Varlitinib is a reversible small-molecule pan human epidermal growth factor receptor (HER) inhibitor with low nanomolar potency against HER1 (EGFR), HER2, and HER4.
TreeTopp1 was a global, multicenter, double-blind, phase 2 study in which patients with biliary tract cancer (BTC) who progressed after first-line therapy that included ≥6 doses of gemcitabine, with radiographically measurable disease based on RECIST v1.1, ECOG PS 0 or 1, and albumin ≥3 g/dL. The patients were randomized (1:1) to varlitinib (V) (300 mg twice daily) plus capecitabine (C) (1000 mg/m2 twice daily 14 days on/7 days off) (V + C) or placebo plus capecitabine (P + C). The dual primary end points were objective response rate (ORR) and progression-free survival (PFS), defined as the time from randomization to radiologic progression assessed by independent central review. Secondary end points included overall survival (OS).
A total of 127 patients were randomized (V + C, n = 64; P + C, n = 63). The odds ratio for ORR with V + C versus P + C was 2.278 (9.4% vs 4.8%; P = .42), the hazard ratio (HR) for PFS for V + C versus P + C was 0.90 (median PFS, 2.8 vs 2.8 months; P = .63), and the HR for OS for P + C versus V + C was 1.11 (median OS, 7.8 vs 7.5 months; P = .66). Although not powered to evaluate subgroup interactions, in a subgroup analysis, V + C showed PFS benefit versus P + C in 2 subgroups: gallbladder cancer (HR, 0.55), median PFS (2.9 vs 1.6 months); and females (HR, 0.59), median PFS, 4.1 versus 2.8 months. There was no PFS benefit for V + C versus P + C among males and non-gallbladder cancer patients. Toxicities were generally balanced between arms apart from a slightly higher incidence of hyperbilirubinemia, diarrhea, and fatigue in the V + C versus P + C arm. Grade 3/4 toxicities were reported in 66% and 59% of patients in the V + C and P + C arms, respectively.
Based on the interim data as of July 15, 2019, the authors concluded that although there was no benefit for V + C for ORR, PFS, or OS versus P + C in second-line advanced BTC, subgroup analysis suggested that patients with gallbladder cancer and female patients achieved a comparatively higher median PFS with V + C versus P + C. ClinicalTrials.gov number NCT03093870.
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