FIGHT-101 (parts 1 and 2) characterised the pharmacokinetics and pharmacodynamics of pemigatinib monotherapy in patients with advanced solid tumours and established 13.5 mg once daily as the recommended dose for further studies. Pemigatinib, a potent and selective FGFR 1–3 inhibitor, was safe and tolerable and demonstrated pharmacologic/clinical activity in cholangiocarcinoma, urothelial carcinoma, recurrent pilocytic astrocytoma, head and neck, pancreatic, gallbladder, uterine, and non-small cell lung cancers. The results supported those of FIGHT-202 that led to pemigatinib approval for advanced FGFR2-rearranged cholangiocarcinoma. The findings also suggest potential benefit of pemigatinib in multiple other cancers with FGFR rearrangements and/or mutations. The final results of the FIGHT-101 study are published by Dr. Vivek Subbiah of the Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center in Houston, TX, US and colleagues on 14 February 2022 in the Annals of Oncology.
Dysregulated FGFR signalling, resulting from somatic FGFR alterations (activating mutations, amplifications, and fusions or rearrangements), has been implicated in numerous malignancies, including urothelial bladder cancer, breast cancer, cholangiocarcinoma, and lung cancer. FGFR alterations occur across a wide range of tumour types, including FGFR3 mutations and fusions in urothelial bladder cancer and FGFR2 fusions or rearrangements in cholangiocarcinoma. Increasing evidence for FGFR alterations as drivers of tumourigenesis has prompted the development of FGFR-targeted therapies in various solid tumours, including urothelial carcinoma and cholangiocarcinoma.
First-generation FGFR tyrosine kinase inhibitors such as ponatinib, dovitinib, lenvatinib, and nintedanib are multitarget inhibitors that target receptor kinases other than FGFRs. Consequently, effective FGFR inhibition in solid tumours could often not be achieved due to toxicity. These limitations prompted the development of selective FGFR inhibitors such as pemigatinib.
Pemigatinib, a potent and selective oral inhibitor of FGFR 1-3, has shown antitumour activity in genetically defined tumour models, and has demonstrated clinical benefit in patients with tumours harbouring certain FGFR alterations. Pemigatinib is approved in Canada, Europe, Japan, and the US for the treatment of adult patients with previously treated, unresectable, locally advanced or metastatic cholangiocarcinoma with FGFR2 fusions or other rearrangements. The approvals were based on efficacy and safety results from the registrational phase II, FIGHT-202 study of patients with previously treated, unresectable, locally advanced or metastatic cholangiocarcinoma, with or without FGF/FGFR alterations.
The initiation of FIGHT-202 was prompted by encouraging safety and efficacy results from FIGHT-101, a phase I/II, dose-escalation/dose-expansion study of pemigatinib in patients with refractory advanced malignancies. A key requirement for enrolment in the dose-expansion cohorts of FIGHT-101 was the presence of tumour-related FGF/FGFR alterations. Enrolment of patients in the pemigatinib monotherapy cohorts is complete and the study team reports in the Annals of Oncology the final results from FIGHT-101 in patients who received pemigatinib monotherapy, including safety and tolerability, the pharmacokinetic and pharmacodynamic profile of pemigatinib, and the relationship between efficacy outcomes and FGF/FGFR alteration status in multiple malignancies.
Eligible, molecularly unselected patients with advanced malignancies were included in part 1, dose escalation (3+3 design) to determine maximum tolerated dose (MTD). Part 2 (dose expansion) evaluated recommended phase II dose (RP2D) in tumours with or where FGF/FGFR activity is relevant.
In total, 128 patients were included of whom 70 patients received pemigatinib 1–20 mg once daily intermittently (two-weeks on/one-week off) and 58 patients received it continuously. No dose limiting toxicities were reported. Doses ≥4 mg were pharmacologically active; MTD was not reached and RP2D was determined as 13.5 mg once daily.
The most common treatment-emergent adverse event (TEAE) was hyperphosphatemia (75.0%, with grade ≥3 in 2.3%); the most common grade ≥3 TEAE was fatigue (10.2%). Dose interruption, dose reduction, and TEAE-related treatment discontinuation occurred in 66 patients (51.6%), 14 patients (10.9%) and 13 patients (10.2%), respectively.
Overall, 12 partial responses were achieved, most commonly in cholangiocarcinoma in 5 cases, as well as in a broad spectrum of tumours including head and neck, pancreatic, gallbladder, uterine, urothelial carcinoma, recurrent pilocytic astrocytoma, and non-small cell lung cancer (1 case each). Median duration of response was 7.3 months (95% confidence interval [CI] 3.3-14.5). Overall response rate was highest for patients with FGFR fusions/rearrangements (25.0%; 95% CI 8.7-49.1), followed by those with FGFR mutations (23.1%; 95% CI 5.0-53.8).
The study team concluded that pemigatinib was associated with a manageable safety profile and pharmacodynamic and clinical activity, with responses seen across tumours and driven by FGFR fusions/rearrangements and mutations.
Phase II studies of pemigatinib monotherapy are ongoing in multiple tumour types, including a study in patients with myeloid/lymphoid neoplasms with FGFR1 rearrangements (FIGHT-203). In addition, a randomised phase III study (FIGHT-302) is underway to evaluate the efficacy and safety of pemigatinib versus gemcitabine plus cisplatin as first-line therapy for patients with advanced cholangiocarcinoma harbouring FGFR2 rearrangements.
This study was sponsored by Incyte Corporation (Wilmington, DE, USA).
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. Annals of Oncology; Published online 14 February 2022. DOI: https://doi.org/10.1016/j.annonc.2022.02.001