Reprinted with permission ? 2014 American Society of Clinical Oncology

Reprinted with permission ? 2014 American Society of Clinical Oncology. the target population to those patients whose tumours were WT for MS023 and exons 2, 3 and 4 (i.e., those with WT status). Here, we review key clinical data for panitumumab ANK3 in mCRC across the lines of treatment, assessing in detail the impact of more comprehensive selection on patient outcomes. Panitumumab data across first- to third-line therapy consistently demonstrate that by testing tumour status, it is possible to select patients more likely to benefit from treatment. Key Points mutations predict a lack of response to panitumumab.Detecting mutations improves patient selection in mCRC.Panitumumab has an optimal risk/benefit profile in tumours without mutations. Open in a separate window Introduction A MS023 predictive biomarker is a characteristic that can be objectively measured and evaluated as an indicator of treatment response (positively predictive) or lack of response (negatively predictive) [1]. Biomarker-guided treatment has the potential to improve clinical outcomes by allowing physicians to tailor therapy to those patients most likely to benefit, thereby sparing potential side effects in patients who are unlikely to respond to treatment. Avoiding treating patients who are unlikely to benefit improves the overall risk/benefit profile of targeted agents; it also has the advantage of being potentially cost-saving, in terms of reducing the use of ineffective drugs, the strain on hospital resources and the need for side-effect management. Tumour biomarker status is increasingly used to guide treatment decisions in patients with cancer and has been a rapidly developing area of research in metastatic colorectal cancer (mCRC). Improved patient selection through the use of biomarkers is likely to be particularly beneficial in mCRC because of the heterogeneity of response amongst these patients and the costs and toxicities associated with the available targeted therapies [2]. Approximately 27C43?% of mCRC tumours harbour exon 2 mutations that lead to constitutive activation of downstream signalling pathways [3]. Results of several uncontrolled [4, 5] and phase II [6] studies led to the hypothesis that the presence of exon 2 mutations might be associated with a lack of response to the epidermal growth factor receptor (EGFR)-targeted monoclonal antibodies (mAbs) panitumumab and cetuximab (Fig.?1) [6C15]. Initial analyses from the 408 study comparing panitumumab?+?best supportive care (BSC) with BSC alone in patients with mCRC receiving predominantly third-line treatment, supported the use of as a biomarker [13]. Open in a separate window Fig.?1 The cycle of hypothesis generation/testing to refine the target metastatic colorectal cancer population for panitumumab treatment. American Society of Clinical Oncology, National Comprehensive Cancer Networknext-generation sequencing, polymerase chain reaction, prospectiveCretrospective analysis As the availability of tumour samples for biomarker analysis was a requirement for entry into several phase III panitumumab trials [10, 11, 13], prospectiveCretrospective analyses were possible to further test the hypothesis that tumour status may predict response to anti-EGFR therapy in mCRC. In this context, a prospectiveCretrospective analysis is defined as the prospective analysis of a new biomarker hypothesis that was not prespecified at study start; these analyses are conducted on banked tumour samples from a clinical trial [16]. Wang et al. [17] defined such analyses as a completed or post-interim analysis from a trial where biomarker samples were collected prior to treatment initiation and where the mechanistic hypothesis would be prospectively specified prior to an approved diagnostic assay testing. Hence, MS023 the data analysis is considered a prospective analysis of the hypothesis. As more data were generated around the sensitivity of tumours to EGFR inhibitors, there was an ongoing cycle of hypothesis generation and testing. As a result, study protocols were developed to enable prospective analysis of new biomarkers, including prospective analyses of in the phase III PRIME [10] and 181 [11] panitumumab studies (Fig.?1; Table?1). The subsequent confirmation of exon 2 mutations as being negatively predictive of EGFR-targeted mAb.