Investigational FGFR4 Inhibitor Shows Early Signs of Activity in HCC and ICC

In an interview with Targeted Oncology, Martin E. Gutierrez, MD, discussed the findings from the first-in-human phase I study investigating H3B-6527 in patients with HCC and ICC. He also highlighted the potential role for combination therapy with H3B-6527 and the next steps planned for subsequent phase II and III trials in HCC and ICC.

Martin E. Gutierrez, MD

H3B-6527, an investigational FGFR inhibitor, has demonstrated early signs of activity in patients with hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), according to findings presented in a poster at the 2019 ASCO Annual Meeting. The first-in-human phase I study also showed the agent is well tolerated.

H3B-6527 is highly selective of FGFR4.Investigators believe the FGF19-FGFR4 signaling pathway is a rational target for the treatment of patients with HCC and ICC as FGFR4 can enhance tumor growth in HCC and ICC.

Thirty-seven previously treated patients were enrolled and treated with H3B-6527 orally once daily in a 21-day cycle, with 23 included in the dose-escalation phase of the trial and 14 included in the expansion phase. Investigators assessed toxicities, pharmacokinetics, and pharmacodynamics.

Durable stable disease was observed in patients who receiving H3B-6527 once daily with a fasting schedule. Two of the 17 patients with HCC achieved a partial response while an additional 7 patients who had received treatment for at least 5 months achieved stable disease.

Overall, there were no dose-limiting toxicities seen with H3B-6527. Additionally, investigators did not observe any grade 3 or greater treatment-related adverse events (TRAEs) with escalation. The most common TRAEs included diarrhea, nausea, and vomiting. Based on these findings, the recommended phase II dose of H3B-6527 was set at 1000 mg, administered once daily.

Interest in FGFR inhibitors has been growing recently for the treatment of several solid tumor types, especially as in April 2019, the FGFR inhibitorerdafitinib (Balversa) was approved by the FDA for the treatment of adult patients with locally advanced or metastatic bladder cancerharboring anFGFR2orFGFR3alteration who have progressed on a platinum-based chemotherapy. H3B-6527 induced an objective response rate of 32.2% in a pivotal trial that led to the approval of the first targeted agent in metastatic bladder cancer.

In an interview withTargeted Oncology, Martin E. Gutierrez, MD, director, Drug Discovery/Phase I Unit, and co-chief and medical oncologist, Divisions of Thoracic Oncology and Gastrointestinal Oncology, John Theurer Cancer Center, Hackensack University Medical Center, discussed the findings from the first-in-human phase I study investigating H3B-6527 in patients with HCC and ICC. He also highlighted the potential role for combination therapy with H3B-6527 and the next steps planned for subsequent phase II and III trials in HCC and ICC.

TARGETED ONCOLOGY: What makes H3B-6527 unique in this space?

Gutierrez:FGFR [inhibitors] have become a very competitive space. There was recently an approved FGFR inhibitor in bladder cancer, erdafitinib. Erdafitinib had a phenomenal response rate with a progression-free survival between the 7- to 8-month window. Clearly, this is an area that is in development for ICC and HCC. This is where the field is at the moment.

Each FGFR inhibitor may be different because they each target different fusions with the FGFR receptor, such asFGFR1, 2, 3,and4. Most of those areFGFR2, but this is particular with FGF19, which is different than the other FGFRs, such as erdafitinib that was just approved for patients with bladder cancer.

TARGETED ONCOLOGY: What was the rationale for investigating H3B-6527 in patients with HCC or ICC?

Gutierrez:We are participating in a first-in-human study with an FGFR inhibitor. FGFR, or specifically FGF19, has been implicated in biliary tract development, therefore as a biomarker and as a target, it makes sense to target HCC and ICC. We set up a phase I as a dose-escalation study. The drug was very well tolerated, and then we started to specify selected [populations of] patients with HCC or ICC [harboring] FGF19 fusions. The adverse effect profile was actually very well tolerated. In terms of activity, we started to see some responses of stable disease in HCC, specifically. This is clearly an unmet need.

TARGETED ONCOLOGY: Do you have any next steps planned for H3B-6527?

Gutierrez:The next steps will be to have a large dose-expansion [phase II] with a group of patients [with HCC and ICC] as proof of concept. Subsequently, we would like to move to a phase III study design with H3B-6527. We already have the dose [of H3B-6527] determined, and we have the adverse effect profile determined. We are going to head into a specific dose-expansion phase for this particular group of patients.

TARGETED ONCOLOGY: What is the frequency ofFGFRalterations in liver cancer?

Gutierrez:The frequency is probably around 7%. Obviously, this is diverse among different diseases, but in liver cancer, the [rate of] incidence of FGFR or FGF homologous [factors] in HCC and ICC is around 7% to 10%.

TARGETED ONCOLOGY: Do you see this agent potentially working in combination with other drugs?

Gutierrez:There have already been studies done investigating FGFR inhibitors in combination with checkpoint inhibitors, and there have not been any additional toxicities in those studies. We are actually participating in another phase I study with another sponsor that was not presented at ASCO, but we have not seen any additional toxicities with those combinations.


Mercade TM, Moreno V, John B, et al. A phase I study of H3B-6527 in hepatocellular carcinoma (HCC) or intrahepatic cholangiocarcinoma (ICC) patients (pts).J Clin Oncol.2019;37(suppl; abstr 4095).