CT Response-Related Tumour Parameters Linked To FIRE-3 OS Outcomes

Early tumour shrinkage may contribute to superior overall survival achieved by FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab

medwireNews: Post hoc analysis of the phase III FIRE-3 trial indicates that using computed tomography (CT) images to measure tumour parameters may help increase the understanding of overall survival (OS) outcomes in clinical trials.

The study sheds light on why the first-line FOLFIRI (5-fluorourcil , leucovroin and irinotecan ) plus cetuximab regimen achieved better OS in patients with RAS wild-type metastatic colorectal cancer than FOLFIRI plus bevacizumab despite showing comparable rates of investigator-assessed objective response or progression-free survival.

Centralised radiological review of 330 CT-assessable patients showed that the cetuximab and bevacizumab treatment groups had comparable time to tumour response and duration of response.

But cetuximab-treated patients had a significantly higher rate of RECIST objective response than their bevacizumab-treated counterparts (72.0 vs 56.1%), report lead investigator Sebastian Stintzing, from the University of Munich in Germany, and team.

Patients given FOLFIRI plus cetuximab also had a significantly higher rate of early tumour shrinkage, defined as at least a 20% reduction in tumour diameter within 6 weeks (68.2 vs 49.1%), and a higher median depth of response, calculated as a continuous parameter at each staging over the course of treatment (–48.9 vs –32.3%).

Indeed, further analysis showed that OS was comparable in patients with early shrinkage who received the FOLFIRI cetuximab and bevacizumab regimens, at 38.3 and 31.9 months, respectively, and that median OS was “markedly shorter” for patients without early shrinkage regardless of regimen received, at 20.5 and 21.2 months, respectively.

Multivariate analysis confirmed a significant association between OS and post-progression survival and both early shrinkage and depth of response, the team adds in The Lancet Oncology.

“Superior novel response-related outcome parameters (such as early tumour shrinkage and depth of response) clearly relate to the overall survival benefit conferred by FOLFIRI plus cetuximab relative to FOLFIRI plus bevacizumab in FIRE-3 study patients with RAS wild-type metastatic colorectal cancer”, the researchers say.

“The present findings therefore not only afford a plausible model for the previously unexplained observation of differential overall survival in the absence of differences in investigator-assessed objective response and progression-free survival in the FIRE-3 trial, but also provide a new framework that connects innovative metrics of response to overall survival.”


Stintzing S, Modest DP, Rossius L, et al. 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 double-blind phase 3 trial. Lancet Oncol 2016; Advance online publication 26 August. DOI: http://dx.doi.org/10.1016/S1470-2045(16)30269-8

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