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Jul 15, 2013 - combination to FOLFOX-6 improved ORR, PFS, or OS compared with .... the axitinib arm versus the axitinib plus bevacizumab arm. All patients ...
Original Article

Axitinib and/or Bevacizumab With Modified FOLFOX-6 as First-Line Therapy for Metastatic Colorectal Cancer: A Randomized Phase 2 Study Jeffrey R. Infante, MD1; Tony R. Reid, MD2; Allen L. Cohn, MD3; William J. Edenfield, MD4; Terrence P. Cescon, MD5; John T. Hamm, MD6; Imtiaz A. Malik, MD7; Thomas A. Rado, MD8; Philip J. McGee, MD9; Donald A. Richards, MD10; Jamal Tarazi, MD11; Brad Rosbrook, MS11; Sinil Kim, MD11; and Thomas H. Cartwright, MD12

BACKGROUND: In this multicenter, open-label, randomized phase 2 trial, the authors evaluated the vascular endothelial growth factor receptor inhibitor axitinib, bevacizumab, or both in combination with chemotherapy as first-line treatment of metastatic colorectal cancer (mCRC). METHODS: Patients with previously untreated mCRC were randomized 1:1:1 to receive continuous axitinib 5 mg twice daily, bevacizumab 5 mg/kg every 2 weeks, or axitinib 5 mg twice daily plus bevacizumab 2 mg/kg every 2 weeks, each in combination with modified 5-fluorouracil/leucovorin/oxaliplatin (FOLFOX-6). The primary endpoint was the objective response rate (ORR). RESULTS: In all, 126 patients were enrolled from August 2007 to September 2008. The ORR was numerically inferior in the axitinib arm (n 5 42) versus the bevacizumab arm (n 5 43; 28.6% vs 48.8%; 1-sided P 5.97). Progression-free survival (PFS) (11.0 months vs 15.9 months; 1-sided P 5.57) and overall survival (OS) (18.1 months vs 21.6 months; 1-sided P 5.69) also were numerically inferior in the axitinib arm. Similarly, efficacy endpoints for the axitinib/bevacizumab arm (n 5 41) were numerically inferior (ORR, 39%; PFS, 12.5 months; OS, 19.7 months). The patients who received axitinib had fewer treatment cycles compared with other arms. Common allgrade adverse events across all 3 treatment arms were fatigue, diarrhea, and nausea (all 49%). Hypertension and headache were more frequent in the patients who received axitinib. Patients in the bevacizumab arm had the longest treatment exposures and the highest rates of peripheral neuropathy. CONCLUSIONS: Neither the addition of continuous axitinib nor the axitinib/bevacizumab combination to FOLFOX-6 improved ORR, PFS, or OS compared with bevacizumab as first-line treatment of mCRC. Cancer C 2013 American Cancer Society. 2013;119:2555-63. V KEYWORDS: axitinib; bevacizumab; colorectal cancer; FOLFOX.

INTRODUCTION Colorectal cancer (CRC) is the third most common cause of cancer-related deaths in both men and women in the United States.1 The prognosis is poor for patients who present with distant metastases (approximately 20% of those diagnosed), in whom the 5-year survival rate is approximately 12%.1 Standard first-line chemotherapy for metastatic CRC (mCRC) consists of infusional 5-fluorouracil (5-FU)/leucovorin plus oxaliplatin (FOLFOX) or infusional 5-FU/leucovorin plus irinotecan (FOLFIRI).2 First-line treatment with either regimen, followed by transfer to the alternate regimen upon progression, is associated with a median survival of 20.6 to 21.5 months.3 The addition of bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor-A (VEGF-A) ligand, to chemotherapy reportedly prolongs the survival of patients with previously untreated mCRC compared with placebo plus chemotherapy.4 In a pivotal phase 3 study, bevacizumab added to irinotecan, bolus fluorouracil, and leucovorin (IFL) significantly prolonged progression-free survival (PFS) (10.6 months vs 6.2 months; hazard ratio [HR], 0.54; P < .001) and overall survival (OS) (20.3 months vs 15.6 months; HR 0.66; P < .001) compared with IFL plus placebo.4 Subsequently, it was shown that bevacizumab numerically improved survival when added to first-line FOLFIRI5,6 or

Corresponding author: Jeffrey R. Infante, MD, Sarah Cannon Research Institute, 250 25th Ave North, Suite 110, Nashville, TN 37203; Fax: (615) 340-1576; [email protected] 1 Sarah Cannon Research Institute/Tennessee Oncology, PLLC, Nashville, Tennessee; 2Rebecca and John Moores University of California San Diego Cancer Center, La Jolla, California; 3Rocky Mountain Cancer Centers, Denver, Colorado; 4Cancer Centers of the Carolinas, Greenville, South Carolina; 5Berks Hematology-Oncology Associates Ltd., West Reading, Pennsylvania; 6Norton Cancer Institute, Louisville, Kentucky; 7Loma Linda Oncology Medical Group, Redlands, California; 8Columbia Basin Hematology and Oncology Group, Kennewick, Washington; 9Clearview Cancer Institute, Huntsville, Alabama; 10Texas Oncology-Tyler, Tyler, Texas; 11Pfizer Oncology, San Diego, California; 12Ocala Oncology Center, Ocala, Florida.

Medical writing support was provided by Giles Brooke, PhD, Joanna Bloom, PhD, and Joseph Ramcharan, PhD, of UBC Scientific Solutions and was funded by Pfizer Inc. We thank the study investigators, their staff, clinical trial personnel, and the patients who participated. DOI: 10.1002/cncr.28112, Received: December 15, 2012; Revised: February 12, 2013; Accepted: February 19, 2013, Published online April 19, 2013 in Wiley Online Library (wileyonlinelibrary.com)

Cancer

July 15, 2013

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Original Article

FOLFOX.7 Toxicities associated with bevacizumab include hypertension, proteinuria, hemorrhage, impaired surgical wound healing, infusion-related hypersensitivity reactions, thromboembolism, and gastrointestinal perforation.8,9 Axitinib is a potent and selective second-generation inhibitor of VEGF receptor 1 (VEGFR1), VEGFR2, and VEGFR3 that blocks the VEGFRs at subnanomolar drug concentrations with minimal inhibition of other targets.10 Axitinib is approved in the United States for the treatment of advanced renal cell carcinoma after failure of 1 prior systemic therapy,11 having demonstrated superior efficacy compared with sorafenib in the second-line setting.12 Simultaneous inhibition of the VEGF-A ligand and the VEGFRs may result in additive antitumor activity when axitinib is used in combination with bevacizumab in addition to chemotherapy. In a phase 1 study, axitinib plus FOLFOX with or without bevacizumab was feasible and was devoid of pharmacokinetic interactions in patients with previously treated solid tumors, including mCRC.13 Consequently, we conducted the current randomized phase 2 study to evaluate the safety and efficacy of axitinib in combination with the modified FOLFOX-6 regimen (referred to herein as FOLFOX) with or without bevacizumab in patients with previously untreated mCRC. The dosage of bevacizumab in combination with axitinib was chosen based on the results of the phase 1 study of axitinib in combination with chemotherapy for solid tumors, including mCRC.13 The primary endpoint was the objective response rate (ORR), defined as the percentage of patients who achieved a complete response (CR) or a partial response (PR). Secondary endpoints included safety, duration of response, PFS, and OS.

MATERIALS AND METHODS Study Design

This was a multicenter, open-label, randomized phase 2 study conducted in the United States. A web-based, centralized randomization system was used to assign patients in a 1:1:1 ratio to receive axitinib plus FOLFOX (axitinib arm), bevacizumab plus FOLFOX (bevacizumab arm), or combined axitinib and bevacizumab plus FOLFOX (axitinib plus bevacizumab arm). Randomization, in block sizes of 3 patients, was stratified according to the receipt of prior adjuvant chemotherapy (yes vs no) and prior pelvic irradiation (yes vs no). This study was conducted in accordance with the Declaration of Helsinki, the International Conference on 2556

Harmonization Guidelines on Good Clinical Practice, the study protocol, and applicable local regulatory requirements and laws. Study protocol, amendments, and informed consent forms were approved by an institutional review board/independent ethics committee. Written informed consent was provided by all participants before entering the study. The study is registered on ClinicalTrials.gov as national clinical trial 00460603 (NCT00460603). Patients

Eligible adult patients (aged 18 years) had previously untreated, histologically or cytologically documented, locally advanced CRC or mCRC. Patients who had received previous adjuvant chemotherapy were eligible if the last dose of adjuvant therapy was >12 months before enrollment. Patients also were required to have measurable disease according to the Response Evaluation Criteria in Solid Tumors (RECIST) (version 1.0)14; an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1; life expectancy 12 weeks; no evidence of preexisting uncontrolled hypertension, ie, blood pressure (BP) >140/90 mm Hg (antihypertensive medications were permitted); and adequate liver function, renal function (serum creatinine 1.5 3 upper limit of normal and 500 mg urinary protein/24 hours or dipstick 150 mm Hg or diastolic BP >100 mm Hg while receiving maximal antihypertensive therapy. Axitinib was interrupted in patients who had grade 4 nonhematologic AEs, 2 readings of systolic BP >160 mm Hg or diastolic BP >105 mm Hg, or 2 g protein/24 hours; and axitinib was resumed at 1 dose level lower when AEs improved to grade 2, BP