Mutation-based selection to identify patients suitable for panitumumab treatment

Patients with RAS wild-type (WT) metastatic colorectal cancer (mCRC) without gene alterations had superior health outcomes with mFOLFOX6 plus panitumumab compared with mFOLFOX6 and bevacizumab, regardless of primary tumour side location, a biomarker analysis of the phase 3 PARADIGM trial showed. Therefore, negative hyperselection using ctDNA may identify patients who will benefit from panitumumab more effectively than selection based on primary tumour side.

The PARADIGM trial (NCT02394795) randomised 733 patients with RAS WT mCRC 1:1 to mFOLFOX6 and panitumumab or to mFOLFOX6 plus bevacizumab [1]. Previous results displayed an overall survival benefit for patients in the panitumumab arm with left-sided primary tumours [2]. Before treatment, plasma samples were sequenced with a custom ctDNA panel to identify mutations. Dr Kohei Shitara (National Cancer Center Hospital East, Japan) presented the findings from an analysis on the effects of the assessed therapies in respect to patients’ mutations. Preplanned gene alterations for hyperselection included KRAS, NRAS, PTEN, and extracellular domain EGFR mutations, HER2 and MET amplifications, and ALK, RET, or NTRK1 fusions.

In total, 27.8% of the patients had gene alterations, whereas 72.2% of the patients did not. The panitumumab arm performed better than the bevacizumab arm in terms of overall survival (OS) in patients without gene alterations (median OS 41.3 months vs 34.4 months; HR 0.75; 95% CI 0.62–0.92). The corresponding data for patients with gene alterations showed no difference between the 2 treatment groups (median OS 19.0 months vs 22.2 months; HR 1.14; 95% CI 0.84–1.54). In addition, a significant P-value for interaction was reported (P=0.029). Interestingly, this trend was also visible in patients with right-sided tumours and no gene alterations (median OS 38.9 months vs 30.9 months; HR 0.82; 95% CI 0.50–1.35). The hazard ratio for patients with gene-altered right-sided tumours was 1.33, numerically favouring the bevacizumab arm over the panitumumab arm (median OS 14.1 months vs 18.5 months; 95% CI 0.84–2.11; P-value for interaction 0.145).

Dr Shitara argued that these results indicate that negative hyperselection of patients with RAS WT mCRC using ctDNA analysis rather than primary tumour side may select the right patients for treatment with panitumumab in the first line.

1. Shitara K, et al. Negative hyperselection of patients with RAS wild-type metastatic colorectal cancer for panitumumab: A biomarker study of the phase III PARADIGM trial. Abstract 11, ASCO GI 2023, 19–21 January, San Francisco, CA, USA.
2. Yoshino T, et al. JCO. 2022;40:17suppl LBA1.

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Posted on 17 March, 2023