Charité– Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität Zu Berlin, Department of Hematology, Oncology, and Cancer Immunology (CCM), Berlin, Germany
Arndt Stahler , Dominik Paul Modest , Sebastian Stintzing , Swantje Held , Ludwig Fischer von Weikersthal , Lothar Müller , Ullrich Graeven , Thomas Decker , Tobias Heintges , Christoph Kahl , Werner Scheithauer , Alexander Kiani , Florian Kaiser , Ingo Schwaner , Stefan Fruehauf , Meinolf Karthaus , Tanja Trarbach , Frederik Klauschen , David Horst , Volker Heinemann
Background: CMS were associated with prognostic relevance in RAS WT mCRC, while their role as predictive biomarker is debatable. We aimed to assess the predictive impact of CMS on treatment with anti-EGFR vs. anti-VEGF antibodies vs. cytotoxic treatment alone in a pooled analysis. Methods: Available CMS data (called by predictedCMS method) of the randomized controlled trials FIRE-1 (FUFIRI vs. mIrOx); FIRE-3 (FOLFIRI+ cetuximab vs. bevacizumab), XELAVIRI (sequential vs. initially combined FOLFIRI+bevacizumab) and PanaMa (FOLFOX+panitumumab followed by FU/FA +/- panitumumab) of RAS WT mCRC were included. Non-evaluable CMS were excluded. Kaplan-Meier estimated overall survival (OS) and progression-free survival (PFS). Uni- and multivariate Cox regression analysis (including all baseline characteristics) was used to calculate hazard ratio (HR) and 95% confidence interval (95% CI). Results: 1147 tumors had available CMS data and 746 (65.0%) were RAS wild-type (WT): CMS1, n=89; CMS2, n=346; CMS3, n=71; CMS4, n=240. CMS were significant prognostic biomarkers in terms of PFS (median months, CMS1, 6.7; CMS2, 11.1; CMS3, 8.1; CMS4, 10.0, P<0.001) and OS (median months: CMS1, 14.8; CMS2, 28.7; CMS3, 19.5; CMS4, 26.5; P<0.001). CMS remained significant in a multivariate backward elimination Cox regression analysis including all baseline characteristic variables and BRAF status with regard to PFS (P=0.03) and OS (P=0.04) Interaction of CMS and treatment was significant regarding OS (P<0.001) and PFS (P=0.001). The longest OS was observed using anti-VEGF antibodies in CMS1 and anti-EGFR antibodies in CMS2 or CMS4 RAS WT tumors (Table). Conclusions: CMS were confirmed as prognostic biomarkers and might contain predictive information for the choice of anti-EGFR or anti-VEGF antibodies in RAS WT mCRC. Prospective validation remains mandatory.
CMS as predictive biomarkers in FIRE-1, FIRE-3, XELAVIRI, PanaMa. | ||||||||||||
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CMS1 n=89 | CMS2 n=346 | CMS3 n=71 | CMS4 n=240 | |||||||||
anti-EGFR n=42 | anti-VEGF n=37 | Ctx n=10 | anti-EGFR n=164 | anti-VEGF n=134 | Ctx n=48 | anti-EGFR n=49 | anti-VEGF n=16 | Ctx n=6 | anti-EGFR n=139 | anti-VEGF n=84 | Ctx n=17 | |
PFS, months (median) | 5.7 | 8.3 | 4.4 | 11.8 | 11.1 | 8.8 | 7.9 | 10.0 | 6.3 | 10.1 | 9.8 | 11.0 |
P (log rank) | 0.207 | 0.163 | 0.788 | 0.507 | ||||||||
Interaction test | <0.001 | |||||||||||
OS, months (median) | 12.9 | 18.7 | 8.7 | 32.5 | 29.1 | 21.6 | 16.5 | 20.8 | 50.7 | 30.7 | 23.5 | 27.3 |
P (log rank) | 0.307 | 0.003 | 0.287 | 0.001 | ||||||||
Interaction test | 0.001 |
Legend: CMS = consensus molecular subtype; PFS = progression-free survival; OS = overall survival, Ctx = chemotherapy
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