In a phase II study (FOENIX-CCA2) published in The New England Journal of Medicine, Lipika Goyal, MD, and colleagues found that the next-generation, covalently binding FGFR1-4 inhibitor futibatinib showed activity in previously treated patients with unresectable or metastatic FGFR2-altered intrahepatic cholangiocarcinoma.

Lipika Goyal, MD

Study Details

One hundred and three patients with FGFR2 fusion–positive or FGFR2 rearrangement–positive disease and disease progression after one or more previous lines of systemic therapy, excluding FGFR inhibitors, were enrolled in the international trial between April 2018 and November 2019. Patients received oral futibatinib at 20 mg once daily continuously in 21-day cycles, with treatment continuing until imaging-based or clinical disease progression or unacceptable toxicity. The primary endpoint was objective response assessed by independent central review.

Responses

Objective response was observed in 43 (42%; 95% confidence interval [CI] = 32%–52%) of 103 patients, with complete response seen in 1. An additional 42 patients (41%) had stable disease, with disease control achieved in 85 patients (83%, 95% CI = 74%–89%). Median duration of response was 9.7 months (95% CI = 7.6–17.0 months); responses lasted for ≥ 6 months in 31 responders (72% of responders) and ≥ 12 months in 6 (14%). Median duration of treatment was 9.1 months; median time to response was 2.5 months (range = 0.7–7.4 months).

Objective response rates were consistent across patient subgroups, including heavily pretreated patients (54.2% among 24 patients with ≥ 3 prior regimens), older adults (65.2% among 23 patients aged ≥ 65 years), and patients who had co-occurring TP53 mutations (38.5% among 13 patients).  

At a median follow-up of 17.1 months (range = 10.1–29.6 months), median progression-free survival was 9.0 months (95% CI = 6.9–13.1 months), with 6- and 12-month rates of 66% and 40%, respectively. Median overall survival was 21.7 months (95% CI = 14.5 months to not reached), with a 12-month rate of 72%.

Adverse Events

The most common treatment-related adverse events of any grade were hyperphosphatemia (85%), alopecia (33%), dry mouth (30%), diarrhea (28%), dry skin (27%), and fatigue (25%). Treatment-related grade 3 adverse events occurred in 56% of patients, most commonly hyperphosphatemia (30%), increased aspartate aminotransferase (7%), stomatitis (6%), and fatigue (6%); one treatment-related grade 4 adverse event was observed (increased alanine aminotransferase). Hyperphosphatemia (median time to onset = 5 days) was managed with phosphate-lowering therapy (in 78% of cases), dose interruptions (in 17%), and dose reductions  (in 20%); all grade 3 cases resolved in a median of 7 days. Serious treatment-related adverse events occurred in 10% of patients, with migraine—occurring in two patients—being the only event to occur in more than one patient. Treatment-related adverse events led to discontinuation of treatment in two patients (2%), due to stomatitis/oral dysesthesia/pharyngeal inflammation in one patient and esophagitis in one patient. There were no treatment-related deaths.

The investigators concluded: “In previously treated patients with FGFR2 fusion or rearrangement–positive intrahepatic cholangiocarcinoma, the use of futibatinib, a covalent FGFR inhibitor, led to measurable clinical benefit.”

Dr. Goyal, of the Stanford Cancer Institute, is the corresponding author for The New England Journal of Medicine article.

Disclosure: The study was funded by Taiho Oncology and Taiho Pharmaceutical. For full disclosures of the study authors, visit nejm.org.