While currently-approved treatments for HCC are typically associated with responses rates of 10% or less, findings presented at the 11th Annual Conference of the ILCA, BLU-554, a potent and highly selective inhibitor of fibroblast growth factor receptor 4 (FGFR4), induced an overall response rate of 16% (95% CI, 6-31) in patients with FGF 19 IHC-positive HCC.
Richard D. Kim, MD
While currently-approved treatments for hepatocellular carcinoma (HCC) are typically associated with responses rates of 10% or less, findings presented at the 11th Annual Conference of the International Liver Cancer Association in Seoul, South Korea, BLU-554, a potent and highly selective inhibitor of fibroblast growth factor receptor 4 (FGFR4), induced an overall response rate of 16% (95% CI, 6-31) in patients with FGF 19 immunohistochemistry (IHC)-positive HCC.
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, 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.