Pemigatinib Demonstrates Manageable Safety Profile in FGF/FGFR Altered Tumors

In patients with a variety of tumors with FGFR fusions/rearrangements and mutations, pemigatinib (Pemazyre) showed a manageable safety profile and positive pharmacodynamic and clinical activity. Investigators in the phase 1/2 FIGHT-101 study (NCT02393248) evaluated safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of pemigatinib monotherapy or in combination therapy for patients with refractory advanced malignancies with and without fibroblast growth factor (FGF) and receptor (FGFR) gene alterations.¹

No dose limiting toxicities were reported in any dose cohort, and the maximum tolerated dose for pemigatinib monotherapy was not reached. Among all treated patients (N = 128), 99.2% had a treatment emergent adverse event (TEAE). Most TEAEs (90.6%) were treatment related. Investigators decided the recommended phase 2 dose to be 13.5 mg of pemigatinib once daily.

Seventy patients received daily doses of pemigatinib ranging from 1 to 20 mg on an intermittent dosing (ID) schedule, and 58 were in a continuous dosing (CD) group, receiving daily doses of 9, 13.5, or 20 mg continuously. Eligible, molecularly unselected patients with advanced malignancies were included in part 1, which followed a dose escalation design of 3 + 3 to determine the maximum tolerated dose. The second part was a dose expansion trial that evaluated the recommended phase 2 dose in tumors with FGF/FGFR activity. In part 1, 24 of 49 patients (49.0%) had available FGF/FGFR status assessments; in part 2, 72 of 79 patients (91.1%) had documented FGF/FGFR status.

Primary end points included safety and tolerability, and the pharmacodynamics.The secondary end points included the objective response rate (ORR) in patients with measurable disease based on investigator assessment of response and pharmacokinetics. Exploratory end points included duration of response (DOR), progression-free survival (PFS), and biomarkers that may identify patients who would benefit most from pemigatinib.

The most common TEAE in the whole patient population was hyperphosphatemia, found in 75% of patients (ID, 68.6%; CD, 82.8%). The most common grade 3 TEAE of any cause was fatigue in 10.2% of patients (ID, 5.7%; CD, 15.5%). The most common treatment related TEAE was hyperphosphatemia (73.4%) with grade 3 hyperphosphatemia occurring in 1.6% of patients. TEAEs led to dose interruptions in 66 (51.6%) of patients, dose reductions in 14 (10.9%) of patients, and treatment discontinuation in 13 (10.2%) patients.

Patients in the ID group had fewer dose interruptions than patients in the CD group (32.9% vs 74.1%, respectively. The same can be said about dose reduction as the ID group experienced 5.7% dose reductions compared with 17.2% in the CD group. Treatment discontinuations due to TEAEs occurred in 8.6% of the ID group vs 12.1% of the CD group.

Investigators observed the highest ORR in patients with FGFR fusions/rearrangements (n = 5; 25.0%; 95% CI, 8.7%-49.1%), followed by patients with FGFR mutations (n = 3; 23.1%; 95% CI, 5.0%-53.8%). The median DOR was 7.3 months (95% CI, 3.3-14.5) for all the 12 responders, and 7.3 months (95% CI, 2.8%-11.3%) for the 10 patients who tested positive for FGF/FGFR alterations. The median PFS was 2.8 months (95% CI, 1.9-3.8) for all patients. Median PFS for patients who tested positive for FGF/FGFR alterations (n = 79) was and 3.0 months (95% CI, 1.8-4.1 months). The median PFS was 5.7 months (95% CI, 2.8-10.0) in patients with FGFR fusions or rearrangements (n = 20) and 5.0 months (95% CI, 0.7-8.3) in patients with FGFR mutations (n = 13).

The median age of patients was 59 years (range, 21-83), with 32% aged 65 or older. Most patients were White (89.1%), and 60.9% were female. Twenty-five patients (19.5%) had an ECOG performance score of 0, 101 patients (78.9%) had an ECOG performance score of 1, and 2 patients (1.6%) had an ECOG performance score of 2 or greater. A majority of patients (n = 98, 76.6%) received at least 3 prior therapies, 15 patients (11.7%) received 2, 11 (8.6%) received 1, and 4 (3.1%) did not receive any. The most common tumor type was cholangiocarcinoma, found in 21 patients (16.4%). Other common tumor types observed were breast cancer (n = 18, 14.1%), colon cancer (n = 10, 7.8%), and non–small-cell lung cancer (n = 10, 7.8%)

These results will inform the recommended 13.5 mg dose of pemigatinib in future studies. The FIGHT-203 study (NCT03011372), a phase 2 study of pemigatinib monotherapy, is ongoing in multiple tumor types, including in patients with myeloid/lymphoid neoplasms with FGFR1 rearrangements. Also, the FIGHT-302 study (NCT03656536), a randomized phase 3 study, is evaluating the efficacy and safety of pemigatinib vs gemcitabine (Gemzar) plus cisplatin (Platinol) as first-line therapy for patients with advanced cholangiocarcinoma harboring FGFR2 rearrangements.

_REFERENCE

_{Subbiah V, Iannotti NO, Gutierrez M, et al. FIGHT-101, a first-in-human study of potent and selective FGFR 1-3 inhibitor pemigatinib in pan-cancer patients with FGF/FGFR alterations and advanced malignancies. Published online February 14, 2022. Ann Oncol. 2022;S0923-7534(22)00110-7. doi:10.1016/j.annonc.2022.02.001}