Abstract GS01-10: HER2CLIMB-02: Randomized, Double-Blind Phase 3 Trial of Tucatinib and Trastuzumab Emtansine for Previously Treated HER2-Positive Metastatic Breast Cancer

Abstract Background Tucatinib is a highly selective HER2-directed tyrosine kinase inhibitor approved in combination with trastuzumab and capecitabine for previously treated HER2+ locally advanced or metastatic breast cancer (LA/MBC). Trastuzumab emtansine (T-DM1) is a HER2-directed antibody-drug conjugate approved to treat HER2+ LA/MBC previously treated with trastuzumab and a taxane. This is the first report of HER2CLIMB-02 (NCT03975647), a randomized, double-blind, placebo-controlled phase 3 study assessing the efficacy and safety of tucatinib combined with T-DM1 in patients with previously treated HER2+ LA/MBC. Methods Eligible patients had HER2+ LA/MBC previously treated with trastuzumab and a taxane in any setting with ECOG performance status ≤1 and adequate hepatic, renal, hematologic, and cardiac function. Patients with previously treated stable, progressing, or untreated brain metastases (BMs) not requiring immediate local therapy were also eligible. Patients were randomly assigned 1:1 to receive 21-day cycles of either tucatinib (300 mg orally twice a day [PO BID]) or placebo (PO BID), combined with T-DM1 (3.6 mg/kg intravenously every 3 weeks). The primary endpoint was progression-free survival (PFS) by investigator assessment per RECIST v1.1. Alpha-controlled secondary endpoints included overall survival (OS) and objective response rate (ORR) per RECIST v1.1 for the overall population, and PFS and OS for the subset of patients with BMs at baseline. Safety was analyzed as a secondary endpoint. Results From October 8, 2019, to June 16, 2022, 463 patients were randomly assigned, comprising 228 to the tucatinib arm (tucatinib + T-DM1) and 235 to the control arm (placebo + T-DM1). The median duration of follow-up (OS) was 24.4 months for the overall population. Patient demographics and baseline characteristics were balanced between the 2 arms. Almost half (44.1%) of the overall population had either active or stable BMs at baseline. As of the data cutoff (June 29, 2023), the study met its primary endpoint with a statistically significant improvement in PFS in the tucatinib arm vs control arm. The risk of progression or death decreased by 24.1% in the tucatinib arm (hazard ratio [HR]=0.759 [95% CI, 0.607-0.950]; P=0.0163). Median PFS was 9.5 months (95% CI, 7.4-10.9) vs 7.4 months (95% CI, 5.6-8.1) for the tucatinib and control arms, respectively. HRs for PFS across all prespecified subgroups were consistent with the HR of the overall population, including patients with BMs at baseline (HR=0.639 [95% CI, 0.459-0.891]). The interim OS results were immature with 134 of 253 total required events (53%) and did not meet the prespecified crossing boundary. The confirmed ORR was numerically higher in the tucatinib arm (42.0%) vs the control arm (36.1%). The most common treatment-emergent adverse events (TEAEs) included nausea (65.4% vs 49.4% for tucatinib and control arms, respectively), diarrhea (56.7% vs 26.6%), and fatigue (48.9% vs 37.3%). The most common grade ≥3 TEAEs in the tucatinib arm were alanine and aspartate aminotransferase elevations, each reported in 38 patients (16.5%) in the tucatinib arm and 6 patients (2.6%) in the control arm. TEAEs associated with any treatment discontinuation occurred in 51 patients (22.1%) in the tucatinib arm and 27 (11.6%) in the control arm. TEAEs leading to deaths occurred in 3 patients (1.3%) in the tucatinib arm and 2 patients (0.9%) in the control arm. Conclusion HER2CLIMB-02 demonstrated that the addition of tucatinib to T-DM1 significantly improved median PFS in patients with previously treated HER2+ LA/MBC, including those with BMs. Although discontinuations due to TEAEs were more common in the tucatinib arm, no new safety signals emerged for the combination therapy. Citation Format: Sara Hurvitz, Sherene Loi, Joyce O'Shaughnessy, Alicia Okines, Sara Tolaney, Joo Hyuk Sohn, Cristina Saura, Xiaofu Zhu, David Cameron, Thomas Bachelot, Erika Hamilton, Giuseppe Curigliano, Antonio Wolff, Nadia Harbeck, Norikazu Masuda, Linda Vahdat, Khalil Zaman, Frances Valdes-Albini, Margaret Block, Timothy Pluard, Tira Tan, Chelsea Gawryletz, Arlene Chan, Philippe Bedard, Rinat Yerushalmi, Binghe Xu, Konstantinos Tryfonidis, Michael Schmitt, Joan Xie, Virginia Borges. HER2CLIMB-02: Randomized, Double-Blind Phase 3 Trial of Tucatinib and Trastuzumab Emtansine for Previously Treated HER2-Positive Metastatic Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr GS01-10.

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