Panitumumab versus cetuximab in patients with chemotherapy-refractory wild-type KRAS exon 2 metastatic colorectal cancer (ASPECCT): a randomised, multicentre, open-label, non-inferiority phase 3 study

Summary

Background

The anti-EGFR monoclonal antibodies panitumumab and cetuximab are effective in patients with chemotherapy-refractory wild-type KRAS exon 2 metastatic colorectal cancer. We assessed the efficacy and toxicity of panitumumab versus cetuximab in these patients.

Methods

For this randomised, open-label, phase 3 head-to-head study, we enrolled patients (from centres in North America, South America, Europe, Asia, Africa, and Australia) aged 18 years or older with chemotherapy-refractory metastatic colorectal cancer, an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less, and wild-type KRAS exon 2 status. Using a computer-generated randomisation sequence, we assigned patients (1:1; stratified by geographical region and ECOG performance status, with a permuted block method) to receive panitumumab (6 mg/kg once every 2 weeks) or cetuximab (initial dose 400 mg/m²; 250 mg/m² once a week thereafter). The primary endpoint was overall survival assessed for non-inferiority (retention of ≥50% of the cetuximab treatment effect; historical hazard ratio [HR] for cetuximab plus best supportive care vs best supportive care alone of 0·55). The primary analysis included patients who received one or more dose of panitumumab or cetuximab, analysed per allocated treatment. Recruitment for this trial is closed. The trial is registered with ClinicalTrials.gov, number NCT01001377.

Findings

Between Feb 2, 2010, and July 19, 2012, we enrolled and randomly allocated 1010 patients, 999 of whom began study treatment: 499 received panitumumab and 500 received cetuximab. For the primary analysis of overall survival, panitumumab was non-inferior to cetuximab (Z score −3·19; p=0·0007). Median overall survival was 10·4 months (95% CI 9·4–11·6) with panitumumab and 10·0 months (9·3–11·0) with cetuximab (HR 0·97; 95% CI 0·84–1·11). Panitumumab retained 105·7% (81·9–129·5) of the effect of cetuximab on overall survival seen in this study. The incidence of adverse events of any grade and grade 3–4 was similar across treatment groups. Grade 3–4 skin toxicity occurred in 62 (13%) patients given panitumumab and 48 (10%) patients given cetuximab. The occurrence of grade 3–4 infusion reactions was lower with panitumumab than with cetuximab (one [<0·5%] patient vs nine [2%] patients), and the occurrence of grade 3–4 hypomagnesaemia was higher in the panitumumab group (35 [7%] vs 13 [3%]). We recorded one treatment-related fatal adverse event: a lung infection in a patient given cetuximab.

Interpretation

Our findings show that panitumumab is non-inferior to cetuximab and that these agents provide similar overall survival benefit in this population of patients. Both agents had toxicity profiles that were to be expected. In view of the consistency in efficacy and toxicity seen, small but meaningful differences in the rate of grade 3–4 infusion reactions and differences in dose scheduling can guide physician choice of anti-EGFR treatment.

Funding

Amgen Inc.

Introduction

Colorectal cancer is the fourth-leading cause of cancer-related death worldwide.¹ For patients with metastatic colorectal cancer, irinotecan-based and oxaliplatin-based chemotherapy in combination with targeted therapy can improve median overall survival to more than 2 years,2, 3 increasing the number of patients with chemotherapy-refractory disease eligible for third-line treatment. The anti-EGFR monoclonal antibodies cetuximab (a chimeric immunoglobulin G1 antibody) and panitumumab (a fully-human immunoglobulin G2 antibody) provide clinical benefit in patients with chemotherapy-refractory metastatic colorectal cancer. In the phase 3 CO.17 study,⁴ cetuximab monotherapy improved overall survival and progression-free survival (PFS) compared with best supportive care. Retrospective analysis showed that benefit was restricted to patients with wild-type KRAS exon 2 disease.⁵ In the phase 3 408 study,6, 7 panitumumab plus best supportive care improved PFS and the proportion of patients who had an objective response compared with best supportive care.6, 7 Subsequent analysis showed that these benefits of panitumumab treatment were restricted to patients with wild-type KRAS exon 2 disease.⁸ Panitumumab did not improve overall survival, but the study had a crossover design, and 90 (76%) of 119 patients in the best supportive care group received panitumumab post-progression, which might have affected the overall survival results.6, 7 Consequently, the effect of panitumumab on overall survival has been uncertain.

We know of no previous direct prospective comparison of efficacy and safety between panitumumab and cetuximab in chemotherapy-refractory metastatic colorectal cancer. Cross-study comparisons have been hampered by differences in patient demographics, study design, and KRAS ascertainment. Moreover, standards of care have evolved since approval of these agents. In addition to anti-EGFR therapy, guidelines for treatment of metastatic colorectal cancer incorporate several targeted agents including bevacizumab, aflibercept, and regorafenib.9, 10 These agents are typically used in combination with chemotherapy or, in the case of regorafenib for patients with KRAS wild-type disease, after failure of chemotherapy, anti-VEGF therapy, and anti-EGFR therapy. Consequently, re-assessment of safety and efficacy in this setting is important and necessary. The global, randomised, open-label, phase 3 ASPECCT study (A Study of Panitumumab Efficacy and Safety Compared to Cetuximab) is, to the best of our knowledge, the first head-to-head comparison of panitumumab and cetuximab in chemotherapy-refractory metastatic colorectal cancer, the first to prospectively screen for patients with wild-type KRAS exon 2 disease, the largest prospective comparison of anti-EGFR agents in metastatic colorectal cancer, and is among the largest head-to-head comparisons of biological agents in metastatic colorectal cancer. We used a non-inferiority design to assess whether panitumumab preserved the overall survival benefit noted previously with cetuximab, the standard of care in this population of patients.4, 5, 9, 10