced or Metastatic Breast Cancer: An Open-Label, Randomized, Phase III Trial (TULIP)
Abstract
PURPOSE Human epidermal growth factor receptor 2 (HER2)–targeted therapy is standard of care for HER2-positive (HER2+) breast cancer, but most patients develop progressive disease with persistent HER2 expression. No definitive treatment guidance currently exists beyond second line. Trastuzumab duocarmazine (T-Duo) is a third-generation, HER2-targeted antibody-drug conjugate that demonstrated efficacy and acceptable safety in phase I studies of heavily pretreated patients with HER2+/HER2-low breast cancer. METHODS In this open-label, randomized, phase III trial, T-Duo was compared with physician's choice (PC) in patients with unresectable locally advanced/metastatic HER2+ breast cancer with progression during/after ≥2 HER2-targeted therapies or after trastuzumab emtansine (T-DM1). The primary endpoint was progression-free survival (PFS) by blinded independent central review. RESULTS In total, 437 patients were randomly assigned 2:1 to T-Duo (n = 291) or PC (n = 146). The median age was 56.0 years (range, 24-86); most patients (93.6%) had metastatic disease. The median time from diagnosis of metastatic disease to trial entry was 3.5 years; the median number of prior HER2-targeted therapies in metastatic setting was three. The median PFS was 7.0 months (95% CI, 5.4 to 7.2) with T-Duo versus 4.9 months (95% CI, 4.0 to 5.5; hazard ratio [HR], 0.64 [95% CI, 0.49 to 0.84]; P = .002) with PC. PFS benefit was maintained across most predefined subgroups. The median overall survival (first analysis) was 20.4 (T-Duo) versus 16.3 months (PC; HR, 0.83 [95% CI, 0.62 to 1.09]; P = .153). Objective response rate was 27.8% (T-Duo) versus 29.5% (PC); other efficacy end points—clinical benefit rate, duration of response, and reduction in target lesion measurement—tended to favor T-Duo. Grade ≥3 treatment-emergent adverse events occurred in 52.8% (T-Duo) versus 48.2% (PC). CONCLUSION Treatment with T-Duo was manageable, but tolerability was affected by prevalent ocular toxicity, leading to a higher discontinuation rate in the T-Duo arm. T-Duo significantly reduced the risk of progression in patients with advanced HER2+ breast cancer who have progressed during/after ≥2 HER2-targeted therapies or after T-DM1.
Article Details
Journal Info
Journal of Clinical Oncology
Lippincott Williams & Wilkins
Authors (91)
Cristina Saura
Vall d’Hebron University Hospital, Barcelona
Evelyn van den Tweel
Byondis B.V., Nijmegen, the Netherlands
Mayke Oesterholt
Byondis B.V., Nijmegen, the Netherlands
Norbert Koper
Byondis B.V., Nijmegen, the Netherlands
Joline Si Jing Lim
National University Hospital, Singapore, Singapore
Nathalie Quenel-Tueux
Department of Medical Oncology, Institut Bergonié, Comprehensive Cancer Centre, Bordeaux, France
Tira J. Tan
Division of Medical Oncology, National Cancer Centre, Singapore, Singapore
Santiago Escrivá-de-Romaní
Vall d’Hebron Institut of Oncology, Hospital Vall d’Hebron, Barcelona
Evelien Kuip
Elisabeth G.E. de Vries
Willemien Menke-van der Houven van Oordt
Philippe Aftimos
Institut Jules Bordet, Hôpital Universitaire de Bruxelles, Brussels
Konstantinos Papadimitriou
Hannelore Denys
Ghent University Hospital, Department of Medical Oncology, Ghent, Belgium
Kevin Punie
Medical Oncology, Oncology Center Antwerp, Ziekenhuis aan de Stroom, Antwerp, Belgium
Guy Jerusalem
Marleen Borms
Francois Duhoux
Nicholas Turner
Iain Macpherson
Anne Armstrong
Medical Oncology, The Christie NHS Foundation Trust and the University of Manchester, Manchester, United Kingdom
Nicola Levitt
Carlo Palmieri
Annabel Borley
Timothy Crook
Cromwell, London, United Kingdom
Estela Vega Alonso
Serafin Morales
Santiago Escriva de Romani Muñoz
Agostina Stradella
Department of Medical Oncology, Institut Catala d'Oncologia – IDIBELL (ICO L'Hospitalet), Barcelona, Spain
Yolanda Jerez Gilarranz
Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, CIBERONC. GEICAM Spanish Breast Cancer Group, Madrid, Spain
Antonio Antón
Hospital Universitario Miguel Servet, Zaragoza, Spain
Jose Juan Ponce
Barbara Adamo
Institute of Cancer and Blood Diseases, Hospital Clinic of Barcelona / Translational Genomics and Targeted Therapies in Solid Tumors group, August Pi i Sunyer Biomedical Research Institute IDIBAPS, Barcelona, Spain
Javier Cortes Castan
Maria Martinez
3Universidad de los Andes, Facultad de Medicina, Bogotá, Colombia
Thierry Petit
Emilie Kaczmarek
Sylvain Ladoire
Centre Georges Francois Leclerc, Dijon, France
Nathalie Quenel Tueux
Luis Teixeira
Jean Christophe Thery
Université de Rouen Normandie, Inserm U1245, FHU G4 Genomics, CHU Rouen, Département de Génétique, Rouen, France
Sophie Abadie-Lacourtoisie
Alain Lortholary
Groupe d'Investigateurs National des Etudes des Cancers Ovariens et du sein (GINECO) and Hôpital Privé du Confluent, Nantes, France
Elisabeth Luporsi
Hubert Orfeuvre
Nathalie Bonnin
Giampaolo Bianchini
IRCCS Ospedale San Raffaele, Milan
Federico Piacentini
Francesco Cognetti
Paolo Marchetti
IDI-IRCCS, Roma, Italy
Evaristo Maiello
Marina Cazzaniga
Phase 1 Research Unit, Fondazione IRCCS San Gerardo, Monza, Italy
Valentina Guarneri
Veneto Institute of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico, Padua, Italy
Marco Colleoni
Laura Doni
Roberto Bordonaro
Claudio Zamagni
IRCCS Azienda Ospedaliero Universitaria di Bologna, Bologna, Italy
Giulia Bianchi
Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
Laura Biganzoli
Michael Thirlwell
Xinni Song
The Ottawa Hospital Cancer Centre, Ottawa, ON, Canada
Anil Joy
Sara Taylor
Teresa Helsten
Madhu Chaudhry
Haythem Ali
Shaker Dakhil
11Cancer Center of Kansas, Wichita, United States
Rex Mowat
Adam Brufsky
Hillman Cancer Center, Magee-Womens Hospital, University of Pittsburgh Medical Center, Pittsburgh
Melody Cobleigh
Manuel Modiano
Michelina Cairo
Michael Meshad
Michael A. Danso
Department of Medical Oncology, Brock Cancer Center, Virginia Oncology Associates, Norfolk
Jay Andersen
Allyson Harroff
Rami Owera
Anne Favret
Virginia Cancer Specialists, PC, Fairfax, VA
Joyce O'Shaughnessy
Baylor University Medical Center, Texas Oncology, Sarah Cannon Research Institute, Dallas, TX
Timothy Pluard
Paula Rosenblatt
University of Maryland Greenebaum Comprehensive Cancer Center, Baltimore, MD
Sharad Jain
Jeanette Dupont Jensen
Nina Jeppesen
Kim Wedervang
Per Edlund
Henrik Lindman
Renske Altena
Department of Oncology-Pathology, Karolinska Institutet and Karolinska Comprehensive Cancer Center, Karolinska University Hospital, Stockholm, Sweden
Leif Klint
Tira Tan Jing Ying
Joline Lim Si Jing