FGFR4 Inhibitor Demonstrates Promising Activity in HCC Subgroup

Targeted Therapies in Oncology, October 2017, Volume 6, Issue 10

An overall response rate of 16% was demonstrated in patients with FGF 19 immunohistochemistry-positive hepatocellular carcinoma treated with BLU-554, which was higher than the response rates of 10% or less that are seen with the currently approved HCC treatments.

Richard Kim, MD

An overall response rate of 16% (95% CI, 6%-31%) was demonstrated in patients with FGF 19 immunohistochemistry (IHC)-positive hepatocellular carcinoma (HCC) treated with BLU-554, which was higher than the response rates of 10% or less that are seen with the currently approved HCC treatments, according to a presentation during the 2017 International Liver Cancer Association Annual Meeting.

Liver cancer is the second leading cause of cancer-related deaths worldwide, and HCC is the most common form of the disease. In the United States, HCC is the fastest rising cause of cancer-related death. Over the past 2 decades, the incidence of HCC has tripled and the 5-year survival rate has remained below 12%.

“Patients with hepatocellular carcinoma face a very poor prognosis with few therapeutic options,” said lead investigator Richard Kim, MD, associate professor, Moffitt Cancer Center. “The new BLU- 554 data [presented] showed that in heavily pretreated patients, BLU-554 demonstrated encouraging clinical activity, with approximately half of patients with FGF 19 IHC-positive HCC having tumor shrinkage. These data compare well to historical data for currently approved agents showing response rates of approximately 10% or less, and BLU-554 has the potential to change the treatment paradigm for patients with FGF 19 IHC-positive HCC.”

As of the data cutoff date of August 18, 2017, 49% of patients with FGF 19 IHC-positive HCC had radiographic tumor reduction.

In an interview with Targeted Therapies in Oncology™, Kim explained that BLU-554 is an irreversible kinase inhibitor that “exquisitely” binds to fibroblast growth factor receptor 4 (FGFR4) and does not bind to other receptors. Investigators have also identified FGF 19 as a potential biomarker that may predict response to the drug. He said the research team plans to finish the expanded cohort in the phase I study and add more patients who are kinase-naïve in order to gather more efficacy data in that setting.

These results include an analysis of the first 77 patients enrolled in the dose-escalation and -expansion portions of the phase I clinical trial, which ranged from 140 to 900 mg of BLU-554 daily. The group included 44 patients with FGFR4-driven HCC, defined as at least 1% tumor expression of FGF19.

These patients were heavily pretreated. More than 4 in 5 patients underwent prior tyrosine kinase inhibitor (TKI) treatment, 23% received prior immunotherapy, and 91% received prior systemic therapy.

The dose-escalation portion of the trial established 600 mg of daily BLU-554 as the maximum-tolerated dose, and investigators are currently recruiting patients for the expansion portion of the trial at that dose.

The disease control rate was 68%. One patient had an unconfirmed complete response, 5 patients had partial responses (4 confirmed), and 20 patients had stable disease. Investigators found that patients who were FGF 19 IHC-negative (n = 29) did not demonstrate response to BLU-554.

“It is clear that patients with HCC who are FGF 19 IHC-negative do not respond to BLU-554,” Kim said. “On the other hand, relative response is 16% in HCC patients who are FGF 19-positive, [which is very similar to that seen with] nivolumab (Opdivo) in the second-line setting.”

He added that most patients in this study failed on TKI treatment. Future research will focus on TKI-naïve patients with FGF19-positive tumors.

Most adverse events (AEs) were grade 1/2. The most common all-grade treatment-related AEs reported by investigators included diarrhea (71%), nausea (42%), vomiting (36%), transaminase elevation (AST 34% and ALT 32%), and fatigue (29%). Grade ≥3 treatment-related AEs observed in 5 or more patients included anemia, diarrhea, and transaminase elevation (AST and ALT).

Fifty-eight patients discontinued treatment with BLU-554. Forty-two stopped due to disease progression, 11 due to treatment-related AEs, 2 due to the investigator’s decision, and 3 withdrew their consent.


Kang Y-K, Macarulla T, Yau T, et al. Clinical activity of Blu-554, a potent, highly-selective FGFR4 inhibitor in advanced hepatocellular carcinoma (HCC) with FGFR4 pathway activation. Presented at: 2017 ILCA Annual Conference; September 15-17, 2017; Seoul, South Korea. Abstract O-032.