The development of FGFR inhibitors, Multi-Tyrosine Kinase Inhibitors (MTKI) and specific FGFR1-4 inhibitors (FGFRinh) has been focused in FGFR-amplified (FGFRamp) BC patients (pt). However, previous results suggested that clinical benefit with FGFRinh was limited to tumours with high FGFR copy number alterations (CNA), resulting in high FGFR expression. Here, we aimed to study whether FGFR1-4 mRNAh is a predictive biomarker for both MTKI and/or FGFRinh.
We generated an FGFR1amp BC PDXs’ collection within the FGFR 360° RESISTANCE project. We tested the efficacy of FGFRinh rogaratinib (FGFR1-4) in 17 models and the MTKI lucitanib (FGFR1/2, VEGFR1-3, PDGFRA/B) in 7 FGFR1amp BC PDXs. A cohort of BC pts (8/9 FGFR1amp) treated with MTKI was used to validate the findings. PDXs and pt tumour samples were analysed by nCounter® and by HTG EdgeSeq® platform with Oncology Biomarker Panel (OBP).
FGFR1-4 mRNAh showed better correlation with efficacy to FGFRinh compared with FGFR CNA, being able to differentiate responders (R) from non-responders (NR) BC PDXs without FGFR mutations. Of note, some sensitive FGFR1amp PDXs expressed low FGFR1 mRNA levels whilst FGFR2-4 mRNAh. MTKI demonstrated higher antitumour activity than FGFRinh, specifically in PDXs with low FGFR1-4 mRNA levels. In agreement, FGFR1-4 mRNAh did not discriminate R (5) from NR (4) in pts treated with MTKI. Interestingly, we identified 3 pts who achieved prolonged responses (14-50 months), of which only one had FGFR1 mRNAh. Also, we noticed 2 pts that had previously received FGFRinh, who still presented clinical benefit with MTKI. When assessing mRNA expression levels of other angiogenic targets, such as VEGFR1-3 or PDGFRA/B and their ligands, none of them correlated with MTKI sensitivity, neither in PDXs nor in our BC pt cohort.
In this exploratory study, total FGFR1-4 mRNAh is a predictive biomarker for FGFRinh (e.g. rogaratinib) but not for MTKI such as lucitanib in BC PDXs. MTKI efficacy does not rely on mRNAh levels of its targets in BC. Future development of FGFR inhibitors should consider optimized enrolment strategies according to these results. Co-funded by ISCIII-FEDER (PI15/00360) and Grants4Targets Bayer (ID 2015-08-1441).
Vall d'Hebron Institute of Oncology (VHIO).
Vall d'Hebron Institute of Oncology (VHIO).
C. Hierro: Research grant/Funding (institution): Bayer; Speaker Bureau/Expert testimony: Ignyta; Speaker Bureau/Expert testimony: Lilly; Travel/Accommodation/Expenses: Roche; Travel/Accommodation/Expenses: Amgen; Travel/Accommodation/Expenses: Merck. E. Garralda: Research grant/Funding (institution): Novartis; Research grant/Funding (institution): Roche; Research grant/Funding (institution): ThermoFisher; Non-remunerated activity/ies, Clinical Investigator as PI or co-PI: Agios Pharmaceuticals; Non-remunerated activity/ies, Clinical Investigator as PI or co-PI: Amgen; Non-remunerated activity/ies, Clinical Investigator as PI or co-PI: Bayer; Non-remunerated activity/ies, Clinical Investigator as PI or co-PI: Beigene USA; Non-remunerated activity/ies, Clinical Investigator as PI or co-PI: Blueprint Medicines; Non-remunerated activity/ies, Clinical Investigator as PI or co-PI: Genmab B.V.; Non-remunerated activity/ies, Clinical Investigator as PI or co-PI: GSK; Non-remunerated activity/ies, Clinical Investigator as PI or co-PI: Glycotope Gmbh; Non-remunerated activity/ies, Clinical Investigator as PI or co-PI: Incyte Biosciences; Non-remunerated activity/ies, Clinical Investigator as PI or co-PI: Incyte Corporation; Non-remunerated activity/ies, Clinical Investigator as PI or co-PI: ICO; Non-remunerated activity/ies, Clinical Investigator as PI or co-PI: Kura Oncology Inc; Non-remunerated activity/ies, Clinical Investigator as PI or co-PI: Lilly S.A.; Non-remunerated activity/ies, Clinical Investigator as PI or co-PI: Loxo Oncology Inc; Non-remunerated activity/ies, Clinical Investigator as PI or co-PI: Macrogenics Inc; Non-remunerated activity/ies, Clinical Investigator as PI or co-PI: Menarini Ricerche Spa; Non-remunerated activity/ies, Clinical Investigator as PI or co-PI: Merck, Sharp & Dohme de España S.A.; Non-remunerated activity/ies, Clinical Investigator as PI or co-PI: Nanobiotix S.A.; Non-remunerated activity/ies, Clinical Investigator as PI or co-PI: Novartis Farmacéutica S.A.; Non-remunerated activity/ies, Clinical Investigator as PI or co-PI: Pfizer SLU; Non-remunerated activity/ies, Clinical Investigator as PI or co-PI: PharmaMar S.A.U.; Non-remunerated activity/ies, Clinical Investigator as PI or co-PI: Pierre Fabre Medicament; Non-remunerated activity/ies, Clinical Investigator as PI or co-PI: Principia Biopharma Inc; Non-remunerated activity/ies, Clinical Investigator as PI or co-PI: Poises Therapeutics Ltd; Non-remunerated activity/ies, Clinical Investigator as PI or co-PI: Sanofi; Non-remunerated activity/ies, Clinical Investigator as PI or co-PI: Sierra Oncology Inc; Non-remunerated activity/ies, Clinical Investigator as PI or co-PI: Sotio A.S.; Non-remunerated activity/ies, Clinical Investigator as PI or co-PI: Symphogen A/S; Advisory/Consultancy: Roche/Genentech; Advisory/Consultancy: F.Hoffmann/La Roche; Advisory/Consultancy: Ellipses Pharma; Advisory/Consultancy: Neomed Therapeutics1 Inc; Advisory/Consultancy: Boehringer Ingelheim; Advisory/Consultancy: Janssen Global Services; Advisory/Consultancy: SeaGen; Advisory/Consultancy: TFS; Advisory/Consultancy: Alkermes; Advisory/Consultancy: ThermoFisher; Advisory/Consultancy: Bristol-Mayers Squibb; Travel/Accommodation/Expenses: Bristol-Mayers Squibb; Travel/Accommodation/Expenses: Merck, Sharp & Dohme ; Travel/Accommodation/Expenses: Menarini; Travel/Accommodation/Expenses: Glycotope; Speaker Bureau/Expert testimony: Merck, Sharp & Dohme; Speaker Bureau/Expert testimony: Roche; Speaker Bureau/Expert testimony: ThermoFisher. J. Tabernero: Advisory/Consultancy: Array Biopharma; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Bayer; Advisory/Consultancy: BeiGene; Advisory/Consultancy: Boehringer Ingelheim; Advisory/Consultancy: Chugai; Advisory/Consultancy: Genentech; Advisory/Consultancy: Inc.; Advisory/Consultancy: Genmab A/S; Advisory/Consultancy: Halozyme; Advisory/Consultancy: Imugene Limited; Advisory/Consultancy: Inflection Biosciences Limited; Advisory/Consultancy: Ipsen; Advisory/Consultancy: Kura Oncology; Advisory/Consultancy: Lilly; Advisory/Consultancy: MSD; Advisory/Consultancy: Menarini; Advisory/Consultancy: Merck Serono; Advisory/Consultancy: Merrimack; Advisory/Consultancy: Merus; Advisory/Consultancy: Molecular Partners; Advisory/Consultancy: Novartis; Advisory/Consultancy: Peptomyc; Advisory/Consultancy: Pfizer; Advisory/Consultancy: Pharmacyclics; Advisory/Consultancy: ProteoDesign SL; Advisory/Consultancy: Rafael Pharmaceuticals; Advisory/Consultancy: Rafael Pharmaceuticals; Advisory/Consultancy: Sanofi; Advisory/Consultancy: SeaGen; Advisory/Consultancy: Seattle Genetics; Advisory/Consultancy: Servier; Advisory/Consultancy: Symphogen; Advisory/Consultancy: Taiho; Advisory/Consultancy: VCN Biosciences; Advisory/Consultancy: Biocartis; Advisory/Consultancy: Foundation Medicine; Advisory/Consultancy: HalioDX SAS ; Advisory/Consultancy: Roche Diagnostics. J. Rodon: Travel/Accommodation/Expenses: European Journal of Cancer; Travel/Accommodation/Expenses: Vall d'Hebron Institute of Oncology; Travel/Accommodation/Expenses: Chinese University of Hong Kong; Travel/Accommodation/Expenses: SOLTI; Travel/Accommodation/Expenses: Elsevier; Travel/Accommodation/Expenses: GlaxoSmithKline; Advisory/Consultancy: Novartis; Advisory/Consultancy: Eli Lilly; Advisory/Consultancy: Orion Pharmaceuticals; Advisory/Consultancy: Servier; Advisory/Consultancy: Peptomyc; Advisory/Consultancy: Merck Sharp & Dohme; Advisory/Consultancy: Kelun Pharmaceutical/Klus Pharma; Advisory/Consultancy: Spectrum Pharmaceuticals Inc; Advisory/Consultancy: Pfizer; Advisory/Consultancy: Roche Pharmaceuticals; Advisory/Consultancy: Ellipses Pharma; Advisory/Consultancy: NovellusDx; Advisory/Consultancy: Ionctura; Advisory/Consultancy: Molecular Partners; Research grant/Funding (institution): Bayer; Research grant/Funding (institution): Blueprint Pharmaceuticals; Research grant/Funding (institution): Novartis; Travel/Accommodation/Expenses: ESMO; Travel/Accommodation/Expenses: US Department of Defense; Travel/Accommodation/Expenses: Louissiana State University; Travel/Accommodation/Expenses: Hunstman Cancer Institute; Travel/Accommodation/Expenses: Cancer Core Europe; Travel/Accommodation/Expenses: Karolinska Cancer Institute ; Travel/Accommodation/Expenses: King Abdullah International Medical Research Center (KAIMRC); Travel/Accommodation/Expenses: Molecular Partners; Non-remunerated activity/ies, Clinical Investigator in clinical trials: Spectrum Pharmaceuticals; Non-remunerated activity/ies, Clinical Investigator in clinical trials: Tocagen; Non-remunerated activity/ies, Clinical Investigator in clinical trials: Symphogen; Non-remunerated activity/ies, Clinical Investigator in clinical trials: BioAtla; Non-remunerated activity/ies, Clinical Investigator in clinical trials: Pfizer; Non-remunerated activity/ies, Clinical Investigator in clinical trials: GenMab; Non-remunerated activity/ies, Clinical Investigator in clinical trials: CytomX; Non-remunerated activity/ies, Clinical Investigator in clinical trials: Kelun-Biotech; Non-remunerated activity/ies, Clinical Investigator in clinical trials: Takeda-Millenium; Non-remunerated activity/ies, Clinical Investigator in clinical trials: GlaxoSmithKline; Non-remunerated activity/ies, Clinical Investigator in clinical trials: Ipsen. V. Serra: Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): Genentech; Research grant/Funding (institution): Novartis. All other authors have declared no conflicts of interest.