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TreeTopp: Phase 2 Study of Varlitinib plus Capecitabine versus Placebo as Second-Line Therapy for Patients with Advanced or Metastatic Biliary Tract Cancer

August 2020, Vol 1, No 1

Varlitinib is a reversible small-molecule, pan-human epidermal growth factor receptor (HER) inhibitor with low nanomolar potency against HER1 (EGFR), HER2, and HER4.

The global, multicenter, double-blind, phase 2 TreeTopp study included patients with biliary tract cancer whose disease progressed after receiving first-line therapy that included ≥6 doses of gemcitabine, and had radiographically measurable disease based on RECIST version 1.1 criteria, Eastern Cooperative Oncology Group performance status 0 or 1, and albumin ≥3 g/dL.1

The study’s results were reported by Milind M. Javle, MD, Professor, Department of Gastrointestinal Medical Oncology, M.D. Anderson Cancer Center, Houston, TX, and colleagues, in a poster at the 2020 ASCO annual meeting.

The study patients were randomized (1:1) to varlitinib 300 mg twice daily plus capecitabine 1000 mg/m2 twice daily, given in a schedule of 14 days on and 7 days off, or to placebo plus capecitabine.

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. A secondary end point was overall survival (OS).

The study randomized 127 patients, including 64 patients who received varlitinib plus capecitabine and 63 patients who received placebo plus capecitabine.

The ORR was 9.4% with varlitinib plus capecitabine versus 4.8% with placebo plus capecitabine (odds ratio, 2.278; P = .42). The median PFS was the same for patients who received varlitinib plus capecitabine and for those who received placebo plus capecitabine, at 2.8 months (hazard ratio [HR], 0.9; P = .63). The median OS was 7.8 months with varlitinib plus capecitabine versus 7.5 months with placebo plus capecitabine (HR, 1.11; P = .66).

Although this study was not powered to evaluate subgroup interactions, in a subgroup analysis, varlitinib plus capecitabine showed PFS benefit versus placebo plus capecitabine in the subgroup of patients with gallbladder cancer (median PFS, 2.9 months vs 1.6 months; HR, 0.55), and among female patients (median PFS, 4.1 months vs 2.8 months; HR, 0.59).

There was no PFS benefit for varlitinib plus capecitabine compared with placebo plus capecitabine among male patients and in patients without gallbladder cancer.

The adverse events were generally balanced between the study arms, apart from a slightly higher incidence of hyperbilirubinemia, diarrhea, and fatigue in the varlitinib plus capecitabine arm versus the placebo plus capecitabine arm. Grade 3 or 4 toxicities were reported in 66% and 59% of patients in the varlitinib plus capecitabine and placebo plus capecitabine arms, respectively.

Based on the interim data as of July 15, 2019, the investigators concluded that although no benefit was found with varlitinib plus capecitabine in terms of ORR, PFS, or OS versus placebo plus capecitabine in the second-line treatment of advanced biliary tract cancer, a subgroup analysis suggested that patients with gallbladder cancer and female patients achieved a comparatively higher median PFS with varlitinib plus capecitabine therapy compared with placebo plus capecitabine.


  1. Javle MM, Oh DY, Ikeda M, et al. Results from TreeTopp: a randomized phase II study of the efficacy and safety of varlitinib plus capecitabine versus placebo in second-line (2L) advanced or metastatic biliary tract cancer (BTC). J Clin Oncol. 2020;38(15_suppl):Abstract 4597.

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