Colorectal cancer trial endpoints: time for dynamic thinking?

Abstract

Assessment of early tumour shrinkage and depth of response in relation to survival outcomes has recently emerged as a topical research topic. Initial results of the FIRE-3 study 1 Heinemann V von Weikersthal LF Decker T et al. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial. Lancet Oncol. 2014; 15: 1065-1075 Summary Full Text Full Text PDF PubMed Scopus (1273) Google Scholar in 2014 caused much debate: a benefit in overall survival was noted with FOLFIRI (fluorouracil, leucovorin, and irinotecan) plus cetuximab as compared with FOLFIRI plus bevacizumab in first-line treatment of metastatic colorectal cancer in the absence of significant differences in either the proportion of patients who achieved an objective response or progression-free survival. The original trial was powered to detect an improvement in the proportion of patients who had an objective response in a population of 592 patients whose tumours were wild-type for KRAS exon 2 mutations, with progression-free survival and overall survival as secondary outcomes. Further controversy arose as the overall survival benefit was not confirmed in the much larger CALGB 80405 study, 2 Venook A Niedzwiecki D Lenz H-J et al. CALGB/SWOG 80405: phase III trial of irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6) with bevacizumab (BV) or cetuximab (CET) for patients (pts) with KRAS wild-type (wt) untreated metastatic adenocarcinoma of the colon or rectum (MCRC). Proc Am Soc Clin Oncol. 2014; 32 (abstr LBA3.) Google Scholar in which overall survival was used as the primary endpoint, although most patients were treated with a FOLFOX (fluorouracil, leucovorin, and oxaliplatin) backbone. The secondary analysis 3 Stintzing S Modest DP Rossius L et al. on behalf of the FIRE-3 investigatorsFOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab for metastatic colorectal cancer (FIRE-3): a post-hoc analysis of tumour dynamics in the final RAS wild-type subgroup of this randomised open-label phase 3 trial. Lancet Oncol. 2016; 17: 1426-1434 Summary Full Text Full Text PDF PubMed Scopus (275) Google Scholar reported by Sebastian Stintzing and colleagues in The Lancet Oncology involves a subgroup of 330 patients whose tumours were wild-type for RAS (including both KRAS and NRAS) mutations with imaging available for independent external review and evaluates early tumour shrinkage (defined as a ≥20% reduction in the diameter sum of target lesions at the first 6 week tumour assessment timepoint), depth of response (defined as the smallest sum of target lesion diameters compared with baseline), and survival outcomes. In the group treated with FOLFIRI plus cetuximab, early tumour shrinkage occurred significantly more frequently than in the FOLFIRI plus bevacizumab group (107 [68·2%; 95% CI 60·3–75·4] of 157 patients in the FOLFIRI plus cetuximab group vs 85 [49·1%; 41·5–56·8] of 173 patients in the FOLFIRI plus bevacizumab group; p=0·0005). Median depth of response was also greater in the FOLFIRI plus cetuximab group compared with the FOLFIRI plus bevacizumab group (−48·9% [–54·3 to −42·0] tumour shrinkage vs −32·3% [–38·2 to −29·2]; p<0·0001), with patients in the FOLFIRI plus cetuximab showing a greater depth of response at all assessed timepoints. Early tumour shrinkage and depth of response were highly correlated with each other, and both were associated with improved post progression survival and overall survival irrespective of treatment arm. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab for metastatic colorectal cancer (FIRE-3): a post-hoc analysis of tumour dynamics in the final RAS wild-type subgroup of this randomised open-label phase 3 trialThis analysis provides a new framework that connects alternative metrics of response to overall survival. Superior response-related outcome parameters, such as early tumour shrinkage and depth of response, obtained by centralised radiological review correlated with the overall survival benefit conferred by FOLFIRI plus cetuximab compared with FOLFIRI plus bevacizumab in the extended RAS wild-type subgroup. Full-Text PDF