Elsevier

Clinical Colorectal Cancer

Volume 12, Issue 4, December 2013, Pages 239-247
Clinical Colorectal Cancer

Original study
Axitinib or Bevacizumab Plus FOLFIRI or Modified FOLFOX-6 After Failure of First-Line Therapy for Metastatic Colorectal Cancer: A Randomized Phase II Study

https://doi.org/10.1016/j.clcc.2013.09.001Get rights and content

Abstract

Objective

Axitinib, a potent and selective second-generation inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, shows activity in multiple tumor types, including those refractory to previous antiangiogenic therapy. This randomized, multicenter, parallel-group, open-label phase II trial compared axitinib with bevacizumab each in combination with 5-fluorouracil/leucovorin/oxaliplatin (FOLFOX) or 5-fluorouracil/leucovorin/irinotecan (FOLFIRI) for second-line treatment of metastatic colorectal cancer.

Methods

Patients were randomized 1:1 to axitinib 5 mg twice daily or bevacizumab 5 mg/kg every 2 weeks plus modified FOLFOX-6 (if previously treated with irinotecan) or FOLFIRI (if previously treated with oxaliplatin) and were stratified by performance status and prior bevacizumab therapy. Primary endpoint was progression-free survival.

Results

In 171 patients, progression-free survival was 7.6 months with axitinib/FOLFOX vs. 6.4 months with bevacizumab/FOLFOX (hazard ratio [HR], 1.04; 95% confidence interval [CI], 0.55-1.96; 1-sided P = .55) and 5.7 months with axitinib/FOLFIRI vs. 6.9 months with bevacizumab/FOLFIRI (HR, 1.27; 95% CI, 0.77-2.11; 1-sided P = .83). Overall survival was 17.1 vs. 14.1 months with axitinib/FOLFOX and bevacizumab/FOLFOX (HR, 0.69; 95% CI, 0.37-1.27; 1-sided P = .12) and 12.9 vs. 15.7 months with axitinib/FOLFIRI and bevacizumab/FOLFIRI (HR, 1.36; 95% CI, 0.82-2.24; 1-sided P = .88). More grade ≥ 3 adverse events (eg, diarrhea, fatigue, decreased appetite) and treatment discontinuations due to adverse events occurred with axitinib.

Conclusions

Compared with bevacizumab, axitinib did not improve outcomes when added to second-line chemotherapy for metastatic colorectal cancer. With current dosing regimens, axitinib plus FOLFOX or FOLFIRI seems to be less well tolerated than bevacizumab-based regimens.

Introduction

Currently recommended first-line chemotherapy regimens for metastatic colorectal cancer (mCRC) include 5-fluorouracil (5-FU)/leucovorin/oxaliplatin (FOLFOX) and 5-FU/leucovorin/irinotecan (FOLFIRI).1 FOLFOX and FOLFIRI have similar efficacy in this setting, and second-line chemotherapy after disease progression generally uses the regimen not used in the first line, yielding similar progression-free survival (PFS) and overall survival (OS).2 In the United States, FOLFOX-based regimens are more commonly used in first-line mCRC.3

Recent research in mCRC has focused on agents that inhibit angiogenesis, a process critical for tumor growth and metastasis. Bevacizumab, a monoclonal antibody that binds vascular endothelial growth factor (VEGF)-A, improves survival in patients with mCRC when added to first-line chemotherapy and in bevacizumab-naïve and pretreated second-line settings.4, 5, 6 Data from the VELOUR study show that the addition of aflibercept, an agent that binds VEGF-A, VEGF-B, and placental growth factor, to second-line chemotherapy for mCRC improves OS in patients who are both bevacizumab-naïve and pretreated.7 A randomized phase III trial of single-agent regorafenib, an inhibitor of multiple angiogenic tyrosine kinase receptors, has shown survival benefit vs. placebo in patients with refractory mCRC.8 These data suggest antiangiogenic therapy is effective through multiple lines of treatment in patients with mCRC.

Axitinib, a potent and selective second-generation inhibitor of VEGF receptors (VEGFRs) 1 to 3,9 has shown promising single-agent activity against a variety of tumor types.10, 11, 12, 13, 14 Whereas bevacizumab specifically binds VEGF-A, inhibition of VEGFR1 to 3 by axitinib may result in more complete blockade of VEGF signaling.9 A phase I study showed that axitinib may be safely co-administered with FOLFOX or FOLFIRI without affecting plasma drug concentrations.15 Our study sought to characterize these regimens in second-line treatment of mCRC. We report the results of this multicenter, randomized, open-label phase II trial comparing axitinib with bevacizumab each in combination with FOLFOX or FOLFIRI as second-line therapy for patients with mCRC.

Section snippets

Patients

Eligible patients were aged ≥ 18 years (≥ 20 years in Japan) with histologically documented mCRC and disease progression per Response Evaluation Criteria in Solid Tumors (RECIST version 1.0)16 within 6 months of the last dose of first-line irinotecan or oxaliplatin-containing therapy or adjuvant irinotecan-or oxaliplatin-containing therapy. Other eligibility criteria included Eastern Cooperative Oncology Group performance status (ECOG PS) 0 or 1, life expectancy ≥ 12 weeks, adequate organ

Patient Characteristics

Between March 2008 and August 2009, 171 patients were randomized to treatment with axitinib/FOLFIRI (n = 49), bevacizumab/FOLFIRI (n = 51), axitinib/FOLFOX (n = 36), or bevacizumab/FOLFOX (n = 35) (Fig. 1). The study was stopped early because of slow enrollment in FOLFOX arms. As of July 29, 2011 (data cutoff date), 4 patients were still receiving treatment. Patient characteristics (Table 1) were generally similar among arms, although there was a higher proportion of female patients in the

Discussion

In this phase II study, no significant differences in PFS (the primary endpoint) were detected between axitinib and bevacizumab when combined with second-line FOLFOX or FOLFIRI; OS and ORR results were consistent with PFS results; however, results should be interpreted in the context of the open-label design, small sample size, and inclusion of both bevacizumab-pretreated and bevacizumab-naïve patients.

Benefits of second-line antiangiogenic therapy in combination with chemotherapy were

Conclusions

This study did not achieve its primary endpoint of significantly improved PFS with axitinib vs. bevacizumab in patients with treatment-refractory mCRC receiving chemotherapy and therefore does not provide a strong signal to proceed to phase III clinical trials of axitinib plus chemotherapy in second-line mCRC. The results may have been influenced by suboptimal axitinib dosing regimens and earlier discontinuations in the axitinib/FOLFIRI arm, likely secondary to increased AEs. From this and

Disclosure

This study was sponsored by Pfizer Inc. Pfizer Inc participated in the design of the study and collection and analysis of the data. The authors thank all the patients who participated in this study, the physicians who referred them, and the study coordinators. Editorial support was provided by Giles Brooke, PhD, and Joseph Ramcharan, PhD, of Engage Scientific Solutions and was funded by Pfizer Inc. C. Barone received a commercial research grant (Pfizer Inc), honoraria from speakers bureaus

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    Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen

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    ∗

    Employed at Pfizer Inc at the time of the study described and development of this manuscript.

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