FGFR Inhibitor ARQ-087 Safe, Effective in Early Cholangiocarcinoma Study

Brian Schwartz, MD

Treatment with ARQ-087 demonstrated promising signs of clinical activity with a manageable safety profile for patients with FGFR2 fusion-positive advanced and/or metastatic intrahepatic cholangiocarcinoma, according to findings from an ongoing phase I/II study presented at the 2016 World Congress on Gastrointestinal Cancer.

In the open-label study, the objective response rate (ORR) with ARQ-087 was 25% in 12 evaluable patients with FGFR2-positive intrahepatic cholangiocarcinoma. In those with tumors that did not have the FGFR2 fusion (n = 7), a response was not seen with ARQ-087, suggesting a distinct biomarker of response.

"There is scientific evidence that this disease can be caused by a number of different genetic alterations, one being FGFR2, thus making the use of precision medicine essential in treating these patients," Brian Schwartz, MD, head of Research and Development and chief medical officer at the company developing the drug, ArQule, said in a statement.

ARQ-087 is an oral bioavailable inhibitor of FGFR 1, 2, and 3. Inhibition of FGFR using a pan inhibitor, such as ARQ-087, is thought to disrupt the FGFR-mediated signal transduction pathways, which blocks tumor cell proliferation and angiogenesis. FGFR is upregulated across several types of cancer.

At the data cutoff of June 6, 2016, 21 patients had received treatment with ARQ-087 at 400 mg or 300 mg daily. Mutation analyses using next-generation sequencing (NGS) or FISH were available for 20 patients, including 14 with FGFR2 fusions.

The median age of patients was 64 years and a majority were women (62%). Forty-three percent of patients had an ECOG performance status of 1 and 52% had undergone prior surgery. Ninety percent of patients had received a prior systemic therapy, with 52% having received ≥2 prior regimens.

The primary endpoint of the study was safety and tolerability across the full population and for those with the FGFR2 fusion. Secondary outcome measures focused on pharmacokinetics, pharmacodynamics, and antitumor activity. Exploratory analyses focused on biomarkers.

In addition to responses, 50% of evaluable patients treated with ARQ-087 had stable disease at the time of the analysis. The overall disease control rate was 75%, and disease control was observed for ≥16 weeks in 50% of patients.

In the pharmacodynamic evaluation, FGF19 levels increased following treatment by nearly 2000% in some instances for those with FGFR2 fusions. This biomarker could serve as an indicator of FGFR receptor engagement, according to the authors of the study. Exploration of other biomarkers, such as FGF21 and FGF23 did not yield directly actionable findings.

At the time of the analysis, 33% of patients remained on treatment with ARQ-087. The primary reason for treatment discontinuation was progressive disease (52%). There were no treatment discontinuations or deaths from ARQ-087-related adverse events (AEs). Dose interruptions related to AEs were required for 29% of patients.

All patients experienced at least 1 AE. The most common grade ≥3 AEs with ARQ-087 were aspartate aminotransferase (AST) increase (2 patients; 10%), fatigue, alanine aminotransferase (ALT) increase, blurred vision, vomiting, stomatitis, and anemia (1 patient each). The most common AEs of any grade were dry mouth (38%), fatigue (38%), ALT increase (24%), dysgeusia (24%), AST increase (14%), decreased appetite (14%), blurred vision (14%), vomiting (14%), diarrhea (14%), and stomatitis (14%).

"The data we presented, while preliminary, are very encouraging and offer evidence that ARQ-087 is active in those patients with a FGFR2 genetic alteration," said Schwartz. "We look forward to concluding the study late in the third quarter of 2016."

The phase I/II study exploring ARQ-087 continues to enroll participants with intrahepatic cholangiocarcinoma. The trial plans to include 120 total patients, with an estimated primary completion date of December 2016 (NCT01752920).

Mazzaferro V, Shaib W, Rimassa L, et al. ARQ 087, an oral pan- fibroblast growth factor receptor (FGFR) inhibitor, in patients (pts) with advanced and/or metastatic intrahepatic cholangiocarcinoma (iCCA). Presented at: 2016 World Congress on GI Cancer; June 28 - July 2, 2016; Barcelona, Spain. Abstract PD-019.

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