Phase II Trial Reports Anticancer Activity With Novel FGFR Inhibitor in Advanced Intrahepatic Cholangiocarcinoma

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Futibatinib—a selective, fibroblast growth factor receptor (FGFR) inhibitor—demonstrated anticancer activity in patients with advanced intrahepatic cholangiocarcinoma and FGFR2 fusions or rearrangements. These findings are based on the primary results of the phase II FOENIX-CCA2 trial, which were reported during the virtual edition of the American Association for Cancer Research (AACR) Annual Meeting 2021.1

More than 40% of patients with advanced intrahepatic cholangiocarcinoma had objective responses that were durable on treatment with futibatinib. In 103 futibatinib-treated patients, the objective response rate was 41.7%, and the duration of response was 9.7 months. Median progression-free survival was 9 months. Survival data continue to mature, but at the time of the meeting, the median overall survival was 21 months.

“The phase II FOENIX-CCA2 study met its primary endpoint, with an objective response rate of 41.7% in these heavily pretreated patients with advanced intrahepatic cholangiocarcinoma harboring FGFR2 fusions or rearrangements. Responses were consistent across subgroups and were durable. Promising progression-free survival and overall survival were observed. Treatment-related discontinuations were rare. Hyperphosphatemia, the most frequent adverse event, was manageable,” said lead author Lipika Goyal, MD, a medical oncologist at Massachusetts General Hospital Cancer Center, Boston. “Exploratory analysis showed that responses occurred in patients with BICC1 and non-BICC1 fusion partners as well as in patients with co-occurring genomic alterations, including TP53.”

Lipika Goyal, MD

Lipika Goyal, MD

Intrahepatic cholangiocarcinoma is an aggressive bile duct cancer. If it is diagnosed early, surgery is the primary treatment. Once the disease becomes locally advanced or metastatic, recurrence is rapid, and it tends to be chemotherapy-refractory, with poor survival outcomes. Dr. Goyal noted that first-line treatment of patients with advanced intrahepatic cholangiocarcinoma with gemcitabine plus cisplatin has been associated with a median overall survival of 1 year; median overall survival with second-line chemotherapy is 6.2 months, with an overall response rate of 5%.

“Intrahepatic cholangiocarcinoma is a molecularly heterogeneous disease. The good news is that 40% to 50% of these tumors harbor actionable mutations, and 13% to 14% have FGFR2 fusions or rearrangements. Treatment is an unmet need. The discovery of these genetic alterations has opened up investigational avenues,” Dr. Goyal told listeners.

FGFR Inhibitors

Several FGFR inhibitors have been investigated in intrahepatic cholangiocarcinoma. Pemigatinib is the first and only approved therapy specifically indicated for advanced refractory cholangiocarcinoma with FGFR2 fusions or rearrangements, based on a phase II study showing an objective response rate of 35.5%.2 Subgroup analysis showed that patients with co-expression of tumor-suppressor genes had a worse response, Dr. Goyal noted.

Infigratinib, another FGFR2 inhibitor, was recently granted Priority Review status and a new drug application by the U.S. Food and Drug Administration.

Futibatinib is an investigational, orally available, highly selective, irreversible FGFR1–4 inhibitor. In preclinical studies, the drug has shown activity against tumors of diverse tissue origins harboring various FGFR alterations. Phase I studies of futibatinib demonstrated activity against previously treated cholangiocarcinoma, including tumors with FGFR2 alterations. Futibatinib has a unique mechanism of action in that it binds to a different kinase domain than other FGFR inhibitors.

Study Details

The global phase II FOENIX-CCA2 study recruited 103 patients across 36 international sites. To be included, patients had to have unresectable or metastatic cholangiocarcinoma harboring FGFR2 fusions or rearrangements; measurable disease; prior treatment with gemcitabine plus platinum-based chemotherapy; disease progression after at least one systemic therapy; an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; and no prior FGFR inhibitor.

Treatment consisted of oral futibatinib at 20 mg/d continuously in 21-day cycles. Treatment was continued until disease progression, drug intolerance, or withdrawal of consent.

The primary endpoint was objective response rate according to central radiology review. Secondary endpoints included duration of response, disease control rate, progression-free survival, overall survival, and safety. As of data cutoff in 2020, all patients had at least 6 months of follow-up. Median follow-up was 17.1 months.

“This is the first presentation of data on all 103 patients,” Dr. Goyal noted.

At baseline, the median age of patients was 58 years; 56% were female; 47% had an ECOG performance status of 0, and 53% had an ECOG performance status of 1. A total of 47% had one prior line of treatment, 30% had two prior lines, and 23% had three or more prior lines of treatment. FGFR2 fusions were identified in 78%, and FGFR2 rearrangements were noted in 22%.

Key Findings

At a median follow-up of 17.1 months, the objective response rate was 41.7%, including 42 patients with a confirmed partial response and 1 with a confirmed complete response. Stable disease was documented in an additional 42 patients. The disease control rate was 82.5%. “It is unusual that several patients with unconfirmed responses were counted as stable disease, but among these patients, 95% had documented tumor shrinkage,” Dr. Goyal said.

The median duration of response was 9.7 months; the median time to response was 2.5 months. Among responders, 72% had responses lasting longer than 6 months, and 14% had responses lasting longer than 12 months.

Analysis of prespecified subgroups showed that responses were achieved independent of age, sex, and number of prior therapies. “Even patients with a worse prognosis experienced response to futibatinib. Dosing modifications did not seem to affect response,” Dr. Goyal continued.

Median progression-free survival was 9 months. The 6-month progression-free survival rate was 68%, and the 12-month progression-free survival rate was 40%.

At this early time point, median overall survival is 21.7 months, and 12-month overall survival is 72%. Further follow-up is ongoing. “This is the first presentation of overall survival in this trial,” she noted.

Safety Profile

“The safety profile of futibatinib is similar to that of other FGFR inhibitors,” Dr. Goyal said. Nearly all patients experienced at least one adverse event; 57% had treatment-related adverse events of grade 3 or higher. No patient discontinued treatment due to treatment-related adverse events.

The frequency of serious treatment related adverse events was 10%; for grade 3 and higher, it was 7%. “Treatment-related adverse events were effectively managed with dose interruptions [50%] and dose reductions [54%],” reported Dr. Goyal.

Drug discontinuations were needed in 2% of patients. No deaths attributed to treatment-related adverse events were reported.

The most commonly reported adverse events were hypophosphatemia, alopecia, dry mouth, diarrhea, dry skin, fatigue, and hand-foot syndrome. Most treatment-related adverse events were grades 1 and 2. Notable grades 3 and 4 adverse events included increases in liver enzymes (13%) and hyperphosphatemia (31%). Grade 3 hyperphosphatemia was managed with phosphate binders or dosing reductions or interruptions. “Hyperphosphatemia may be related to dosing schedule,” Dr. Goyal suggested.

Exploratory Analysis

In an exploratory analysis, 46 different fusion partners were identified in 80 patients; BICC1 was the most common (31%). The objective response rate did not seem to be affected by BICC1 as a fusion partner or genetic co-alterations in tumor-suppressor genes (as identified by Foundation Medicine). 

DISCLOSURE: Dr. Goyal has served as a consultant or advisor to Agios Pharmaceuticals, Alentis Therapeutics AG, AstraZeneca, Debiopharm Group, Exelixis, Genentech, H3 Biomedicine, Incyte, Klus Pharma, QED, Sirtex, and Taiho Pharmaceutical; and has held uncompensated relationships with Agios, Debiopharm Group, Merck, and Taiho Pharmaceutical.


1. Goyal L, Meric-Bernstam F, Hollebecque A, et al: Primary results of phase II FOENIX-CCA2 trial: The irreversible FGFR1-4 inhibitor futibatinib in intrahepatic cholangiocarcinoma with FGFR2 fusions/rearrangements. AACR Annual Meeting 2021. Abstract CT010. Presented April 11, 2021.

2. Abou-Alfa GK, Sahai V, Hollebecque A, et al: Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: A multicentre, open-label, phase 2 study. Lancet Oncol 21:671-684, 2020.


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