Sensitivity to previous irinotecan treatment does not predict the efficacy of combination chemotherapy with cetuximab plus irinotecan for wild-type KRAS metastatic colorectal cancer

Abstract

The aim of this study was to evaluate the association of sensitivity to previous irinotecan-based chemotherapy with efficacy of cetuximab plus irinotecan therapy in metastatic colorectal cancer (MCRC) patients with wild-type KRAS. We analysed a pooled data set consisting of data from 87 MCRC patients from two previous phase II studies (n = 60) and a group given off-protocol treatment (n = 27) following irinotecan-, oxaliplatin-, and fluoropyrimidine-based chemotherapy. Overall objective response rate to cetuximab plus irinotecan was 28.7%, median progression-free survival (PFS) was 5.3 months, and median overall survival was 12.2 months. Objective response rate did not significantly differ between patients with a favourable response to previous irinotecan (n = 23), stable disease (n = 38), or progressive disease (n = 26), with observed rates of 29.2%, 31.6%, and 23.1%, respectively. Additionally, the non-parametric Spearman rank correlation coefficients (ρ) between the PFS of previous irinotecan-based chemotherapy and that of cetuximab plus irinotecan were quite low (ρ = 0.067 and 0.057 in patients with previous irinotecan as first- and second-line therapies, respectively). Although exploratory nature and small sample size may be limitations of this study, these findings indicate that the efficacy of irinotecan plus cetuximab in MCRC patients with wild-type KRAS did not differ by previous sensitivity to irinotecan.

Introduction

Cetuximab, a recombinant human/mouse chimeric monoclonal IgG1 antibody that specifically targets the epidermal growth factor receptor (EGFR), significantly improves the prognosis for metastatic colorectal cancer (MCRC) compared to best supportive care alone as a third-line treatment.¹ Furthermore, the BOND-1 study, which examined over 300 patients with irinotecan-pretreated MCRC, demonstrated that combining cetuximab with irinotecan results in higher response rates and longer progression-free survival (PFS) than cetuximab alone (22.9% vs. 10.8%, respectively).² Based on these results, cetuximab plus irinotecan has become one of the standard chemotherapies in MCRC patients after failure with 5-fluorouracil (5-FU), oxaliplatin, and irinotecan.³ Although the BOND-1 study also suggested that cetuximab may restore chemosensitivity to irinotecan in MCRC patients with irinotecan-refractory disease,² to our knowledge, only one study has reported the relationship between the efficacies of previous irinotecan-based chemotherapy and cetuximab plus irinotecan for MCRC.⁴ Notably, neither this study⁴ nor the BOND-1 study² evaluated KRAS status, which may have affected treatment response, on the basis of several retrospective findings that the indications for cetuximab are limited to MCRC patients with wild-type KRAS.5, 6, 7, 8, 9

Here, we examined the association of sensitivity to previous irinotecan-based chemotherapy with outcomes after cetuximab plus irinotecan treatment in MCRC patients with wild-type KRAS using a pooled data set consisting of data from two phase II studies10, 11 and a group of other eligible patients who had received off-protocol treatment.