US FDA Accepts Priority Review of NDA for Pemigatinib in Cholangiocarcinoma

The U.S. Food and Drug Administration (FDA) has granted a priority preview status to Incyte‘s New Drug Application (NDA) for pemigatinib (also known as INCB054828) , a drug that may offer a major advance in treatment options. The designation shortens the review period to eight months compared to 12 months for the FDA’s Standard Review.

Pemigatinib is a selective fibroblast growth factor receptor or FGFR inhibitor for the treatment for adult patients (≥ 18 years) with previously treated, locally advanced or metastatic cholangiocarcinoma with documented FGFR2 fusions or rearrangements.

FGFRs, a family of receptor tyrosine kinases upregulated in many tumor cell types, plays an key role in cellular proliferation, migration, survival and angiogenesis. Activating fusions, rearrangements, translocations and gene amplifications in FGFRs are closely correlated with the development of various cancers.

Pemigatinib is a potent, selective, oral inhibitor of FGFR isoforms 1, 2 and 3 which, in preclinical studies, has demonstrated selective pharmacologic activity against cancer cells with FGFR alterations.

A rare cancer
Cholangiocarcinoma is a rare cancer that forms in the bile duct. It is the second most common primary liver tumor and the incidence is increasing worldwide. It is classified based on its origin: intrahepatic cholangiocarcinoma (iCCA) occurs in the bile duct inside the liver and extrahepatic cholangiocarcinoma occurs in the bile duct outside the liver.

The disease has high mortality owing to its aggressiveness, resulting in patients being diagnosed at a late or refractory (advanced) stage, when the prognosis is poor.[1][2] The incidence of cholangiocarcinoma, which varies regionally and ranges between 0.3 – 3.4 per 100,000 in North America and Europe, influenced by factors such as treatment allocation, including age, education, comorbidities, cancer stage, grade, and treatment center. [1][2]

FGFR2 fusions or rearrangements occur almost exclusively in iCCA, where they are observed in 10-16% of patients. [3][4][5]

“Patients with advanced cholangiocarcinoma face a poor prognosis, and currently there is no standard of care beyond first-line chemotherapy,” noted Peter Langmuir, M.D., Group Vice President, Targeted Therapeutics, Incyte.

Treatment disparities
Researchers at the Yale School of Medicine (New Haven, CT, USA) and the Department of Diagnostic and Interventional Radiology, University Medical Center Goettingen (Goettingen, Germany), observed a decreased in treatment likelihood for male African Americans with Medicaid insurance and those with low income (multivariable p < 0.05). They further noted socioeconomic treatment discrepancies translated into decreased overall survival for patients of male sex (vs. female; hazard ratio [HR] 1.21, 95% confidence interval [CI] 1.16-1.26, p < 0.001), with low income (< $37,999 vs. ≥ $63,000 annually; HR 1.07, 95% CI 1.01-1.14, p = 0.032), and with Medicaid insurance (vs. private insurance; HR 1.13, 95% CI 1.04-1.23, p = 0.006).[2]

NDA Submission
The NDA submission is based on data from the phase II FIGHT-202 study (NCT02924376), an open-label, multicenter study evaluating the safety and efficacy of pemigatinib, which was funded by Incyte.

Participating patients were enrolled into one of three cohorts – Cohort A (FGFR2 fusions or rearrangements), Cohort B (other FGF/FGFR genetic alterations) or Cohort C (no FGF/FGFR genetic alterations). All patients received 13.5 mg pemigatinib orally once daily (QD) on a 21-day cycle (two weeks on/one week off) until radiological disease progression or unacceptable toxicity.

The study results, presented earlier this year at the annual meeting of the European Society for Medical Oncology (ESMO) in Madrid, Spain, during a late-breaking oral session (Abstract #LBA40), demonstrated an overall response rate (ORR) in Cohort A, assessed by independent review per RECIST v1.1 (primary endpoint)

The study results showed that in patients harboring FGFR2 fusions or rearrangements (Cohort A), pemigatinib monotherapy resulted in an overall response rate (ORR) of 36% (primary endpoint), and median duration of response (DOR) of 7.5 months (secondary endpoint) with a median follow-up of 15 months.

Secondary endpoints also included ORR in Cohorts B, A plus B, and C and progression free survival (PFS), overall survival (OS), duration of response (DOR), disease control rate (DCR) and safety in all cohorts.

The results of the study also show that the adverse events were manageable and consistent with the mechanism of action of pemigatinib.

“There is a significant need for new therapies for patients with cholangiocarcinoma, who have limited treatment options beyond first-line chemotherapy and often face a poor prognosis,” Langmuir said.

“We are very pleased that the FDA has accepted our NDA for Priority Review which we believe represents an important step toward providing the first treatment option for patients with previously treated, locally advanced or metastatic cholangiocarcinoma with FGFR2 fusions or rearrangements,” Langmuir added.

“We intend to work closely with the FDA to bring this innovative targeted therapy to patients suffering from this devastating disease as soon as possible,” he concluded.

Phase II FIGHT-202 study (NCT02924376)

Overall Response Rates (ORR), Durability of Response (DOR), Disease Control Rates / (DCR) and Progression-Free Survival (PFS) by Patient Cohort.

Cohort A
FGFR2 Fusions or
Rearrangements

Cohort B
Other FGF/FGFR Genetic
Alterations

Cohort C
No FGF/FGFR Genetic
Alterations

(N=107)

(N=20)

(N=18)

ORR, % (95% CI)36 (27-45)00
Best OR, n (%)

3 CR (3)

35 PR (33)

50 SD (47)

0

0

8 SD (40)

0

0

4 SD (22)

Median DOR,
Months (95% CI)
7.5 (5.7-14.5)
DCR, % (95% CI)82 (74-89)40 (19-64)22 (6-48)
Median PFS,
Months (95% CI)
6.9 (6.2-9.6)2.1 (1.2-4.9)1.7 (1.3-1.8)
Median OS, Months
(95% CI)
21.1 (14.8-NE)6.7 (2.1-10.6)4.0 (2.3-6.5)

NE: not evaluable

Note:

  • One patient did not have confirmed FGF/FGFR status by central laboratory and was included in the safety analysis but was not assigned to any cohort for efficacy.
  • The safety analysis, including 146 patients, showed that pemigatinib was generally well tolerated. Grade 1 or 2 hyperphosphatemia, the most common treatment-emergent adverse event (TEAE; 60%), was managed with a low phosphate diet, phosphate binders and diuretics, or dose reduction or interruption. The most common Grade ≥3 TEAE was hypophosphatemia (12%); none of the cases was considered clinically significant or serious and none led to dose reduction or discontinuation. Serous retinal detachment was observed in 4 percent of patients (Grade ≥3, 1%) with none of the cases resulting in clinical sequelae.

 

Additional Trials
Incyte novel agent is also investigated in other FGFR-driven malignancies, including metastatic or surgically unresectable bladder cancer (FIGHT-201 trial), myeloproliferative neoplasms with activating FGFR1 fusions/rearrangements (FIGHT-203 trial). The drug is also studied in patients with previously treated, locally-advanced/metastatic or surgically unresectable solid tumor malignancies harboring activating FGFR mutations or fusions/rearrangements, irrespective of tumor type (FIGHT-207).

Combination therapy
In addition to monotherapy, pemigatinib is also investigatined in combination with pembrolizumab combination therapy and pemigatinib monotherapy in patients with previously untreated, metastatic or unresectable bladder cancer harboring FGFR3 mutations or fusions/rearrangements who are not eligible to receive cisplatin.

Finally, FIGHT-302 is a recently initiated Phase III study investigating pemigatinib as a first-line treatment for patients with cholangiocarcinoma with FGFR2 fusions or rearrangements.

Clinical trials
– Efficacy and Safety of Pemigatinib in Subjects With Advanced/Metastatic or Surgically Unresectable Cholangiocarcinoma Who Failed Previous Therapy – (FIGHT-202) – NCT02924376

References
[1] Banales JM, Cardinale V, Carpino G, et al. Expert consensus document: Cholangiocarcinoma: current knowledge and future perspectives consensus statement from the European Network for the Study of Cholangiocarcinoma (ENS-CCA). Nat Rev Gastroenterol Hepatol. 2016;13(5):261–280. doi:10.1038/nrgastro.2016.51
[2] Uhlig J, Sellers CM, Cha C, et al. Intrahepatic Cholangiocarcinoma: Socioeconomic Discrepancies, Contemporary Treatment Approaches and Survival Trends from the National Cancer Database. Ann Surg Oncol. 2019;26(7):1993–2000. doi:10.1245/s10434-019-07175-4
[3] Graham RP, Barr Fritcher EG, Pestova E, et al. Fibroblast growth factor receptor 2 translocations in intrahepatic cholangiocarcinoma. Hum Pathol. 2014;45(8):1630–1638. doi:10.1016/j.humpath.2014.03.014
[4] Farshidfar F, Zheng S, Gingras MC, et al. Integrative Genomic Analysis of Cholangiocarcinoma Identifies Distinct IDH-Mutant Molecular Profiles [published correction appears in Cell Rep. 2017 Jun 27;19(13):2878-2880]. Cell Rep. 2017;18(11):2780–2794. doi:10.1016/j.celrep.2017.02.033
[5] Ross JS, Wang K, Gay L, et al. New routes to targeted therapy of intrahepatic cholangiocarcinomas revealed by next-generation sequencing. Oncologist. 2014;19(3):235–242. doi:10.1634/theoncologist.2013-0352