Safety and efficacy of fruquintinib in patients with previously treated metastatic colorectal cancer: a phase Ib study and a randomized double-blind phase II study
Xu et al. Journal of Hematology & Oncology
Safety and efficacy of fruquintinib in patients with previously treated metastatic colorectal cancer: a phase Ib study and a randomized double-blind phase II study
Jin Li 0 1
Junning Cao 0
0 Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai Medical College , Shanghai 200032 , China
1 Department of Oncology, Tongji University Shanghai East Hospital , No. 150 Jimo RoadPudong District, Shanghai 200120 , China
Background: To assess the efficacy and safety of fruquintinib, a vascular endothelial growth factor receptor (VEGFR) inhibitor, in metastatic colorectal cancer (mCRC) patients. Methods: A phase Ib open-label study and phase II randomized, placebo-controlled trial compared the efficacy of fruquintinib plus best supportive care (BSC) with placebo plus BSC in mCRC patients with ≥2 lines of prior therapies. The primary endpoint was progression-free survival (PFS). Results: In the phase Ib study, 42 patients took fruquintinib 5 mg for 3 weeks on/1 week off. The median PFS was 5. 80 months, and the median overall survival (OS) was 8.88 months. In the phase II study, 71 patients were randomized (47 to fruquintinib, 24 to placebo). PFS was significantly improved with fruquintinib plus BSC (4.73 months; 95% confidence interval [CI] 2.86-5.59) versus placebo plus BSC (0.99 months; 95% CI 0.95-1.58); (hazard ratio [HR] 0.30; 95% CI 0.15-0.59; P < 0.001). The median OS was 7.72 versus 5.52 months (HR 0.71; 95% CI 0.38-1.34). The most common grade 3-4 adverse events were hypertension and hand-foot skin reaction. Conclusions: Fruquintinib showed a significant PFS benefit of 3.7 months in patients with treatment-refractory mCRC. The safety profile was consistent with that of VEGFR tyrosine kinase inhibitors. A randomized phase III confirmatory study in mCRC is underway. Trial registration: NCT01975077 and NCT02196688
Fruquintinib; Metastatic colorectal cancer; Progression-free survival; VEGFR
In patients with metastatic colorectal cancer (mCRC),
addition of anti-vascular endothelial growth factor (VEGF)
and anti-endothelial growth factor receptor (EGFR) biologic
agents to chemotherapy regimens, either in the first or
second line, improves overall survival (OS), progression-free
survival (PFS), and anti-tumor response compared with
chemotherapy alone [1–3]. However, patients frequently
develop resistance and ultimately experience disease
progression, highlighting a demand for more therapeutic
strategies after failure of standard chemotherapy [4, 5].
Angiogenesis is an important hallmark of cancer
development and progression. The VEGF and vascular
epidermal growth factor receptor (VEGFR) signaling
pathways strongly promote tumor growth and
metastasis. Inhibition of these pathways has demonstrated
strong clinical anti-tumor activity against multiple types
of cancer, leading to the successful approval of both
monoclonal antibody drugs and small molecule VEGFR
inhibitors [6–8]. For instance, bevacizumab, a
VEGFdirected monoclonal antibody, has been approved for
the treatment of mCRC . Recently, regorafenib has
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been approved by the US Food and Drug Administration
based on the results from the CORRECT study .
Fruquintinib is a potent and highly selective small
molecule inhibitor of VEGFR-1, VEGFR-2, and VEGFR-3
tyrosine and has shown strong anti-tumor activity in
various preclinical models [11, 12]. In phase I trials,
fruquintinib demonstrated good pharmacokinetic
properties, tolerable safety, and promising anti-tumor activity
against multiple tumor types . A further
tworegimen comparison study was carried out , and a
regimen of 5 mg once daily oral dose on a
3-week-on/1week-off treatment cycle was determined as the
recommended phase II dose (RP2D). We report here data on a
phase Ib expansion trial (NCT01975077) and a
randomized, double-blind, placebo-controlled, multicenter phase
II trial (NCT02196688) to further assess the safety and
efficacy of fruquintinib at the RP2D in patients with
mCRC who failed at least two prior standard treatments.
Study design and participants
We conducted an open-label phase Ib trial in two
hospitals (NCT01975077) and a randomized, double-blind,
placebo-controlled phase II trial in eight hospitals
(NCT02196688) in China. Most of the inclusion and
exclusion criteria were common to both the studies.
Patients were eligible to participate when they had
histological or cytological documentation of
adenocarcinoma of the colon or rectum. Patients had to have
received at least a second-line standard therapy, including
fluoropyrimidine, oxaliplatin, or irinotecan-based
regimens and to have disease progression within 3 months
after the last administration of the last standard therapy
or to have stopped such therapy due to unacceptable
toxicities. Pre-treatment with EGFR and VEGF inhibitors
(bevacizumab and aflibercept) were allowed but were
Patients had to be aged between 18 and 75 years and
have an Eastern Cooperative Oncology Group
performance status of 0 or 1, life expectancy of at least
12 weeks, and adequate bone marrow, liver, and renal
function at the start of the trial. Patients could not
participate if they had previously received any VEGFR
inhibitors (regorafenib, ramucirumab, apatinib, axitinib,
famitinib, or other tyrosine kinase inhibitors) or had
other uncontrolled medical disorders. Additional files 1
and 2 show full inclusion and exclusion criteria for both
of the studies.
These studies were conducted in accordance with the
laws and regulations in China regarding patient
protection. The studies were approved by the independent
ethics committees of each involved institution. Informed
consent was obtained from all the participants.
Randomization and treatment
Patients who met the eligibility criteria for the phase Ib
study took fruquintinib 5 mg once daily, for 3 weeks on
and 1 week off. In the phase II trial, the eligible
participants were randomly assigned in a 2:1 ratio to receive
fruquintinib plus BSC or placebo plus BSC. The participants,
investigators, and the study funder were masked to
treatment group assignment. Randomization was performed
centrally using the interactive web response system
(IWRS), and no stratified randomization was performed.
Unblinding could occur for individual patients via the
IWRS in the case of emergencies only, and serious adverse
events (AEs) did not necessarily precipitate immediate
unblinding. All eligible participants repeated the 28-day
treatment cycle until disease progression, death,
unacceptable toxicity, withdrawal of consent by the patient, or
decision by the treating physician that discontinuation would
be in the patient’s best interest. The primary study
endpoint was PFS.
Toxicity was graded using the National Cancer
InstituteCommon Terminology Criteria for Adverse Events version
4.03. Tumor assessment was performed every 8 weeks in
the phase Ib trial and every 4 weeks during the first 4 cycles
and every 8 weeks thereafter in the phase II trial until
disease progression, which was based on computed
tomography and/or magnetic resonance imaging evaluation as
defined by the Response Evaluation Criteria In Solid
Tumors version 1.1.
We allowed predefined treatment modifications to
manage clinically significant toxicity. Patients who needed dose
reductions could not re-escalate. The detailed treatment
protocols are provided in Additional files 1 and 2.
No formal statistical hypothesis testing was planned for
the phase 1b study, and the planned primary population
for the evaluation of efficacy was the intent-to-treat (ITT)
Based on the anti-tumor efficacy observed for
fruquintinib in the phase Ib trial, the placebo-controlled phase II
study was designed to have 67% statistical power to detect
a 50.0% increase in the median PFS, assuming a 2-month
median PFS for the placebo group. Assuming a two-sided
overall α of 0.05, statistical power of 67%, randomization
ratio of 2:1 between fruquintinib and placebo, and no
interim analyses during the study, 6 months had to elapse
after the last patient enrolled for the primary endpoint
analysis of PFS and until mature OS data could be
obtained for 80% of the patients for the final analysis. We
planned to randomize approximately 70 patients.
All statistical analyses were performed using SAS
(version 9.2). PFS and OS were compared between the
treatment groups using a stratified log-rank test; HRs (with
95% confidence interval [CI]) were calculated using the
Cox proportional hazards model, adjusting for
stratification factors, and Kaplan–Meier survival estimates were
calculated for each treatment group. The stratified
factors included previous chemotherapy lines (2 versus ≥3),
previous treatment with VEGF-targeting drugs (yes
versus no), and liver metastases (yes versus no).
Phase Ib trial
The demographic and baseline characteristics for the 42
participants with mCRC who were enrolled into the phase
Ib study between December 26, 2012, and January 24,
2014, are shown in Table 1.
Thirty-one (73.8%) participants completed at least
three treatment cycles in 12 weeks, and 28 (66.7%)
participants completed at least four treatment cycles in
16 weeks. Dose reduction and interruption was
necessary in 20 participants (47.6%).
The median PFS was 5.80 months (95% CI 4.01–7.60),
and the median OS was 8.88 months (95% CI 7.53–
15.53). Four participants had partial response (PR) with
an objective response rate of 9.5%, and 28 participants
had stable disease for at least 8 weeks, with a disease
control rate (DCR) of 76.2%. The treatment efficacy is
summarized in Table 2.
Treatment-related treatment-emergent AEs (TEAEs)
were reported in all 42 participants. The most common
TEAEs of grade 3 or higher were hypertension (21.4%),
hand-foot skin reaction (HFSR, 9.5%), and diarrhea
(9.5%). Overall, fruquintinib was permanently
discontinued in five participants (11.9%) due to related TEAEs,
including skin lesion (n = 1), chest pain (n = 1),
hemoptysis (n = 1), pancreatitis (n = 1), and proteinuria
(n = 1). The incidences of grade 3 or higher TEAEs
related to the study drugs are summarized in Table 3. Only
one death, of a patient with lung metastasis who had
fatal hemoptysis, was considered to be possibly
treatment related by the investigator. The most common
TEAEs needing treatment modification (treatment
interruption or dose reduction) were thrombocytopenia
(11.9%), HFSR (11.9%), and hypertension (9.5%).
Phase II trial
Between April 1, 2014, and August 20, 2014, 93 patients
were screened and 71 patients were randomized to
receive fruquintinib (n = 47) or placebo (n = 24). All 71
participants underwent treatment for efficacy and safety
analyses (Fig. 1).
The baseline characteristics for all randomized
patients are shown in Table 1. In general, the two groups
were well balanced in terms of baseline demographics
and oncology disease history.
Participants in the fruquintinib group were treated for
a longer period than were those in the placebo group,
with mean treatment durations (from the first dose to
the end of treatment) of 3.2 versus 0.8 months,
respectively. Dose modifications were required in 29 (61.7%) of
47 participants who received fruquintinib and 7 (29.2%)
of 24 participants who received placebo. AEs were the
most frequent reasons for dose modification.
PFS was significantly prolonged for patients who were
treated with fruquintinib compared with patients who
received placebo (stratified HR 0.30; 95% CI 0.15–0.59;
two-sided P < 0.001; Fig. 2), which was consistent with
the results of a blinded independent central review
(stratified HR 0.26; 95% CI 0.14–0.50; two-sided P <
0.001). The median PFS was 4.73 months (95% CI 2.86–
5.59) in the fruquintinib group and 0.99 months (95% CI
0.95–1.58) in the placebo group. Pre-specified subgroup
analyses showed significantly superior PFS in the
fruquintinib group in most of the subgroups examined
(Additional file 3). Patients who received fruquintinib
showed a trend of prolonged median OS (7.72 months)
compared with those who received placebo
(5.52 months); however, the difference was not
significant (stratified HR 0.71; 95% CI 0.38–1.34; Fig. 3). Only
one patient (2.1%) in the fruquintinib group achieved
PR. The DCR was significantly higher in the fruquintinib
group than in the placebo group (68.1% versus 20.8%;
two-sided P < 0.001). The waterfall plots for tumor
responses are shown in Additional file 4. The summary of
drug efficacy is shown in Table 2.
All 47 (100%) participants in the fruquintinib group
and 21 (87.5%) of the 24 participants in the placebo
group had AEs; the AEs were deemed treatment-related
in 44 (93.6%) participants in the fruquintinib group and
14 (58.3%) participants in the placebo group. The most
common (incidence >5%) treatment-related grade 3 or
higher TEAEs were hypertension (29.8%) and HFSR
(14.9%). The summary of grade 3 or higher
treatmentrelated TEAEs is shown in Table 3. Frequencies of AEs
leading to death, irrespective of relationship to study
drug, were similar, at three in the fruquintinib group
(one [2.1%] upper gastrointestinal hemorrhage, one
[2.1%] bilirubin increased, and one [2.1%] hemoptysis)
and two in the placebo group (one [4.3%] sudden death
and one [4.3%] hepatic coma). Serious AEs occurred in
12 (25.5%) of the 47 participants receiving fruquintinib
and 5 (20.8%) of the 24 participants receiving placebo.
Treatment was interrupted because of AEs in 15 (34.0%)
patients in the fruquintinib group and in 4 (16.7%) in
the placebo group. The study dose was reduced due to
AEs in 13 (27.7%) participants in the fruquintinib group
and none in the placebo group. The common AEs that
required treatment modification were HFSR (17.0%),
hypertension (12.8%), and diarrhea (4.3%).
Table 1 Baseline characteristics of participants in the phase Ib and the phase II trials
Characteristics Phase Ib Phase II
N (%) N (%)
(n=42) Fruquintinib group (n=47)
Median, range 55.5, 33.0–70.0 50.0, 25.0–69.0
Male 25 (59.5) 35 (74.5)
Female 17 (40.5) 12 (25.5)
Baseline ECOG PS score
0 8 (19.0) 6 (12.8)
1 34 (81.0) 41 (87.2)
Duration from first metastasis Diagnosis to randomization
≤18 months NA 20 (42.6)
>18 months NA 27 (57.4)
Prior treatment line on or above metastatic disease
2–3 18 (42.9) 30 (63.8)
>3 24 (57.1) 17 (36.2)
Previous chemotherapy lines
2 5 (11.9) 12 (25.5)
≥3 37 (88.1) 35 (74.5)
Prior VEGF inhibitor treatment
Yes 10 (23.8) 15 (31.9)
No 32 (76.2) 29 (61.7)
Unknown 0 3 (6.4)
Colon 21 (50.0) 24 (51.1)
Rectal 20 (47.6) 23 (48.9)
Cecum 1 (2.4) 0
Single 5 (11.9) 2 (4.3)
Multiple 37 (88.1) 45 (95.7)
Yes 29 (69.0) 29 (61.7)
No 13 (31.0) 18 (38.3)
ECOG PS Eastern Cooperative Oncology Group performance status, VEGF vascular endothelial growth factor, NA not available
Placebo group (n=24)
Table 3 Grade 3 or above treatment-related TEAEs occurring in at least 4% of patients in the phase Ib and the phase II trials
Serum sodium decreased
Blood bilirubin increased
Platelet count decreased
Blood alkaline phosphatase increased
TEAE treatment-emergent adverse event, HFSR hand-foot skin reaction, AST aspartate aminotransferase
In the phase II trial, fruquintinib significantly prolonged
PFS to approximately 4.7 versus 1.0 month for placebo.
This supports the significantly higher DCR in the
fruquintinib group. Moreover, a blinded independent central
review of this randomized phase II study confirmed the PFS
benefit conferred by fruquintinib (3.71 versus 0.95 months,
Additional file 5). A similar anti-tumor efficacy with a
5.8month PFS was observed for patients who were enrolled
in the phase Ib trial. These two studies show the potential
of fruquintinib as a third-line treatment for mCRC.
In accordance with the results obtained from other
studies investigating anti-VEGF/VEGFR drugs, our
study verified that this pathway is an effective target
Fig. 1 Trial profile
Fig. 2 Kaplan–Meier curves of progression-free survival (PFS) in the phase II study
for the treatment of mCRC. Similar to the results
obtained from the administration of regorafenib and
aflibercept as monotherapies in previously treated
mCRC patients, very few patients reached PR and a
general benefit was mainly observed in patients with
stable disease [10, 15, 16]. However, more than half
of the patients who received fruquintinib showed
tumor shrinkage to different degrees, as demonstrated
in the waterfall plots (Additional file 4), suggesting a
substantial anti-tumor effect for fruquintinib.
Compared with BSC, OS was prolonged for about
2.2 months in patients who received fruquintinib,
although no statistically significant difference was
observed. The improvement of OS by 2.2 months was
similar to the results of the regorafenib CONCUR trial
 that was predominantly conducted in the Chinese
population. Considering the small sample size in the
present phase II trial, it was speculated that a more
defined OS benefit might be observed if the sample size
was expanded in future clinical studies. Thus, a phase III
clinical trial (NCT02314819) with OS as the primary
endpoint is currently underway in patients with mCRC
who have failed standard treatment.
The safety profile in the phase II trial was consistent
with that of the patients in the phase Ib trial, and the
AEs included HFSR, hypertension, and proteinuria.
These results were consistent with the results of studies
conducted using other selective VEGFR inhibitors such
as regorafenib . In general, treatment with
fruquintinib was well tolerated. As has been reported elsewhere
for other multi-kinase inhibitors, we observed that the
occurrence of grade 3 hypertension was more frequent
in our trial (21.4% of the 42 participants in the phase Ib
trial and 29.8% of the 47 participants in the phase II
trial). Nonetheless, neither grade 4 hypertension nor
hypertensive crisis were reported and no patients
discontinued treatment. Hypertension is commonly
observed with anti-angiogenic agents, and it could be
managed using standard anti-hypertensive agents if
required. Moreover, some retrospective analyses have
suggested that the development of high blood pressure
might be a predictor of good clinical outcome [17, 18].
The incidence of HFSR (64%) in the present study was
slightly higher than that reported by the CORRECT trial
; however, it was consistent with that of the
CONCUR study . Approximately 15% of the patients were
reported to have developed grade 3 HFSR; however, the
symptoms were clinically manageable by dose
interruption or reduction. Frequencies of treatment modification
(treatment interruption or dose reduction) were similar
between the phase II study (34% and 27%, respectively)
and phase 1b study (47.6%) but were slightly lower than
Fig. 3 Kaplan–Meier curves of overall survival (OS) in the phase II study
in CONCUR (63% and 40%, respectively)  or
CORRECT (61% and 38%, respectively) . Unexpected
safety issues did not arise, and no patient had bowel
perforation, which has been related to other VEGF agents.
One limitation of this study was that a predictive
biomarker for fruquintinib was not investigated.
However, considering the lack of a definitive predictive
biomarker for bevacizumab, another anti-VEGF drug
that has been widely used in clinical practice, it is
expected that identifying a predictive biomarker for
fruquintinib would require some time . In addition,
we did not collect any information on the RAS and
BRAF expression status of the tumors and therefore
could not investigate whether any relationship existed
between the RAS status of the tumor and the efficacy
of fruquintinib. However, it should be noted that
previous studies suggested that the RAS and BRAF status
had no predictive value for outcome in mCRC
patients treated with bevacizumab .
In conclusion, based on the present trials,
fruquintinib showed good performance in both safety and
efficacy and might be a suitable treatment for mCRC
resistant to standard treatment. The phase III trial
(NCT02314819) that is currently ongoing will help to
achieve a definitive assessment of the safety and
efficacy of fruquintinib in mCRC patients who failed the
second-line or above treatment.
Additional file 1: Protocol for phase Ib study (NCT 01975077). (PDF 636 kb)
Additional file 2: Protocol for phase II study (NCT 02196688). (PDF 1031 kb)
Additional file 3: Forest plot of subgroup analysis in phase II study.
(PDF 104 kb)
Additional file 4: The waterfall plots for tumor responses in phase II
study. (PDF 49 kb)
Additional file 5: Analysis of progression-free survival in phase II study
by blinded independent central review. (PDF 129 kb)
Availability of data and materials
Due to our internal policy, raw data cannot be shared.
JL and RX were responsible for the overall conception and design of
the project and for the interpretation of the data and editing of the
manuscript. RX, JL, YB, JX, TL, LS, LW, HP, JC, and DZ carried out the
study during the clinical observation and follow-up and provided the
clinical data. RX and JL wrote the manuscript. SH, YH, and WS
participated in the manuscript preparation and revisions. All authors
read and approved the final manuscript.
JL’s institution, Fudan University, has received grants from Merck and Amgen.
SF, YH, and WS are employees of Hutchison MediPharma Limited. The other
authors declare that they have no competing interests.
Ethics approval and consent to participate
These two study protocols were approved by the ethics committees of each
involved site in accordance with the Declaration of Helsinki. Patients provided
informed consent authorizing the use of their personal information for research
1. Fakih MG . Metastatic colorectal cancer: current state and future directions . J Clin Oncol . 2015 ; 33 : 1809 - 24 .
2. Bai L , Zhang DS , Xu RH , et al. Clinical outcomes of Chinese patients with metastatic colorectal cancer receiving first-line bevacizumab-containing treatment . Med Oncol . 2015 ; 32 : 469 .
3. Seow HF , Yip WK , Fifis T. Advances in targeted and immunobased therapies for colorectal cancer in the genomic era . Onco Targets Ther . 2016 ; 9 : 1899 - 920 .
4. Schirripa M , Lenz HJ . Colorectal cancer: overcoming resistance to anti-EGFR therapy-where do we stand ? Nat Rev Gastroenterol Hepatol . 2016 ; 13 ( 5 ): 258 - 9 .
5. De Mattia E , Cecchin E , Toffoli G. Pharmacogenomics of intrinsic and acquired pharmacoresistance in colorectal cancer: toward targeted personalized therapy . Drug Resist Updat . 2015 ; 20 : 39 - 70 .
6. Jayson GC , Kerbel R , Ellis LM , et al. Antiangiogenic therapy in oncology: current status and future directions . Lancet . 2016 ; 388 : 518 - 29 .
7. Carmeliet P , Jain RK . Molecular mechanisms and clinical applications of angiogenesis . Nature . 2011 ; 473 : 298 - 307 .
8. Goel G , Sun W. Ramucirumab , another anti-angiogenic agent for metastatic colorectal cancer in second-line setting-its impact on clinical practice . J Hematol Oncol . 2015 ; 8 : 92 .
9. Saltz LB , Clarke S , Diaz-Rubio E , et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study . J Clin Oncol . 2008 ; 26 : 2013 - 9 .
10. Grothey A , Van Cutsem E , Sobrero A , et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial . Lancet. 2013 ; 381 : 303 - 12 .
11. Sun Q , Zhou J , Ren Y , et al. Discovery of fruquintinib, a potent and highly selective small molecule inhibitor of VEGFR 1, 2, 3 tyrosine kinases for cancer therapy . Cancer Biol Ther . 2014 ; 15 : 1635 - 45 .
12. Gu Y , Wang J , Su W , et al. Preclinical pharmacokinetics and disposition of a novel selective VEGFR inhibitor fruquintinib (HMPL-013) and the prediction of its human pharmacokinetics . Cancer Chemother Pharmacol . 2014 ; 74 : 95 - 115 .
13. Cao J , Zhang J , Li J , et al. A phase I study of safety and pharmacokinetics of fruquintinib, a novel selective inhibitor of vascular endothelial growth factor receptor-1, -2, and -3 tyrosine kinases in Chinese patients with advanced solid tumors . Cancer Chemother Pharmacol . 2016 ; 78 : 259 - 69 .
14. Li J , Cao J , Xu R , et al. A phase 1b study of VEGFR inhibitor fruquintinib in patients with pretreated advanced colorectal cancer . J Clin Oncol . 2014 ; 32 (15 suppl): 3548 .
15. Li J , Qin S , Xu R , et al. Regorafenib plus best supportive care versus placebo plus best supportive care in Asian patients with previously treated metastatic colorectal cancer (CONCUR): a randomised, double-blind, placebo-controlled, phase 3 trial . Lancet Oncol . 2015 ; 16 : 619 - 29 .
16. Van Cutsem E , Tabernero J , Lakomy R , et al. Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatinbased regimen . J Clin Oncol . 2012 ; 30 ( 28 ): 3499 - 506 .
17. Cheng AL , Kang YK , Lin DY , et al. Sunitinib versus sorafenib in advanced hepatocellular cancer: results of a randomized phase III trial . J Clin Oncol . 2013 ; 31 : 4067 - 75 .
18. Duffaud F , Sleijfer S , Litiere S , et al. Hypertension (HTN) as a potential biomarker of efficacy in pazopanib-treated patients with advanced non-adipocytic soft tissue sarcoma . A retrospective study based on European Organisation for Research and Treatment of Cancer (EORTC) 62043 and 62072 trials. Eur J Cancer . 2015 ; 51 : 2615 - 23 .
19. Ince WL , Jubb AM , Holden SN , et al. Association of k-ras, b-raf, and p53 status with the treatment effect of bevacizumab . J Natl Cancer Inst . 2005 ; 97 : 981 - 9 .