Multicenter phase 2 trial of varlitinib versus lapatinib in combination with capecitabine in patients with HER2+ metastatic breast cancer (MBC) who failed prior trastuzumab therapy

Abstract

Background: Varlitinib, a tyrosine kinase inhibitor of the ErbB family (EGFR, HER2 and HER4), showed anti-tumor activity in trastuzumab-resistant models and in patients with trastuzumab-resistant, chemotherapy-refractory MBC in a phase 1 study. This study compared the efficacy and safety of varlitinib plus capecitabine (VC) versus lapatinib plus capecitabine (LC) in HER2θ MBC patients who failed prior trastuzumab therapy. Methods: The primary objective was to assess percentage change in tumor size at week 12. Objective response rate (ORR), safety and drug exposure were also assessed. Patients who received at least one dose of study treatment were included in primary analysis. Sensitivity analysis for primary objective and ORR were performed in patients who remained on study for more than 30days. Results: From Dec 2014toAug 2016, 24 patients were randomized to the VC arm (400mg BID) and 26to theLC arm (1250mg QD)in 16sites in 6countries. Percentage of tumor size reduction was numerically higher in VC than LC (-31.00% vs.-19.37%, one-sidedp=0.132). ORR in theVCarm (40.9%) was similar toLC arm (45.5%), p = 1.000. Sensitivity analysis showed numerically superior ORR and statistically significant higher reduction of tumor size in VC compared to LC (60% vs. 45.5%, p = 0.508; mean,-34.6% vs.-19.4%, one-sided p = 0.075) All patients had at least 1 AE. Severe AE(s) were observed in 13 patients (54.2%) in the VC arm and 11(42.3%) in the LC arm. The most common AE was diarrhea (66.7%) in theVCarm and were diarrhea and palmar-plantar erythrodysaesthesia syndrome (both 50%) in the LC arm. Median intended exposure and percentage of intended dose were lower in the VC arm (115.5 days, 74.6%) indicating more frequent dose interruption, dose reduction and treatment discontinuation than the LC arm (135.0 days, 99.05%). Conclusions: Sensitivity analysis showed greater tumor size reduction and improved ORR forVC arm when the combination was administrated for more than30 days. Reduced intended exposure and dose intensity for the VC arm suggests a dose reduc-tion of varlitinib may be considered when combined with capecitabine for the 2nd line treatment ofHER2θ MBC.