On April 17, 2020, pemigatinib was granted accelerated approval for the treatment of adults with previously treated unresectable locally advanced or metastatic cholangiocarcinoma with a fibroblast growth factor receptor 2 (FGFR2) fusion or other rearrangement as detected by a U.S. Food and Drug Administration (FDA)-approved test.^1,2 The FDA also approved the FoundationOne CDx test as a companion diagnostic for patient selection.

Supporting Efficacy Data

Approval was based on findings in the multicenter phase II FIGHT-202 trial (ClinicalTrials.gov identifier NCT02924376).^2,3 In the trial, 107 patients with locally advanced unresectable or metastatic cholangiocarcinoma with disease progression after at least one prior therapy who had an FGFR2 gene fusion or rearrangement on central laboratory assessment received oral pemigatinib at 13.5 mg once daily for 14 consecutive days followed by 7 days off therapy.

The median age of study patients was 56 years (range = 26–77 years); 61% were female, 74% were white, 95% had an Eastern Cooperative Oncology Group performance status of 0 (42%) or 1 (53%), and 98% had intrahepatic cholangiocarcinoma. In-frame FGFR2 gene fusions were identified in 86% of patients, with the most commonly identified FGFR2 fusion being FGFR2-BICC1 (34%). All patients had received at least one prior line of systemic therapy, 27% had received two prior lines, and 12% had three or more prior lines; 96% of patients had received prior platinum-based therapy, including gemcitabine/cisplatin in 76%.

Objective response as assessed by an independent review committee using Response Evaluation Criteria in Solid Tumors, version 1.1, was observed in 38 patients (36%, 95% confidence interval = 27%–45%), with a complete response observed in 3 patients. The median duration of response was 9.1 months, with responses lasting at least 6 months in 63% of responding patients and at least 12 months in 18%.

How It Works

Pemigatinib is a small-molecule kinase inhibitor that targets FGFR1, FGFR2, and FGRF3; it also inhibits FGFR4 at a concentration approximately 100 times higher than those that inhibit FGFR1, 2, and 3. Pemigatinib inhibited FGFR1–3 phosphorylation and signaling and decreased cell viability in cancer cell lines with activating FGFR amplifications and fusions that resulted in constitutive activation of FGFR signaling. Constitutive FGFR signaling can support the proliferation and survival of malignant cells. Pemigatinib exhibited antitumor activity in mouse xenograft models of human tumors with FGFR1, FGFR2, or FGFR3 alterations resulting in constitutive FGFR activation, including a patient-derived xenograft model of cholangiocarcinoma that expressed an oncogenic FGFR2 Transformer-2 beta homolog fusion protein.

How It Is Used

Patients must be selected for pemigatinib treatment based on the presence of an FGFR2 fusion or rearrangement as detected by an FDA-approved test. The recommended dosage of pemigatinib is 13.5 mg once daily for 14 consecutive days followed by 7 days off therapy in 21-day cycles, with treatment continued until disease progression or unacceptable toxicity.

Recommended dose reductions for adverse reactions are sequentially to 9 mg once daily for the first 14 days of each 21-day cycle and then to 4.5 mg once daily for the first 14 days of each 21-day cycle. Treatment should be discontinued in patients who cannot tolerate pemigatinib at the 4.5-mg once-daily dose level.

Prescribing information provides instructions on dosage modification for and management of retinal pigment epithelial detachment, hyperphosphatemia, and grade 3 or 4 adverse reactions. Treatment should be permanently discontinued for grade 4 adverse reactions.

Concomitant use with strong or moderate CYP3A inhibitors should be avoided. If such use cannot be avoided, pemigatinib dosage should be reduced from the 13.5-mg dose level to the 9-mg dose level or from the 9-mg dose level to the 4.5-mg dose level. Concomitant use with strong or moderate CYP3A inducers should be avoided.

Safety Profile

Safety data are from a total of 146 patients receiving pemigatinib in FIGHT-202. The median duration of treatment was 181 days (range = 7–730 days).

The most common adverse events of any grade were hyperphosphatemia (60%), alopecia (49%), diarrhea (47%), nail toxicity (43%), fatigue (42%), dysgeusia (40%), nausea (40%), constipation (35%), stomatitis (35%), dry eye (35%), dry mouth (34%), and decreased appetite (33%). Other adverse events included vomiting, arthralgia, abdominal pain, hypophosphatemia, back pain, and dry skin (each occurring in ≥ 20%). The most common grade ≥ 3 adverse events were hypophosphatemia (12%), arthralgia (6%), stomatitis (5%), abdominal pain (5%), and fatigue (5%). The most common grade 3 or 4 laboratory abnormalities were decreased levels of phosphate (38%) and sodium (12%) as well as increased levels of alkaline phosphatase (11%) and urate (10%).

Serious adverse events were observed in 45% of patients, with those occurring in at least 2% of patients including abdominal pain, pyrexia, cholangitis, pleural effusion, acute kidney injury, cholangitis infection, failure to thrive, hypercalcemia, hyponatremia, small intestinal obstruction, and urinary tract infection. Adverse events led to dosage interruption in 43% of patients and to dose reduction in 14%. Adverse events led to discontinuation of treatment in 9%, with those occurring in at least 1% being intestinal obstruction and acute kidney injury. Adverse events led to death in 4.1% of patients, with causes including failure to thrive, bile duct obstruction, cholangitis, sepsis, and pleural effusion.

Pemigatinib has warnings/precautions for retinal pigment epithelial detachment, hyperphosphatemia, and embryofetal toxicity. Patients should undergo an ophthalmologic examination that includes optical coherence tomography prior to initiation of therapy every 2 months during the first 6 months of treatment and every 3 months thereafter. In addition, patients should receive immediate examination upon occurrence of visual symptoms. Increases in phosphate levels are a pharmacodynamic effect of pemigatinib; patients should have phosphate levels monitored and treatment should be withheld, reduced in dose, or permanently discontinued based on the duration and severity of hyperphosphatemia. Patients should be advised not to breastfeed while receiving pemigatinib. 

REFERENCES

1. U.S. Food and Drug Administration: FDA grants accelerated approval to pemigatinib for cholangiocarcinoma with an FGFR2 rearrangement or fusion. Available at https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-pemigatinib-cholangiocarcinoma-fgfr2-rearrangement-or-fusion. Accessed May 11, 2020.

2. Pemazyre (pemigatinib) tablets prescribing information, Incyte Corporation, April 2020. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/213736s000lbl.pdf. Accessed May 11, 2020.

3. Vogel A, Sahai V, Hollebecque A, et al: FIGHT-202: A phase II study of pemigatinib in patients with previously treated locally advanced or metastatic cholangiocarcinoma (CCA). Ann Oncol 30(suppl 5):v876, 2019.