A Randomized Phase II Study of Axitinib as Maintenance Therapy After First-line Treatment for Metastatic Colorectal Cancer

Abstract

Introduction

The aim of this study was to evaluate the efficacy and safety of maintenance therapy with axitinib versus placebo following induction therapy in patients with metastatic colorectal cancer (mCRC).

Patients and Methods

In this double-blinded, phase II trial, patients with mCRC who had not progressed after 6 to 8 months of first-line chemotherapy were randomized to receive axitinib (5 mg twice a day) (arm A) or placebo (arm B).

Results

Forty-nine patients were included: 25 in arm A and 24 in arm B. The median follow-up was 26.07 months (95% confidence interval [CI], 18.44-31.73 months). Progression-free survival (PFS) rate at 6 months was 40.00% (95% CI, 21.28%-58.12%) in the axitinib arm versus 8.33% (95% CI, 1.44%-23.30%) in the placebo arm (P = .0141). The median PFS was statistically significantly longer in the axitinib group than in the placebo group (4.96 vs. 3.16 months; hazard ratio, 0.46; 95% CI, 0.25-0.86; P = .0116). Median overall survival was also longer in the axitinib arm but did not reach statistical significance (27.61 vs. 19.99 months; hazard ratio, 0.68; 95% CI, 0.31-1.48; P = .3279). Grade 3 to 4 treatment-related toxicities were experienced by 7 patients (28%) in cohort A and 1 patient (4%) in cohort B (P = .0488). The most frequent grade 3 to 4 treatment-related toxicities were hypertension, diarrhea, and asthenia. There were no toxic deaths. The study was prematurely closed because of slow recruitment.

Conclusions

In our study, maintenance treatment with axitinib monotherapy showed a significant increase in PFS and a good safety profile. Axitinib should be further explored as a possible option for first-line chemotherapy maintenance treatment in patients with mCRC.

Introduction

Introduction of the cytotoxic agents irinotecan and oxaliplatin into regimens based on fluoropyrimidines, with or without biologic agents such as vascular endothelial growth factor (VEGF) and epidermal growth factor receptor monoclonal antibodies, has significantly improved survival of patients with metastatic colorectal cancer (mCRC).1, 2 However, these chemotherapy agents have also contributed to added toxicities, mainly cumulative oxaliplatin peripheral sensitive neuropathy, usually regressing after drug discontinuation, but disabling in some cases.³ Therefore, strategies to reduce the toxicity and improve quality of life without compromising efficacy are needed, making maintenance therapy one of the key issues in patients with mCRC who achieve disease control (stable disease [SD] or response) following induction therapy. A recently published systematic review⁴ concluded that fluoropyrimidine-based maintenance with bevacizumab has better results in progression-free survival (PFS) when compared with bevacizumab alone or with observation in patients with mCRC with disease control after 3 to 6 months of first-line induction chemotherapy. There are fewer evidences with cetuximab in RAS wild type or with erlotinib-bevacizumab maintenance than with bevacizumab. Nevertheless, none of the evaluated maintenance strategies has shown a significant overall survival (OS) benefit. Therefore, the optimal strategy is still to be determined.

Axitinib, a potent and selective second generation inhibitor of VEGF receptors (VEGFRs) 1, 2, and 3,⁵ has shown promising single-agent activity against a variety of tumor types, including metastatic renal cell carcinoma, melanoma, thyroid cancer and non–small-cell lung cancer.6, 7, 8, 9, 10 Whereas bevacizumab specifically binds VEGF-A, inhibition of VEGFR 1 to 3 by axitinib may result in more complete blockade of VEGF signaling.⁵

We conducted this randomized phase II study to evaluate the efficacy and safety of axitinib as maintenance therapy, compared with placebo, in patients achieving disease control from a first-line induction chemotherapy ± bevacizumab or cetuximab (KRAS wild-type tumor).