Tucatinib versus Placebo, Plus Capecitabine and Trastuzumab, in HER2+ Breast Cancer with and without Brain Metastases (HER2CLIMB)

Although significant advances have been made in the treatment of patients with HER2+ metastatic breast cancer (MBC), treatment of metastatic disease remains a clinical challenge for which no curative options are available. For these patients previously treated with trastuzumab, pertuzumab, and ado-trastuzumab emtansine (T-DM1), no single regimen is considered the standard of care.^1,2 The management of HER2+ central nervous system metastases (which occur at any time during the disease course in 30% to 50% of those with HER2+ MBC) remains an area of unmet clinical need. Tucatinib is an investigational, oral tyrosine kinase inhibitor that is highly specific to HER2 with minimal inhibition of the EGFR receptor. In a phase 1b study, tucatinib plus capecitabine and trastuzumab showed an acceptable toxicity profile and encouraging anti-tumor activity, including in patients with active brain metastases.³

At SABCS 2019, the primary analysis was presented from the HER2CLIMB study on the efficacy and safety of tucatinib, trastuzumab, and capecitabine, a treatment regimen under investigation for patients with advanced HER2+ MBC refractory to standard-of-care regimens.⁴

HER2CLIMB was a double-blind, international, multicenter study in which 612 patients with locally advanced or metastatic HER2+ breast cancer previously treated with trastuzumab, pertuzumab, and T-DM1 were randomized 2:1 to receive tucatinib (300 mg twice daily) or placebo, in combination with capecitabine (1000 mg/m² twice daily, days 1-14 of each 21-day cycle) and trastuzumab (6 mg/kg once every 21 days). Patients with newly diagnosed, progressing, or stable brain metastases not requiring immediate local therapy were included in the study. The primary end point was progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors version 1.1 by blinded independent central review for the first 480 patients enrolled. Secondary end points, including PFS in patients with brain metastases, confirmed overall response rate (ORR) in patients with measurable disease, and overall survival (OS), were evaluated in all 612 patients. Safety was assessed in all 612 patients who had received ≥1 doses of study treatment. Patient demographics were balanced in the tucatinib and placebo arms; approximately half the patients in each arm demonstrated the presence or history of brain metastases.

The study met its primary end point; risk for progression or death was reduced by 46% in the tucatinib arm compared with placebo, with a 1-year PFS of 33% and 12% in the tucatinib and placebo arms, respectively (P <.00001). Median PFS was 7.8 months in the tucatinib arm versus 5.6 months in the placebo arm. Importantly, risk for death was reduced by 34% in the tucatinib arm compared with placebo, with a median OS of 21.9 months versus 17.4 months in the tucatinib and placebo arms, respectively (P = .00480). In addition, risk for progression or death in patients with MBC and brain metastases was reduced by 52% in patients in the tucatinib arm versus placebo; 1-year PFS in these patients was 25% versus 0% in the tucatinib and placebo arms, respectively. The confirmed ORR was 41% in the tucatinib arm versus 23% in the placebo arm, mainly consisting of partial responses.

The incidence of adverse events (AEs) was comparable in the 2 arms, with many of the more serious AEs attributable to capecitabine. Key AEs included diarrhea, liver transaminase elevations, and palmar-plantar erythrodysesthesia. The authors concluded that in patients with MBC with and without progressing brain metastases who were previously treated with trastuzumab, capecitabine, and T-DM1, the combination of tucatinib with capecitabine and trastuzumab significantly improved PFS and OS, and was well-tolerated. This combination has the potential to become a new standard of care in this population with and without brain metastases. Along with being presented, the results of this study were published online December 11, 2019.⁵

References

1. Giordano SH, et al. J Oncol Pract. 2018;14:501-504.
2. Cardoso F, et al. Ann Oncol. 2018;29:1634-1657.
3. Borges VF, et al. JAMA Oncol. 2018;4:1214-1220.
4. Murthy R, et al. SABCS 2019. Abstract GS1-01.
5. Murthy RK, et al. N Engl J Med. December 11, 2019. DOI: 10.1056/NEJMoa1914609.