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More than 40% of patients with advanced cholangiocarcinoma (CCA) had objective responses that were durable in most cases following treatment with a multitargeted fibroblast growth factor receptor (FGFR) inhibitor, a preliminary study showed.

Treatment with the investigational agent futibatinib led to an overall response rate (ORR) of 41.7% in 103 patients and a median duration of response of 9.7 months. Another 40% of the patients had stable disease.

Median overall survival (OS) approached 2 years, and 72% of the patients were alive at 12 months, reported Lipika Goyal, MD, of Massachusetts General Hospital Cancer Center in Boston, at the American Association for Cancer Research (AACR) virtual meeting.

"Responses occurred early, were durable, and occurred across all patient subgroups," said Goyal. "Promising PFS [progression-free survival] and overall survival were observed. Futibatinib safety was regularly monitored and manageable. Exploratory analyses showed that responses occurred in patients with BICC1 and non-BICC1 fusion partners and also in patients with co-occurring genomic alterations, including TP53."

"Overall, these results represent another example of the promise of precision medicine in cholangiocarcinoma and indicate that futibatinib could be an option for patients with refractory cholangiocarcinoma, if approved," she stated.

About 15% of intrahepatic CCAs have alterations in FGFR, particularly FGFR2 fusions and rearrangements. Until a year ago, standard chemotherapy formed the basis for treatment in the first- and second-line settings. In April 2020, the FDA approved the first therapy developed specifically for CCA. Pemigatinib (Pemazyre) received accelerated approval on the basis of a phase II open-label trial that showed an ORR of 35.5% in 146 previously treated patients, including 102 with FGFR2 fusions or rearrangements.

As reported earlier this year, the FGFR inhibitor infigratinib resulted in confirmed responses in 28 of 108 patients with previously treated CCAs. An additional 12 patients had unconfirmed responses.

Futibatinib is a selective irreversible inhibitor of FGFR1-4 with activity against FGFR2 kinase domain mutations, said Goyal. In a phase I clinical trial, futibatinib showed tolerability and antitumor activity in previously treated CCA, including tumors with FGFR2 aberrations.

Goyal reported findings from the , which involved patients with unresectable or metastatic intrahepatic CCA associated with FGFR2 fusions or other rearrangements. Eligible patients had prior exposure to gemcitabine-platinum chemotherapy and disease progression after one or more prior regimens. Patients previously treated with an FGFR inhibitor were not eligible.

Treatment consisted of futibatinib once daily until disease progression, unacceptable toxicity, or withdrawal of patient consent. The primary endpoint was ORR as determined by independent radiologic review.

The patients had a median age of 58, and women accounted for 56% of the study population. A majority (53%) of the patients had received two or more prior regimens. Fusions accounted for 78% of FGFR2 aberrations and rearrangements for the remaining 22%.

With a median follow-up of 17.1 months, the primary analysis showed objective responses in 43 patients and stable disease in an additional 42 for a disease control rate of 82.5%.

"An unusual phenomenon seen in this trial and other trials of FGFR inhibitors was that several patients had unconfirmed responses," said Goyal. "These were counted as stable disease, but its notable that 95% of patients who had stable disease had target lesion shrinkage."

The median time to response was 2.5 months, and 72% of responses lasted ≥6 months, including 14% with persistence ≥12 months. The cohort had a median PFS of 9.0 months, including 6-month PFS of 66% and 12-month PFS of 40%. Immature survival data showed a median OS of 21.7 months, 6-month OS of 88%, and 12-month OS of 72%.

Grade ≥3 adverse events occurred in 77% of patients, including grade ≥3 treatment-related adverse events (TRAEs) in 57% of the cohort. Most severe TRAEs were managed by dose interruption or reduction. Goyal said 2% of patients discontinued because of TRAEs. No fatal TRAEs occurred during the trial. The most common any-grade TRAEs were hyperphosphatemia (91%), nail toxicity (47%), increased liver enzymes (27%), and palmar-plantar erythrodysesthesia (21%). The most frequent grade ≥3 AEs of special interest were hyperphosphatemia (31%) and increased liver enzymes (13%).

AACR invited discussant Ezra Cohen, MD, of the University of California San Diego and Moores Cancer Center, briefly reiterated the trial's high points and then devoted much of his allotted time to emerging findings and "rules" of targeted therapy in oncology.

"The molecular profiling of cancers must become universally available," he said. "This is no longer a question of if, but we do it in each patient and what methodology is best. We need to develop health policies and guidelines that accommodate universal testing. These agents are tremendously effective, but in small groups of patients. We need to know which patients are going to benefit."

"Selectivity appears to beat promiscuity," he noted. "The more selective the agent, the higher the efficacy. Resistance: It always emerges. Preclinical modeling has utility, and we need to think about proactive approaches. Lastly, toxicity profiles among classes are unique, and education of providers is essential."

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