Paired tumor evaluations before randomization and at best response (nadir) of 270 patients with RAS WT tumors treated with first-line therapy with cetuximab (cet) vs. bevacizumab (bev)- in combination with FOLFIRI were reviewed for resectability of metastates. We assessed parameters influencing resectability, conversion to resectability and survival after nadir.
Baseline information and resectability were correlated with Fisher’s exact tests. Conversion to resectability was defined as unresectable disease before randomization and resectable disease at nadir. Univariate and multivariate logistic models were fitted with resectability at nadir as response variable. A Cox model comparing the survival from nadir was used to measure the influence of treatment, resectability at nadir and resection (time dependent variable). Interaction of resection and treatment arm on survival was tested by likelihood ratio test.
Initial Lung metastases (OR = 0.35 95% CI = (0.19 - 0.63), p = 0.001), BRAF mutation (OR = 0.33 95% CI = (0.12-0.82), p = 0.03) and high alkaline phosphatase (OR = 0.51, 95% CI = (0.31-0.81), p = 0.006) were associated with less chance of conversion to resectability and in case of lung metastases also of being resected if resectability at nadir was observed (OR = 0.33, 95% CI = (0.08-1.04) p = 0.046). Early tumor shrinkage (=ETS: -20% tumor diameter after 6 weeks therapy) and depth of response (DpR) were associated with conversion to resectability (ETS: OR = 1.86, 95% CI = (1.06-3.3), p = 0.034, DpR: OR = 1.02, 95% CI = (1.01-1.03), p < 0.001). Metastatic resection improved post-nadir survival (HR = 0.53, 95% CI = (0.29- 0.97), p = 0.04). This was pronounced in cet-treated patients as compared to bev-treated patients (HR (cet)=0.17, 95% CI = (0.04-0.69), p = 0.01; HR (bev)=0.89, 95% CI = (0.47-1.69), p = 0.73; interaction test p = 0.02).
Conversion to resectability is associated with baseline characteristics like lung metastases and BRAF mutation as well as with early efficacy parameters (ETS, DpR). In FIRE-3, resection of metastases was associated with improved post-nadir survival, this effect originated predominantly from the cetuximab-based study arm.
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Legal entity responsible for the study
Klinikum der Universität (LMU), Munich, Germany.
D.P. Modest: Grants: Merck KGaA, Pfizer, Visage Imaging, during the conduct of the study; Grants and personal fees: Merck KGaA, Amgen, Roche, Bayer; Grants: Sanofi, outside the submitted work. V. Heinemann: Grants: Merck, Pfizer during the conduct of this study, Grants: Amgen, Roche, Sanofi Sirtex outside the submitted work. G. Folprecht: Honoraries: Roche/Genentech, Bayer, Amgen, Lilly and Servier, Study grant, Honoraries: Merck-Serono, outside the submitted work. T. Denecke: Grants and personal fees: Bayer and B.E Imaging; Personal fees: Toshiba, Novartis, Ipsen and Parexel; Grants, personal fees and non-financial support: Siemens, GE; Grants: Guerbet; Non-financial support: Visage Imaging, outside the submitted work. C. Bruns: Personal fees: Merck, Sirtex, Grant: Celgene, outside the submitted work B. Gebauer: Personal fees: Merck KGaA, Pfizer; Personal fees, Study support: Visage Imaging, during the conduct of the study; Personal fees: Parexel, C.R. Bard, Sirtex Medical, Roche, Merck, Bayer, Icon, Ipsen, Siemens outside the submitted work; Travel support: Cook Medical, 3M, St Jude Medical; Travel and study support: AngioDynamics; Study support: Philips, outside the submitted work U. Neumann: Study grant: Merck during the conduct of the study; Study grant and personal fees: Merck outside the submitted work; Personal fees: Roche, Amgen, Novartis, Chiesi and Astellas during the submitted work. All other authors have declared no conflicts of interest.