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Trastuzumab duocarmazine in pretreated human epidermal growth factor receptor 2-positive advanced or metastatic breast cancer: an open-label, randomized, phase III trial (TULIP)
Turner, N. Saura, C. Aftimos, P. van den Tweel, E. Oesterholt, M. Koper, N. Colleoni, M. Kaczmarek, E. Punie, K. Song, X. N.
Turner, N.
Saura, C.
Aftimos, P.
van den Tweel, E.
Oesterholt, M.
Koper, N.
Colleoni, M.
Kaczmarek, E.
Punie, K.
Song, X. N.
Abstract
PURPOSEHuman 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.METHODSIn 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.RESULTSIn 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).CONCLUSIONTreatment 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.
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Date
2025
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Citation
Turner N, Saura C, Aftimos P, van den Tweel E, Oesterholt M, Koper N, et al. Trastuzumab Duocarmazine in Pretreated Human Epidermal Growth Factor Receptor 2-Positive Advanced or Metastatic Breast Cancer: An Open-Label, Randomized, Phase III Trial (TULIP). JOURNAL OF CLINICAL ONCOLOGY. 2025 FEB 10;43(5). PubMed PMID: WOS:001415606400003. English.