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
References
- NCCN. NCCN Guidelines Colon Cancer Version 2.2017. 2017.
- Schmiegel W, Buchberger B, Follmann M. et al. S3-leitlinie – kolorektales karzinom. Z Gastroenterol 2017; 55: 1344–1498.
- Van Cutsem E, Cervantes A, Adam R. et al. ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Ann Oncol 2016; 27(8): 1386–1422.
- Yoshino T, Arnold D, Taniguchi H. et al. Pan-Asian adapted ESMO consensus guidelines for the management of patients with metastatic colorectal cancer: a JSMO-ESMO initiative endorsed by CSCO, KACO, MOS, SSO and TOS. Ann Oncol 2018; 29(1): 44–70.
- Guinney J, Dienstmann R, Wang X. et al. The consensus molecular subtypes of colorectal cancer. Nat Med 2015; 21(11): 1350–1356.
- Dienstmann R, Vermeulen L, Guinney J. et al. Consensus molecular subtypes and the evolution of precision medicine in colorectal cancer. Nat Rev Cancer 2017; 17(4): 268.
- 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 open-label phase 3 trial. Lancet Oncol 2016; 17(10): 1426–1434.
- 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(10): 1065–1075.
- Eisenhauer EA, Therasse P, Bogaerts J. et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45(2): 228–247.
- Song N, Pogue-Geile KL, Gavin PG. et al. Clinical outcome from oxaliplatin treatment in stage II/III colon cancer according to intrinsic subtypes: secondary analysis of NSABP C-07/NRG oncology randomized clinical trial. JAMA Oncol 2016; 2(9): 1162–1169.
- Marisa L, Aydi M, Balogoun R. et al. Clinical utility of colon cancer molecular subtypes: validation of two main colorectal molecular classifications on the PETACC-8 phase III trial cohort. J Clin Oncol 2017; 35: 3509.
- Mooi JK, Wirapati P, Asher R. et al. The prognostic impact of consensus molecular subtypes (CMS) and its predictive effects for bevacizumab benefit in metastatic colorectal cancer: molecular analysis of the AGITG MAX clinical trial. Ann Oncol 2018; 29(11): 2240–2246.
- Lenz HJ, Ou F-S, Venook A. et al. Impact of consensus molecular subtyping (CMS) on overall survival (OS) and progression free survival (PFS) in patients (pts) with metastatic colorectal cancer (mCRC): analysis of CALGB/SWOG 80405 (Alliance). J Clin Oncol 2019; 37: 1876–1885.
- Okita A, Takahashi S, Ouchi K. et al. Consensus molecular subtypes classification of colorectal cancer as a predictive factor for chemotherapeutic efficacy against metastatic colorectal cancer. Oncotarget 2018; 9(27): 18698–18711.
- Aderka D, Stintzing S, Heinemann V.. Explaining the unexplainable: discrepancies in results from the CALGB/SWOG 80405 and FIRE-3 studies. Lancet Oncol 2019; 20(5): e274–e283.
- Bennouna J, Hiret S, Bertaut A. et al. Continuation of bevacizumab vs cetuximab plus chemotherapy after first progression in KRAS wild-type metastatic colorectal cancer: the UNICANCER PRODIGE18 randomized clinical trial. JAMA Oncol 2019; 5(1): 83–90.
- Colangelo T, Polcaro G, Muccillo L. et al. Friend or foe? The tumour microenvironment dilemma in colorectal cancer. Biochim Biophys Acta Rev Cancer 2017; 1867(1): 1–18.
Source: PubMed