Adding tucatinib to T-DM1 significantly delays disease progression in patients with HER2+ locally advanced/metastatic breast cancer

Patients with HER2-positive breast cancer (BC) have a high disposition to develop brain metastases, contributing to a poor prognosis alongside limited treatment options. Results from the HER2CLIMB-02 trial, recently presented at SABCS 2023, demonstrated that the addition of tucatinib to T-DM1 significantly improved median progression-free survival in patients with previously treated HER2+ locally advanced/metastatic BC, including those with brain metastases.

Patients with HER2-positive breast cancer (BC) have a high disposition to develop brain metastases (BMs), contributing to a poor prognosis alongside limited treatment options. Unlike most HER2-targeted drugs, tucatinib, a small-molecule inhibitor of HER2, effectively delays disease progression in the central nervous system (CNS). In the HER2CLIMB trial, the addition of tucatinib to trastuzumab and chemotherapy significantly improved progression-free (PFS) and overall survival (OS) in heavily pretreated patients with locally advanced/metastatic BC (LA/mBC), including those with BMs, leading to the approval of this regimen. In contrast, T-DM1 is an antibody-drug conjugate (ADC) comprised of trastuzumab and the cytotoxic drug emtansine, approved as monotherapy for patients with early- and late-stage HER2-positive BC. However, not all patients have durable responses to T-DM1, prompting the exploration of T-DM1-based combination regimens. In this respect, HER2CLIMB-02 assessed the efficacy and safety of tucatinib combined with T-DM1 in patients with previously treated HER2+ locally advanced/ metastatic BC (LA/mBC).

Methods

The phase III HER2CLIMB-02 study enrolled HER2+ LA/mBC patients who were previously treated with trastuzumab and a taxane (in any setting). Patients with previously treated stable, progressing, or untreated BMs that did not require immediate local therapy were eligible for the study. Patients were randomly assigned (1:1) to receive 21-day cycles of either tucatinib (300 mg orally twice a day) or placebo, combined with T-DM1 (3.6 mg/kg intravenously every 3 weeks). The primary endpoint was PFS, with OS, PFS and OS in patients with BMs and objective response rate (ORR) as key secondary study objectives

Results

HER2CLIMB-02 randomly assigned 463 patients with unresectable LA/mBC HER2+ BC to receive tucatinib plus T-DM1 (228 patients) or placebo plus T-DM1 (235 patients). Of note, 44.1% of participants had BMs at baseline. The addition of tucatinib to T-DM1 reduced the risk of disease progression or death by 24%, with a median PFS of 9.5 vs. 7.4 months in the tucatinib plus T-DM1 and T-DM1 alone arms, respectively (HR[95%CI]: 0.76[0.61-0.95];p=0.0163). HRs for PFS across all pre specified subgroups were consistent with the HR of the overall population, favouring the combination of tucatinib and T-DM1. Among patients who had BMs at baseline, the addition of tucatinib reduced the risk of disease progression or death by 36 %, with a median PFS of 7.8 and 5.7 months for tucatinib plus T-DM1 and T-DM1 alone, respectively (HR[95%CI]:0.64 [0.46-0.89]). The confirmed ORR was 42% vs. 36.1% in the tucatinib plus T-DM1 and T-DM1 arms, respectively, with 37.8% vs. 31.9% of patients achieving a complete response. The OS data remained immature after a median follow-up of 24.4 months. No significant difference in OS was observed between the 2 arms at this point.

Patients in the tucatinib plus T-DM1 arm experienced more grade ≥3 treatment-emergent adverse events (TEAEs) compared to T-DM1 alone (68.8% vs. 41.2%, respectively). The most common (at least 20% of patients) TEAEs included nausea (65.4% vs. 49.4% in the tucatinib and control arms, respectively), diarrhoea (56.7% vs. 26.6%), and fatigue (48.9% vs. 37.3%). Grade ≥3 hepatic TEAEs were more common with tucatinib plus T-DM1 arm (28.6% vs. 7.3%), primarily due to a higher incidence of AST/ALT elevations. However, 85% of all-grade hepatic TEAEs in the tucatinib plus T-DM1 arm resolved or returned to grade 1, with a median resolution time of 22 days. Grade ≥3 diarrhoea events were reported in 4.8% vs. 0.9% of patients. Both hepatic and diarrhoea events were effectively managed with dose holds or discontinuations.

Conclusions

HER2CLIMB-02 demonstrated that adding tucatinib to T-DM1 significantly prolonged the 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.

Reference

Loi S, O’Shaughnessy J, Okines A, et al. HER2CLIMB-02: Primary Analysis of a Randomized, Double-blind Phase 3 Trial of Tucatinib and Trastuzumab Emtansine for Previously Treated HER2-positive Metastatic Breast Cancer. Presented at SABCS 2023; Abstract GS01-10.