Varlitinib Misses PFS, ORR Endpoints in Biliary Tract Cancer

Varlitinib combined with capecitabine did not improve progression-free survival nor overall response rate compared with capecitabine/placebo as a second-line treatment in patients with biliary tract cancer.

Carl Firth

Varlitinib combined with capecitabine (Xeloda) did not improve progression-free survival (PFS) nor overall response rate (ORR) compared with capecitabine/placebo as a second-line treatment in patients with biliary tract cancer (BTC), missing both primary endpoints of the phase III TreeTopp trial (NCT03093870).1

Results specifically showed that the median PFS was 2.83 months in the varlitinib arm compared with 2.79 months in the control arm (HR, 0.90), and the ORRs was 9.4% and 4.8%, respectively; neither endpoint of which reached statistical significance. The safety data were consistent with the known tolerability of varlitinib.

ASLAN Pharmaceuticals, the developer of varlitinib, stated in a press release that pre-planned exploratory analyses did identify a subgroup of patients in which varlitinib did demonstrate improved efficacy. Further analyses of those findings are ongoing.

"The results from the study are disappointing. They will, however, provide the scientific community with important insights into an aggressive and under-researched disease that presents a growing burden of care worldwide as prevalence rises," Carl Firth, chief executive officer of Aslan Pharmaceuticals, stated in the press release.

The company also stated that it will focus on development of ASLAN004, an IL-4/IL-13 blocker monoclonal antibody, of which interim topline results of an ongoing study are expected in early 2020.

Varlitinib is a highly potent, oral, reversible, small molecule pan-HER inhibitor that targets HER1, HER2, and HER4, which can be mutated or overexpressed in many cancers.

In the international, double-blind, two-arm, randomized, TreeTopp trial, 127 patients with biliary tract cancer who failed on first-line therapy were randomized to receive the combination of varlitinib plus capecitabine or capecitabine plus placebo. Varlitinib was given orally at 300 mg twice daily until disease progression, along with 1000 mg/m2 of oral capecitabine twice daily followed by a 1-week rest period in 3-week cycles until disease progression, unacceptable toxicity, or withdrawal. The coprimary endpoints were incidence of adverse events, ORR, PFS, and overall survival.

To be eligible for enrollment, patients must have had histologically or cytologically confirmed advanced or metastatic biliary tract cancer; received 1 prior line of systemic therapy, which included gemcitabine; had no evidence of biliary duct obstruction; an ECOG performance status of 0 or 1; and have adequate organ and hematological function. The receipt of anti-cancer therapy or radiation within the past 3 weeks prior to receiving varlitinib, evidence of ≥2 peritoneal metastases or ascites at baseline, had major surgery within 14 days prior to varlitinib, had known metastatic brain lesion(s), were some of the exclusion criteria.

Varlitinib was previously granted orphan drug status by the FDA for gastric cancer and cholangiocarcinoma and was also granted orphan drug designation for the treatment of patients with biliary tract cancer by the Ministry of Food and Drug Safety in South Korea.

"I would like to extend our thanks to the patients, trial investigators and site personnel who participated in the study and to the ASLAN team for their commitment to the development of varlitinib," Firth stated in the press release. "ASLAN remains focused on the promising molecules in its portfolio, including the ongoing study in atopic dermatitis of ASLAN004, our IL-13 receptor antibody which blocks signaling through IL-4 and IL-13. We look forward to the interim readout in early 2020."

In January 2019, frontline varlitinib also showed disappointing findings in a phase II gastric cancer trial.2 Adding varlitinib to mFOLFOX6 was not found to significantly reduce tumor size after 12 weeks of therapy versus mFOLFOX6 alone in patients with HER1/HER2 co-expressing advanced or metastatic gastric cancer.

Results showed that patients who received varlitinib and mFOLFOX6 had an average tumor shrinkage of 22.0% after 12 weeks versus 12.5% in those who received mFOLFOX6 alone, which did not reach statistical significance. Following review of 17 PFS events to date, data did show a trend toward an improvement in PFS in the varlitinib arm.


  1. ASLAN Pharmaceuticals announces topline results from TreeTopp global pivotal study of varlitinib in biliary tract cancer. ASLAN Pharmaceuticals. Published November 11, 2019. .Accessed November 11, 2019.
  2. ASLAN Pharmaceuticals announces study results from phase 2 study of varlitinib in first-line gastric cancer. Aslan Pharmaceuticals. Published January 14, 2019." . Accessed January 14, 2019.