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Ref Type Journal Article
PMID (38986210)
Authors Saleh M, Barve M, Subbiah V, Papadopoulos KP, Morgensztern D, Mettu NB, Roychowdhury S, Spanggaard I, Veronese ML, Tian C, Silverman IM, Gutierrez M
Title Open-label, dose-escalation FIGHT-101 study of pemigatinib combined with targeted therapy, chemotherapy, or immunotherapy in patients with advanced malignancies.
Journal Vol Issue Date Pages Journal Short Title
ESMO open 9 7 2024 Jul 103625 ESMO Open
URL
Abstract Text Pemigatinib is an oral, potent, selective fibroblast growth factor receptor (FGFR) 1-3 inhibitor. FIGHT-101, a three-part, open-label, first-in-human, phase I/II study (NCT02393248), evaluated pemigatinib in patients with advanced solid tumors. In parts 1 and 2, pemigatinib monotherapy had a manageable safety profile and antitumor activity in FGFR-altered tumors. Part 3 (pemigatinib combination therapies) results are presented here.Patients received 9, 13.5, or 20 mg oral once-daily pemigatinib on continuous or intermittent schedules with gemcitabine and cisplatin (pemi/gem/cis), docetaxel (pemi/doc), trastuzumab (pemi/tras), pembrolizumab (pemi/pembro), or retifanlimab (pemi/reti) irrespective of whether the tumor was confirmed as FGFR altered. Primary endpoints were safety and pharmacodynamics. Secondary endpoints were investigator-assessed tumor objective response rates (ORRs) and pharmacokinetics (PK).Of 65 enrolled patients (pemi/gem/cis, n = 8; pemi/doc, n = 7; pemi/tras, n = 6; pemi/pembro, n = 26; pemi/reti, n = 18), all discontinued. Treatment-emergent adverse events (TEAEs) were generally consistent with individual drug AEs. Serious and grade ≥3 TEAEs occurred in 0%-85.7% and 33.3%-100.0% of patients across treatment groups, respectively. All pemigatinib combinations demonstrated steady-state PK comparable to monotherapy. Pharmacodynamic effects in all pemigatinib combinations, except pemi/gem/cis, were consistent with monotherapy. Less inhibition of FGFR2α phosphorylation was observed with this combination. ORRs (95% confidence interval) were 37.5% [8.5% to 75.5% (pemi/gem/cis)], 14.3% [0.4% to 57.9% (pemi/doc)], 0% (pemi/tras), 26.9% [11.6% to 47.8% (pemi/pembro)], and 11.1% [1.4% to 34.7% (pemi/reti)]. All groups had instances of tumor shrinkage. ORRs in assessable patients with FGFR rearrangements and mutations were 50% and 33%, respectively.Pemigatinib combination therapy showed no unexpected toxicities. PK and pharmacodynamics were mostly consistent with pemigatinib monotherapy. Pemi/gem/cis (37.5%) and pemi/pembro (26.9%) had the highest ORR; most responders had FGFR alterations.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
FGFR1 M532T missense unknown FGFR1 M532T lies within the protein kinase domain of the Fgfr1 protein (UniProt.org). M532T has been identified in the scientific literature (PMID: 38986210, PMID: 36446043), but has not been biochemically characterized and therefore, its effect on Fgfr1 protein function is unknown (PubMed, Aug 2024).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
FGFR3 S249C bladder urothelial carcinoma predicted - sensitive Pembrolizumab + Pemigatinib Case Reports/Case Series Actionable In a Phase I trial (FIGHT-101), treatment with the combination of Pemazyre (pemigatinib) and Keytruda (pembrolizumab) demonstrated safety in patients with advanced solid tumors and resulted in an objective response rate of 26.9% (7/26, all partial responses), including a partial response with a duration of response of 50.3 months in a patient with urothelial bladder cancer harboring FGFR3 S249C (PMID: 38986210; NCT02393248). 38986210
FGFR3 Y373C transitional cell carcinoma predicted - sensitive Pembrolizumab + Pemigatinib Case Reports/Case Series Actionable In a Phase I trial (FIGHT-101), treatment with the combination of Pemazyre (pemigatinib) and Keytruda (pembrolizumab) demonstrated safety in patients with advanced solid tumors and resulted in an objective response rate of 26.9% (7/26, all partial responses), including a partial response with a duration of response of 4.2 months in a patient with urothelial cancer harboring FGFR3 Y373C (PMID: 38986210; NCT02393248). 38986210
FGFR1 M532T transitional cell carcinoma predicted - sensitive Pembrolizumab + Pemigatinib Case Reports/Case Series Actionable In a Phase I trial (FIGHT-101), treatment with the combination of Pemazyre (pemigatinib) and Keytruda (pembrolizumab) demonstrated safety in patients with advanced solid tumors and resulted in an objective response rate of 26.9% (7/26, all partial responses), including a partial response with a duration of response of 6.5 months in a patient with urothelial cancer harboring FGFR1 M532T (PMID: 38986210; NCT02393248). 38986210