Phase 3 HER2CLIMB-02 Trial Results of Tucatinib Plus Trastuzumab Emtansine in Previously Treated HER2+ MBC

Tucatinib is an oral highly selective HER2-targeted tyrosine kinase inhibitor, that has shown promising efficacy in combination with trastuzumab emtansine (T-DM1) in patients with HER2+ metastatic breast cancer (MBC) including those with brain metastasis. Based on this rationale, the randomized phase 3 HER2CLIMB-02 study was conducted to evaluate the efficacy and safety of tucatinib in combination with T-DM1 versus T-DM1 plus placebo patients with HER2+ locally advanced (LA) or MBC.

The HER2CLIMB-02 trial is a double-blind, placebo-controlled phase 3 study that enrolled patients who had progressed after prior trastuzumab and taxane therapy in any setting, an ECOG ≤1, and previously treated stable progressing or untreated brain metastases not requiring immediate local therapy. Eligible patients were randomized 1:1 to receive tucatinib (300 mg PO BID) or placebo in addition to T-DM1 (3.6 mg/kg IV). Stratification was based on line of treatment for metastatic disease (first-line vs other), hormone receptor status (positive vs negative), presence or history of brain metastasis (yes vs no), and ECOG PS (0 vs 1). The primary endpoint is progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors version 1.1 by investigator assessment; secondary endpoints included overall survival (OS) and objective response rate (ORR) for the overall population, and PFS, and OS in the group of patients with brain metastases at baseline. The primary analysis for PFS was planned after ~331 PFS events to provide 90% power for a hazard ratio of 0.7 at a two-sided alpha level of 0.05. The first interim analysis for OS was planned at the time of the primary PFS analysis, if the PFS result was significantly positive.

A total of 463 eligible patients were enrolled in the study. The treatment arms were well-balanced. The majority of patients were hormone receptor-positive, ECOG PS of 0, stage I-III, and received pertuzumab; about 44% had active or treated stable brain metastasis, and received a median of 1 prior therapy in the metastasis setting.

Tucatinib + T-DM1 combination therapy resulted in significant prolongation of PFS (9.5 months vs 7.4 months; hazard ratio [HR], 0.76; P=.0163) compared with the placebo arm. The PFS benefit also extended to patients with brain metastasis; tucatinib + T-DM1 therapy led to a 36% reduction in risk of progression compared to T-DM1 + placebo (7.8 months vs 5.7 months; HR, 0.64). Patients in the tucatinib + T-DM1 arm achieved numerically higher ORR (42% vs 36.1%); the majority of which were partial responses. At median follow-up of 24 months, OS interim data were immature; 134 of 253 (53%) prespecified events for the OS events were observed.

Higher incidences of grade ≥3 treatment-emergent adverse events (TEAEs) were reported in the tucatinib + T-DM1 arm (68.8% vs 41.2%). Higher discontinuations of tucatinib or placebo due to adverse events (17.3% vs 6.9%) were also reported; ALT was the most common TEAE that prompted these discontinuations. Higher discontinuations of T-DM1 due to adverse events (20.3% vs 11.2%) were reported; ALT, thrombocytopenia, and interstitial lung disease were the most common TEAEs. Hepatic events were most common in the combination arm (28.6% vs 7.3%). The most common grade ≥3 TEAEs that occurred in ≥5% of patients included ALT increased (16.5% vs 2.6%), AST increased (16.5% vs 2.6%), anemia (8.2% vs 4.7%), thrombocytopenia (7.4% vs 2.1%), and fatigue (6.1% vs 3.0%); higher grade ≥3 diarrhea was reported in the tucatinib + T-DM1 arm (4.8% vs 0.9%).

Based on these data, the authors concluded that adding tucatinib to T-DM1 significantly improved PFS compared to T-DM1 alone in patients with previously treated HER2+ LA/MBC including those with brain metastasis.


Hurvitz S, Loi S, O’Shaughnessy J, et al. HER2CLIMB-02: randomized, double-blind phase 3 trial of tucatinib and trastuzumab emtansine for previously treated HER2-positive metastatic breast cancer. Presented at the 46th San Antonio Breast Cancer Symposium Annual Meeting, December 5-9, 2023; San Antonio, TX: Abstract GS01-10.

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