Panitumumab in Metastatic Colorectal Cancer: The Importance of Tumour RAS Status

Abstract

Tumour biomarker status is being used more and more frequently to guide treatment decisions in patients with metastatic colorectal cancer (mCRC). Continued cycles of hypothesis generation and biomarker testing in retrospective, prospective-retrospective and prospective analyses from studies of the epidermal growth factor (EGFR)-targeted monoclonal antibodies (mAbs), panitumumab and cetuximab, have resulted in improved patient selection in mCRC. Initial data suggested EGFR-targeted mAb treatment should be limited to patients with KRAS exon 2 wild-type (WT) tumours, but the availability of tumour samples from large phase III studies permitted evaluation of additional potential biomarkers of activity for these agents. Subsequent analyses further refined the target population to those patients whose tumours were WT for KRAS and NRAS exons 2, 3 and 4 (i.e., those with RAS WT status). Here, we review key clinical data for panitumumab in mCRC across the lines of treatment, assessing in detail the impact of more comprehensive RAS selection on patient outcomes. Panitumumab data across first- to third-line therapy consistently demonstrate that by testing tumour RAS status, it is possible to select patients more likely to benefit from treatment.

Fig. 1

The cycle of hypothesis generation/testing to refine the target metastatic colorectal cancer population for panitumumab treatment. ASCO American Society of Clinical Oncology, NCCN National Comprehensive Cancer Network, NGS next-generation sequencing, PCR polymerase chain reaction, PRA prospective–retrospective analysis

Fig. 2

RAS mutation hotspots in the first-line a PRIME [12] and b PEAK [31, 32] studies. Stars denote codon position; percentages denote the proportion of patients with available data who had a mutation within the specified gene exon. N/A not applicable as KRAS exon 2 WT status was defined in the trial eligibility criteria, WT wild type

Fig. 3

PRIME: Hazard ratios (95 % confidence intervals) for a progression-free survival; b overall survival (RAS wild-type primary analysis population) [12]. From Douillard et al. [12]. Copyright© 2013 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society. CI confidence intervals, ECOG Eastern Cooperative Oncology Group, HR hazard ratio, LDH lactate dehydrogenase, Pmab panitumumab, ULN upper limit of normal

Fig. 4

PEAK: progression-free survival in the a Wild-type KRAS exon 2 population (primary analysis, data cut-off 30 May 2012); b Wild-type RAS population (prespecified analysis, data cut-off Jan 3 2013) [31]. From Schwartzberg et al. [31]. Reprinted with permission © 2014 American Society of Clinical Oncology. All rights reserved. CI confidence intervals

Fig. 5

PEAK: overall survival in the a Wild-type KRAS exon 2 population; b Wild-type RAS population (primary analysis, data cut-off 3 January 2013) [31]. From Schwartzberg et al. [31]. Reprinted with permission © 2014 American Society of Clinical Oncology. All rights reserved. CI confidence intervals, NR not recorded