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An explosion of research in the field led to the approval of pemigatinib in April 2020 for patients with unresectable, previously treated advanced or metastatic cholangiocarcinoma with FGFR2 fusion or rearrangement.
Until recently, there were no molecularly targeted therapies for patients with cholangiocarcinoma. As a result of an explosion of research in the field, the first such targeted therapy, pemigatinib (Pemazyre), was approved in April 2020 for patients with unresectable, previously treated advanced or metastatic cholangiocarcinoma with fibroblast growth factor receptor 2 (FGFR2) fusion or rearrangement.1,2
Now pemigatinib is being studied in a phase 3 trial to determine whether it can be used as a first-line treatment for this patient population. The FIGHT-302 study (NCT03656536) aims to assess the efficacy and safety of pemigatinib compared with the combination of gemcitabine and cisplatin (Figure).3
Figure. Pemigatinib Versus Chemotherapy in Cholangiocarcinoma3
“Pemigatinib shows significant activity in a group of patients who don’t typically have much of a treatment option. There are data that suggest it may have even a further effect if you give it to untreated patients,” Tanios S. Bekaii-Saab, MD, said in an interview with OncLive®. A leading investigator into the drug, Bekaii-Saab is a professor at Mayo Clinic College of medicine and science, the Gastrointestinal Cancer Program leader at Mayo Clinic Cancer Center, and medical director for clinical cancer research at Mayo Clinic in Phoenix, Arizona.
As it stands now, surgery is the only curative treatment for the rare biliary tract cancer but that is an option only for about 35% of patients, and of those who do opt for resection, about 35% relapse within 2 years.4 For patients with unresectable biliary tract cancer, the standard of care is combination therapy with gemcitabine plus cisplatin, based on findings from the phase 3 advanced biliary cancer study ABC-02 (NCT00262769), Bekaii-Saab and colleagues note in a recent article in Future Oncology.5
However, investigators said, survival associated with the combination compared with gemcitabine alone is “significant but modest,” with a median overall survival (OS) of 11.7 months versus 8.1 months (HR, 0.64; 95% CI, 0.52-0.80; P < .001). Although studies continue to assess the gemcitabine/cisplatin combination along with other chemotherapies, investigators say there is an unmet need for better first-line treatments, and targeted approaches have the potential to improve prognosis for patients.5
FIGHT-302 seeks to enroll 432 patients with previously untreated unresectable or stage IV cholangiocarcinoma with FGFR2 rearrangements in 154 locations in the United States, Europe, and Japan. Participants will be randomized 1:1 to receive pemigatinib orally at 13.5 mg daily administered continuously on a 3-week cycle or gemcitabine at 1000 mg/m2 plus cisplatin at 25 mg/m2 given intravenously on days 1 and 8 of a 3-week cycle for up to 8 cycles. Patients whose disease progresses on the gemcitabine/cisplatin combination will be eligible to cross over to the pemigatinib arm.3,5
The study schema is consistent with evidence about the efficacy of pemigatinib to date, according to Bekaii-Saab. “We have seen significant advantages in the refractory setting; this subgroup of patients with FGFR2 fusion does not seem to respond well to chemotherapy. The crossover design also makes sense because this agent is now approved for second-line treatment,” he said.
Results from Early Studies
Pemigatinib is small-molecule inhibitor of FGFR1/2/3 that, in preclinical studies, has demonstrated activity against cancer cells with FGFR alterations. Overall, FGFR1/2/3 fusions and amplifications have been observed in 11% to 13% of patients with intrahepatic cholangiocarcinoma. The alterations have not been detected in extrahepatic disease.5
The FDA granted an accelerated approval for pemigatinib based on the results of FIGHT-202 (NCT02924376), a multicenter, open-label, single-arm phase 2 study that evaluated patients with locally advanced unresectable or metastatic cholangiocarcinoma who had been treated with at least 1 prior therapy.2
The agency also approved FoundationOne CDx as a companion diagnostic for pemigatinib. The assay is a next-generation sequencing device that detects alterations in 324 genes using DNA isolated from formalin-fixed paraffin-embedded tumor tissue specimens, including FGFR2 fusions and select rearrangements.6 Bekaii-Saab suggests that other commercially available next-generation tests, specifically those that include RNA analysis, may be preferred since they better capture the presence of FGFR2 fusions.
In FIGHT-202, pemigatinib monotherapy demonstrated an overall response rate of 36% (95% CI, 27%-45%), including 2.8% complete and 33% partial response rates, respectively. The median duration of response was 9.1 months (95% CI, 6.0-14.5); 63% of patients achieved a response for 6 months or more and 18% maintained a response for 12 months or more.2 Of note, all responses were observed among those with FGFR2 fusions or rearrangements (n = 107); none were evident in study participants with other FGF/FGFR genetic alterations (n = 20) or without FGF/FGFR alterations (n = 18).4
Although OS data were immature at the time of data cutoff, pemigatinib demonstrated median OS of 21.1 months (95% CI, 14.8-not estimable), according to results reported in Lancet Oncology.4
“Overall, these are very impressive results for a group of patients that typically does not do well at all. If we think about second, third, plus lines of treatment in cholangiocarcinoma, the historical average survival published in 1 study is less than 6 to 7 months. In this pretreated subgroup with FGFR2 fusions, we are talking about 21 months,” Bekaii-Saab said.
The antitumor activity of pemigatinib in patients with FGFR2 fusions in FIGHT-202 compares favorably with other second-line chemotherapy and targeted therapies, investigators said. However, they were cautious about comparing pemigatinib with other treatment regimens for cholangiocarcinoma because the study enrolled molecularly selected patients, most of whom (98% in the FGFR2-positive group) had intrahepatic cholangiocarcinoma whereas other studies included patients with all biliary tract cancers without molecular profiling.4
In the FIGHT-202 safety population (N = 146), serious adverse effects (AEs) were observed in 45% of patients, with fatal AEs occurring in 4.1% including failure to thrive, bile duct obstruction, cholangitis, sepsis, and pleural effusion. Nine percent of patients discontinued treatment due to AEs, with causes including intestinal obstruction and acute kidney injury. Dose reduction due to an AE was required in 14% of patients.2
Overall, investigators said the safety profile of pemigatinib was “manageable.” Most AEs were of grade 1 or 2 severity, and these events most commonly included hyperphosphatemia (55%), alopecia (46%), dysgeusia (38%), diarrhea (34%), and fatigue (31%).4
Research Continues With FIGHT-302
FIGHT-302 represents “the largest study with an FGFR2 inhibitor in intrahepatic cholangiocarcinoma specifically for FGFR2 fusions,” Bekaii-Saab said. “This is the first-in-class drug that is approved by the FDA for clinical use. The approval is an accelerated approval pending results of phase 3 studies.”
The primary end point is progression-free survival according to RECIST v1.1 criteria as assessed by independent central review. Secondary outcomes include overall response, OS, duration of response, and quality-of-life assessments.
The study is open label because blinding would have been challenging, Bekaii- Saab said. Pemigatinib is an oral therapy whereas both gemcitabine and cisplatin are administered intravenously. “The toxicities also are a bit different,” he said.
Although cholangiocarcinoma accounts for only 3% of all gastrointestinal malignancies,5 Bekaii-Saab said there is a significant level of interest in studying targeted strategies and immune therapies. “Cholangiocarcinoma is a very target-rich disease,” he noted.
Molecular-profiling technologies have identified potentially actionable genetic mutations that may be present in about 40% of patients with cholangiocarcinoma. Frequently altered genes in intrahepatic cholangiocarcinoma include TP53, KRAS, IDH1/2, and CDKN2A/B.
Pemigatinib is being developed by Incyte, a biopharmaceutical company based in Wilmington, Delaware.