Regorafenib for Gastrointestinal

Malignancies

Giuseppe Aprile, Marianna Macerelli &

Francesco Giuliani

BioDrugs

ISSN 1173-8804

BioDrugs
DOI 10.1007/s40259-013-0014-9

1 23
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 Author's personal copy
BioDrugs
DOI 10.1007/s40259-013-0014-9
REVIEW ARTICLE
Regorafenib for Gastrointestinal Malignancies
From Preclinical Data to Clinical Results of a Novel Multi-Target Inhibitor
Giuseppe Aprile • Marianna Macerelli •
Francesco Giuliani
Ó Springer International Publishing Switzerland 2013
Abstract Intracellular signals for cancer cell growth,
proliferation, migration, and survival are frequently trig-
gered by protein tyrosine kinases (TKs). The possibility of
disrupting core disease pathways has led to development
and widespread clinical use of specific TK inhibitors that in
the past decade have markedly changed treatment strate-
gies and impacted on overall outcomes. However, intrinsic
resistance may limit the benefit of these drugs, and multiple
escape routes compensate for the inhibited signaling. The
disruption of several points of the same pathway and the
simultaneous interference with different intracellular
oncogenic processes have both been recognized as valuable
strategies to maximize the therapeutic potential of this class
of agents. In this scenario, regorafenib has emerged as a
novel, orally active, multitarget compound with potent
activity against a number of angiogenic and stromal TKs,
including vascular endothelial growth factor receptor 2
(VEGFR-2), tyrosine kinase with immunoglobulin-like and
EGF-like domains 2 (TIE-2), fibroblast growth factor
receptor 1 (FGFR-1), and platelet-derived growth factor
receptor (PDGFR). Moreover, the drug has the capability
of blocking KIT, RET and V600 mutant BRAF. Starting
from interesting preclinical results, this review describes
the clinical development of regorafenib in gastrointestinal
malignancies, focusing on data derived from cutting edge
clinical trials that have provided evidence of efficacy in
G. Aprile (&)
M. Macerelli
Department of Medical Oncology, University and General
Hospital, Piazzale S Maria Misericordia, 1, 33100 Udine, Italy
e-mail: aprile.giuseppe@aoud.sanita.fvg.it
F. Giuliani
Department of Medical Oncology, National Cancer Institute
‘‘G. Paolo II’’, Bari, Italy
pretreated patients with advanced colorectal cancer or
gastrointestinal stromal tumors.
1 Introduction
Preclinical evidence of the importance of phosphorylation
by protein tyrosine kinases (TKs) in cancer cells [1–3]
triggered a widespread hope that anticancer compounds
targeting TKs would be useful agents in solid malignancies
[4]. Interesting preclinical suggestions were soon followed
by convincing clinical results [5] that showed how the use
of the TK inhibitor (TKI) imatinib mesilate could change
the natural history of gastrointestinal stromal tumors
(GISTs) that were characterized by constitutive activation
of the oncogenic kinase KIT. At the same time, the study of
the human kinome helped to unfold the intricate network of
the phosphorylation-based intracellular signaling [6]. Not
surprisingly, in the following years a notable pipeline of
oral TKIs was developed, with the aim of reshaping the
treatment horizon of several solid tumors [7]. Despite the
great interest surrounding all these novel targets and
the initial success of specific inhibitors, clinical progress
has been uneven and the need for further fine tuning has
become progressively clear [8].
Indeed, while TKIs were revolutionary in the treatment
of tumors driven by a single oncogenic kinase [9], the
average survival benefit provided to patients with more
complex diseases, though noteworthy, has been limited
[10–14] or restricted to molecularly selected subpopula-
tions [15]. Moreover, the issue of primary and secondary
resistance has emerged. While redundant feedback loops
and crosstalk between different signaling pathways create
multiple salvage conduits and may compensate early on
for the inhibited signaling, acquired mutations in the
 Author's personal copy
downstream effectors may cause secondary resistance
within the course of therapy. Two main strategies have
been pursued to delay or overcome resistance: (i) the par-
allel block of multiple points of the same pathway and (ii)
the simultaneous inhibition of different oncogenic path-
ways, with the latter strategy being the more plausible [16].
Whether a combination of highly selective agents or a
single multitarget drug should be used upfront to simulta-
neously inhibit different pathways is unclear [17, 18].
Combining selective agents may produce additive or syn-
ergistic effects and, although it is a potential source of
unforeseen drug interactions, this strategy may allow high
target selectivity with limited systemic toxicities [19].
On the contrary, the use of a single multitarget agent
offers an advantage with its unique property of optimal
target promiscuity. The flipside of having a wide target
scope is the potential disadvantage of a narrow therapeutic
window, because of likely increased toxicity from cross-
reactivity with normal tissues [20]. Nevertheless, clinically
approved TKIs have, in general, shown favorable safety
profiles, with low frequencies of serious adverse events
(AEs) reported in phase III clinical trials [9, 11, 13, 14]. A
potential limitation of the use of single multitarget inhibi-
tors is inadequate activity against multiple intracellular
targets, rather than an increase of toxicities; differing
affinities for the receptors may result in diverse target
inhibition.
In the past decade, the development of novel therapies
that target critical biologic pathways has greatly expanded
treatment options for patients with advanced GIST or
metastatic colorectal cancer (CRC). However, new drugs
are needed to further extend patients’ overall survival.
In this moving landscape, regorafenib (BAY 73-4506)
was developed, an orally active multikinase inhibitor that is
being developed and commercialized by a joint venture of
Bayer and Onyx Pharmaceuticals [21]. Notably, regorafe-
nib has shown promising results in patients with TKI-
resistant GIST or heavily pretreated advanced CRC, for
whom there is currently no other therapy approved by any
regulatory authority. This review aims at describing its
mechanisms of action as well as preclinical and clinical
development, specifically focusing on gastrointestinal
malignancies.
2 Regorafenib: Mechanisms of Action and Targeted
Pathways
Regorafenib (BAY 73-4506) is a novel oral diphenylurea-
based multikinase inhibitor that simultaneously targets
angiogenic and stromal TKs, including human vascular
endothelial growth factor receptor 2 (VEGFR-2), tyrosine
kinase with immunoglobulin-like and EGF-like domains 2
G. Aprile et al.
(TIE-2), fibroblast growth factor receptor 1 (FGFR-1),
PDGFR, and oncogenic kinases such as KIT and RET,
along with p38 mitogen-activated protein kinase (MAPK),
v-raf murine sarcoma viral oncogene homolog B1 (BRAF)
and its V600 mutant [22]. Its complex chemical structure
(4-[4-({[4-choro-3-(trifluoromethyl)phenyl]carbamoyl}am-
ino)-3-fluorophenoxy]-n-methylpyridine-2-carboxamide) is
very similar to that of sorafenib (BAY 43-9006), except for
the substitution of a hydrogen atom with a fourth fluorine
atom in the central aromatic ring that is responsible for a
broader spectrum of action.
Angiogenesis is a key hallmark of cancer that contrib-
utes to tumor growth and metastases [23]. Amongst the
many proangiogenic molecules that have been intensively
studied, the different isoforms of VEGF, PDGF, and their
receptors are the mainstay actors of tumor neovasculari-
zation [24]. Once activated, they trigger a number of pro-
angiogenic pathways that increase vascular permeability,
mediate degradation of the extracellular matrix, provide
endothelial cells with mitogenic and survival signals,
and eventually facilitate blood vessel growth and remod-
eling [25]. This complex mechanism is targeted by the
TKIs, thus contributing to interrupt the downstream sig-
naling [26]. Regorafenib, among its specific antiangiogenic
properties, inhibits TIE-2.
Primary activating mutations of KIT and PDGFRa genes
encoding structurally aberrant TK receptors serve as pri-
mary drivers for the development of around 90 % of GIST,
while a minority of patients has no mutations in these
kinases (wild-type GIST). Despite the fact that patients
may benefit from prolonged disease control with imatinib
[9] and may further extend the advantage with sunitinib
[27], there is the urgent need for other active TKIs to
overcome acquired resistance to those compounds, which
usually appears within 2 years for imatinib and 6 months
for sunitinib after imatinib failure [28]. Multitarget inhib-
itors may fulfill this gap, and two independent phase II
trials have shown a median progression-free survival (PFS)
of approximately 5 months when resistant GIST patients
are exposed to sorafenib [29, 30].
Along with sorafenib [31] and vandetanib [32], rego-
rafenib may also inhibit the RET pathway. RET is a
transmembrane receptor tyrosine kinase with an extracel-
lular cadherin domain that binds calcium, cysteine-rich
region, transmembrane domain, and intracellular kinase
domain [33]. Mutations in the extracellular coding region
(exons 8, 10, and 11) or in the intracellular kinase domain
(exons 13 to 16) activate multiple transduction pathways,
including RAS/ERK, phosphatidylinositol-4,5-bisphos-
phate 3-kinase (PI3K), v-src sarcoma viral oncogene
homolog (SRC), PLCc, JNK, and STAT3 [34].
At the same time, regorafenib inhibits the ERK-
MAPK activated pathway, which is activated during the
 Author's personal copy
Regorafenib for Gastrointestinal Malignancies
differentiation of intestinal epithelial cells; also, there is
evidence that this pathway results in the activation of the
pathogenesis and progression of CRC [35]. MAPK is a
major signaling pathway in cell proliferation and integrates
signals that affect differentiation, survival, and migration.
Its signaling cascade is involved in different steps of both
the proinflammatory response and the metastatic process
[36], and, frequently, p38 MAPK is found to be aberrant in
human cancers.
Since the activation of the RAS/RAF/MEK/ERK cas-
cade induces expression of VEGF [37], there is a link
between angiogenesis and the MAPK pathway in CRC.
Finally, regorafenib also acts against BRAF, a well
known target for cancer therapy [38].
Somatic point mutations in exon 11 or exon 15 of BRAF
occur in approximately 8 % of human tumors, most fre-
quently in melanomas, colorectal adenocarcinomas, and
thyroid cancers [39]. A single point mutation, V600E,
accounts for approximately 90 % of cases, determines the
lock of the kinase in the active conformation, and confers
CRC cancer patients a dismal prognosis [40]. Currently,
specific inhibitors of BRAF V600E have produced excellent
results in melanomas [41, 42], but their usefulness for CRC
patients is still unproven [43].
3 Preclinical Development of Regorafenib
In vitro biochemical and cellular assays have shown that
regorafenib may inhibit a number of important kinases
within the nanomolar range [35]. Additional inhibited
kinases include DDR2, EphA2, PTK5, p38a and b, while a
few others (EGFR, PKC, MET, MEK, ERK1/2 and AKT)
were unrepressed, even at high drug concentrations. In the
same assays, regorafenib was shown to be a potent inhib-
itor of mutant receptor kinase KIT K642E and RET
C634W, continually activated in GIST-882 and TT-thyroid
cell lines, respectively.
In addition, MAPK pathway inhibition has been evalu-
ated and was interrupted via KRAS inhibition. Actually,
regorafenib potently inhibits the serine/threonine kinase
BRAF, a downstream target of the RAS signaling pathway,
and its oncogenic mutant BRAF V600E. However, the
inhibition of this pathway has not been reported in vivo.
Notably, regorafenib showed antimetastatic activity in
19 out of 25 different human CRC cell lines [44]. In murine
xenograft models, regorafenib has shown potent broad-
spectrum antitumor efficacy [35]. Tumor-bearing mice
treated with a daily regorafenib dose of 10 or 30 mg/kg had
significant tumor shrinkage. Remarkably, no animal
lethality was noted, suggesting a high apparent therapeutic
index with doses in the range of clinical efficacy. In vivo
potent antiangiogenic activity was linked to simultaneous
inhibition of VEGFR-2, TIE-2 and PDGFRb, that was
shown to be more profound than inhibition of VEGF sig-
naling alone. The pharmacodynamic effect of the drug on
tumor vasculature has been assessed by dynamic contrast-
enhanced magnetic resonance imaging that showed sig-
nificant decrease in tumor perfusion and extravasation of
the tracer in tumor-bearing rats. Interestingly, no tumor
regrowth was observed for 4 days after the last regorafenib
dose. In preclinical tumor CRC cell line xenograft models
in athymic mice (Colo-205, BRAF mut and KRAS wt;
HT-29, BRAF mut and KRAS wt; HCT 15, BRAF wt and
KRAS mut), as well as in MDA-MB-231 (breast cancer cell
line, KRAS G13D or BRAF G464V mut), or 786-O (renal
cancer cell lines, VHL gene deleted) murine models,
regorafenib inhibits growth in a dose-dependent manner. A
slow regrowth was observed at all doses within 9 days
from treatment termination. With these compelling pre-
clinical results shaping a strong rationale, regorafenib has
been further studied in several early clinical trials con-
ducted in different solid tumors.
4 Clinical Development of Regorafenib
In the first-in-man phase I dose-escalation trial [45], 53
heavily pretreated patients with a median of three previous
treatment lines were enrolled to evaluate the safety, phar-
macokinetic, pharmacodynamic and efficacy profile of
regorafenib. In the study, CRC, ovarian cancer, and mel-
anoma were the most represented tumor types. Regorafenib
was administrated as an oral solution for dose levels
between 10 and 120 mg or as coprecipitate tablets (of
20 mg or 100 mg) for dose levels of 120, 160 or 220 mg,
because of comparable bioavailability of the two oral for-
mulations at higher doses. Eight dose cohorts were evalu-
ated, with 220 mg once daily being the highest dose tested.
In cohort 1, patients received regorafenib at a dose of
10 mg on day 1 and days 8–14 every 28 days; in the fol-
lowing cohorts, patients received increasing doses of
regorafenib in a 21-days-on, 7-days-off schedule. Overall,
the median treatment duration was 78 days (range 3–1,239)
and across all dose levels, 50 patients (94 %) received
50 % or more of the planned dose, with 38 patients (72 %)
receiving 70 % or more. Forty-four patients (83 %) expe-
rienced at least one treatment-related AE. The most fre-
quently reported AEs were hoarseness (55 %), hand-foot
skin reaction (HFSR) (40 %), mucositis (36 %), diarrhea
(32 %), and hypertension (30 %). The most common grade
3–4 treatment-related AEs were HFSR (19 %), hyperten-
sion (11 %), diarrhea (8 %), and rash/desquamation (6 %).
No toxic deaths were reported. As expected, the frequency
of treatment-related AEs increased with dose levels.
Patients enrolled in dose level cohorts of 10–60 mg
 Author's personal copy
tolerated the drug very well, without reporting dose-lim-
iting toxicities (DLTs), dose reductions, temporary
interruptions, or permanent discontinuation. After the
evaluation of dose-limiting toxicities occurred in cohort 7
(160 mg) and cohort 8 (220 mg), the daily dose of
160 mg was established as the maximum tolerated dose
(MTD) for regorafenib given in the 21-days-on, 7-days-
off schedule.
Pharmacokinetic data have been also provided [45].
Among regorafenib-derived active metabolites, M-2
(N-oxyde metabolite; BAY 75-7495) and M-5 (N-oxyde/
N-desmethyl metabolite; BAY 81-8752) have multiple
peaks of plasma concentration at steady-state, the first
occurring after 1–4 hours and the others at 8 and 24 hours
from administration. Preclinical studies have demonstrated
pharmacological activity of M-2 and M-5 with efficacy
similar to the parental compound. M2 and regorafenib itself
may be further modified by glucuronidation. A dose-
dependent increase of plasma concentration of regorafenib
was demonstrated up to 60 mg, but the same correlation
was lacking for dose escalation up to 120 mg. Regorafenib,
M-2, and M-5 present a long half-life (about 20–40 hours)
that explained the accumulation of the drug and its
metabolites in plasma after multiple doses. Regorafenib has
time-linear pharmacokinetics and its accumulation is pre-
dictable. On the contrary, M-2 and M-5 concentrations
vary with time. Elimination of M-2 is similar to that of the
parent drug, while data suggested that M-5 may have a
slower elimination with a prolonged half-life.
In the above-quoted phase I study [45], antiangiogenic
activity of the experimental drug was assessed by mea-
suring changes in tumor perfusion with dynamic contrast-
enhanced magnetic resonance imaging (DCE-MRI). A
significant decrease of 40 % was reported after 21 days
with the dose levels of 120 mg (solution), 160 mg (tablet),
and 220 mg (tablet). A decrease in plasma VEGFR-2
concentrations during cycles 1 and 3 was reported to be
dose-dependent. Accordingly, plasma VEGF concentration
increased during the 21 days of exposure to regorafenib
and returned to baseline levels during the following 7 days
off, suggesting that the intermittent schedule might cause
angiogenic flares during the break periods. In the study,
tumor response was assessed by RECIST (Response
Evaluation Criteria In Solid Tumors) in 47 patients (88 %).
Three patients had partial response (PR) and 32 had stable
disease (SD) at 2 months on study treatment. Responding
patients had renal cell carcinoma (60 mg oral solution,
time to progression [TTP] 20.6 months), CRC (220 mg
tablet, treatment discontinued for AE) and osteosarcoma
(120 mg solution, TTP 8.3 months). The study recom-
mended a 160 mg oral daily dose to be used in phase II
trials testing a 21-days-on, 7-days-off schedule of
regorafenib.
G. Aprile et al.
Since activity of the drug was noted in patients with
advanced CRC, the study was expanded to further evaluate
the drug in this population [46]. Overall, 38 heavily pre-
treated Caucasian patients (median of four prior lines of
therapy) were included in the analysis (15 in the dose-
escalation cohort and 23 in the extension cohort); 26 of
them received regorafenib at 160 mg daily. Median age
was 64 years (range 36–85), and the performance status
(PS) was generally good (0–1 95 %). Previous systemic
treatments included oxaliplatin (84 %), irinotecan (84 %),
bevacizumab (53 %) and anti-EGFR antibodies (53 %).
For the 26 patients included in the 160 mg dose level
cohort, the median treatment duration was 49 days.
Although six patients permanently discontinued regorafe-
nib because of treatment-related AE, toxicities were easily
manageable in the outpatient setting with few treatment
reductions or interruptions. Twenty-seven (71 %) patients
were evaluable for response. Disease control rate lasting at
least 2 months was 74 %, with a median PFS of 107 days
(95 % CI 66–161). The role of KRAS status in predicting
regorafenib activity was also tested. An exploratory sur-
vival analysis showed slightly longer median PFS for
mutant KRAS tumors compared with wild-type (84 vs
161 days), although the difference was not statistically
significant. Nevertheless, the small sample size and the
nature of the analysis prevented drawing any definitive
conclusion about the impact of KRAS status on response to
regorafenib therapy.
The second phase I dose-escalation trial reported in the
literature [47] assessed safety, pharmacokinetics and effi-
cacy of continuous regorafenib in 38 heavily pre-treated
advanced cancer patients (including CRC 16 %, thyroid
13 %, and head and neck cancer 13 %). AE frequencies
were similar to those previously reported. DLTs in cycles
1–2 occurred in 2 out of 11 patients at a daily dose of
100 mg (HFSR, anemia/thrombocytopenia), in 3 out of 6
(HFSR n = 2; thrombocytopenia n = 1) at 120 mg, and in
4 out of 10 (HFSR n = 2; diarrhea n = 1; hyperbilirubi-
nemia/AST increase n = 1) exposed to a dose of 140 mg.
Consequently, the continuous daily dose of 100 mg was
defined as MTD with clinical activity. Interestingly, dis-
ease control lasting at least 6 weeks was reported for 61 %
of included patients. The same Investigators’ group pre-
sented a parallel phase I dose-escalation study conducted in
advanced refractory non-small cell lung cancer (NSCLC)
patients [48]. Twenty-three patients were treated with two
different doses of regorafenib of 100 or 120 mg adminis-
tered orally once daily. Median treatment duration was
84 days (range 12–281). AEs noted were similar to those
already reported, except for mild-to-moderate hypothy-
roidism in 26 % of treated patients. Pharmacokinetic data
confirmed plasma increase of the drug proportionally to
dose exposure. Among 17 evaluable patients, 13 reached
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Regorafenib for Gastrointestinal Malignancies
SD at 6 weeks after the start of treatment and 4 patients
after 12 weeks. One patient with SD had a PFS of
279 days.
4.1 Phase II Trials
Three phase II trials on regorafenib have been reported so
far (49–51).
The first is an open-label, phase II study that enrolled 49
untreated patients with renal cell carcinoma, with PS 0–1
and low or intermediate risk according to the Motzer cri-
teria score [49]. Patients received regorafenib at a dose of
160 mg on a 21-days-on, 7-days-off schedule. The primary
endpoint of the study was response rate. Renal failure
occurred in 8 % of patients, most likely due to continued
drug intake despite having dehydration. Of 33 evaluable
patients, 27 % reported PR and 42 % SD. At the time of
interim analysis, 35 patients were still on study.
The second is a phase II, uncontrolled, open-label,
international safety study in pretreated hepatocellular car-
cinoma (HCC) patients [50]. The primary aims of the trial
were safety and tolerability; secondary endpoints were
TTP, overall survival (OS), response rate, and disease
control rate. A pharmacokinetic study of regorafenib and
its M2 and M5 metabolites was also included. Thirty-six
Child-Pugh A patients (median age 61 years) previously
exposed to sorafenib were recruited and treated with an
oral daily dose of 160 mg in a 3-weeks-on, 1-week-off
schedule until disease progression (DP), patients’ refusal,
or unacceptable toxicity. Median treatment duration was
15.5 weeks (range 2–36), with 15 patients still on treatment
at the time of analysis. Regorafenib was discontinued
because of DP in six patients, AE in 12 patients, consent
withdrawn in two patients and death in one case. Overall,
grade 3–4 AEs were limited, with fatigue (17 %), HFSR
(14 %), and diarrhea (6 %) being the more frequently
observed. Median TTP was 4.1 months. The disease con-
trol rate of 72 % (one PR and 25 SD) and the very inter-
esting 6-month OS rate of 80 % suggested a promising
activity of regorafenib in this population. The mechanism
by which regorafenib may overcome resistance to sorafe-
nib remains to be investigated in future studies.
Finally, based on its ability to inhibit c-KIT and PDGFR
in GIST cell lines [35], regorafenib has been investigated
in patients with advanced or metastatic GIST who have
progressed after treatment with imatinib and sunitinib, the
only approved drugs to treat this disease. The primary
objective of a recent multicenter, phase II trial was to
assess clinical benefit, as defined by the composite of
complete response, PR, and SD lasting at least 16 weeks, in
34 TKI-resistant GIST patients [51]. Secondary goals were
PFS, safety, and tolerability of the drug. Any number of
previous therapies for GIST was permitted, but previous
exposure to sorafenib was among the exclusion criteria.
Regorafenib was administrated at 160 mg/day with the
usual 3-weeks-on, 1-week-off schedule until RECIST 1.1
DP, unacceptable toxicity, or patients’ withdrawal. Addi-
tionally, tumor genotyping (KIT, PDGFRa, and BRAF) was
performed, while a separate consent was asked for optional
tumor biopsies to be performed before the first dose of
regorafenib and between day 10 and 21 of the first cycle.
Median age of enrolled patients was 56 years (range
25–76), median number of prior regimens was 2 (range
2–10). Disease progression was the main reason for stop-
ping both imatinib and sunitinib, and median times on the
drugs were 21 and 13 months, respectively. Primary kinase
mutation was available for 30 patients, and resulted in KIT
exon 11 (19 patients), KIT exon 9 (3 patients), BRAF exon
15, or wild-type status for KIT and PDGFRa (8 patients).
The median number of cycles administered per patient was
8 (range 2–17). At the final analysis, clinical benefit was
documented in 25 patients (4 PR, 22 SD); two patients
progressed early, and one withdrew consent. Median PFS
for the whole cohort was 10 months, while median OS was
not reached after a median follow-up of 11 months. The
scope of toxicities was not different from expected, with
grade 3 hypertension, HFSR and hypophosphatemia
reported in 36 %, 24 %, and 15 % of patients, respectively.
Three life-threatening AEs were reported (two cases of
hyperuricemia and one thrombotic event). Although the
small sample size precludes the drawing of strong con-
clusions, there was no statistically significant difference in
the rate of clinical benefit among genotype groups.
Immunoblotting analysis of biopsies repeated before
treatment start and at day 15 demonstrated *50 % inhi-
bition of KIT and AKT phosphorylation in 75 % of
patients, all with SD lasting at least four cycles. Clinical
activity of regorafenib was also studied, utilizing FDG-
PET/CT, a pharmacodynamic biomarker with imatinib and
sunitinib in patients with GIST, documenting metabolic
responses even when radiological assessment according to
RECIST criteria confirmed the disease as stable [52].
4.2 Phase III Trials
Two phase III trials have been published: the first inves-
tigating regorafenib treatment in CRC, the second in
GISTs.
Following the rationale for regorafenib use in CRC and
preliminary positive results in phase I trials, the multicenter,
randomized, double-blind, placebo-controlled, phase III
CORRECT (Patients with metastatic COloRectal cancer
treated with REgorafenib or plaCebo after failure of stan-
dard Therapy, BAY 73-4506/14387) trial was conducted in
16 countries with 114 active centers to evaluate efficacy and
safety of regorafenib in patients with advanced disease who
 Author's personal copy
had progressed during or within 3 months following last
administration of approved standard therapy [53]. The pri-
mary efficacy endpoint of the study was OS, the secondary
endpoints were PFS, objective response rate (ORR) and
disease-control rate (DCR). Other endpoints included
duration of response/SD, quality of life, pharmacokinetics,
and evaluation of plasma biomarkers. Among others, key
inclusion criteria to be fully satisfied at time of screening
included age C18 years, pathological evidence of advanced
colorectal adenocarcinoma, DP during or within 3 months
after last therapy, life expectancy of at least 3 months, good
Eastern Cooperative Oncology Group (ECOG) PS (0 or 1),
and adequate bone marrow, liver, and renal function. Pre-
vious therapies included fluoropyrimidine, oxaliplatin, iri-
notecan, bevacizumab, and cetuximab or panitumumab (if
KRAS wild-type). As expected, baseline characteristics were
well balanced in the two study groups, including KRAS
mutational status and number of prior anticancer therapies
(approximately 60 % of patients had received C4 regimens
of chemotherapy). To demonstrate a 33 % improvement in
median OS (from 4.5 to 6 months), 760 patients were ran-
domized 2:1 to regorafenib (160 mg daily in a 3-weeks-on,
1-week-off schedule) plus best supportive care (BSC) or
placebo plus BSC. Stratification factors included prior
treatment with VEGF-targeting drugs (yes versus no), time
from diagnosis of metastatic disease (C18 months versus
\18 months), and geographical origin. Before the final
analysis, scheduled soon after approximately 582 death
events were observed (1-sided overall a of 0.025), two
interim analyses were preplanned and conducted by an
Independent Data Monitor Committee. At the time of the
second interim analysis (75 % of events required for final
analysis) data showed an estimated hazard ratio (HR) for
OS of 0.77 (95 % CI: 0.63–0.94; 1-sided p = 0.0051) with
a median OS of 6.4 months for regorafenib versus
5.0 months for placebo. The estimated HR for PFS was 0.49
(95 % CI: 0.42–0.58; 1-sided p \ 0.000001) with a median
PFS of 1.9 months (95 % CI: 1.88–2.17) for regorafenib
and 1.7 months for placebo (95 % CI: 1.68–1.74). Notably,
ORR was only 1.6 % for regorafenib versus 0.4 % for
placebo while the DCR was 44.8 % for regorafenib (PR
1 %, SD 43.8 %) and 15.3 % (DP 0.4 %, SD 14.9 %) for
placebo (p \ 0.000001), indicating that the strength of the
drug is more in delaying progression than inducing tumor
shrinkage. Thus, regorafenib is the first small molecule
multitarget TKI with demonstrated efficacy in advanced
CRC. Frequencies of AEs were as expected: fatigue 47.4 %
(grade 3–4, 9.6 %); HFSR 46.6 % (grade 3, 16.6 %);
diarrhea 33.8 % (grade 3–4, 7.2 %); anorexia 30.4 %
(grade 3, 30.2 %); voice changes 29.4 % (grade 3, 0.2 %);
hypertension 27.8 % (grade 3, 7.2 %); oral mucositis
27.2 % (grade 3, 3 %); and rash/desquamation 26 % (grade
3, 5.8 %). Mutated KRAS status was reported for 54.1 % of
G. Aprile et al.
patients exposed to regorafenib and for 61.6 % of those that
received placebo. Interestingly, no apparent effect of KRAS
status on the primary efficacy outcome (PFS) was observed,
even if a subgroup analysis showed that regorafenib pro-
duced significant OS advantage for patients with KRAS wt
tumors (HR 0.65, 95 % CI 0.48–0.91) but not for those with
mutated tumors (HR 0.87, 95 % CI 0.67–1.12) [54]. Wait-
ing for marketing authorization, an ‘expanded access’,
phase IIIb, prospective, interventional, open-label, single-
arm, multicenter study of regorafenib started, providing the
drug to CRC patients who have failed after all available
standard therapies [55].
Based on preliminary results, the randomized, double-
blind, placebo-controlled, phase III GRID (GIST, Rego-
rafenib In Progressive Disease) trial, a collaborative
worldwide effort among academic and industrial research
teams, was funded by Bayer HealthCare Pharmaceuticals
and conducted in 17 countries across Europe, North
America and Asia-Pacific [56]. The aim of the study was to
evaluate efficacy and safety of regorafenib in patients with
metastatic and/or unresectable GIST who have already
failed on at least imatinib and sunitinib. Six months were
sufficient to screen 234 patients. Of those, 199 were ran-
domized 2:1 to receive regorafenib at 160 mg once daily on
a 3-weeks-on, 1-week-off schedule plus BSC or placebo
(same schedule) plus BSC, with the ambitious goal of
obtaining a 100 % increase in PFS (HR 0.5). Patients who
had been treated with any VEGFR inhibitors other than
sunitinib were excluded. The same was true for patients
with cardiovascular dysfunctions, including congestive
heart failure, myocardial infarction within 6 months before
study entry, cardiac arrhythmias requiring medical treat-
ment, uncontrolled hypertension, or unstable angina. The
primary endpoint was PFS judged as per independent
blinded central review. Co-secondary endpoints were OS,
TTP, ORR, DCR and duration of response. In addition,
exploratory analyses were planned in order to verify the
impact of tumor genotype on outcomes, screen for com-
prehensive kinase mutations in the plasma, and examine
health-related quality of life. As expected, baseline char-
acteristics such as median age, sex, race, number of prior
lines of therapy, and ECOG PS were all well balanced
between the two groups. Notably, heavily pretreated
patients exceeded 40 % in both treatment arms (44.4 % in
the regorafenib arm versus 40.9 % in the placebo arm), with
nilotinib being the most frequent third-line treatment
(21.8 % and 30.3 %, respectively). The primary endpoint
was clearly met, since regorafenib significantly improved
median PFS compared with placebo (4.8 versus 0.9 months,
HR 0.27, 95 % CI; 0.19–0.39; 1-sided p \ 0.0001), and the
PFS benefit was confirmed in all prespecified subgroups. At
time of DP, patients were eligible for unblinding and
crossover to open-label regorafenib if initially assigned to
 Author's personal copy
Regorafenib for Gastrointestinal Malignancies
placebo. In all, 85 % were able to receive regorafenib after
progression and, even among those patients, a 5-month PFS
was reported. The small number of deaths (29 in the rego-
rafenib arm, 17 in the placebo arm), makes data currently
immature to evaluate overall survival, even if this parameter
will most probably be uninformative, suffering the cross-
over effect because of this trial design. Median OS was not
reached in either group, although a non-significant trend
was noted in favor of patients who started regorafenib
earlier in the course of care with an estimated HR of 0.77
(95 % CI 0.42–1.41). Interestingly, patients exposed to
regorafenib had higher response rates (4.5 versus 1.5 %)
and disease control rates (52.6 versus 9.1 %) compared with
those who received placebo. The safety profile of rego-
rafenib was commensurated with previous studies. The
most common severe drug-related AEs were HFSR
(19.7 %), hypertension (22.7 %), and diarrhea (5.3 %).
Baseline GIST genotype was available for approximately
half of the included patients. Exon 11 KIT mutation was
found in 53.1 % of patients, exon 9 KIT mutation in 15.6 %.
In the exploratory analysis, the advantage in PFS among
those patients treated with regorafenib was similar to that
reported for the entire population, regardless of mutational
status. Results of regorafenib in progressive GIST after
failure of imatinib and sunitinib satisfy an unmet clinical
need, and this multitarget inhibitor may be proposed as a
potential new standard of care for this patient population
[56].
5 Ongoing Trials, Future Research, and Open
Questions
The ultimate goal to introduce new drugs in the advanced
setting is to offer more opportunities to cancer patients who
have failed standard therapies and are running out of
valuable treatment options. Along this line, the benefit
provided by a new drug to heavily pretreated patients with
GIST, colorectal cancer or HCC may at least cover an area
of high unmet need. Undoubtedly, regorafenib is a novel,
orally active multikinase inhibitor with a strong preclinical
rationale and promising clinical results. Still, a number of
puzzling questions regarding regorafenib remains to be
answered, and future clinical studies are still being
designed to investigate on these issues.
5.1 Regorafenib as Single-Agent or in Combination
Therapy?
First of all, it is unclear whether it is better to employ
regorafenib as a single agent or in combination with other
drugs and if it should be used as last salvage treatment or
moved to front-line therapy. Regarding its use as a single
agent or in combination, a phase I study [57] is ongoing to
evaluate the safety profile, MTD and pharmacokinetic
interactions of first-line regorafenib in combination with
pemetrexed and cisplatin in lung cancer. Moreover, a
number of studies are ongoing in patients with advanced
CRC to evaluate the safety and efficacy of the combina-
tion of regorafenib in first- and second-line treatment with
common backbone regimens such as FOLFIRI or FOL-
FOX [58–60] [Table 1]. Hopefully, regorafenib will suc-
ceed where other TKI (e.g., vatalanib PTK787/ZK222584
in the CONFIRM (Colorectal Oral Novel Therapy for the
Inhibition of Angiogenesis and Retarding of Metastases)
trials, cediranib AZ2171 in the HORIZON studies) have
failed.
5.2 Which is the Optimal Dose and Schedule?
The intermittent 160 mg/day schedule (3 weeks on,
1 week off) has been tested in two randomized, phase III
trials conducted in CRC and GIST, and may therefore be
considered as the standard. However, a continuous daily
dose of 100 mg was also proven to be feasible and have the
potential advantage to avoid angiogenic flares during the
rest period. Likewise, different doses of sunitinib (50 mg/
day 4 weeks on, 2 weeks off or 37.5 mg/day continuously)
are equally effective and safe [61]. In the Strumberg phase
I trial [46], regorafenib was reduced or interrupted in two
out of three patients, and 25 % of those treated at the
160 mg dose level permanently discontinued the drug
because of AEs. Moreover, in the CORRECT trial [54], the
proportion of regorafenib-treated patients experiencing
AEs leading to treatment discontinuation was seven times
higher than that of patients who received placebo, while in
GIST patients [51], approximately one third of patients
could tolerate a maximum dose of 80 mg per day. Theo-
retically, pharmacokinetic studies may help clinicians in
defining the ideal treatment dose and schedule.
In a cohort of 79 GIST patients exposed to a daily i-
matinib dose of 400 mg (n = 36) or 600 mg (n = 37) [62],
a lower trough level measured at steady-state seemed to be
associated with outcome. Specifically, patients with mini-
mum concentration lower than 1,110 ng/mL at day 29
had significantly shorter median TTP compared with those
with a higher steady-state concentration of imatinib
(11.3 months vs [30 months, p \ 0.0029). Although no
survival differences were reported for patients with dif-
ferent trough levels, this preliminary report suggested that a
low steady-state plasma level may contribute to imatinib
failure. Plasma concentration-time profile at steady state of
regorafenib and its major metabolites have also been
reported [46]. Further studies, however, are needed to
verify the relationships between drug plasma levels and
clinical outcomes of imatinib and other TKIs.
Table 1 Major ongoing trials with regorafenib as monotherapy or in combination with chemotherapy in gastrointestinal malignancies
Trial identifier Study title (acronym) Phase Treatment Schedule Included population Primary endpoints Estimated
study
completion
date

NCT01538680 An Open-label Phase IIIb Study of IIIb expanded Regorafenib 160 mg po daily for 3 weeks Pretreated CRC Safety Spring
Regorafenib in Patients With access of every 4-week cycle patients who have 2014
Metastatic Colorectal Cancer failed all available
Who Have Progressed After standard therapies
Standard Therapy
NCT00934882 Phase I, Open-label, Non-placebo I Regorafenib ? mFOLFOX6 160 mg po once daily from CRC patients Adverse event Spring
Controlled Study to Determine or FOLFIRI days 4–10 and from days pretreated with no collection; 2012
the Safety, Pharmacokinetics, 18–24 in combination with more than one effect of
and Pharmacodynamics of mFOLFOX6 or FOLFIRI previous regorafenib on
BAY73-4506 in Combination chemotherapy for the PK of
With mFOLFOX6 or FOLFIRI advanced disease mFOLFOX6
as First or Second Line Therapy and FOLFIRI
in Patients With Metastatic
Colorectal
NCT01584830 A Randomized, Double-blind, III Regorafenib 160 mg po daily for 3 weeks Pretreated Asian OS Spring
Placebo-controlled Phase III of every 4-week cycle CRC patients who 2014
Study of Regorafenib Plus Best have failed all
Supportive Care Versus Placebo available standard
Plus BSC in Asian Subjects With therapies
Metastatic Colorectal Cancer
Who Have Progressed After
Standard Therapy (CONCUR)
NCT01298570 Multi-Center, Randomized, II randomized Regorafenib/ 160 mg, po, daily, per 7-day Second-line therapy PFS Winter
Placebo-Controlled Phase II 2:1 placebo ? FOLFIRI cycle in pretreated 2019
Study of Regorafenib in patients with
Author's personal copy

Combination With FOLFIRI FOLFOX, KRAS

Versus Placebo With FOLFIRI as or BRAF mutant
Second-Line Therapy in Patients with metastatic
With Metastatic Colorectal CRC
Cancer
NCT01289821 An Uncontrolled, Open-label, II Regorafenib ? mFOLFOX6 Regorafenib 160 mg po on First-line therapy in Objective October
Phase II Study in Subjects With days 4–10 and 18–24. In patients with response rate 2013
Metastatic Adenocarcinoma of case of administration as a metastatic CRC
the Colon or Rectum Who Are single agent during the
Receiving First Line study, 160 mg po daily for
Chemotherapy With 3 weeks on, 1 week off
mFOLFOX6 (Oxaliplatin/
Folinic Acid/5-fluorouracil
[5-FU]) in Combination With
Regorafenib (CORDIAL)
G. Aprile et al.
 Author's personal copy
Regorafenib for Gastrointestinal Malignancies

5.3 Will Mutational Analyses Ever Help in Selecting

completion

specified
Estimated Patients with a Higher Chance to Benefit?

Autumn
2012
study

date

Not
Available data does not seem to substantiate this hypoth-
Primary endpoints

esis. In the exploratory analysis of a phase I trial [46], no

biomarker data
Biomarker data.
Evaluation of
clear difference in PFS between KRAS mutated and wild-

relationships

and clinical
potential type group were noted, even though median PFS of the

between

activity
wild-type group was 90 % longer (161 vs 84 days).

Safety
Moreover, in the phase III trial enrolling CRC patients, a
very low overall response rate was reported (1 %), and the

from treatments of
Included population

efficacy and have

likelihood to obtain prolonged SD seemed to be indepen-
pretreated Asian
Biopsy amenable,

failed sorafenib
cannot benefit
dent from KRAS or BRAF status [54]. Finally, despite the
CRC patients

patients who
Child A HCC

established
significantly longer PFS of patients with GIST tumors
carrying the primary exon 11 KIT mutations compared with

CRC colorectal cancer, HCC hepatocellular carcinoma, OS overall survival, PFS progression-free survival, PK pharmacokinetics, po orally
the PFS of patients with tumors with primary exon 9
mutations (p = 0.01), there was no statistically significant
160 mg po daily for 3 weeks

160 mg po daily for 3 weeks

difference in the rate of clinical benefit among different

genotype groups [51, 56].
of every 4-week cycle

of every 4-week cycle

5.4 Do Patients Previously Exposed to VEGF

Inhibitors Still Respond to Regorafenib?
Schedule

The answer seems to be yes. In the CORRECT trial, all the

patients were previously exposed to (and failed) bev-
acizumab. Moreover, to carry on with antiangiogenic
treatment beyond bevacizumab failure is a reasonable
strategy, confirmed by the post-progression use of bev-
acizumab itself combined with a different backbone che-
motherapy as in the ML18147 trial [63] or aflibercept
combined with second-line FOLFIRI in the VELOUR
Regorafenib

Regorafenib
Treatment

(Aflibercept Versus Placebo in Combination With Irino-

tecan and 5-FU in the Treatment of Patients With Meta-
static Colorectal Cancer After Failure of an Oxaliplatin-
Based Regimen) study [64]. Accordingly, 100 % of GIST
patients exposed to regorafenib in the US study [51] and in
the GRID trial [56] have previously failed sunitinib.
Phase

IIa

II

5.5 How May Regorafenib Benefit Patients with GIST?

Multicenter Phase II Safety Study
Asian Colorectal Cancer Patients

of BAY73-4506 in Patients With

Preclinical and clinical data have shown that secondary

73-4506) in Biopsy-amenable
Study of Regorafenib (Bayer
A Phase IIA Proof of Concept

An Uncontrolled Open Label

mutations in KIT account for the vast majority of TKI

Hepatocellular Carcinoma

resistance. Based on the hypothesis that individual KIT

Study title (acronym)

mutant oncoproteins may affect drug sensitivity [65],

Antonescu and colleagues investigated the efficacy of
sorafenib, nilotinib, and dasatinib on a set of Ba/F3 cells
expressing various imatinib-resistant KIT mutants. The
exposure to sorafenib, the parental compound of rego-
rafenib, resulted in inhibition of all the double KIT mutants
Table 1 continued

tested, included those resistant to other TKIs. These

NCT01189903

NCT01003015
Trial identifier

mutations occur in exons 13 and 14, which encode the ATP

binding pocket, or in exons 17 and 18, which encode the
kinase activation loop. Since both imatinib and sunitinib
are virtually useless against mutations affecting the
 Author's personal copy
activation loop of KIT or PDGFRa, it has been hypothe-
sized that this could be the target of regorafenib. Alterna-
tively, the new TKIs may inhibit other salvage signaling
pathways. Indeed, the main hurdle in overcoming second-
ary resistance in GIST patients is due to the fact that
multiple secondary mutations can be synchronously present
at multiple metastatic locations in the same patient, hin-
dering the efficacy of most TKIs, including regorafenib.
6 Conclusions
In summary, regorafenib is a potent, orally active, multi-
target inhibitor, exhibiting robust efficacy data in patients
with heavily pretreated metastatic colorectal cancer or
advanced TKI-refractory GIST. Interestingly, it appears to
inhibit the cancer-promoting signals in a very unique way,
retaining its broad activity even in patients whose cancers
have developed resistance to all other standard treatments.
Ongoing and future trials will shed light on a number of
unanswered questions and help oncologists to optimize the
use of the drug. A decade after the introduction of targeted
agents in the clinical practice, there is need for new drugs
that may extend survival and provide new hope to patients
with life-threatening gastrointestinal malignancies. Rego-
rafenib, indeed, is part of this story.
Acknowledgements The authors want to thank Dr Jessica Menis,
Clinical Fellow, EORTC, Brussels, Belgium and Dr Masoud Saman,
Department of Otolaryngology – Head and Neck Surgery, New York
Eye and Ear Infirmary, NY, USA for their valuable comments and
friendly contribution in reviewing the manuscript.
Competing interest statement The authors declare they have no
competing financial interests.
Funding source No sponsors were involved in the writing of the
manuscript or in the decision to submit the manuscript for
publication.
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