Sorafenib in Combination with Oxaliplatin, Leucovorin, and Fluorouracil (Modified FOLFOX6) As First-Line Treatment of Metastatic Colorectal Cancer: the RESPECT Trial

Published OnlineFirst March 26, 2013; DOI: 10.1158/1078-0432.CCR-13-0107

Clinical Cancer Cancer Therapy: Clinical Research

Sorafenib in Combination with Oxaliplatin, Leucovorin, and Fluorouracil (Modiﬁed FOLFOX6) as First-line Treatment of Metastatic Colorectal Cancer: The RESPECT Trial

Josep Tabernero1, Rocio Garcia-Carbonero3, James Cassidy5, Alberto Sobrero8, Eric Van Cutsem9, Claus-Henning Kohne€ 10, Sabine Tejpar9, Oleg Gladkov11, Irina Davidenko12, Ramon Salazar2, Liubov Vladimirova13, Sergey Cheporov14, Olga Burdaeva15, Fernando Rivera4, Leslie Samuel6, Irina Bulavina16, Vanessa Potter7, Yu-Lin Chang17, Nathalie A. Lokker17, and Peter J. O'Dwyer18

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). Experimental Design: Patients were randomized to sorafenib (400 mg b.i.d.) 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 (two-sided a ¼ 0.20) to detect an HR ¼ 0.65. Results: Of 198 patients randomized, median PFS for sorafenib plus mFOLFOX6 was 9.1 months versus 8.7 months for placebo plus mFOLFOX6 (HR ¼ 0.88; 95% CI, 0.64–1.23; P ¼ 0.46). There was no difference between treatment arms for overall survival. Subgroup analyses of PFS and overall survival 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% vs. 22%), peripheral neuropathy (16% vs. 21%), and grade 3 hand–foot skin reaction (20% vs. 0%). Treatment discontinuation because of 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 seem 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. Clin Cancer Res; 19(9); 1–10. 2013 AACR.

Authors' Affiliations: 1Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology (VHIO), Universitat Autonoma de Barcelona; 2Instituto Introduction Catalan de Oncología, Barcelona, Spain; 3Hospital Universitario Virgen del Rocio – Instituto de Biomedicina de Sevilla [IBIS (Universidad de Sevilla, Several fluorouracil-based chemotherapy regimens have CSIC, HUVR)], Sevilla; 4Hospital Marques de Valdecilla, Santander, Spain; been successfully developed for patients with metastatic 5Beatson Laboratories, Glasgow; 6Aberdeen Royal Infirmary, Aberdeen; colorectal cancer (mCRC). Incremental improvements in 7Nottingham University Hospital NHS Trust, Nottingham, United Kingdom; 8Oncologia Medica, Genova, Italy; 9University Hospitals Leuven and KU response rates, progression-free survival (PFS), and overall Leuven, Leuven, Belgium; 10University Oldenburg, Oldenburg, Germany; survival have been observed with fluorouracil in combina- 11 12 Chelyabinsk Regional Clinical Oncology Center, Chelyabinsk; Clinical tion with leucovorin and oxaliplatin (FOLFOX), leucovorin Oncology Center #1, Krasnodar; 13Rostov Research Institute of Oncology; 14Regional Clinical Oncology Hospital, Yaroslavl, Yaroslavl; 15Arkhangelsk and irinotecan (FOLFIRI), and leucovorin, oxaliplatin, and Regional Clinical Oncology Center, Arkhangelsk; 16Sverdlovsk Regional irinotecan (FOLFOXIRI). Nonetheless, survival remains Oncology Center, Ekaterinburg, Russia; 17Onyx Pharmaceuticals, South San Francisco, California; and 18Abramson Cancer Center, Philadelphia, limited with a 5-year rate of less than 8% (1). Strategies to Pennsylvania further improve outcomes have focused on adding targeted Note: Supplementary data for this article are available at Clinical Cancer therapies to established regimens. Research Online (http://clincancerres.aacrjournals.org/). Advances in our understanding of the molecular basis of cancer proliferation, angiogenesis, and metastasis Current address for J. Cassidy: Roche Pharmaceuticals, Nutley, NJ. enabled the development of therapies that target signal- Corresponding Author: Josep Tabernero, Medical Oncology Department, ing pathways associated with cellular differentiation, pro- Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology (VHIO), Universitat Autonoma de Barcelona, P. Vall d'Hebron 119-129, liferation, and survival. Among these, EGF and VEGF are 08035 Barcelona, Spain. Phone: 34-93-489-4301; Fax: 34-93-274-6059; key targets (1). The addition of monoclonal antibodies E-mail: [email protected] (mAbs) that target tyrosine kinase activity (ligands or doi: 10.1158/1078-0432.CCR-13-0107 receptors) to mCRC chemotherapy regimens improved 2013 American Association for Cancer Research. clinical outcomes with acceptable toxicity. These include

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in mCRC, such as irinotecan, oxaliplatin, and 5- fluoroura- Translational Relevance cil/leucovorin, with encouraging activity in solid tumors Fluorouracil-based treatment regimens have provided including mCRC (22–24). In a phase I study of 37 patients incremental improvements in outcomes for patients with advanced solid tumors, 7/9 patients with CRC treated with metastatic colorectal cancer (mCRC). Adding tar- with oxaliplatin (130 mg/m2 on Day 1 of a 3-week cycle) geted therapies to these regimens may provide addition- and the standard sorafenib dose (400 mg b.i.d. continu- al benefit. Monoclonal antibodies that target signaling ously) achieved stable disease for at least 6 weeks (23). pathways associated with cellular differentiation, prolif- Here we present results from a phase IIb, double-blind, eration, and survival have been developed in mCRC, placebo-controlled, randomized trial that assessed the addi- with epidermal growth factor and vascular endothelial tion of sorafenib to first-line modified FOLFOX6 (mFOL- growth factor being key targets. Targeting a broader FOX6) in patients with mCRC. The standard sorafenib spectrum of molecules involved in CRC cell proliferation regimen (400 mg b.i.d. continuously) was used based on and death, such as receptor and intracellular tyrosine the collective results from the phase I combination studies kinases, may confer anticancer activity with less risk of (22–24) as well as its proven benefit in other difficult-to- tumor resistance. Sorafenib is an oral multikinase inhib- treat adenocarcinomas (14–16). Modified FOLFOX6 was itor that targets both intracellular kinases and cell surface chosen because it was the most commonly used FOLFOX receptor kinases. A randomized, double-blind, placebo- regimen across the various centers and countries of this controlled phase II trial was carried out to assess the international study. The objective was to determine whether combination of sorafenib with modified FOLFOX6 (leu- efficacy and tolerability results would support a phase III covorin, oxaliplatin, and fluorouracil) as a first-line confirmatory trial. therapy in patients with mCRC. Patients and Methods Patients Eligible patients were 18 years old, with histologically bevacizumab (inhibits VEGF; refs. 2–5), and the EGF confirmed, measurable metastatic adenocarcinoma of the receptor (EGFR) inhibitors cetuximab and panitumumab colon or rectum (stage IV; ref. 25), and an Eastern Coop- (6–9). Nonetheless, response can be absent if the target is erative Oncology Group (ECOG) performance status 0 to 1. notadiseasedriver,andresistancecanbepresentatthe Prior radiotherapy was allowed, but at least 1 measurable, start of treatment or can emerge when tumor or stromal nonirradiated, metastatic lesion was required, as was a cells switch to alternative pathways. The constitutive tumor tissue sample for analysis of KRAS and BRAF muta- KRAS BRAF and mutations confer resistance to cetuximab tions. Patients who had received prior chemotherapy for KRAS and panitumumab, and is now a valid biomarker metastatic disease were not eligible, nor were patients with for cetuximab and panitumumab (10). Approximately brain metastases, active cardiac disease, or serious bone KRAS 40% of patients with CRC have a mutation, mean- marrow, liver, or renal dysfunction. Patients who had ing a significant proportion will not be eligible for EGFR received adjuvant treatment for CRC, including a FOLFOX inhibitors (10). regimen, were eligible provided that they had completed Targeting a broader spectrum of molecules involved in treatment at least 12 months before randomization. The CRC cell proliferation and death, such as receptor and protocol was approved by the independent ethics commit- intracellular tyrosine kinases, may confer anticancer activity tees/institutional review boards of all participating sites or with less risk of resistance (11). Sorafenib is an oral multi- countries. The trial was conducted according to Good kinase inhibitor that targets intracellular kinases (CRAF, Clinical Practice Guidelines and in accordance with the BRAF, mutant BRAF), as well as cell surface receptor kinases, Declaration of Helsinki. All patients provided written including platelet-derived growth factor receptor (PDGFR), informed consent. The study is registered at Clinical- VEGFR-1–3, stem cell factor receptor (KIT), and Feline Trials.gov (NCT00865709). McDonough Sarcoma (FMS)-related tyrosine kinase 3 (FLT3; refs. 12 and 13). Clinical efficacy and tolerability of sorafenib have been shown in renal cell carcinoma (14) and Study design hepatocellular carcinoma (15, 16). Preclinical evidence This was a phase IIb, randomized, double-blind trial indicates the primary target of sorafenib in renal cell carci- conducted at centers in Belgium, Romania, Russia, Spain, noma is angiogenesis via VEGFR, whereas in hepatocellular the United Kingdom, and the United States. Patients were carcinoma, cell proliferation, and survival are targeted via stratified by radiologic evidence of liver involvement and < the RAF/MEK/ERK pathway, and angiogenesis via VEGFR number of metastatic sites ( 3or 3) and randomly and PDGFR (12, 17, 18). assigned (1:1) to mFOLFOX6 plus sorafenib or matching Preclinical studies also showed the activity of sorafenib placebo. against colon cancer cells, but also indicated differential targeting of cell proliferation and/or angiogenesis by tumor Treatment model (12, 19–21). Early clinical studies showed the fea- The mFOLFOX6 regimen was administered every 14 days sibility of combining sorafenib with chemotherapies used and consisted of oxaliplatin, levo-leucovorin (or leucovorin

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if levo-leucovorin not available), and fluorouracil. On Day versus placebo was estimated with a stratified Cox regres- 1 of each 14-day cycle, patients received oxaliplatin 85 mg/ sion model. m2, levo-leucovorin 200 mg/m2, then a fluorouracil 400 Secondary analyses of PFS included a per-protocol anal- mg/m2 bolus followed by a 2400 mg/m2 continuous infu- ysis (patients with no major protocol violations), and a sion (46–48 hours). All patients received prophylactic anti- nonstratified analysis. Planned subgroup analyses of PFS emetic treatment with intravenous dexamethasone and a 5- and overall survival were done using the Kaplan–Meier hydroxytryptamine-3 antagonist 30 minutes before each method and a nonstratified Cox regression for subgroups infusion. Sorafenib and the matching placebo were initiated defined by baseline factors of liver involvement (yes or no), on Day 1 at 400 mg b.i.d. Dose reductions of sorafenib/ number of metastatic sites (<3or3), region (East or West), placebo were required for hand–foot skin reaction (HFSR, KRAS status (wild-type or mutant), and BRAF status (wild- grades 2/3), hypertension (symptomatic grade 2 and grades type or mutant). KRAS and BRAF mutant status was deter- 3/4), proteinuria (>2 g/24 hours), hematologic toxicities mined by allelic discrimination (Supplementary Appendix) (grades 3/4), or other grade 3/4 toxicities associated with and centrally evaluated at University Hospital Gasthuisberg, sorafenib/placebo. Leuven, Belgium (S.T.). Exploratory analyses of PFS and In the case of dose modification or discontinuation of 1 overall survival were done for subgroups defined by NRAS study drug (oxaliplatin, fluorouracil/levo-leucovorin, or and PIK3CA status (wild-type or mutant), age (<65 or 65 sorafenib or placebo), administration of the other study years), gender, ECOG performance status (0 or 1), disease drugs could be continued at the protocol-specified doses. stage at diagnosis (I–III or IV), and months since initial Any patient who continued treatment with at least 1 study diagnosis (<2or2). ORR was compared between groups drug was considered on study. using the Cochran–Mantel–Haenszel test, adjusting for the stratification factors. Descriptive statistics summarized safe- Study endpoints ty and tolerability variables, including study drug exposure The primary endpoint was PFS. Secondary endpoints and adverse events rates. Statistical analyses were done with included overall survival, time to progression (TTP), overall SAS version 9.1 or later (SAS Institute). The lead author (J. response rate (ORR), duration of response (DOR), safety, T.) had full access to study data and analyses, which were and tolerability. Tumor response was investigator assessed available to all authors upon request. and evaluated radiologically at baseline and every 8 weeks using Response Evaluation Criteria in Solid Tumors Results (RECIST; ref. 26). Active follow-up was extended to patients who discontinued treatment without disease progression. Patient recruitment occurred between March 2009 and Adverse events were graded using Common Terminology February 2010 with 198 patients randomized (Fig. 1). Data Criteria for Adverse Events (version 3.0). Serious adverse cut-off for the primary analysis of PFS, response, safety, and events (SAEs) included events that resulted in death, were tolerability was January 31, 2011. An analysis of overall life-threatening, required or extended hospitalization, or survival was subsequently conducted after 123 deaths with a resulted in persistent or significant disability. cut-off date of December 1, 2011, and a median follow-up of 22.4 months. Statistical analyses Baseline characteristics were generally balanced between Analysis of PFS was based on the log-rank test. Based on treatment arms (Table 1). Most patients had an ECOG historical data, the expected PFS in the control arm was 8 performance status of 1 (64.6%), stage IV disease as initial < months (4). A sample size of 120 events would provide diagnosis (68.2%), 3 metastatic sites (71.7%), and liver >85% power with a 2-sided a ¼ 0.20, assuming a target HR involvement (80.8%). Of note, the sorafenib arm had fewer of 0.65 between sorafenib and placebo. The target study males compared with the placebo arm (43.3% vs. 62.4%), population was 180 patients. Analysis of overall survival less exposure to adjuvant chemotherapy (7.2% vs. 12.9%), KRAS was planned after 120 deaths. and lower rates of mutations (37.1% vs. 48.5%). BRAF Time-to-event endpoints were analyzed by the Kaplan– mutations were infrequent in both arms (3.1% vs. Meier method in the intent-to-treat (ITT) population. For 5.0%). PFS, patients without documentation of progression or death at the time of analysis were censored at final tumor Efficacy outcomes assessment or postrandomization visit; patients who initi- Median PFS was 9.1 months for the sorafenib arm and 8.7 ated nonstudy cancer treatment and were without disease months for the placebo arm [HR ¼ 0.88; 95% confidence progression were censored at last tumor assessment before interval (CI), 0.64–1.23; P ¼ 0.46; Fig. 2]. Similar results the start of the new treatment; patients with no postbaseline were observed in the prespecified subgroup analyses (Table tumor assessment were censored at Day 1; and patients who 2). In patients with wild-type KRAS, the median PFS was 9.5 experienced progressive disease or death 18 weeks or longer months versus 9.2 months, respectively (HR ¼ 0.84; 95% from the last tumor assessment were censored at the last CI, 0.52–1.36), with corresponding medians of 7.8 months tumor assessment. A stratified log-rank test with the ran- versus 7.6 months, respectively, in the mutant KRAS sub- domization stratification factors as covariates was used to group (HR ¼ 0.96; 95% CI, 0.59–1.58). In patients with compare treatment arms, and the relative risk for sorafenib wild-type BRAF, the median PFS was 9.2 months versus 9.0

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(n = 230) (n = 32) (n = 22) (n = 3) (n = 3) (n = 198) (n = 4)

(n = 97) (n = 101) (n = 97) (n = 101)

(n = 0) (n = 0) (n = 85) (n = 85) (n = 49) (n = 65) (n = 9) (n = 6) (n = 6) (n = 2)

(n = 21) (n = 12)

(n = 97) (n = 101) a (n = 97) a (n = 101) b (n = 82) b (n = 90) (n = 15) (n = 11) (n = 2) (n = 1) (n = 11) (n = 5) (n = 2) (n = 5)

a b

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

months, respectively (HR ¼ 0.91; 95% CI, 0.64–1.29), and gender and ECOG status (Table 2). There were no differ- the median PFS for mutant BRAF was 8.6 months versus 7.3 ences in survival outcomes between treatment arms in the months, respectively (HR ¼ 0.89; 95% CI, 0.15–5.42). PIK3CA or in the NRAS subgroups (Supplementary Appen- Median overall survival was 17.6 months in the sorafenib dix Tables SA1 and SA2). arm and 18.1 months in the placebo arm (HR ¼ 1.13; 95% Median TTP was 9.2 months in the sorafenib arm and 9.0 CI, 0.79–1.61; P ¼ 0.51). In patients with wild-type KRAS, months in the placebo arm (HR ¼ 0.83; 95% CI, 0.59– median overall survival was 19.9 months versus 16.8 1.17), and the ORR was 46.4% and 60.4%, respectively months, respectively (HR ¼ 0.89; 95% CI, 0.54–1.48), and (Table 3). Partial response was lower in the sorafenib arm 17.0 months versus 19.4 months, respectively, in patients compared with mFOLFOX6 alone (44.3% vs. 59.4%), but with mutant KRAS (HR ¼ 1.29; 95% CI, 0.74–2.24). In the rate of stable disease was higher (40.2% vs. 30.7%). patients with wild-type BRAF, median overall survival was Complete response was achieved by 2 patients in the 18.8 months versus 18.3 months, respectively (HR ¼ 1.09; sorafenib arm and 1 patient in the placebo arm. 95% CI, 0.74–1.60), and 13.9 months versus 11.9 months, respectively, in patients with mutant BRAF (HR ¼ 0.46; 95% Safety and tolerability CI, 0.09–2.39). Exploratory subgroup analyses showed Treatment-related adverse events occurring in 10% of slightly different outcomes between treatment arms by patients are shown in Table 4. The most common adverse

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Table 1. Baseline characteristics 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). Sorafenib + Placebo + More frequent dose interruptions and reductions were FOLFOX6 FOLFOX6 observed for sorafenib than placebo (Supplementary n ¼ n ¼ Variable ( 97) ( 101) Appendix Table SA3). The average daily dose of sorafenib Age (years), mean (range) 59.2 (33–82) 60.3 (44–77) was lower than placebo (mean 553.1 mg vs. 728.1 mg), Sex, n (%) which corresponded to a greater frequency of dose reduc- Male 42 (43.3) 63 (62.4) tions (66.0% vs. 27.7%) and a shorter mean duration of Female 55 (56.7) 38 (37.6) treatment (30.5 weeks vs. 33.7 weeks). Similar trends were Race/ethnicity, n (%) observed for components of mFOLFOX6, although the Caucasian 95 (97.9) 101 (100) magnitude of the difference between treatment arms was Asian 2 (2.1) 0 less pronounced. Overall, 9.4% of patients discontinued Region, n (%) treatment because of adverse events in the sorafenib arm West regiona 40 (41.2) 41 (40.6) compared with 5.9% in the placebo arm. East regionb 57 (58.8) 60 (59.4) ECOG performance status, n (%) Discussion 0 34 (35.1) 36 (35.6) In this randomized phase IIb trial, the addition of 1 63 (64.9) 65 (64.4) sorafenib 400 mg b.i.d. to mFOLFOX6 compared with Stage IV disease at initial diagnosis, n (%) placebo did not show an improvement in PFS to support Yes 68 (70.1) 67 (66.3) a phase III trial. Generally, there was no differential No 28 (28.9) 33 (32.7) outcome across subgroups, including KRAS and BRAF Missing 1 (1.0) 1 (1.0) subgroups. There was also no improvement in TTP or Metastatic sites, n (%) ORR. There were no unexpected toxicities associated with <3 71 (73.2) 71 (70.3) the addition of sorafenib, but there were increases in 3 26 (26.8) 30 (29.7) some grade 3/4 adverse event rates, most notably neu- Liver involvement, n (%) tropeniaandHFSR,whichledtoincreasedratesofdose Yes 79 (81.4) 81 (80.2) modifications and treatment discontinuations for reasons No 18 (18.6) 20 (19.8) other than disease progression.Overall,theaveragedaily Prior diagnostic/therapeutic 93 (95.9) 99 (98.0) dose of sorafenib was lower than placebo, and exposure procedure, n (%) to each of the mFOLFOX6 components was also lower in Prior adjuvant 7 (7.2) 13 (12.9) the sorafenib arm. chemotherapy, n (%) Although these results allow us to exclude a strong KRAS status, n (%) therapeutic benefit with sorafenib plus mFOLFOX6, a Wild type 52 (53.6) 45 (44.6) number of factors may have influenced the results and Mutant 36 (37.1) 49 (48.5) should be considered. First, the sample size would have Missing 9 (9.3) 7 (6.9) been too small to adequately assess a modest therapeutic BRAF status, n (%) benefit. Given the inter- and intrapatient heterogeneity in Wild type 85 (87.6) 89 (88.1) primary and metastatic CRC tumor types (27, 28), a more Mutant 3 (3.1) 5 (5.0) modest benefit would not be unexpected for a targeted Missing 9 (9.3) 7 (6.9) therapy. Second, use of sorafenib in mCRC may be better Abbreviations: ECOG, Eastern Cooperative Oncology suited for regimens that are less active than mFOLFOX6 Group; KRAS, Kirsten rat sarcoma viral oncogene homolog. but more tolerable and where an increase in activity aSpain, United Kingdom, Belgium, United States. would be more easily detected. Third, the 400 mg b.i.d. bRussia, Romania. 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 events (any grade) in the sorafenib and placebo arms over the course of treatment. included neutropenia (62% vs. 38%), peripheral neurop- Thus far, results of studies with targeted therapies in athy (61% vs. 65%), diarrhea (48% vs. 35%), nausea (36% combination with mCRC chemotherapy have been mixed, vs. 47%), HFSR (54% vs. 10%), and asthenia (28% vs. ranging from significant improvements in PFS or overall 19%). Other adverse events (any grade) of interest were survival to decreases in PFS or overall survival, depending stomatitis (22% vs. 4%), rash (23% vs. 9%), and hyperten- on the chemotherapy regimen and patient population (2– sion (19% vs. 5%). The most common grade 3/4 adverse 5, 9, 29–31). A number of phase III studies have shown that events in the sorafenib and placebo arms were neutropenia adding bevacizumab to fluorouracil-based regimens (48% vs. 22%), peripheral neuropathy (16% vs. 21%), and improves PFS with or without a corresponding improve- HFSR (20% vs. 0%). Treatment-related SAEs occurred in 21 ment in overall survival (2–4, 29), but the magnitude of the (22%) patients in the sorafenib arm and 16 (16%) patients benefits have been inconsistent (5). This may be related to

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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).

the fluorouracil backbone combined with bevacizumab with FOLFOX in mCRC in 3 different phase II/III trials (42– and/or the line of therapy (2–4). Variability in results has 44), with only 1 study demonstrating a statistically signif- also been observed across cetuximab (6, 9, 31) and pani- icant but clinically modest improvement in median PFS tumumab studies (7, 8). It has been hypothesized that (þ0.4 months; ref. 45). Nevertheless, other multikinase inconsistencies in outcomes with mAbs could also be relat- inhibitors may have potential in mCRC. In a phase III trial, ed to their high specificity, which may make them suscep- regorafenib (targets VEGFR1-3, Tie-2, PDGFR, FGFR, KIT, tible to resistance through redundant signaling pathways RET, and BRAF) provided a survival benefit when added to (11). Attempts to broaden activity by combining different best supportive care in patients with refractory mCRC (46, mAbs have not proven fruitful in mCRC (32–34). 47). It is notable that regorafenib was active in the refractory Results with small-molecule multikinase inhibitors with setting as monotherapy, whereas mCRC studies with other a broader spectrum of inhibitory targets than mAbs (35) targeted agents lacked single-agent activity or were paired have also been mixed, although limited data are available in with chemotherapy in the first- or second-line setting. addition to the results reported here (36–40). In 2 phase III Several factors may explain the variability in results with trials in mCRC, adding vatalanib (targets VEGFR1-3, targeted therapies in mCRC. It is becoming evident that the PDGFRb, and KIT) to first- or second-line FOLFOX4 did genetic profiles of tumors are predictive of treatment not improve PFS or overall survival (36, 37), and a phase III response to targeted therapies. In our study, by adding study of sunitinib (targets VEGFR1-3, PDGFRa/b, KIT, sorafenib to a standard first-line chemotherapy for mCRC, FLT3, CSF1R, RET) with FOLFIRI failed to show an improve- several pathways shown to be critical in mCRC were tar- ment in the primary endpoint of PFS (41). Cediranib geted, such as angiogenesis via extracellular tyrosine kinase (targets VEGFR1-3, PDGFRb, and KIT), has been evaluated receptors VEGFR1-3 and PDGFR, as well as downstream

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

Median overall survival Median PFS (months) (months)

Sorafenib + Placebo + Sorafenib + Placebo + Subgroup (n) mFOLFOX6 FOLFOX6 HR (95% CI) mFOLFOX6 mFOLFOX6 HR (95% CI) 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)a 7.7 9.0 0.98 (0.64–1.50) 16.4 18.0 1.19 (0.76–1.87) West (81)b 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) 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)

Abbreviations: 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. aRussia, Romania. bSpain, United Kingdom, Belgium, United States.

protein effectors of tyrosine kinase receptors (e.g., EGFR) BRAF status had a significant impact on outcomes in including CRAF, BRAF, and mutant BRAF (12, 13, 20, 21). patients receiving sorafenib. However, the size of the study As RAF is targeted by sorafenib and is downstream of RAS, population and subgroups limits the interpretation of these we hypothesized that mCRC patients could potentially data. Sorafenib may be more active with other chemother- derive benefit by the addition of sorafenib independent of apy regimens and/or in more specific patient populations. KRAS and BRAF gene mutation status. However, this is a Although a pharmacokinetic interaction between sorafenib highly redundant pathway with complex feedback loops, and oxaliplatin was not detected in a phase I trial of solid which makes it unlikely for RAF inhibition alone to be tumors (23), some preclinical evidence suggests that sor- sufficient for antitumoral activity (48). afenib may reduce cellular uptake of platinum compounds In this study, the tumor sample was taken from either the (49). The addition of sorafenib to other mCRC regimens, primary or metastatic site, and it does not seem that KRAS or such as irinotecan alone (50) or FOLFIRI (NCT00839111),

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Tabernero et al.

Table 3. Secondary efﬁcacy endpoints

Variable Sorafenib + mFOLFOX6 Placebo + mFOLFOX6 (n ¼ 97) (n ¼ 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 (%)a 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 5 (5.2) 7 (6.9) Median duration of response, monthsb 7.5 6.7

Abbreviations: CI, conﬁdence interval; HR, hazard ratio; TTP, time to progression. aPatients with missing or nonevaluable best response data are not listed. bOnly responders (CR or PR) are included in this summary.

are being explored. In addition, studies in various mCRC targeted therapies across mCRC models may help us to models showed differential response to sorafenib better understand and predict treatment response of pri- (12, 20, 21). Sorafenib showed inhibition of tumor growth mary and metastatic tumors in CRC patients. and angiogenesis in HT-29 colon cells (BRAF V600E muta- In conclusion, the dose and schedule of sorafenib with tion), inhibition of tumor growth in HCT-116 cells (acti- ﬁrst-line mFOLFOX6 in this study did not show a PFS vating KRAS mutation), but notably less activity in DLD-1 beneﬁt in patients with mCRC to support a phase III (activating KRAS mutation) and Colo-205 (BRAF V600E trial of similar design. KRAS and BRAF status did not seem mutation) cells. Further assessment of sorafenib and other to impact response to sorafenib, but patient numbers

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

Sorafenib + FOLFOX6 Placebo + FOLFOX6 (N ¼ 97) (N ¼ 101) All grades Grade 3/4 All grades Grade 3/4 n (%) n (%) n (%) n (%) Neutropenia 60 (62) 47 (48) 38 (38) 22 (22) Peripheral neuropathya 59 (61) 16 (16) 66 (65) 21 (21) Hand–foot skin reactionb 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)

aPeripheral neuropathy, peripheral sensory neuropathy, dysesthesia, neurotoxicity, paraesthesia. bGrade 3 is the most severe grade.

OF8 Clin Cancer Res; 19(9) May 1, 2013 Clinical Cancer Research

Sorafenib and mFOLFOX6 for Metastatic Colorectal Cancer

were small. Further assessment of tumor samples for Analysis and interpretation of data (e.g., statistical analysis, biosta- tistics, computational analysis): J. Tabernero, R. Garcia-Carbonero, E. Van biomarkers are ongoing and includes gene expression Cutsem, C.-H. Kohne,€ S. Tejpar, R. Salazar, F. Rivera, Y.-L. Chang, N.A. proﬁling. Although the results of this study do not sup- Lokker, P.J. O’Dwyer port further development of sorafenib with this combi- Writing, review, and/or revision of the manuscript: J. Tabernero, R. Garcia-Carbonero, J. Cassidy, A. Sobrero, E. Van Cutsem, C.-H. Kohne,€ S. nation in an unselected patient population, they may Tejpar, O. Gladkov, I. Davidenko, R. Salazar, L. Vladimirova, F. Rivera, L. help to guide the design of future clinical trials in mCRC Samuel, V. Potter, Y.-L. Chang, N.A. Lokker, P.J. O’Dwyer Study supervision: J. Tabernero, R. Garcia-Carbonero, A. Sobrero, C.-H. with targeted therapies focusing on molecularly charac- Kohne,€ L. Samuel, V. Potter, N.A. Lokker, P.J. O’Dwyer terized populations.

fl Acknowledgments Disclosure of Potential Con icts of Interest The authors thank Melanie Watson, PhD and Michael Raffin (Fishawack J. Tabernero is a consultant/advisory board member of Onyx and Bayer. Communications) for providing writing and editorial assistance, which was J. Cassidy has a commercial research grant, honoraria from speakers funded by Bayer HealthCare Pharmaceuticals and Onyx Pharmaceuticals. E. bureau, and is a consultant/advisory board member of Onyx/Bayer. A. Van Cutsem and S. Tejpar are senior investigators of the Fund for Scientific Sobrero has honoraria from speakers bureau and is a consultant/advisory Research Flanders and are supported by the Belgian Foundation against board member of Roche, Sanofi, Amgen, and Bayer. F. Rivera has a comme- Cancer. rical research grant from Onyx and is a consultant/advisory board member of Bayer. The other authors disclosed no potential conflicts of interest. Grant Support Authors' Contributions This study was supported by Bayer Healthcare LLC and Onyx Pharma- Conception and design: J. Tabernero, J. Cassidy, A. Sobrero, E. Van Cutsem, ceuticals, Inc. C.-H. Kohne,€ N.A. Lokker, P.J. O’Dwyer The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked Development of methodology: J. Tabernero, A. Sobrero, E. Van Cutsem, C.- advertisement H. Kohne,€ S. Tejpar in accordance with 18 U.S.C. Section 1734 solely to indicate Acquisition of data (provided animals, acquired and managed patients, this fact. provided facilities, etc.): J. Tabernero, R. Garcia-Carbonero, J. Cassidy, A. Sobrero, E. Van Cutsem, S. Tejpar, O. Gladkov, R. Salazar, L. Vladimirova, S. Received January 12, 2013; revised February 20, 2013; accepted March 7, Cheporov, O. Burdaeva, F. Rivera, L. Samuel, V. Potter 2013; published OnlineFirst March 26, 2013.

References 1. Gravalos C, Cassinello J, Fernandez-Ranada I, Holgado E. Role of 10. Pritchard CC, Grady WM. Colorectal cancer molecular biology moves tyrosine kinase inhibitors in the treatment of advanced colorectal into clinical practice. Gut 2011;60:116–29. cancer. Clin Colorectal Cancer 2007;6:691–9. 11. Petrelli A, Giordano S. From single- to multi-target drugs in cancer 2. Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, therapy: when a specificity becomes an advantage. Curr Med Chem Heim W, et al. Bevacizumab plus irinotecan, fluorouracil, and 2008;15:422–32. leucovorin for metastatic colorectal cancer. N Engl J Med 2004;350: 12. Wilhelm SM, Adnane L, Newell P, Villanueva A, Llovet JM, Lynch M. 2335–42. Preclinical overview of sorafenib, a multikinase inhibitor that targets 3. Giantonio BJ, Catalano PJ, Meropol NJ, O'Dwyer PJ, Mitchell EP, both Raf and VEGF and PDGF receptor tyrosine kinase signaling. Mol Alberts SR, et al. Bevacizumab in combination with oxaliplatin, fluo- Cancer Ther 2008;7:3129–40. rouracil, and leucovorin (FOLFOX4) for previously treated metastatic 13. Strumberg D. Preclinical and clinical development of the oral multi- colorectal cancer: results from the Eastern Cooperative Oncology kinase inhibitor sorafenib in cancer treatment. Drugs Today (Barc) Group Study E3200. J Clin Oncol 2007;25:1539–44. 2005;41:773–84. 4. Saltz LB, Clarke S, Diaz-Rubio E, Scheithauer W, Figer A, Wong R, et al. 14. Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Staehler M, Bevacizumab in combination with oxaliplatin-based chemotherapy as et al. Sorafenib for treatment of renal cell carcinoma: final efficacy and first-line therapy in metastatic colorectal cancer: a randomized phase safety results of the phase III treatment approaches in renal cancer III study. J Clin Oncol 2008;26:2013–9. global evaluation trial. J Clin Oncol 2009;27:3312–8. 5. Loupakis F, Bria E, Vaccaro V, Cuppone F, Milella M, Carlini P, et al. 15. Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, et al. Magnitude of benefit of the addition of bevacizumab to first-line Sorafenib in advanced hepatocellular carcinoma. N Engl J Med chemotherapy for metastatic colorectal cancer: meta-analysis of ran- 2008;359:378–90. domized clinical trials. J Exp Clin Cancer Res 2010;29:58. 16. Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, et al. Efficacy and 6. Van Cutsem E, Kohne CH, Hitre E, Zaluski J, Chang Chien CR, safety of sorafenib in patients in the Asia-Pacific region with advanced Makhson A, et al. Cetuximab and chemotherapy as initial treatment hepatocellular carcinoma: a phase III randomised, double-blind, pla- for metastatic colorectal cancer. N Engl J Med 2009;360:1408–17. cebo-controlled trial. Lancet Oncol 2009;10:25–34. 7. Douillard JY, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M, 17. Liu L, Cao Y, Chen C, Zhang X, McNabola A, Wilkie D, et al. Sorafenib et al. Randomized, phase III trial of panitumumab with infusional blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 induces tumor cell apoptosis in hepatocellular carcinoma model PLC/ alone as first-line treatment in patients with previously untreated PRF/5. Cancer Res 2006;66:11851–8. metastatic colorectal cancer: the PRIME study. J Clin Oncol 18. Chang YS, Adnane J, Trail PA, Levy J, Henderson A, Xue D, et al. 2010;28:4697–705. Sorafenib (BAY 43-9006) inhibits tumor growth and vascularization 8. Peeters M, Price TJ, Cervantes A, Sobrero AF, Ducreux M, Hotko Y, and induces tumor apoptosis and hypoxia in RCC xenograft models. et al. Randomized phase III study of panitumumab with fluorouracil, Cancer Chemother Pharmacol 2007;59:561–74. leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as 19. Walker T, Mitchell C, Park MA, Yacoub A, Graf M, Rahmani M, second-line treatment in patients with metastatic colorectal cancer. J et al. Sorafenib and vorinostat kill colon cancer cells by CD95- Clin Oncol 2010;28:4706–13. dependent and -independent mechanisms. Mol Pharmacol 2009; 9. Bokemeyer C, Bondarenko I, Makhson A, Hartmann JT, Aparicio J, de 76:342–55. Braud F, et al. Fluorouracil, leucovorin, and oxaliplatin with and without 20. Wilhelm SM, Carter C, Tang L, Wilkie D, McNabola A, Rong H, et al. cetuximab in the first-line treatment of metastatic colorectal cancer. J BAY 43-9006 exhibits broad spectrum oral antitumor activity and Clin Oncol 2009;27:663–71. targets the RAF/MEK/ERK pathway and receptor tyrosine kinases

www.aacrjournals.org Clin Cancer Res; 19(9) May 1, 2013 OF9

Tabernero et al.

involved in tumor progression and angiogenesis. Cancer Res 2004; 37. Van Cutsem E, Bajetta E, Valle J, Kohne CH, Hecht JR, Moore M, et al. 64:7099–109. Randomized, placebo-controlled, phase III study of oxaliplatin, fluo- 21. Wilhelm S, Chien DS. BAY 43-9006: preclinical data. Curr Pharm Des rouracil, and leucovorin with or without PTK787/ZK 222584 in patients 2002;8:2255–7. with previously treated metastatic colorectal adenocarcinoma. J Clin 22. Mross K, Steinbild S, Baas F, Gmehling D, Radtke M, Voliotis D, et al. Oncol 2011;29:2004–10. Results from an in vitro and a clinical/pharmacological phase I study 38. Chen E, Jonker D, Gauthier I, MacLean M, Wells J, Powers J, et al. with the combination irinotecan and sorafenib. Eur J Cancer 2007; Phase I study of cediranib in combination with oxaliplatin and infu- 43:55–63. sional 5-fluorouracil in patients with advanced colorectal cancer. Clin 23. Kupsch P, Henning BF, Passarge K, Richly H, Wiesemann K, Hilger RA, Cancer Res 2009;15:1481–6. et al. Results of a phase I trial of sorafenib (BAY 43-9006) in combi- 39. Stewart MW. Aflibercept (VEGF-TRAP): the next anti-VEGF drug. nation with oxaliplatin in patients with refractory solid tumors, including Inflamm Allergy Drug Targets 2011;10:497–508. colorectal cancer. Clin Colorectal Cancer 2005;5:188–96. 40. Carrato A, Swieboda-Sadlej A, Staszewska-Skurczynska M, Lim R, 24. Figer A, Moscovici M, Bulconic S, Radu P, Atsmon J, Shmuely E, et al. Roman L, Shparyk Y, et al. Final results from a randomized, double- Phase I trial of BAY 43-9006 in combination with 5-fluorouracil (5-FU) blind, phase III study of sunitinib plus FOLFIRI vs. placebo plus and leucovorin (LCV) in patients with advanced refractory solid tumors. FOLFIRI in first-line treatment of patients (pts) with metastatic colo- Ann Oncol 2004;15:iii87. Abstract 327. rectal cancer (mCRC). Ann Oncol 2010;21:vi19. Abstract O-0026. 25. Edge S, Byrd D, Compton C, Fritz A, Greene F, Trotti A, editors. AJCC 41. Mross K, Buchert M, Fasol U, Jaehde U, Kanefendt F, Strumberg D, cancer staging manual. 7th ed. New York, NY: Springer; 2010. et al. A preliminary report of a Phase II study of folinic acid, 5- 26. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubin- fluorouracil, irinotecan (FOLFIRI) plus sunitinib with toxicity, efficacy, stein L, et al. New guidelines to evaluate the response to treatment in pharmacokinetics, biomarker, imaging data in patients with colorectal solid tumors. European Organization for Research and Treatment of cancer with liver metastases as 1st line treatment. Int J Clin Pharmacol Cancer, National Cancer Institute of the United States, National Cancer Ther 2011;49:96–8. Institute of Canada. J Natl Cancer Inst 2000;92:205–16. 42. Cunningham D, Wong RP, D'haens G, Douillard J, Robertson J, 27. Li Z, Jin K, Lan H, Teng L. Heterogeneity in primary colorectal cancer Saunders O, et al. A phase II, double-blind, randomized multicenter and its corresponding metastases: a potential reason of EGFR-tar- study of cediranib with FOLFOX versus bevacizumab with FOLFOX in geted therapy failure? Hepato-gastroenterology 2011;58:411–6. patients with previously treated metastatic colorectal cancer (mCRC): 28. Baldus SE, Schaefer KL, Engers R, Hartleb D, Stoecklein NH, Gabbert final PFS results. ASCO Meeting Abstracts 2008;26:4028. HE. Prevalence and heterogeneity of KRAS, BRAF, and PIK3CA 43. Hoff PM, Hochhaus A, Pestalozzi BC, Tebbutt NC, Li J, Kim TW, et al. mutations in primary colorectal adenocarcinomas and their corre- Cediranib plus FOLFOX/CAPOX versus placebo plus FOLFOX/CAPOX sponding metastases. Clin Cancer Res 2010;16:790–9. in patients with previously untreated metastatic colorectal cancer: a 29. Hurwitz HI, Fehrenbacher L, Hainsworth JD, Heim W, Berlin J, Holmg- randomized, double-blind, phase iii study (HORIZON II). J Clin Oncol ren E, et al. Bevacizumab in combination with fluorouracil and leu- 2012;30:3596–603. covorin: an active regimen for first-line metastatic colorectal cancer. J 44. Schmoll HJ, Cunningham D, Sobrero A, Karapetis CS, Rougier P, Clin Oncol 2005;23:3502–8. Koski SL, et al. Cediranib with mFOLFOX6 versus bevacizumab with 30. Stathopoulos GP, Batziou C, Trafalis D, Koutantos J, Batzios S, mFOLFOX6 as first-line treatment for patients with advanced colo- Stathopoulos J, et al. Treatment of colorectal cancer with and without rectal cancer: a double-blind, randomized phase III study (HORIZON bevacizumab: a phase III study. Oncology 2010;78:376–81. III). J Clin Oncol 2012;30:3588–95. 31. Van Cutsem E, Kohne CH, Lang I, Folprecht G, Nowacki MP, Cascinu 45. Hoff PM, Hochhaus A, Pestalozzi BC, Tebbutt NC, Li J, Kim TW, et al. S, et al. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first- Cediranib þFOLFOX/XELOX versus placebo þ FOLFOX/XELOX in line treatment for metastatic colorectal cancer: updated analysis of patients (pts) WITH previously untreated metastatic colorectal cancer overall survival according to tumor KRAS and BRAF mutation status. J (mCRC): a randomized, double-blind, phase III study (HORIZON II). Clin Oncol 2011;29:2011–9. Ann Oncol 2010;21:viii9. Abstract LBA 19. 32. Saltz L, Badarinath S, Dakhil S, Bienvenu B, Harker WG, Birchfield G, 46. Grothey A, Van Cutsem E, Sobrero A, Siena S, Falcone A, Ychou M, et al. Phase III trial of cetuximab, bevacizumab, and 5-fluorouracil/ et al. Regorafenib monotherapy for previously treated metastatic leucovorin vs. FOLFOX-bevacizumab in colorectal cancer. Clin Colo- colorectal cancer (CORRECT): an international, multicentre, rando- rectal Cancer 2012;11:101–11. mised, placebo-controlled, phase 3 trial. Lancet 2013;381:303–12 33. Hecht JR, Mitchell E, Chidiac T, Scroggin C, Hagenstad C, Spigel 47. Wilhelm SM, Dumas J, Adnane L, Lynch M, Carter CA, Schutz G, et al. D, et al. A randomized phase IIIB trial of chemotherapy, bevaci- Regorafenib (BAY 73-4506): a new oral multikinase inhibitor of angio- zumab, and panitumumab compared with chemotherapy and bev- genic, stromal and oncogenic receptor tyrosine kinases with potent acizumab alone for metastatic colorectal cancer. J Clin Oncol preclinical antitumor activity. Int J Cancer 2011;129:245–55. 2009;27:672–80. 48. Prahallad A, Sun C, Huang S, Di Nicolantonio F, Salazar R, Zecchin D, 34. Tol J, Koopman M, Cats A, Rodenburg CJ, Creemers GJ, Schrama JG, et al. Unresponsiveness of colon cancer to BRAF(V600E) inhibition et al. Chemotherapy, bevacizumab, and cetuximab in metastatic through feedback activation of EGFR. Nature 2012;483:100–3. colorectal cancer. N Engl J Med 2009;360:563–72. 49. Heim M, Scharifi M, Zisowsky J, Jaehde U, Voliotis D, Seeber S, et al. 35. Broekman F, Giovannetti E, Peters GJ. Tyrosine kinase inhib- The Raf kinase inhibitor BAY 43-9006 reduces cellular uptake of itors: multi-targeted or single-targeted?World J Clin Oncol 2011; platinum compounds and cytotoxicity in human colorectal carcinoma 2:80–93. cell lines. Anticancer Drugs 2005;16:129–36. 36. Hecht JR, Trarbach T, Hainsworth JD, Major P, Jager E, Wolff RA, et al. 50. Samalin E, Bouche O, Thezenas S, Francxois E, Adenis A, Bennouna J, Randomized, placebo-controlled, phase III study of first-line oxalipla- et al. Final results of a multicentre phase II trial assessing sorafenib in tin-based chemotherapy plus PTK787/ZK 222584, an oral vascular combination with irinotecan as 2nd or later-line treatment in metastatic endothelial growth factor receptor inhibitor, in patients with metastatic colorectal cancer (MCRC) patients with KRAS mutated tumors (MT) colorectal adenocarcinoma. J Clin Oncol 2011;29:1997–2003. (NEXIRI). Ann Oncol 2011;22:v10. Abstract O-0001.

OF10 Clin Cancer Res; 19(9) May 1, 2013 Clinical Cancer Research

Sorafenib in Combination with Oxaliplatin, Leucovorin, and Fluorouracil (Modified FOLFOX6) as First-line Treatment of Metastatic Colorectal Cancer: The RESPECT Trial

Josep Tabernero, Rocio Garcia-Carbonero, James Cassidy, et al.

Clin Cancer Res Published OnlineFirst March 26, 2013.

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