Barcelona, Spain—Alterations in the fibroblast growth factor receptor (FGFR)2 gene have been identified as driver mutations in cholangiocarcinoma (CCA). Durable objective responses were observed in >33% of patients with locally advanced or metastatic CCA and FGFR2 rearrangements or fusions who received treatment with pemigatinib, a selective oral inhibitor of FGFR1, FGFR2, and FGFR3. Data from the single-arm, open-label phase 2 clinical trial FIGHT-202, which was presented at the ESMO Congress 2019, revealed that investigational pemigatinib induced a response in 35.5% of the 107 patients with FGFR2 fusions or rearrangements (cohort A), with a median duration of response of 7.5 months.
No responses were reported in the 20 patients with other FGF/FGFR genetic alterations (cohort B) or in the 18 patients with no FGF/FGFR alterations (cohort C), reported lead investigator Arndt Vogel, MD, PhD, Professor of Gastrointestinal Oncology, Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Germany.
“In many CCAs, you can detect genetic alterations, which allow targeted therapies,” Dr Vogel said. “Among them, there are many patients with FGFR2 fusions or rearrangements. They exclusively occur in intrahepatic CCA and are detectable in around 15% of the patients, indicating that this might be an interesting patient population to be treated by an FGFR inhibitor.”
All patients had locally advanced or metastatic CCA and had received at least 1 line of previous therapy. In the study, patients in the 3 cohorts received treatment with oral pemigatinib, 13.5 mg (2 weeks on, 1 week off). The primary end point was the confirmed objective response rate in cohort A by independent central review. The study was not designed to make statistical comparisons between the 3 cohorts.
Of the 1206 patients screened, 127 patients with CCA had FGFR2 alterations. A total of 61% of patients were enrolled in North America, 24% in Western Europe, and 15% in the rest of the world.
Among the 107 patients in cohort A, 92 fusions and 15 rearrangements were discovered, including 56 unique fusion partners, with BICC1 being the most common (29%). A total of 42 partners were unique to a single patient, “indicating that we really need an infusion partner-agnostic test to find those patients,” Dr Vogel said. No fusion partner was identified in 5% of the patients.
Cohort A had 3 (2.8%) complete responses, 35 (32.7%) partial responses, and 50 (46.7%) patients with stable disease, for a total disease control rate of 82%. The responses were consistent across subgroups, including when patients were stratified by the number of previous lines of therapy and by FGFR2 rearrangement partner.
The higher response rate in cohort A with pemigatinib translated to a longer median progression-free survival (PFS)—6.9 months in cohort A versus 2.1 months in cohort B and 1.7 months in cohort C.
The overall survival (OS) data were not yet mature. With a 15.4-month median duration of follow-up and a 7.2-month median duration of treatment, the median OS was 21.1 months in the cohort with FGFR2 fusions or rearrangements compared with 6.7 months in the cohort with other FGF/FGFR alterations after a median follow-up of 19.9 months, and 4.0 months in the cohort without an FGF/FGFR alteration after a median follow-up of 24.2 months.
“Overall, I think these data indicate that FGFR inhibition is a meaningful treatment for this genetically defined subgroup of patients with CCA,” said Dr Vogel.
The most common adverse event reported was hyperphosphatemia, which occurred in 60% of patients and was managed with a low-phosphate diet, phosphate binders, diuretics, and a reduction or interruption in the pemigatinib dose. Only 3 patients required dose reductions or interruptions because of hyperphosphatemia. No grade ≥3 cases of hyperphosphatemia were reported.
A total of 9% of patients discontinued treatment because of adverse events; the most frequent reasons were intestinal obstruction and acute kidney injury (2 each). Treatment has been discontinued because of disease progression in all patients in cohorts B and C, and in 57 of the 107 patients in cohort A.
Based on these findings, a phase 3 clinical trial comparing pemigatinib with gemcitabine plus cisplatin in the first-line setting in patients with CCA and FGFR2 fusions or rearrangements has been started.
Historically, the PFS reported with second-line chemotherapy in patients with metastatic CCA is approximately 4 months, according to discussant Per Pfeiffer, MD, PhD, Experimental Research in Medical Cancer Therapy, Odense University Hospital, Denmark.