Trastuzumab Duocarmazine in Pretreated Human Epidermal Growth Factor Receptor 2–Positive Advanced or Metastatic Breast Cancer: An Open-Label, Randomized, Phase III Trial (TULIP)
Authors: Nicholas Turner, Cristina Saura, Philippe Aftimos, Evelyn van den Tweel, Mayke Oesterholt, Norbert Koper, Marco Colleoni, Emilie Kaczmarek, Kevin Punie, Xinni Song, Anne Armstrong, Giulia Bianchi, Agostina Stradella, Sylvain Ladoire, Joline Si Jing Lim, Nathalie Quenel-Tueux, Tira J. Tan, Santiago Escrivá-de-Romaní, Joyce O'Shaughnessy, Evelien Kuip, Elisabeth G.E. de Vries, Willemien Menke-van der Houven van Oordt, Philippe Aftimos, Konstantinos Papadimitriou, Hannelore Denys, Kevin Punie, Guy Jerusalem, Marleen Borms, François Duhoux, Nicholas Turner, Iain Macpherson, Anne Armstrong, Nicola Levitt, Carlo Palmieri, Annabel Borley, Timothy Crook, Estela Vega Alonso, Serafin Morales, Santiago Escriva de Romani Muñoz, Agostina Stradella, Yolanda Jerez Gilarranz, Antonio Anton, Jose Juan Ponce, Barbara Adamo, Javier Cortes Castan, Maria Martinez, Thierry Petit, Emilie Kaczmarek, Sylvain Ladoire, Nathalie Quenel Tueux, Luis Teixeira, Jean Christophe Thery, Sophie Abadie-Lacourtoisie, Alain Lortholary, Elisabeth Luporsi, Hubert Orfeuvre, Nathalie Bonnin, Giampaolo Bianchini, Federico Piacentini, Francesco Cognetti, Paolo Marchetti, Evaristo Maiello, Marina Cazzaniga, Valentina Guarneri, Marco Colleoni, Laura Doni, Roberto Bordonaro, Claudio Zamagni, Giulia Bianchi, Laura Biganzoli, Michael Thirlwell, Xinni Song, Anil Joy, Sara Taylor, Teresa Helsten, Madhu Chaudhry, Haythem Ali, Shaker Dakhil, Rex Mowat, Adam Brufsky, Melody Cobleigh, Manuel Modiano, Michelina Cairo, Michael Meshad, Michael A. Danso, Jay Andersen, Allyson Harroff, Rami Owera, Anne Favret, Joyce O'Shaughnessy, Timothy Pluard, Paula Rosenblatt, Sharad Jain, Jeanette Dupont Jensen, Nina Jeppesen, Kim Wedervang, Per Edlund, Henrik Lindman, Renske Altena, Leif Klint, Tira Tan Jing Ying, Joline Lim Si Jing
Journal: Journal of Clinical Oncology (2024)

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.