This document discusses fibroblast growth factor receptors (FGFRs) and FGFR inhibitors. It provides details on FGFR signaling pathways and the role of FGFRs in various cancers like urothelial carcinoma, osteosarcoma, and chondrosarcoma. It summarizes a phase 2 clinical trial investigating the FGFR inhibitor erdafitinib in patients with FGFR-altered metastatic or unresectable urothelial carcinoma, finding an objective response rate of 40% and median progression-free and overall survival of 5.5 and 13.8 months respectively. It concludes that FGFR inhibitors show promise for treating cancers driven by FGFR alterations.

1. Dr Prashant Kumbhaj
DM, MRCP SCE(Medical Oncology),ECMO,PDCR.
Associate Professor ,Medical Oncology
M.G.H Medical college ,Jaipur.

2.  Introduction of FGFR
 FGF/FGFR Signalling pathway
 FGFR Inhibitor
 Evidence
 Future Perspectives
 Take home massage.

3.  The FGFRs are receptors that bind to
members of the FGF family of proteins.
 The receptors consist of an extracellular
ligand domain with three immunoglobulin-
like domains (I-III),
 A transmembrane domain, and an
intracellular tyrosine kinase domain that
transmits the signal to the interior of the cell

4.  An acid box, located between the domains
Ig-I and Ig-II, plays a role, together with the
Ig-I-like domain, in receptor auto-inhibition.
 Ig-II and Ig-III compose the ligand-binding
site

5.  There are only four FGFRs (FGFR1, FGFR2,
FGFR3 and FGFR4) in the cell surface with
seven isoforms FGFR-(1b, 1c, 2b, 2c, 3b, 3c
and 4) owing to alternative splicing in the Ig-
III-like domain, with different ligand-binding
specificities.

6.  Each receptor can be activated by several
FGFs, and the FGFs can also activate more
than one receptor in many cases. For
example, FGF1 can bind all seven principal
FGFRs, while FGF7 can only activate FGFR2b

8.  The binding of FGFs to FGFRs (aided by
HSPGs) induces receptor dimerization, which
triggers the activation of the FGFRs.
 The activation of FGFRs brings the
intracellular kinases into close proximity,
enabling them to transphosphorylate each
other.

9.  This sets in motion a cascade of downstream
signals, finally affecting mitogenesis and
differentiation.

10. Several intracellular proteins have been
implicated in promoting FGF-mediated
signaling.
(1)Phospholipase Cγ (PLCγ)
(2) Fibroblast growth factor receptor substrate
2 (FRS2),
(3)Src homology 2 domain-containing
transforming protein B (Shb),

11. (4) Src kinase, ribosomal S6 protein kinase
(RSK),
(5)Signal transducers and activators of
transcription (STATs),
(6) CT10 regulator of kinase (Crk).

12.  Specifically, the adaptor growth-factor-
receptor-bound protein 2 (GRB2) triggers the
Ras/MAPK pathway and PI3K/Akt intracellular
signaling cascades by binding to
phosphorylated FRS2.
 Rab5 small GTPase, a binding partner of
activated FGFRs, is involved in maintaining
the RAS-MAPK signaling but not PI3K-AKT
signaling.

13.  The FGFR signaling pathway plays important
biological roles in multiple processes include.
 (1)Pro-survival signals
 (2) anti-apoptotic signals
 (3)stimulation of cell proliferation
 (4)cell migration.

14.  Urothelial carcinoma
 Osteosarcoma
 Cholangiocarcinoma
 Squamous cell carcinoma lung

15.  CHONDROSARCOMA -In addition,
immunohistochemistry revealed high
expression of FGFR3 and aberrant cellular
localization of heparan sulfate
proteoglycansin in 42 dedifferentiated, 23
clear cell, and 23 mesenchymal
chondrosarcoma tissues of human.

16.  Taken together, FGF and FGFR may be a
potential therapeutic target in
chondrosarcoma.

17.  RMS -Recently, several FGFR4 tyrosine kinase
domain mutations were found in 7.5%
primary human RMS tumors, and the mutants
K535 and E550 showed autophosphorylation
of the receptor.

18.  Small-molecule tyrosine kinase inhibitors
targeting the ATP-binding site of the
intracellular tyrosine kinase domain in a
number of different receptor tyrosine kinases
(RTKs) have been successfully used for
therapy for cancers .

19.  However, most of these inhibitors show broad
specificity and target not only FGFRs, but also
VEGFRs and/or PDGFRs, as they share
structural similarities and have similar kinase
domains

20.  Recent FGF/FGFR signaling pathway research
suggests that the FGFR inhibitor combination
with surgery, radiation and chemotherapy
might enhance the therapy responses for
sarcoma patients.

21.  BALVERSA (erdafitinib) is a once-daily, oral
fibroblast growth factor receptor (FGFR)
kinase inhibitor
 Indication- for the treatment of adults with
locally advanced or metastatic urothelial
carcinoma (mUC) with FGFR3 or FGFR2
genetic alterations and who have progressed
during or following at least one line of prior
platinum-containing chemotherapy, including
within 12 months of neoadjuvant or adjuvant
platinum-containing

23. BLC2001: Phase II Trial of FGFR
Inhibitor Erdafitinib in Patients With
FGFR-Altered Metastatic or
Unresectable Urothelial Carcinoma
This activity is supported by educational grants from Amgen;
Astellas; AstraZeneca; Celgene Corporation; Eisai; Genentech;
Janssen; Merck & Co., Inc.; and Seattle Genetics.
CCO Independent Conference
Highlights*
of the 2018 ASCO Annual Meeting; June 1-5, 2018;
Chicago, Illinois
*CCO is an independent medical education company that provides state-of-the-art
medical information to healthcare professionals through conference coverage and
other educational programs.

24.  In patients with advanced UC, second-line single-
agent CT with vinflunine or taxanes historically
associated with ORR of ~ 10% and median OS of 7-
9 mos.
 More therapy options needed in this setting
because while outcomes have improved with PD-
1/PD-L1 checkpoint inhibitors (ORR ~ 15-20%;
mOS ~ 10 mos), many patients do not derive
benefit.
References in slidenotes. Slide credit: clinicaloptions.c

25.  FGFR altered in 15-20% of advanced UC cases
(mutated FGFR3 in 54% of upper tract UC).
 Current report presents primary analysis of
efficacy and safety in phase II trial of
erdafitinib in FGFR-altered metastatic or
unresectable UC.

26.  Erdafitinib (JNJ-42756493): oral pan-FGFR
inhibitor with IC50 in low nanomolar range
for FGFR1-4
◦ Durable inhibitory activity may be related to
sustained intracellular release after taken up by
lysosomes
◦ Associated with antitumor activity in FGFR-altered
advanced UC and other tumor types

30.  After follow-up of 11 mos, 21.2% of patients
remain on erdafitinib
◦ Median PFS: 5.5 mos (95% CI: 4.2-6.0)
◦ Median OS: 13.8 mos (95% CI: 9.8-NE)

31.  Based on results from BLC2001, FDA granted
erdafitinib Breakthrough Therapy Designation
status in March 2018.

34.  Erdafitinib under further investigation in
FGFR-altered UC
◦ Phase III THOR trial of erdafitinib vs CT or
pembrolizumab currently enrolling.
◦ Phase Ib/II NORSE trial of erdafitinib + PD-1
inhibitor JNJ-63723283 currently enrolling.

35.  Infigratinib
 Rogaratinib
 Pemigatinib
 VOFATAMAB

36.  FGF and FGFR may be a potential therapeutic target
in dIfferent tumor types.
 FGFR inhibitors are likely to continue to change the
treatment armamentarium for UC, and the
development of newer therapeutic combinations
appears a promising treatment approach in
unselected patients.

37.  Erdafitinib at 8 mg QD was well tolerated with
safety profile permitting continuous dosing
and titration up to 9 mg QD.
 With an ORR of 40% in pretreated patients
with prespecified FGFR alterations, erdafitinib
qualifies as a primary salvage therapy option
for molecularly-eligible patients

38.  Its results appear to be favourable if
compared to the data of chemotherapy
(taxanes or vinflunine). Erdafitinib shows
higher ORR than anti PD (L)-1 inhibitors.
 As FGFR alterations are observed most
frequently in the localized stage compared to
advanced disease, there is a strong rationale
to investigate FGFR inhibitors in earlier
disease settings like NMIBC and MIBC.

39.  Fibroblast growth-factor receptor (FGFR)
alterations can be found in up to 70% of low-
grade and in approximately 20% of muscle-
invasive or metastatic urothelial bladder
carcinoma .
 FGFR alterations are enriched in luminal-1 UC
subtype, which is endowed with predicted
poor responsiveness to immune-checkpoint
inhibition