Fibroblast growth factor (FGF) signaling has a fundamental role in cancer development and tumor maintenance. FP-1039/GSK3052230 is a soluble decoy receptor that sequesters FGFs, including FGF2, blocking their ability to bind to and activate FGFRs, particularly FGFR1. This unique mechanism of action should avoid the on-target toxicities associated with small molecule pan FGFR kinase inhibitors, such as hyperphosphatemia and retinal, nail, and skin changes. MPM remains a disease with poor prognosis and few effective therapies, and preclinical models of MPM are particularly sensitive to inhibition of FGF/FGFR signaling by FP-1039/GSK3052230.
Herein, the analysis of patients with untreated, unresectable MPM is reported. The MPM arm of the study evaluated the safety and efficacy of FP-1039/GSK3052230 (IV weekly) in combination with standard pemetrexed+cisplatin. The study design involved dose escalation until MTD followed by a cohort expansion phase. Endpoints included safety, overall response rate by modified RECIST 1.1, disease control rate (DCR), PFS, and exploratory translational objectives.
As of the cutoff date of 17 Mar 2017, 36 patients were dosed at 10, 15 and 20 mg/kg doses of FP-1039/GSK3052230. Three DLTs were observed at 20 mg/kg but none occurred at 15 mg/kg; therefore, MTD was declared at this dose. Most common related adverse events (all grades) were: nausea (56%) decreased appetite (36%), fatigue (33%), and infusion reaction (33%). The confirmed objective response rate (ORR) of all evaluable patients at or below the MTD was 48% (13/27 PRs), with disease control rate (DCR) of 100%. The median PFS was 7.4 months. As of 8 May 2017, six patients stayed on the study for over 1 year, of which 3 were still ongoing. Results of exploratory biomarker analyses will also be presented.
The MTD of FP-1039/GSK3052230 (15 mg/kg) in combination with pemetrexed+cisplatin in MPM was well tolerated, and durable responses were observed. Importantly, AEs associated with small-molecule pan FGFR kinase inhibitors were not observed, as predicted by the unique mechanism of action of this drug. Study sponsored by GSK; clinical trial information: NCT01868022.
Clinical trial identification
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D.A. Fennell: Advisory Board/consultant – Astra Zeneca, BMS, Bayer, Boehringer Ingelheim, Clovis, Roche, Eli Lilly, MSD H.L. Kindler: Advisor: Aduro; AZ; Bayer; Celgene; Genentech/Roche; Gilead; GSK; MedImmune; Merck; Plexxikon; Verastem. Grants: AB Science; Aduro; Astellas Pharma; AZ; Bayer; Celgene; GSK; Incyte; MedImmune; Merck; Verastem. Expert Testimony: Aduro S. Viteri: Grants: AbbVie, ARIAD, Astex, AZ, BI, Clovis, CytRx, Daiichi Sankyo, GSK, Hanmi, Incyte, Merck KGaA, Novartis, Pfizer, Puma, Roche, Servier, Vaxon. Advisor: BI, Clovis, Idea Pharma, Novartis, Promega Biotech Ibérica, Roche, Targovax S. Gadgeel: Advisor/Board member: Genentech/Roche, Pfizer, Ariad, Astra-Zeneca Speakers bureau: Genetech/Roche, Astra-Zeneca Travel Compensation: Genentech/Roche P. Garrido Lopez: Advisor/Board member: MSD, Pfizer, BMS, Novartis, Roche, BI, Guardant Speakers bureau: MSD, Pfizer, BMS, Novartis, Roche Honorarium recipient: BI D. Morgensztern: Advisor/Board member: Abbvie, Celgene, Bristo-Myers Squibb J.F. Vansteenkiste: Grants/research support recipient: AZ Honorarium/consulting: AZ, Novartis, MSD, BI, Eli-Lilly, Roche X. Wang: Full-time employee with GlaxoSmithkline A. Sharabidze: Consultant at GSK M.P. Deyoung: Full time employee and stock owner of GSK K.P. Baker: Full time employee of Five Prime Therapeutics L. Yan, I. Mitrica: Full time employee of GSK and stock owner All other authors have declared no conflicts of interest.