3.4.4 Safety Profile
The safety and tolerability profiles observed for orally administered lenvatinib (49)
in the SELECT clinical study were consistent with those of VEGF-VEGFR-targeted
therapies and mostly manageable through dose modifications and standard clinical
interventions [123, 130, 131].
Most frequent treatment-related adverse events (TRAEs) occurred in 75.9% of
lenvatinib (49) recipients versus 9.9% of placebo recipients including hypertension,
proteinuria, diarrhea, fatigue or asthenia, decreased appetite, decrease in
bodyweight, nausea, and stomatitis. In the SELECT trial, the incidence of grade
!3 TRAEs in the lenvatinib-treated group was as follows: hypertension (42.9%);
proteinuria (10.0%); arterial thromboembolic effects (2.7%); venous thromboembolic effects (3.8%); renal failure (including acute renal failure; 1.9%); hepatic
failure (0.4%); gastrointestinal fistula (0.8%); and corrected QT prolongation
(1.5%). Dose interruptions and reduction of lenvatinib (49) were most commonly
due to diarrhea (22.6% of patients), hypertension (19.9%), and proteinuria (18.8%);
discontinuation of treatment was most commonly due to development of hypertension (1.1%) and asthenia (1.1%) [128, 130].
4 Platelet-Derived Growth Factor Receptor (PDGFR)
The platelet-derived growth factor (PDGF) family consists of four polypeptide
members (A–D) that can generate disulfide-bonded homodimers or the heterodimer
PDGF-AB [132]. PDGF dimers bind to the platelet-derived growth factor receptor
subtypes PDGFR-α and PDGFR-β, inducing receptor dimerization and culminating
in intracellular autophosphorylation and activation [133].
PDGFRs belong to the 7-Ig/5-Ig RTK superfamily, being characterized by an
extracellular (EC) domain containing five immunoglobulin-like (5-Ig) motifs typical
from the type III subclass of RTKs [3, 4].
PDGF-AA, AB, BB, and CC are able to bind to receptor αα-homodimers; PDGFBB and DD to receptor ββ-homodimers; and PDGF-AB, BB, CC, and DD to
receptor αβ heterodimers [133]. The platelet-derived growth factor (PDGF) isoforms
and their receptors (PDGFRs) play key roles in the regulation of several cellular
processes, e.g., survival, growth, and motility of mesenchymal cells, such as fibroblasts, pericytes, and smooth muscle cells; embryonal development; as well as tissue
repair and homeostasis in adults [133, 134].
PDGFR-α signaling is mainly related to the development of several tissues and
organs, e.g., the lungs, intestine, skin, kidney, bones, and neuroprotective tissues. On
the other hand, PDGFR-β signaling is recognized as essential for early hematopoiesis and blood vessel formation [135]. During angiogenesis, the recruitment of
pericytes, which represent the cells in charge of supporting and stabilizing the
vasculature, is mainly driven by activation of PDGFR-β [134]. This receptor also
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The safety and tolerability profiles observed for orally administered lenvatinib (49)
in the SELECT clinical study were consistent with those of VEGF-VEGFR-targeted
therapies and mostly manageable through dose modifications and standard clinical
interventions [123, 130, 131].
Most frequent treatment-related adverse events (TRAEs) occurred in 75.9% of
lenvatinib (49) recipients versus 9.9% of placebo recipients including hypertension,
proteinuria, diarrhea, fatigue or asthenia, decreased appetite, decrease in
bodyweight, nausea, and stomatitis. In the SELECT trial, the incidence of grade
!3 TRAEs in the lenvatinib-treated group was as follows: hypertension (42.9%);
proteinuria (10.0%); arterial thromboembolic effects (2.7%); venous thromboembolic effects (3.8%); renal failure (including acute renal failure; 1.9%); hepatic
failure (0.4%); gastrointestinal fistula (0.8%); and corrected QT prolongation
(1.5%). Dose interruptions and reduction of lenvatinib (49) were most commonly
due to diarrhea (22.6% of patients), hypertension (19.9%), and proteinuria (18.8%);
discontinuation of treatment was most commonly due to development of hypertension (1.1%) and asthenia (1.1%) [128, 130].
4 Platelet-Derived Growth Factor Receptor (PDGFR)
The platelet-derived growth factor (PDGF) family consists of four polypeptide
members (A–D) that can generate disulfide-bonded homodimers or the heterodimer
PDGF-AB [132]. PDGF dimers bind to the platelet-derived growth factor receptor
subtypes PDGFR-α and PDGFR-β, inducing receptor dimerization and culminating
in intracellular autophosphorylation and activation [133].
PDGFRs belong to the 7-Ig/5-Ig RTK superfamily, being characterized by an
extracellular (EC) domain containing five immunoglobulin-like (5-Ig) motifs typical
from the type III subclass of RTKs [3, 4].
PDGF-AA, AB, BB, and CC are able to bind to receptor αα-homodimers; PDGFBB and DD to receptor ββ-homodimers; and PDGF-AB, BB, CC, and DD to
receptor αβ heterodimers [133]. The platelet-derived growth factor (PDGF) isoforms
and their receptors (PDGFRs) play key roles in the regulation of several cellular
processes, e.g., survival, growth, and motility of mesenchymal cells, such as fibroblasts, pericytes, and smooth muscle cells; embryonal development; as well as tissue
repair and homeostasis in adults [133, 134].
PDGFR-α signaling is mainly related to the development of several tissues and
organs, e.g., the lungs, intestine, skin, kidney, bones, and neuroprotective tissues. On
the other hand, PDGFR-β signaling is recognized as essential for early hematopoiesis and blood vessel formation [135]. During angiogenesis, the recruitment of
pericytes, which represent the cells in charge of supporting and stabilizing the
vasculature, is mainly driven by activation of PDGFR-β [134]. This receptor also
182
L. M. Lima et al.