Regorafenib for Gastrointestinal Malignancies

REVIEW ARTICLE

Regorafenib for Gastrointestinal Malignancies

From Preclinical Data to Clinical Results of a Novel Multi-Target Inhibitor

Giuseppe Aprile • Marianna Macerelli •

Francesco Giuliani

Published online: 23 February 2013

� 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

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

G. Aprile (&) � M. Macerelli

Department of Medical Oncology, University and General

Hospital, Piazzale S Maria Misericordia, 1, 33100 Udine, Italy

e-mail: [email protected]

F. Giuliani

Department of Medical Oncology, National Cancer Institute

‘‘G. Paolo II’’, Bari, Italy

BioDrugs (2013) 27:213–224

DOI 10.1007/s40259-013-0014-9

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

(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

214 G. Aprile et al.

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

Regorafenib for Gastrointestinal Malignancies 215

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.

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


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


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

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


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.


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5.3 Will Mutational Analyses Ever Help in Selecting

Patients with a Higher Chance to Benefit?

Available data does not seem to substantiate this hypoth-

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

clear difference in PFS between KRAS mutated and wild-

type group were noted, even though median PFS of the

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

Moreover, in the phase III trial enrolling CRC patients, a

very low overall response rate was reported (1 %), and the

likelihood to obtain prolonged SD seemed to be indepen-

dent from KRAS or BRAF status [54]. Finally, despite the

significantly longer PFS of patients with GIST tumors

carrying the primary exon 11 KIT mutations compared with

the PFS of patients with tumors with primary exon 9

mutations (p = 0.01), there was no statistically significant

difference in the rate of clinical benefit among different

genotype groups [51, 56].

5.4 Do Patients Previously Exposed to VEGF

Inhibitors Still Respond to Regorafenib?

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

(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.

5.5 How May Regorafenib Benefit Patients with GIST?

Preclinical and clinical data have shown that secondary

mutations in KIT account for the vast majority of TKI

resistance. Based on the hypothesis that individual KIT

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

tested, included those resistant to other TKIs. These

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 theTa

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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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