According to findings presented at the 11th Annual Conference on the International Liver Cancer Association in Seoul, South Korea, BLU-554 induced an overall response rate of 16% in patients with FGF 19 immunohistochemistry-positive hepatocellular carcinoma. BLU-554 is a potent and highly selective inhibitor of fibroblast growth factor receptor 4.
Richard D. Kim, MD
According to findings presented at the 11th Annual Conference on the International Liver Cancer Association in Seoul, South Korea, BLU-554 induced an overall response rate of 16% (95% CI, 6-31) in patients with FGF 19 immunohistochemistry (IHC)-positive hepatocellular carcinoma (HCC). BLU-554 is a potent and highly selective inhibitor of fibroblast growth factor receptor 4 (FGFR4).
Current HCC treatments that have previously been approved are associated with responses rates of 10% or less. Liver cancer, the second leading cause of cancer-related deaths in the world, is the most common form of HCC, while HCC is the fastest rising cause of cancer-related death in the United States. Incidences of HCC has tripled over the last 2 decades, while 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 announced today 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 email toTargeted Oncology, Kim said BLU-554 is an irreversible kinase inhibitor that “exquisitely” binds to 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 to add more patients who are kinase-naïve 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 ranging from 140 mg to 900 mg of BLU-554 daily. The cohort includes 44 patients with FGFR4-driven HCC, defined as at least 1% tumor expression of the FGF19.
The cohort was 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 BLU-554 daily 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 a partial response (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 FGF19-positive, very similar to 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, 3 withdrew consent, and 2 patients discontinued due to investigator’s decision.
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.