Targeting the FGF/FGFR axis and its co-alteration allies

Y Uehara; S Ikeda; K H Kim; H J Lim; J J Adashek; H E Persha; R Okamura; S Lee; J K Sicklick; S Kato; R Kurzrock

doi:10.1016/j.esmoop.2022.100647

Targeting the FGF/FGFR axis and its co-alteration allies

ESMO Open. 2022 Dec;7(6):100647. doi: 10.1016/j.esmoop.2022.100647. Epub 2022 Nov 29.

Authors

Y Uehara¹, S Ikeda², K H Kim³, H J Lim⁴, J J Adashek⁵, H E Persha⁶, R Okamura⁷, S Lee⁸, J K Sicklick⁹, S Kato¹⁰, R Kurzrock¹¹

Affiliations

¹ Department of Precision Cancer Medicine, Center for Innovative Cancer Treatment, Tokyo Medical and Dental University, Tokyo; Department of Thoracic Oncology and Respiratory Medicine, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan.
² Department of Precision Cancer Medicine, Center for Innovative Cancer Treatment, Tokyo Medical and Dental University, Tokyo; Center for Personalized Cancer Therapy, Division of Hematology/Oncology, Department of Medicine, University of California San Diego, Moores Cancer Center, La Jolla, USA.
³ Center for Personalized Cancer Therapy, Division of Hematology/Oncology, Department of Medicine, University of California San Diego, Moores Cancer Center, La Jolla, USA; Division of Hematology and Medical Oncology, Department of Internal Medicine, Seoul National University Boramae Medical Center, Seoul.
⁴ Center for Personalized Cancer Therapy, Division of Hematology/Oncology, Department of Medicine, University of California San Diego, Moores Cancer Center, La Jolla, USA; Department of Internal Medicine, Veterans Health Service Medical Center, Seoul, Republic of Korea.
⁵ Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins Hospital, Baltimore.
⁶ Purdue University College of Pharmacy, Purdue University, West Lafayette, USA.
⁷ Center for Personalized Cancer Therapy, Division of Hematology/Oncology, Department of Medicine, University of California San Diego, Moores Cancer Center, La Jolla, USA; Department of Surgery, Kyoto University Hospital, Kyoto, Japan.
⁸ Center for Personalized Cancer Therapy, Division of Hematology/Oncology, Department of Medicine, University of California San Diego, Moores Cancer Center, La Jolla, USA.
⁹ Center for Personalized Cancer Therapy and Division of Surgical Oncology, Department of Surgery, UC San Diego Moores Cancer Center, La Jolla, USA.
¹⁰ Center for Personalized Cancer Therapy, Division of Hematology/Oncology, Department of Medicine, University of California San Diego, Moores Cancer Center, La Jolla, USA. Electronic address: smkato@health.ucsd.edu.
¹¹ WIN Consortium for Personalized Cancer Therapy, Paris, France; Medical College of Wisconsin Cancer Center and Genome Science and Precision Medicine Center, Milwaukee, USA; University of Nebraska (adjunct), Lincoln, Nebraska.

Abstract

Background: We analyzed the FGF/FGFR and co-alteration cancer landscape, hypothesizing that combination therapy might be useful in the presence of co-drivers.

Materials and methods: We describe FGF/FGFR-altered pathways, prognosis, and co-alterations [cBioPortal (N = 7574)] and therapeutic outcomes [University of California San Diego Molecular Tumor Board (MTB) (N = 16)].

Results: Patients whose cancers harbored FGF/FGFR alterations (N = 1074) versus those without them (N = 6500) had shorter overall survival (OS) (median: 23.1 versus 26.4 months, P = 0.038) (cBioPortal). Only 6.1% (65/1074 patients) had no pathogenic co-alterations accompanying FGF/FGFR axis abnormalities. The most frequently co-altered pathways/genes involved: TP53 (70%); cell cycle (58%); PI3K (55%); and receptor tyrosine kinases and mitogen-activated protein kinase (MAPK) (65%). Harboring alterations in both FGF/FGFR and in the TP53 pathway or in the cell cycle pathway correlated with shorter OS (versus FGF/FGFR-altered without those co-altered signals) (P = 0.0001 and 0.0065). Four of 16 fibroblast growth factor receptor (FGFR) inhibitor-treated patients presented at MTB attained durable partial responses (PRs) (9, 12, 22+, and 52+ months); an additional two, stable disease (SD) of ≥6 months (13+ and 15 months) [clinical benefit rate (SD ≥ 6 months/PR) = 38%]. Importantly, six patients with cyclin pathway co-alterations received the CDK4/6 inhibitor palbociclib (75 mg p.o. 3 weeks on, 1 week off) and the multikinase FGFR inhibitor lenvatinib (10 mg p.o. daily); three (50%) achieved a PR [9 (ovarian), 12 (biliary), and 52+ months (osteosarcoma)]. Palbociclib and lenvatinib were tolerated well.

Conclusions: FGF/FGFR alterations portend a poor prognosis and are frequently accompanied by pathogenic co-aberrations. Malignancies harboring co-alterations that activate both cyclin and FGFR pathways can be co-targeted by CDK4/6 and FGFR inhibitors.

Keywords: FGFR; combination therapy; drug resistance; matched therapy; precision cancer medicine; tyrosine kinase inhibitor.

Published by Elsevier Ltd.

MeSH terms

Fibroblast Growth Factors / genetics
Fibroblast Growth Factors / metabolism
Humans
Neoplasms* / drug therapy
Neoplasms* / genetics
Phenylurea Compounds
Quinolines*
Receptors, Fibroblast Growth Factor / genetics

Substances

lenvatinib
Fibroblast Growth Factors
Receptors, Fibroblast Growth Factor
Quinolines
Phenylurea Compounds