sorafenib and mfolfox6 for metastatic colorectal cancer 1

Sorafenib and mFOLFOX6 for Metastatic Colorectal Cancer

1

Sorafenib in Combination with Oxaliplatin, Leucovorin, and Fluorouracil (modified

FOLFOX6) as First-line Treatment of Metastatic Colorectal Cancer: The RESPECT Trial

Josep Tabernero,1 Rocio Garcia-Carbonero,2 James Cassidy,3 Alberto Sobrero,4 Eric Van

Cutsem,5 Claus-Henning Köhne,6 Sabine Tejpar,5 Oleg Gladkov,7 Irina Davidenko,8 Ramon

Salazar,9 Liubov Vladimirova,10 Sergey Cheporov,11 Olga Burdaeva,12 Fernando Rivera,13 Leslie

Samuel,14 Irina Bulavina,15 Vanessa Potter,16 Yu-Lin Chang,17 Nathalie A. Lokker,17 and Peter J.

O'Dwyer18

Authors’ Affiliations

1Vall d’Hebron University Hospital and Vall d’Hebron Institute of Oncology (VHIO), Universitat

Autònoma de Barcelona, Barcelona, Spain; 2Hospital Universitario Virgen del Rocio – Instituto

de Biomedicina de Sevilla [IBIS (Universidad de Sevilla, CSIC, HUVR)], Sevilla, Spain; 3Beatson

Laboratories, Glasgow UK*; 4Oncologia Medica, Genova, Italy; 5University Hospitals Leuven

and KU Leuven, Belgium; 6University Oldenburg, Oldenburg, Germany; 7Chelyabinsk Regional

Clinical Oncology Center, Chelyabinsk, Russia;8Clinical Oncology Center #1, Krasnodar,

Russia; 9Instituto Catalán de Oncología, Barcelona, Spain; 10Rostov Research Institute of

Oncology, Russia; 11Regional Clinical Oncology Hospital, Yaroslavl, Yaroslavl, Russia;

12Arkhangelsk Regional Clinical Oncology Center, Arkhangelsk, Russia; 13Hospital Marques de

Valdecilla, Santander, Spain; 14Aberdeen Royal Infirmary, Aberdeen, UK; 15Sverdlovsk Regional

Oncology Center, Ekaterinburg, Russia; 16Nottingham University Hospital NHS Trust,

Nottingham, UK; 17Onyx Pharmaceuticals, South San Francisco, CA, USA; 18Abramson Cancer

Center, Philadelphia, PA, USA.

*Dr. James Cassidy is currently with Roche Pharmaceuticals, Nutley, NJ, USA

on April 4, 2019. © 2013 American Association for Cancer Research.clincancerres.aacrjournals.org Downloaded from

Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on March 26, 2013; DOI: 10.1158/1078-0432.CCR-13-0107

http://clincancerres.aacrjournals.org/


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Running title: Sorafenib and mFOLFOX6 for Metastatic Colorectal Cancer

Keywords: metastatic colorectal cancer, sorafenib, oxaliplatin, leucovorin, and fluorouracil

Financial Support

Sponsored by Bayer Healthcare LLC and Onyx Pharmaceuticals, Inc.

Corresponding author

Josep Tabernero, MD, PhD

Medical Oncology Department

Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology (VHIO)

Universitat Autònoma de Barcelona

P. Vall d'Hebron 119-129

08035 Barcelona, Spain

Tel +34 93 489 4301

Fax +34 93 274 6059

Email: [email protected]

Disclosures

OB, FR, TS, and EVC have received research funding from Onyx Pharmaceuticals and Bayer.

NL and YLC are employees of Onyx Pharmaceuticals and own stock.

RGC, AS, BI, and TS have consultancy or advisory relationship with Bayer.

AS has received honoraria from Bayer.





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Trial Registry ID: ClinicalTrial.gov NCT00865709

Word count (excluding references): 3188

Tables: 4

Figures: 2

References: 50

Supplementary material: Supplementary Appendix, Tables A1, A2, and A3





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Statement of Translational Relevance

Fluorouracil-based treatment regimens have provided incremental improvements in outcomes

for patients with metastatic colorectal cancer (mCRC). Adding targeted therapies to these

regimens may provide additional benefit. Monoclonal antibodies that target signaling pathways

associated with cellular differentiation, proliferation, and survival have been developed in

mCRC, with epidermal growth factor and vascular endothelial growth factor being key targets.

Targeting a broader spectrum of molecules involved in CRC cell proliferation and death, such as

receptor and intracellular tyrosine kinases, may confer anti-cancer activity with less risk of tumor

resistance. Sorafenib is an oral multikinase inhibitor that targets both intracellular kinases and

cell surface receptor kinases. A randomized, double-blind, placebo-controlled phase II trial was

carried out to assess the combination of sorafenib with modified FOLFOX6 (leucovorin,

oxaliplatin, and fluorouracil) as a first-line therapy in patients with mCRC.





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Abstract

Purpose: This randomized, double-blind, placebo-controlled, phase IIb study evaluated adding

sorafenib to first-line modified FOLFOX6 (mFOLFOX6) for metastatic colorectal cancer

(mCRC).

Patients and Methods: Patients were randomized to sorafenib (400 mg BID) or placebo,

combined with mFOLFOX6 (oxaliplatin 85 mg/m2; levo-leucovorin 200 mg/m2; fluorouracil 400

mg/m2 bolus and 2400 mg/m2 continuous infusion) every 14 days. Primary endpoint was

progression-free survival (PFS). Target sample was 120 events in 180 patients for >85% power

(2-sided α=0.20) to detect a hazard ratio (HR)=0.65.

Results: Of 198 patients randomized, median PFS for sorafenib plus mFOLFOX6 was 9.1

versus 8.7 months for placebo plus mFOLFOX6 (HR=0.88, 95% CI 0.64−1.23; P=.46). There

was no difference between treatment arms for overall survival (OS). Subgroup analyses of PFS

and OS showed no difference between treatment arms by KRAS or BRAF status (mutant and

wild-type). The most common Grade 3/4 adverse events in the sorafenib and placebo arms

were neutropenia (48% v 22%), peripheral neuropathy (16% v 21%), and Grade 3 hand-foot

skin reaction (20% v 0%). Treatment discontinuation due to adverse events was 9% and 6%,

respectively. Generally, dose intensity (duration and cumulative doses) was lower in the

sorafenib arm than in the placebo arm.

Conclusion: This study did not detect a PFS benefit with the addition of sorafenib to first-line

mFOLFOX6 for mCRC. KRAS and BRAF status did not appear to impact treatment outcomes

but the subgroups were small. These results do not support further development of sorafenib in

combination with mFOLFOX6 in molecularly-unselected patients with mCRC.





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Introduction

Several fluorouracil-based chemotherapy regimens have been successfully developed for

patients with metastatic colorectal cancer (mCRC). Incremental improvements in response

rates, progression-free survival (PFS), and overall survival (OS) have been observed with

fluorouracil in combination with leucovorin and oxaliplatin (FOLFOX), leucovorin and irinotecan

(FOLFIRI), and leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI). Nonetheless, survival

remains limited with a 5-year rate of less than 8% (1). Strategies to further improve outcomes

have focused on adding targeted therapies to established regimens.

Advances in our understanding of the molecular basis of cancer proliferation, angiogenesis, and

metastasis enabled the development of therapies that target signaling pathways associated with

cellular differentiation, proliferation, and survival. Among these, epidermal growth factor (EGF)

and vascular endothelial growth factor (VEGF) are key targets (1). The addition of monoclonal

antibodies (mAbs) that target tyrosine kinase (TK) activity (ligands or receptors) to mCRC

chemotherapy regimens improved clinical outcomes with acceptable toxicity. These include

bevacizumab (inhibits VEGF) (2-5), and the EGF receptor (EGFR) inhibitors cetuximab and

panitumumab (6-9). Nonetheless, response can be absent if the target is not a disease driver,

and resistance can be present at the start of treatment or can emerge when tumor or stromal

cells switch to alternative pathways. The constitutive KRAS and BRAF mutations confer

resistance to cetuximab and panitumumab, and KRAS is now a valid biomarker for cetuximab

and panitumumab (10). Approximately 40% of patients with CRC have a KRAS mutation,

meaning a significant proportion will not be eligible for EGFR inhibitors (10).

Targeting a broader spectrum of molecules involved in CRC cell proliferation and death, such as

receptor and intracellular TKs, may confer anti-cancer activity with less risk of resistance (11).

Sorafenib is an oral multikinase inhibitor that targets intracellular kinases (CRAF, BRAF, mutant





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BRAF), as well as cell surface receptor kinases, including platelet-derived growth factor receptor

(PDGFR), VEGFR-1–3, stem cell factor receptor (KIT), and Feline McDonough Sarcoma (FMS)-

related tyrosine kinase 3 (FLT3) (12, 13). Clinical efficacy and tolerability of sorafenib have been

shown in renal cell carcinoma (14) and hepatocellular carcinoma (15, 16). Preclinical evidence

indicates the primary target of sorafenib in renal cell carcinoma is angiogenesis via VEGFR,

whereas in hepatocellular carcinoma, cell proliferation and survival are targeted via the

RAF/MEK/ERK pathway, and angiogenesis via VEGFR and PDGFR (12, 17, 18).

Preclinical studies also demonstrated the activity of sorafenib against colon cancer cells, but

also indicated differential targeting of cell proliferation and/or angiogenesis by tumor model (12,

19-21). Early clinical studies demonstrated the feasibility of combining sorafenib with

chemotherapies used in mCRC, such as irinotecan, oxaliplatin, and 5- fluorouracil/leucovorin,

with encouraging activity in solid tumors including mCRC (22-24). In a phase I study of 37

patients with advanced solid tumors, 7/9 patients with CRC treated with oxaliplatin (130 mg/m2

on Day 1 of a 3-week cycle) and the standard sorafenib dose (400 mg twice daily [BID]

continuously) achieved stable disease for at least 6 weeks (23).

Here we present results from a phase IIb, double-blind, placebo-controlled, randomized trial that

assessed the addition of sorafenib to first-line modified FOLFOX6 (mFOLFOX6) in patients with

mCRC. The standard sorafenib regimen (400 mg BID continuously) was used based on the

collective results from the phase I combination studies (22-24) as well as its proven benefit in

other difficult-to-treat adenocarcinomas (14-16). Modified FOLFOX6 was chosen because it was

the most commonly used FOLFOX regimen across the various centers and countries of this

international study. The objective was to determine whether efficacy and tolerability results

would support a phase III confirmatory trial.





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Patients and Methods

Patients

Eligible patients were ≥18 years old, with histologically confirmed, measurable metastatic

adenocarcinoma of the colon or rectum (stage IV) (25), and an Eastern Cooperative Oncology

Group (ECOG) performance status 0–1. Prior radiotherapy was allowed, but at least 1

measurable, non-irradiated, metastatic lesion was required, as was a tumor tissue sample for

analysis of KRAS and BRAF mutations. Patients who had received prior chemotherapy for

metastatic disease were not eligible, nor were patients with brain metastases, active cardiac

disease, or serious bone marrow, liver, or renal dysfunction. Patients who had received adjuvant

treatment for CRC, including a FOLFOX regimen, were eligible provided that they had

completed treatment at least 12 months before randomization. The protocol was approved by

the independent ethics committees/institutional review boards of all participating sites or

countries. The trial was conducted according to Good Clinical Practice Guidelines and in

accordance with the Declaration of Helsinki. All patients provided written informed consent. The

study is registered at ClinicalTrials.gov (NCT00865709).

Study Design

This was a phase IIb, randomized, double-blind trial conducted at centers in Belgium, Romania,

Russia, Spain, the United Kingdom, and the United States. Patients were stratified by radiologic

evidence of liver involvement and number of metastatic sites (<3 or ≥3) and randomly assigned

(1:1) to mFOLFOX6 plus sorafenib or matching placebo.

Treatment

The mFOLFOX6 regimen was administered every 14 days and consisted of oxaliplatin, levo-

leucovorin (or leucovorin if levo-leucovorin not available), and fluorouracil. On Day 1 of each 14-

day cycle, patients received oxaliplatin 85 mg/m2, levo-leucovorin 200 mg/m2, then a fluorouracil





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400 mg/m2 bolus followed by a 2400 mg/m2 continuous infusion (46–48 hours). All patients

received prophylactic anti-emetic treatment with intravenous dexamethasone and a 5-

hydroxytryptamine-3 antagonist 30 minutes prior to each infusion. Sorafenib and the matching

placebo were initiated on Day 1 at 400 mg BID. Dose reductions of sorafenib/placebo were

required for hand-foot skin reaction (HFSR, Grades 2/3), hypertension (symptomatic Grade 2

and Grades 3/4), proteinuria (>2g/24 hours), hematologic toxicities (Grades 3/4), or other Grade

3/4 toxicities associated with sorafenib/placebo.

In the case of dose modification or discontinuation of 1 study drug (oxaliplatin, fluorouracil/levo-

leucovorin, or sorafenib or placebo), administration of the other study drugs could be continued

at the protocol-specified doses. Any patient who continued treatment with at least 1 study drug

was considered on study.

Study Endpoints

The primary endpoint was PFS. Secondary endpoints included OS, time to progression (TTP),

overall response rate (ORR), duration of response (DOR), safety, and tolerability. Tumor

response was investigator assessed and evaluated radiologically at baseline and every 8 weeks

using Response Evaluation Criteria in Solid Tumors (RECIST) (26). Active follow-up was

extended to patients who discontinued treatment without disease progression. Adverse events

(AEs) were graded using Common Terminology Criteria for Adverse Events (version 3.0).

Serious AEs (SAEs) included events that resulted in death, were life-threatening, required or

extended hospitalization, or resulted in persistent or significant disability.

Statistical Analyses

Analysis of PFS was based on the log-rank test. Based on historical data, the expected PFS in

the control arm was 8 months (4). A sample size of 120 events would provide >85% power with





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a 2-sided α= 0.20, assuming a target hazard ratio (HR) of 0.65 between sorafenib and placebo.

The target study population was 180 patients. Analysis of OS was planned after 120 deaths.

Time-to-event endpoints were analyzed by the Kaplan-Meier method in the intent-to-treat (ITT)

population. For PFS, patients without documentation of progression or death at the time of

analysis were censored at final tumor assessment or post-randomization visit; patients who

initiated non-study cancer treatment and were without disease progression were censored at

last tumor assessment prior to the start of the new treatment; patients with no post-baseline

tumor assessment were censored at Day 1; and patients who experienced progressive disease

(PD) or death 18 weeks or longer from the last tumor assessment were censored at the last

tumor assessment. A stratified log-rank test with the randomization stratification factors as

covariates was used to compare treatment arms, and the relative risk for sorafenib versus

placebo was estimated with a stratified Cox regression model.

Secondary analyses of PFS included a per-protocol analysis (patients with no major protocol

violations), and a non-stratified analysis. Planned subgroup analyses of PFS and OS were

performed using the Kaplan-Meier method and a non-stratified Cox regression for subgroups

defined by baseline factors of liver involvement (yes or no), number of metastatic sites (<3 or

≥3), region (East or West), KRAS status (wild-type or mutant), and BRAF status (wild-type or

mutant). KRAS and BRAF mutant status was determined by allelic discrimination

(Supplementary Appendix) and centrally evaluated at University Hospital Gasthuisberg,

Leuven, Belgium (S.T.). Exploratory analyses of PFS and OS were performed for subgroups

defined by NRAS and PIK3CA status (wild-type or mutant), age (<65 or ≥65 years), gender,

ECOG performance status (0 or 1), disease stage at diagnosis (I–III or IV), and months since

initial diagnosis (<2 or ≥2). ORR was compared between groups using the Cochran-Mantel-

Haenszel test, adjusting for the stratification factors. Descriptive statistics summarized safety





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and tolerability variables, including study drug exposure and AE rates. Statistical analyses were

performed with SAS version 9.1 or later (SAS Institute, Cary, NC). The lead author (JT) had full

access to study data and analyses, which were available to all authors upon request.

Results

Patient recruitment occurred between March 2009 and February 2010 with 198 patients

randomized (Figure 1). Data cut-off for the primary analysis of PFS, response, safety, and

tolerability was January 31, 2011. An analysis of OS was subsequently conducted after 123

deaths with a cut-off date of December 1, 2011, and a median follow-up of 22.4 months.

Baseline characteristics were generally balanced between treatment arms (Table 1). Most

patients had an ECOG performance status of 1 (64.6%), stage IV disease as initial diagnosis

(68.2%), <3 metastatic sites (71.7%), and liver involvement (80.8%). Of note, the sorafenib arm

had fewer males compared with the placebo arm (43.3% v 62.4%), less exposure to adjuvant

chemotherapy (7.2% v 12.9%), and lower rates of KRAS mutations (37.1% v 48.5%). BRAF

mutations were infrequent in both arms (3.1% v 5.0%).

Efficacy Outcomes

Median PFS was 9.1 months for the sorafenib arm and 8.7 months for the placebo arm

(HR=0.88; 95% confidence interval [CI] 0.64–1.23; P=.46) (Figure 2). Similar results were

observed in the prespecified subgroup analyses (Table 2). In patients with wild-type KRAS, the

median PFS was 9.5 versus 9.2 months, respectively (HR=0.84; 95% CI 0.52–1.36), with

corresponding medians of 7.8 versus 7.6 months, respectively, in the mutant KRAS subgroup

(HR=0.96; 95% CI 0.59–1.58). In patients with wild-type BRAF, the median PFS was 9.2 versus

9.0 months, respectively (HR=0.91; 95% CI 0.64–1.29), and the median PFS for mutant BRAF

was 8.6 versus 7.3 months, respectively (HR=0.89; 95% CI 0.15–5.42).





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Median OS was 17.6 months in the sorafenib arm and 18.1 months in the placebo arm

(HR=1.13; 95% CI 0.79–1.61; P=.51). In patients with wild-type KRAS, median OS was 19.9

versus 16.8 months, respectively (HR=0.89; 95% CI 0.54–1.48), and 17.0 versus 19.4 months,

respectively, in patients with mutant KRAS (HR=1.29; 95% CI 0.74–2.24). In patients with wild-

type BRAF, median OS was 18.8 versus 18.3 months, respectively (HR=1.09; 95% CI 0.74–

1.60), and 13.9 versus 11.9 months, respectively, in patients with mutant BRAF (HR=0.46; 95%

CI 0.09–2.39). Exploratory subgroup analyses showed slightly different outcomes between

treatment arms by gender and ECOG status (Table 2). There were no differences in survival

outcomes between treatment arms in the PIK3CA or in the NRAS subgroups (Supplementary

Appendix, Tables A1 and A2).

Median TTP was 9.2 months in the sorafenib arm and 9.0 months in the placebo arm (HR=0.83;

95% CI 0.59–1.17), and the ORR was 46.4% and 60.4%, respectively (Table 3). Partial

response was lower in the sorafenib arm compared with mFOLFOX6 alone (44.3% v 59.4%),

but the rate of stable disease was higher (40.2% v 30.7%). Complete response was achieved by

2 patients in the sorafenib arm and 1 patient in the placebo arm.

Safety and Tolerability

Treatment-related AEs occurring in ≥10% of patients are shown in Table 4. The most common

AEs (any grade) in the sorafenib and placebo arms included neutropenia (62% v 38%),

peripheral neuropathy (61% v 65%), diarrhea (48% v 35%), nausea (36% v 47%), HFSR (54% v

10%), and asthenia (28% v 19%). Other AEs (any grade) of interest were stomatitis (22% v 4%),

rash (23% v 9%), and hypertension (19% v 5%). The most common Grade 3/4 AEs in the

sorafenib and placebo arms were neutropenia (48% v 22%), peripheral neuropathy (16% v

21%), and HFSR (20% v 0%). Treatment-related SAEs occurred in 21 (22%) patients in the





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sorafenib arm and 16 (16%) patients in the placebo arm. There were 2 treatment-related deaths

in the sorafenib arm (1 pancytopenia and 1 renal failure) and 1 in the placebo arm

(cardiovascular insufficiency).

More frequent dose interruptions and reductions were observed for sorafenib than placebo

(Supplementary Appendix Table A3). The average daily dose of sorafenib was lower than

placebo (mean, 553.1 v 728.1 mg), which corresponded to a greater frequency of dose

reductions (66.0% v 27.7%) and a shorter mean duration of treatment (30.5 v 33.7 weeks).

Similar trends were observed for components of mFOLFOX6, although the magnitude of the

difference between treatment arms was less pronounced. Overall, 9.4% of patients discontinued

treatment due to AEs in the sorafenib arm compared with 5.9% in the placebo arm.

Discussion

In this randomized phase IIb trial, the addition of sorafenib 400 mg BID to mFOLFOX6

compared with placebo did not demonstrate an improvement in PFS to support a phase III trial.

Generally, there was no differential outcome across subgroups, including KRAS and BRAF

subgroups. There was also no improvement in TTP or ORR. There were no unexpected

toxicities associated with the addition of sorafenib, but there were increases in some Grade 3/4

AE rates, most notably neutropenia and HFSR, which led to increased rates of dose

modifications and treatment discontinuations for reasons other than disease progression.

Overall, the average daily dose of sorafenib was lower than placebo, and exposure to each of

the mFOLFOX6 components was also lower in the sorafenib arm.

While these results allow us to exclude a strong therapeutic benefit with sorafenib plus

mFOLFOX6, a number of factors may have influenced the results and should be considered.

First, the sample size would have been too small to adequately assess a modest therapeutic





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benefit. Given the inter- and intra-patient heterogeneity in primary and metastatic CRC tumor

types (27, 28), a more modest benefit would not be unexpected for a targeted therapy. Second,

use of sorafenib in mCRC may be better suited for regimens that are less active than

mFOLFOX6 but more tolerable and where an increase in activity would be more easily

detected. Third, the 400 mg BID dose of sorafenib may not have provided sufficient target

inhibition, which may have been accentuated by the decrease in dose intensity of both sorafenib

and mFOLFOX6 over the course of treatment.

Thus far, results of studies with targeted therapies in combination with mCRC chemotherapy

have been mixed, ranging from significant improvements in PFS or OS to decreases in PFS or

OS, depending on the chemotherapy regimen and patient population (2-5, 9, 29-31). A number

of phase III studies have shown that adding bevacizumab to fluorouracil-based regimens

improves PFS with or without a corresponding improvement in OS (2-4, 29), but the magnitude

of the benefits have been inconsistent (5). This may be related to the fluorouracil backbone

combined with bevacizumab and/or the line of therapy (2-4). Variability in results has also been

observed across cetuximab (6, 9, 31) and panitumumab studies (7, 8). It has been hypothesized

that inconsistencies in outcomes with mAbs could also be related to their high specificity, which

may make them susceptible to resistance through redundant signaling pathways (11). Attempts

to broaden activity by combining different mAbs have not proven fruitful in mCRC (32-34).

Results with small-molecule multikinase inhibitors with a broader spectrum of inhibitory targets

than mAbs (35) have also been mixed, although limited data are available in addition to the

results reported here (36-40). In 2 phase III trials in mCRC, adding vatalanib (targets VEGFR1-

3, PDGFRβ, and KIT) to first- or second-line FOLFOX4 did not improve PFS or OS (36, 37), and

a phase III study of sunitinib (targets VEGFR1-3, PDGFRα/β, KIT, FLT3, CSF1R, RET) with

FOLFIRI failed to demonstrate an improvement in the primary endpoint of PFS (41). Cediranib





15

(targets VEGFR1-3, PDGFRβ, and KIT), has been evaluated with FOLFOX in mCRC in 3

different phase II/III trials (42-44), with only 1 study demonstrating a statistically significant but

clinically modest improvement in median PFS (+0.4 months) (45). Nevertheless, other

multikinase inhibitors may have potential in mCRC. In a phase III trial, regorafenib (targets

VEGFR1-3, Tie-2, PDGFR, FGFR, KIT, RET, and BRAF) provided a survival benefit when

added to best supportive care in patients with refractory mCRC (46, 47). It is notable that

regorafenib was active in the refractory setting as monotherapy, whereas mCRC studies with

other targeted agents lacked single-agent activity or were paired with chemotherapy in the first-

or second-line setting.

Several factors may explain the variability in results with targeted therapies in mCRC. It is

becoming evident that the genetic profiles of tumors are predictive of treatment response to

targeted therapies. In our study, by adding sorafenib to a standard first-line chemotherapy for

mCRC, several pathways shown to be critical in mCRC were targeted, like angiogenesis via

extracellular TK receptors VEGFR1-3 and PDGFR, as well as downstream protein effectors of

TK receptors (e.g., EGFR) including CRAF, BRAF, and mutant BRAF (12, 13, 20, 21). As RAF

is targeted by sorafenib and is downstream of RAS, we hypothesized that mCRC patients could

potentially derive benefit by the addition of sorafenib independent of KRAS and BRAF gene

mutation status. However, this is a highly redundant pathway with complex feedback loops,

which makes it unlikely for RAF inhibition alone to be sufficient for antitumoral activity (48).

In the current study, the tumor sample was taken from either the primary or metastatic site, and

it does not appear that KRAS or BRAF status had a significant impact on outcomes in patients

receiving sorafenib. However, the size of the study population and subgroups limits the

interpretation of these data. Sorafenib may be more active with other chemotherapy regimens

and/or in more specific patient populations. Although a pharmacokinetic interaction between





16

sorafenib and oxaliplatin was not detected in a phase I trial of solid tumors (23), some preclinical

evidence suggests that sorafenib may reduce cellular uptake of platinum compounds (49). The

addition of sorafenib to other mCRC regimens, such as irinotecan alone (50) or FOLFIRI

(NCT00839111), are being explored. In addition, studies in various mCRC models showed

differential response to sorafenib (12, 20, 21). Sorafenib demonstrated inhibition of tumor

growth and angiogenesis in HT-29 colon cells (BRAF V600E mutation), inhibition of tumor

growth in HCT-116 cells (activating KRAS mutation), but notably less activity in DLD-1

(activating KRAS mutation) and Colo-205 (BRAF V600E mutation) cells. Further assessment of

sorafenib and other targeted therapies across mCRC models may help us to better understand

and predict treatment response of primary and metastatic tumors in CRC patients.

In conclusion, the dose and schedule of sorafenib with first-line mFOLFOX6 in this study did not

demonstrate a PFS benefit in patients with mCRC to support a phase III trial of similar design.

KRAS and BRAF status did not appear to impact response to sorafenib, but patient numbers

were small. Further assessment of tumor samples for biomarkers are ongoing and includes

gene expression profiling. Although the results of this study do not support further development

of sorafenib with this combination in an unselected patient population, they may help to guide

the design of future clinical trials in mCRC with targeted therapies focusing on molecularly-

characterized populations.





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Acknowledgments

This study was supported by Bayer Healthcare Pharmaceuticals and Onyx Pharmaceuticals.

The authors would like to thank Melanie Watson, PhD and Michael Raffin (Fishawack

Communications) for providing writing and editorial assistance which was funded by Bayer

HealthCare Pharmaceuticals and Onyx Pharmaceuticals. EVC and ST are senior investigators

of the Fund for Scientific Research Flanders and are supported by the Belgian Foundation

against Cancer.





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23

Table 1. Baseline characteristics

Variable

Sorafenib +

FOLFOX6

(n=97)

Placebo +

FOLFOX6

(n=101)

Age, years, mean (range)

59.2 (33–82)

60.3 (44–77)

Sex, n (%)

Male

Female

42 (43.3)

55 (56.7)

63 (62.4)

38 (37.6)

Race/ethnicity, n (%)

Caucasian

Asian

95 (97.9)

2 (2.1)

101 (100)

0

Region, n (%)

West region*

East region†

40 (41.2)

57 (58.8)

41 (40.6)

60 (59.4)

ECOG performance status, n (%)

0

1

34 (35.1)

63 (64.9)

36 (35.6)

65 (64.4)

Stage IV disease at initial diagnosis, n (%)

Yes

No

Missing

68 (70.1)

28 (28.9)

1 (1.0)

67 (66.3)

33 (32.7)

1 (1.0)

Metastatic sites, n (%)

<3

≥3

71 (73.2)

26 (26.8)

71 (70.3)

30 (29.7)





24

Variable

Sorafenib +

FOLFOX6

(n=97)

Placebo +

FOLFOX6

(n=101)

Liver involvement, n (%)

Yes

No

79 (81.4)

18 (18.6)

81 (80.2)

20 (19.8)

Prior diagnostic/therapeutic procedure, n (%) 93 (95.9) 99 (98.0)

Prior adjuvant chemotherapy, n (%) 7 (7.2) 13 (12.9)

KRAS status, n (%)

Wild type

Mutant

Missing

52 (53.6)

36 (37.1)

9 (9.3)

45 (44.6)

49 (48.5)

7 (6.9)

BRAF status, n (%)

Wild type

Mutant

Missing

85 (87.6)

3 (3.1)

9 (9.3)

89 (88.1)

5 (5.0)

7 (6.9)

ECOG, Eastern Cooperative Oncology Group; KRAS, Kirsten rat sarcoma viral oncogene homolog

*Spain, United Kingdom, Belgium, United States; †Russia, Romania





25

Table 2. Progression-free survival and overall survival by planned and

exploratory subgroups

Median PFS, mo Median OS, mo

Subgroup (n)

Sorafenib +

mFOLFOX6

Placebo +

mFOLFOX6 HR (95% CI)

Sorafenib +

mFOLFOX6

Placebo +


Planned

Overall (198) 9.1 8.7 0.88 (0.64–1.23) 17.6 18.1 1.13 (0.79–1.61)

Liver involvement

Yes (160) 8.9 8.0 0.86 (0.60–1.24) 18.3 18.3 1.06 (0.72–1.56)

No (38) 11.0 9.7 1.01 (0.44–2.32) 15.8 17.6 1.11 (0.47–2.61)

No. of metastatic sites

<3 (142) 9.2 8.7 0.85 (0.58–1.25) 20.6 18.7 0.88 (0.56–1.36)

≥3 (56) 7.4 8.3 0.96 (0.53–1.72) 13.9 16.4 1.88 (1.02–3.47)

Region

East (117)* 7.7 9.0 0.98 (0.64–1.50) 16.4 18.0 1.19 (0.76-1.87)

West (81)† 9.2 8.0 0.76 (0.46–1.27) 20.2 18.1 0.92 (0.52–1.62)

KRAS status

Wild-type (97) 9.5 9.2 0.84 (0.52–1.36) 19.9 16.8 0.89 (0.54–1.48)

Mutant (85) 7.8 7.6 0.96 (0.59–1.58) 17.0 19.4 1.29 (0.74–2.24)

BRAF status

Wild-type (174) 9.2 9.0 0.91 (0.64–1.29) 18.8 18.3 1.09 (0.74–1.60)

Mutant (8) 8.6 7.3 0.89 (0.15–5.42) 13.9 11.9 0.46 (0.09–2.39)

Exploratory

Age, years

<65 (137) 8.9 7.8 0.85 (0.58–1.27) 18.9 19.5 0.96 (0.62–1.48)





26

Median PFS, mo Median OS, mo

Subgroup (n)

Sorafenib +

mFOLFOX6

Placebo +


Sorafenib +

mFOLFOX6

Placebo +


≥65 (61) 9.2 9.2 0.90 (0.51–1.59) 15.8 17.6 1.35 (0.73–2.49)

Gender

Male (105) 9.5 7.8 0.69 (0.44–1.08) 15.8 16.9 0.86 (0.53–1.41)

Female (93) 7.8 10.4 1.25 (0.76–2.07) 18.3 22.2 1.53 (0.87–2.69)

ECOG status

0 (70) 9.5 9.0 0.56 (0.31–1.00) 23.7 17.6 0.63 (0.33–1.22)

1 (128) 7.6 8.0 1.15 (0.77–1.72) 13.9 18.2 1.41 (0.92–2.14)

Disease stage at diagnosis

I-III (61) 9.2 9.0 0.86 (0.48–1.54) 19.5 16.9 0.96 (0.51–1.82)

IV (135) 8.9 8.0 0.87 (0.58–1.28) 16.4 18.7 1.11 (0.72–1.70)

Months since initial diagnosis

<2 (57) 9.3 9.0 0.97 (0.52–1.82) 18.9 18.3 1.04 (0.51–2.10)

≥2 (141) 9.1 8.3 0.86 (0.59–1.25) 17.6 17.8 1.09 (0.72–1.66)

*Russia, Romania

†Spain, United Kingdom, Belgium, United States

BRAF, v-raf murine sarcoma viral oncogene homolog B1; CI, confidence interval; ECOG, Eastern

Cooperative Oncology Group; HR, hazard ratio; KRAS, Kirsten rat sarcoma viral oncogene homolog;

PFS, progression-free survival; OS, overall survival





27

Table 3. Secondary efficacy endpoints

Variable

Sorafenib +

mFOLFOX6

(n=97)

Placebo +

mFOLFOX6

(n=101)

Median TTP, months 9.2 9.0

HR (95% CI) 0.83 (0.59–1.17)

Overall response rate, % (95% CI) 46.4 (36.2–56.8) 60.4 (50.2–70.0)

Best response, n (%)*

Complete response (CR) 2 (2.1) 1 (1.0)

Partial response (PR) 43 (44.3) 60 (59.4)

Stable disease (SD) 39 (40.2) 31 (30.7)

Progressive disease (PD) 5 (5.2) 7 (6.9)

Median duration of response, months† 7.5 6.7

*Patients with missing or non-evaluable best response data are not listed.

†Only responders (CR or PR) are included in this summary.

CI, confidence interval; HR, hazard ratio; TTP, time to progression





28

Table 4. Treatment-related adverse events reported in ≥10% (any grade) of patients

Sorafenib + FOLFOX6

(N=97)

Placebo + FOLFOX6

(N=101)

All Grades

n (%)

Grade 3/4

n (%)

All Grades

n (%)

Grade 3/4

n (%)

Neutropenia 60 (62) 47 (48) 38 (38) 22 (22)

Peripheral neuropathy* 59 (61) 16 (16) 66 (65) 21 (21)

Hand-foot skin reaction† 52 (54) 19 (20) 10 (10) 0 (0)

Diarrhea 47 (48) 9 (9) 35 (35) 5 (5)

Nausea 35 (36) 1 (1) 47 (47) 0 (0)

Asthenia 27 (28) 6 (6) 19 (19) 4 (4)

Vomiting 24 (25) 1 (1) 17 (17) 0 (0)

Alopecia 23 (24) 0 (0) 6 (6) 0 (0)

Rash 22 (23) 3 (3) 9 (9) 1 (1)

Mucosal inflammation 21 (22) 2 (2) 16 (16) 0 (0)

Stomatitis 21 (22) 5 (5) 4 (4) 1 (1)

Thrombocytopenia 18 (19) 4 (4) 24 (24) 4 (4)

Fatigue 18 (19) 3 (3) 18 (18) 2 (2)

Hypertension 18 (19) 4 (4) 5 (5) 1 (1)

Anemia 17 (18) 3 (3) 12 (12) 2 (2)

Decreased appetite 13 (13) 0 (0) 10 (10) 0 (0)

Dysgeusia 12 (12) 0 (0) 6 (6) 0 (0)

Erythema 11 (11) 2 (2) 4 (4) 0 (0)

*Peripheral neuropathy, peripheral sensory neuropathy, dysesthesia, neurotoxicity, paraesthesia

†Grade 3 is the most severe grade.





29

Figure Legends

Figure 1. Patient disposition (January 31, 2011).

Figure 2. Survival outcomes by the Kaplan-Meier Method intent-to-treat patient

population: (A) progression-free survival (data cut-off January 31, 2011), and (B) overall

survival (data cut-off December 1, 2011).




Figure 1

Analysis

ITT (n=101)

Safety* (n=101)

Per protocol† (n=90)

• Excluded f rom analysis (n=11)

• Eligibility violation (n=1)

• Non-protocol anticancer therapy (n=5)

• Other (n=5)

ITT (n=97)

Safety* (n=97 )

Per protocol† (n=82)

• Excluded f rom analysis (n=15)

• Eligibility violation (n=2)

• Non-protocol anticancer therapy (n=11)

• Other (n=2)

Lost to follow-up (n=0)

Discontinued treatment (n=85)

• Progressive disease (n=49)

• AEs (n=9)

• Death (n=6)

• Patient consent withdrawn, investigator

decision, or surgery (n=21)

Lost to follow-up (n=0)

Discontinued treatment (n=85)

• Progressive disease (n=65)

• AEs (n=6)

• Death (n=2)

• Patient consent withdrawn, investigator

decision, or surgery (n=12)

Randomized, ITT (n=198)

Follow-Up

Allocation

Randomized to placebo (n=101)

• Received study treatment (n=101)

Randomized to sorafenib (n=97)

• Received study treatment (n=97)

Screened (n=230)

Excluded (n=32)

• Did not meet eligibility criteria (n=22)

• Declined to participate (n=3)

• Due to AE (n=3)

• Other (n=4)

*Received study treatment†No major protocol violations

AE, adverse event; ITT, intent to treat




Figure 2




Published OnlineFirst March 26, 2013.Clin Cancer Res Josep Tabernero, Rocio Garcia-Carbonero, James Cassidy, et al. Metastatic Colorectal Cancer: The RESPECT TrialFluorouracil (modified FOLFOX6) as First-line Treatment of Sorafenib in Combination with Oxaliplatin, Leucovorin, and

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