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