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Retrospective Analyses of the CRYSTAL and FIRE-3 Trials

The chief aim of the research was to see what were the prognostic and predictive relevance of primary tumour location in patients with RAS wild-type (wt) metastatic colorectal cancer (mCRC).

The findings in the RAS wt populations of the CRYSTAL and FIRE-trials showed that patients with left-sided tumours had a markedly better prognosis than those with right-sided tumours.

First-line fluorouracil, leucovorin, and irinotecan (FOLFIRI) plus cetuximab clearly benefitted patients with left-sided tumours (vs FOLFIRI or FOLFIRI plus bevacizumab), whereas patients with right-sided tumours derived limited benefit from standard treatments (FOLFIRI, FOLFIRI plus bevacizumab, and FOLFIRI plus cetuximab). The findings mean that primary tumour locations should be included in the stratification criteria for future trials in patients with mCRC, particularly those involving epidermal growth factor receptor inhibitors.

The randomised phase 3 Cetuximab Combined With Irinotecan in First-line Therapy for Metastatic Colorectal Cancer (CRYSTAL) study demonstrated that adding the antiepidermal growth factor receptor (EGFR) monoclonal antibody cetuximab to infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) significantly improved progression-free survival (PFS; the primary end point), overall survival (OS), and objective response rate (ORR) in the first-line treatment of patients with KRAS wild-type (wt) metastatic colorectal cancer (mCRC). A subsequent analysis revealed that expanded RAS testing (KRAS/NRAS, exons 2-4) resulted in even more  pronounced  treatment effects.

The FOLFIRI Plus Cetuximab Versus FOLFIRI Plus Bevacizumab as First-Line Treatment For Patients With Metastatic Colorectal Cancer (FIRE-3) trial was a randomised phase 3 trial comparing first-line FOLFIRI plus cetuximab vs FOLFIRI plus bevacizumab in patients with KRAS wt mCRC. Objective response rate (the primary end point) and PFS were similar between treatment arms; however, OS was significantly improved in cetuximab-treated patients. Preplanned evaluation of expanded RAS status suggested an increased treatment effect in terms of the cetuximab-conferred OS benefit.

Left-sided tumours (those originating in the splenic flexure, descending colon, sigmoid colon, rectum, or one-third of the transverse colon; referred to as “distal tumours” elsewhere) derive from the embryonic hindgut; in contrast, right-sided tumours (those originating in the appendix, cecum, ascending colon, hepatic flexure, or two-thirds of the transverse colon; alternatively termed “proximal tumours”) derive from the embryonic midgut.

Consistent with these differences in embryological origin, left-sided and right-sided tumours possess unique gene expression profiles. Notably, right-sided tumours are more frequently characterised by a host of adverse prognostic factors, including BRAF mutation positivity, microsatellite instability (prognostic in stage IV disease), hypermutation, serrated path- way signature positivity, and mucinous histology; conversely, left-sided tumours more frequently possess gene expression profiles characteristic of an EGFR inhibitor – sensitive phenotype (ie, EGFR/ERBB2 [formerly HER2 or HER2/neu] amplified, epiregulin high, and possessing classic chromosomal instability). These molecular differences manifest as differential clinical behaviour, with right-sided tumours typically displaying worse prognosis. Nevertheless, primary tumour location has not traditionally been included as a stratification criterion in clinical trials, and the influence of tumour location on responsiveness to particular therapies remains incompletely understood.

Of interest, a retrospective analysis of the NCIC CTG CO.17 trial recently reported that tumour location was predictive of treatment benefit. In this population of chemotherapy refractory patients with KRAS wt mCRC, adding cetuximab to best supportive care significantly benefitted patients with left-sided tumours, but had limited benefit in patients with right-sided tumours; furthermore, a significant interaction was observed between tumour location and treatment for PFS. Similarly, Wang et al recently reported that adding cetuximab to first-line or second-line chemotherapy significantly improved ORR, PFS, and OS in patients with left-sided mCRC, but had limited benefit in patients with right-sided tumours. Also it has been reported that the EGFR pathway is not comparably activated in left-sided vs right-sided tumours, and an EGFR inhibitor-sensitive phenotype appears to be more prevalent in left-sided tumours, leading to the hypothesis that EGFR inhibitors may exhibit differential activity based on primary tumour location. This prompted the examination of the potential prognostic and predictive value of primary tumour location in patients with RAS wt mCRC treated with first-line FOLFIRI plus cetuximab in two large international randomised clinical trials (CRYSTAL and FIRE-3).

Categorisation of primary tumour location

Primary tumours originating in the splenic flexure, descending colon, sigmoid colon, or rectum were classified as left-sided mCRC. Primary tumours originating in the appendix, cecum, ascending colon, hepatic flexure, or transverse colon were classified as right-sided mCRC. If tumours in an individual patient were sited in both left-sided and right-sided locations and the origin could not be ascribed to either side, the patient was excluded from the present analysis and the patient was classified as having tumours of indeterminate origin.

Of CRYSTAL study patients with RAS wt mCRC, 280 (76 per cent) had left-sided tumours and 84 (23 per cent) had right-sided tumours. The remaining one per cent of patients (n = 3) had tumours sited on both the left and right sides whose origin could not be determined and were excluded from the present analysis. In the final RAS wt population of FIRE-3 (n = 400), 306 RAS wt patients had left-sided tumours (76.5 per cent), 88 had right-sided tumours (22 per cent), and six had tumours whose origin could not be determined (1.5 per cent).

Findings from this retrospective analysis of the RAS wt populations of the first-line CRYSTAL and FIRE-3 trials con- firm the prognostic role of primary tumour location. These data further suggest a site and treatment interaction, with poor- prognosis right-sided tumours not significantly benefitting from the addition of cetuximab but with a profound benefit of cetuximab for left-sided tumours, more than what was appreciated before splitting patient populations by site.

The FIRE-3 trial analysed by site indicated that FOLFIRI and cetuximab would be the preferred option for RAS wt left-sided tumors in terms of OS, while right-sided tumours remain tumours of poor prognosis with any of the studied regimens. The data collected to date therefore suggest that primary tumour location should be included in the stratification criteria for future mCRC trials, particularly those involving EGFR inhibitors, as an EGFR inhibitor–sensitive phenotype appears to be more prevalent in left-sided tumors. Additional research is necessary to elucidate the subset of patients with RAS wt right-sided mCRC who may derive benefit from cetuximab.