Consensus molecular subgroups (CMS) of colorectal cancer (CRC) and first-line efficacy of FOLFIRI plus cetuximab or bevacizumab in the FIRE3 (AIO KRK-0306) trial

S Stintzing, P Wirapati, H-J Lenz, D Neureiter, L Fischer von Weikersthal, T Decker, A Kiani, F Kaiser, S Al-Batran, T Heintges, C Lerchenmüller, C Kahl, G Seipelt, F Kullmann, M Moehler, W Scheithauer, S Held, D P Modest, A Jung, T Kirchner, D Aderka, S Tejpar, V Heinemann, S Stintzing, P Wirapati, H-J Lenz, D Neureiter, L Fischer von Weikersthal, T Decker, A Kiani, F Kaiser, S Al-Batran, T Heintges, C Lerchenmüller, C Kahl, G Seipelt, F Kullmann, M Moehler, W Scheithauer, S Held, D P Modest, A Jung, T Kirchner, D Aderka, S Tejpar, V Heinemann

Abstract

Background: FIRE-3 compared first-line therapy with FOLFIRI plus either cetuximab or bevacizumab in 592 KRAS exon 2 wild-type metastatic colorectal cancer (mCRC) patients. The consensus molecular subgroups (CMS) are grouping CRC samples according to their gene-signature in four different subtypes. Relevance of CMS for the treatment of mCRC has yet to be defined.

Patients and methods: In this exploratory analysis, patients were grouped according to the previously published tumor CRC-CMSs. Objective response rates (ORR) were compared using chi-square test. Overall survival (OS) and progression-free survival (PFS) times were compared using Kaplan-Meier estimation, log-rank tests. Hazard ratios (HR) were estimated according to the Cox proportional hazard method.

Results: CMS classification could be determined in 438 out of 514 specimens available from the intent-to-treat (ITT) population (n = 592). Frequencies for the remaining 438 samples were as follows: CMS1 (14%), CMS2 (37%), CMS3 (15%), CMS4 (34%). For the 315 RAS wild-type tumors, frequencies were as follows: CMS1 (12%), CMS2 (41%), CMS3 (11%), CMS4 (34%). CMS distribution in right- versus (vs) left-sided primary tumors was as follows: CMS1 (27% versus 11%), CMS2 (28% versus 45%), CMS3 (10% versus 12%), CMS4 (35% versus 32%). Independent of the treatment, CMS was a strong prognostic factor for ORR (P = 0.051), PFS (P < 0.001), and OS (P < 0.001). Within the RAS wild-type population, OS observed in CMS4 significantly favored FOLFIRI cetuximab over FOLFIRI bevacizumab. In CMS3, OS showed a trend in favor of the cetuximab arm, while OS was comparable in CMS1 and CMS2, independent of targeted therapy.

Conclusions: CMS classification is prognostic for mCRC. Prolonged OS induced by FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab in the FIRE-3 study appears to be driven by CMS3 and CMS4. CMS classification provides deeper insights into the biology to CRC, but at present time has no direct impact on clinical decision-making.The FIRE-3 (AIO KRK-0306) study had been registered at ClinicalTrials.gov: NCT00433927.

Keywords: CMS; bevacizumab; cetuximab; colorectal cancer.

© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society for Medical Oncology.

Figures

Figure 1.
Figure 1.
Survival times according to consensus molecular subgroup (CMS). (A) Progression-free survival (PFS) in rat sarcoma oncogene (RAS) wild-type cases according to CMS. (B) Overall survival (OS) in RAS wild-type cases according to CMS. (C) PFS in rat sarcoma oncogene (RAS) mutant cases according to CMS. (D) Overall survival (OS) in RAS mutant cases according to CMS. n = events occurred; N = number of patients; 95% CI = 95% confidence interval.
Figure 2.
Figure 2.
Forrest plots: predictive value of consensus molecular subgroup (CMS) with respect to either bevacizumab or cetuximab. (A) Rat sarcoma oncogene (RAS) wild-type cases. (B) RAS mutant cases. PFS, progression-free survival; OS, overall survival, HR, hazard ratio; 95% CI, 95% confidence interval; P = cox proportional test P.
Figure 3.
Figure 3.
Forrest plots: predictive value of consensus molecular subgroup (CMS) with respect to either bevacizumab or cetuximab in left- and right-sided rat sarcoma oncogene (RAS) wild-type tumors. (A) (A) Rat sarcoma oncogene (RAS) wild-type right-sided cases. (B) RAS wild-type left-sided cases. PFS, progression-free survival; OS, overall survival; HR, hazard ratio; 95% CI, 95% confidence interval; P, cox proportional test P.

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