An objective response rate of 35.5% was seen with treatment with pemigatinib, a selective oral inhibitor of FGFR1, 2, and 3, in patients with previously treated, locally advanced or metastatic cholangiocarcinoma with an <em>FGFR2 </em>rearrangement or fusion, according to findings from the phase II FIGHT-202 clinical trial presented at ESMO 2019.
Arndt Vogel, MD, PhD
An objective response rate (ORR) of 35.5% was seen with treatment with pemigatinib, a selective oral inhibitor of FGFR1, 2, and 3, in patients with previously treated, locally advanced or metastatic cholangiocarcinoma (CCA) with an FGFR2rearrangement or fusion, according to findings from the phase II FIGHT-202 clinical trial presented at ESMO 2019.
More than one-third of 107 total patients withFGFR2fusions/rearrangements (cohort A) responded, and the median duration of response was 7.5 months. In contrast, there were no responses observed in the 20 patients enrolled with otherFGF/FGFRgenetic alterations (cohort B) or in the 18 patients with noFGF/FGFRalterations (cohort C).
The higher ORR translated into a longer median progression-free survival (PFS) in cohort A. Median PFS was 6.9 months in cohort A compared with 2.1 months in cohort B and 1.7 months in cohort C.
Overall survival (OS) data were not yet mature at the time of data cutoff (March 22, 2019), but with a median duration of follow-up of 15.4 months and a median duration of treatment of 7.2 months, the median OS was 21.1 months in the cohort withFGFR2fusions/rearrangements. Median OS was only 6.7 months in the cohort with otherFGF/FGFRalterations after a median follow-up of 19.9 months, and only 4.0 months in the cohort without an FGF/FGFRalteration 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 lead investigator Arndt Vogel, MD, PhD, professor of gastrointestinal oncology, Hannover Medical School in Germany.
First-line treatment for locally advanced or metastatic CCA is the chemotherapy combination of gemcitabine and cisplatin. Second-line therapies in CCA have shown limited efficacy. Previous studies of second-line treatments have resulted in a median PFS in the range of 2.6 to 3.2 months, a median OS of 6.2 to 7.2 months, and an ORR no higher than 9.5%, said Vogel.
“In many CCAs, you can detect genetic alterations, which allow targeted therapies,” he said. “Among them, there are many patients withFGFR2fusions 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.”
The open-label, single arm FIGHT-202 study was undertaken in the United States, Europe, Middle East, and Asia. Eligible patients had locally advanced or metastatic CCA despite at least 1 line of prior therapy and had theirFGF/FGFRstatus centrally confirmed. Adequate renal function was required. Patients in the 3 cohorts were treated with oral pemigatinib (13.5 mg) using a 2 weeks on/1 week off schedule. The study was not designed to make statistical comparisons between the 3 cohorts. The primary endpoint was the confirmed ORR in cohort A by independent central review.
A total of 1206 patients were screened to find 127 withFGFR2alterations. Median age of the entire 146 patients enrolled was 59 years, but those in cohort A tended to be younger, said Vogel, with 77% being younger than 65 years, compared with 50% in cohort B and 39% in cohort C. Some 58% of patients were women (61% in cohort A), and 61% were enrolled in North America, 24% in Western Europe, and 15% in the rest of the world.
Among the 107 patients in cohort A, there were 92 fusions and 15 rearrangements discovered. A total of 56 unique fusion partners were identified, the most common of which was BICC1, which occurred in 29%. Forty-two partners were unique to a single patient, indicating that, “We really need an infusion partner-agnostic test to find those patients,” Vogel said. No fusion partner was identified in 5%.
In cohort A, the 35.5% ORR consisted of 3 (2.8%) complete responses, 35 (32.7%) partial responses, and 50 (46.7%) patients with stable disease, for a disease control rate of 82%. The ORR was consistent across subgroups, including when stratified by the number of prior lines of therapy and byFGFR2rearrangement partner.
Adverse events (AEs) were manageable and consistent with the mechanism of action of pemigatinib. The most common AE was hyperphosphatemia, which occurred in 60% of patients but no grade ≥3 cases were encountered. Hyperphosphatemia 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/interruptions due to hyperphosphatemia.
Hypophosphatemia of any grade occurred in 23% of patients and was the most common grade ≥3 AE, with a rate of 12%. No case of hypophosphatemia was clinically significant and none led to treatment discontinuation or dose reduction. Serous retinal detachment occurred in 4%, and “and usually resolved spontaneously or after dose interruption,” Vogel said.
Nine percent of patients discontinued due to AEs; the most frequent causes were intestinal obstruction and acute kidney injury (2 each). Treatment has been discontinued due to progressive disease in all patients in cohorts B and C, and in 57 of the 107 patients in cohort A. Dose reduction due to AEs was required in 14%, with the most common reasons being stomatitis (n = 11), palmar-plantar erythrodysesthesia syndrome (n = 5), arthralgia (n = 5), asthenia (n = 2), and onychomadesis (n = 2). Some 42% of patients required dose interruptions due to AEs.
Based on the data from FIGHT-202, a phase III study of pemigatinib compared with gemcitabine plus cisplatin in the first-line setting in patients with CCA andFGFR2fusions/rearrangements is ongoing, said Vogel.
Vogel A, Sahai V, Hollebecque A, et al. FIGHT-202: a phase 2 study of pemigatinib in patients (pts) with previously treated locally advanced or metastatic cholangiocarcinoma (CCA). Presented at: 2019 ESMO Congress; September 27-October 1, 2019; Barcelona, Spain. Abstract LBA40.