A phase Ib study of GSK3052230, an FGF ligand trap in combination with pemetrexed and cisplatin in patients with malignant pleural mesothelioma

• Published in: Investigational new drugs Vol. 38; no. 2; pp. 457 - 467
• Main Authors: van Brummelen, Emilie M. J., Levchenko, Evgeny, Dómine, Manuel, Fennell, Dean A., Kindler, Hedy L., Viteri, Santiago, Gadgeel, Shirish, López, Pilar Garrido, Kostorov, Vladimir, Morgensztern, Daniel, Orlov, Sergey, Zauderer, Marjorie G., Vansteenkiste, Johan F., Baker-Neblett, Katherine, Vasquez, James, Wang, Xiaowei, Bellovin, David I., Schellens, Jan H. M., Yan, Li, Mitrica, Ionel, DeYoung, M. Phillip, Trigo, José
• Format: Journal Article
• Language: English
• Published: New York Springer US 01-04-2020; Springer Nature B.V
• Subjects: Adult; Aged; Aged, 80 and over; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - adverse effects; Antineoplastic Agents - pharmacokinetics; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Appetite loss; Chemotherapy; Cisplatin; Cisplatin - administration & dosage; Cisplatin - adverse effects; Disease control; Dosage; Female; Fibroblast Growth Factor 2 - metabolism; Fibroblast growth factor receptors; Growth factors; Humans; Hyperphosphatemia; Immunoglobulin G - administration & dosage; Immunoglobulin G - adverse effects; Inhibitors; Ligands; Male; Medicine; Medicine & Public Health; Mesothelioma; Mesothelioma, Malignant - drug therapy; Mesothelioma, Malignant - metabolism; Middle Aged; Nausea; Oncogene Proteins, Fusion - administration & dosage; Oncogene Proteins, Fusion - adverse effects; Oncogene Proteins, Fusion - pharmacokinetics; Oncology; Pemetrexed - administration & dosage; Pemetrexed - adverse effects; Pharmacokinetics; Pharmacology; Pharmacology/Toxicology; Phase I Studies; Receptor, Fibroblast Growth Factor, Type 1 - administration & dosage; Retina; Sequestering; Skin; Studies; Toxicity; Treatment Outcome; Mesothelioma; Ligand trap; Phase 1; FGF; Combination therapy
• ISSN: 0167-6997; 1573-0646
• DOI: 10.1007/s10637-019-00783-7

Summary
Background
Fibroblast growth factors (FGFs) have a fundamental role in cancer. Sequestering FGFs with GSK3052230 (FP-1039) blocks their ability to activate FGFRs while avoiding toxicities associated with small molecule inhibitors of FGFR, including hyperphosphatemia and retinal, nail, and skin toxicities.
Methods
A multicenter, open-label, phase Ib study evaluated weekly GSK3052230 added to pemetrexed/cisplatin in patients with treatment-naive, unresectable malignant pleural mesothelioma. Doses were escalated according to a 3 + 3 design, followed by cohort expansion at the maximum tolerated dose (MTD). Endpoints included safety, overall response rate, progression-free survival, and pharmacokinetics.
Results
36 patients were dosed at 10, 15, and 20 mg/kg doses of GSK3052230. Three dose-limiting toxicities were observed at 20 mg/kg and one at 15 mg/kg. The MTD was defined as 15 mg/kg and used for cohort expansion. The most common treatment-related adverse events (AEs) were nausea (56%), decreased appetite (36%), infusion reactions (36%), decreased neutrophil counts (36%), and fatigue (33%). The confirmed ORR was 39% (95% CI: 23.1–56.5) (14/36 PRs) and 47% had stable disease (17/36), giving a disease control rate of 86%. At 15 mg/kg GSK3052230 (
n
 = 25), the ORR was 44% (95% CI: 24.4–65.1), and the median PFS was 7.4 months (95% CI: 6.7–13.4). Four patients had disease control for over 1 year, and three were still ongoing.
Conclusion
At 15 mg/kg weekly, GSK3052230 was well tolerated in combination with pemetrexed/cisplatin and durable responses were observed. Importantly, AEs associated with small molecule inhibitors of FGFR were not observed, as predicted by the unique mechanism of action of this drug.