TAS-120 Shows Promise in Cholangiocarcinoma

Funda Meric-Bernstam, MD

TAS-120 demonstrated a clinically meaningful benefit with a manageable toxicity profile in patients with cholangiocarcinoma harboring FGFR2 gene fusions, including patients who had progressed on an FGFR inhibitor, according to phase I results presented at the 2018 World Congress on GI Cancer.

Among 28 enrolled patients with FGFR2 gene fusions, 24 were evaluable for efficacy. The highly selective, irreversible FGFR1-4 tyrosine kinase inhibitor (TKI) TAS-120 induced a confirmed partial response (cPR) in 7 of these patients. An additional 15 patients achieved stable disease. Overall, 20 patients had some level of tumor shrinkage.

In 17 cholangiocarcinoma patients with non-FGFR2 fusions, 14 were evaluable for efficacy. Three of these patients had a cPR and 10 had stable disease. Eleven patients had tumor shrinkage.

Eight of the 28 patients with an FGFR2 fusion had prior therapy with an FGFR inhibitor, as did 5 of the 17 patients with other FGF/FGFR aberrations.

“TAS-120 demonstrated meaningful clinical benefit in cholangiocarcinoma patients with FGFR2 gene fusions, this includes patients who progressed on prior FGFR inhibitors,” said lead author Funda Meric-Bernstam, MD, chair of the Department of Investigational Cancer Therapeutics, medical director of the Institute for Personalized Cancer Therapy, and a professor in the Divisions of Cancer Medicine and Surgery at The University of Texas MD Anderson Cancer Center.

“Fifteen of the 20 patients are still currently on treatment, suggesting that we have not yet met the final median duration of treatment,” added Meric-Bernstam

At the data cutoff, a total of 132 patients with various advanced solid tumors had been enrolled on the phase I study, including 45 with cholangiocarcinoma. Patients in the cholangiocarcinoma cohort received TAS-120 at 16 mg (n = 24), 20 mg (n = 14), or 24 mg (n = 7) daily.

Of the 45 patients in the cholangiocarcinoma group, 34 (75.6%) were female and 11 (24.4%) were male, with a median age of 54 years (range, 29-73 years). The majority (77.8%) of patients were white. Ninety-one percent had a primary tumor that was intrahepatic, while 9% had an extrahepatic primary tumor. This was a heavily-pretreated group, with 19 patients (42.2%) having ≥3 prior lines of therapy.

In the cholangiocarcinoma cohort, there were 5 patients who had more than one FGF/FGFR abnormality. Overall, 62.2% (n = 28) had an FGFR2 fusion, 11.1% (n = 5) had an FGFR2 rearrangement, 4.4% (n = 2) had an FGFR2 amplification, 11.1% (n = 5) had an FGFR2 mutation, 4.4% (n = 2) had an FGFR1 amplification, 2.2% (n = 1), had an FGFR1 rearrangement, 8.8% (n = 4) had FGF amplification, and 6.6% (n = 3), had unknown FGF/FGFR status.

The most frequent all-grade adverse events (AEs) were expected and manageable, reported Meric-Bernstam, including hyperphosphatemia (78%), and cutaneous and gastrointestinal toxicity. Treatment-related grade 3 AEs occurred in 51.1% of patients, with the most common including hyperphosphatemia (22.2%), ALT increase (6.7%), palmar-plantar erythrodysesthesia syndrome (4.4%), constipation (2.2%), AST increase (2.2%), and diarrhea (2.2%). There were no grade ≥4 AEs observed in this study.

“These results are encouraging for this rare and difficult-to-treat cancer,” Milind Javle, MD, professor of Gastrointestinal Medical Oncology at The University of Texas MD Anderson Cancer Center, and an investigator on the phase I TAS-120 study, said in a press release. “Given the limited number of patients diagnosed each year with cholangiocarcinoma in the United States, we recognize the sense of urgency for and importance of ongoing research to advance potential new therapies.”

TAS-120 was granted orphan drug status by the FDA in May 2018 for the treatment of patients with cholangiocarcinoma, according to Taiho Oncology, the manufacturer of the TKI.

The phase I dose-expansion study is currently recruiting in multiple cohorts, including patients with cholangiocarcinoma with other FGF/FGFR aberrations and gliomas. There is also a basket of other advanced solid tumors with FGFR amplifications, fusions, and mutations.

Additionally, a global phase II study has been initiated in patients with intrahepatic cholangiocarcinoma who had FGFR2 gene fusions.

Meric-Bernstam F, Arkenau H, Tran B, et al. Efficacy of TAS-120, an irreversible fibroblast growth factor receptor (FGFR) inhibitor, in cholangiocarcinoma patients with FGFR pathway alterations who were previously treated with chemotherapy and other FGFR inhibitors. Ann Oncol. 2018;29 (suppl 5; abstr O-001).