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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

Sebastian Stintzing, Pratyaksha Wirapati, Heinz-Josef Lenz, Daniel Neureiter, Ludwig Fischer von Weikersthal, Thomas Decker, et al.

J Clin Oncol 35, 2017 (suppl; abstr 3510)

Editorial comment from Dr Cremolini
The Consensus Molecular Subgroups (CMS) classification of colorectal cancer is based on the identification of different gene signatures characterizing different tumours. Authors of two recent and extremely relevant trials (FIRE-3 and CALGB80405) in the landscape of metastatic colorectal cancer investigated the prognostic and predictive impact of this classification in stage IV patients treated with a chemotherapy doublet plus bevacizumab or cetuximab. CMS1 subtype (immune, enriched in MSI-high and BRAF V600E mutants) is associated with the worse prognosis in both trials, thus confirming results in terms of survival after relapse already reported by Guinney et al. in the original series of mainly stage II and III patients. Less clear and consistent data emerge in terms of predictivity: while in FIRE-3 no differential effect of bevacizumab versus anti-EGFR is evident among CMS subtypes, in CALGB80405 CMS1 tumours seems to derive more benefit from bevacizumab than cetuximab, and CMS2 and 4 cancers seem more sensitive to EGFR than angiogenesis inhibition.

As a major limitation, these analyses are conducted in the RAS (FIRE-3) or KRAS (CALGB80405) wild-type populations, thus not considering the potential impact of other biomarkers routinely used in the daily practice, such as BRAF V600E mutation or microsatellite instability. In spite of the obvious biologic and scientific interest of these findings, they will become relevant for clinical practice only when their added value (as compared with information provided by other easy-to-obtain markers) will be demonstrated.

ABSTRACT

Background:

FIRE-3 compared 1st-line therapy with FOLFIRI plus either cetuximab or bevacizumab in 592 KRAS exon 2 wt mCRC patients. CMS is grouping CRCs according to their gene-signature in 4 different types. Relevance of CMS for the treatment of mCRC remains unclear.

Methods:

Patients were grouped according to tumor CRC-CMSs. Using ALMAC’s Xcel tissue array, gene signatures of FIRE-3 tumor samples were analyzed. Survival was compared using Kaplan-Meier estimation and log-rank tests. Hazard ratios (HR) were estimated according to the Cox proportional hazard method.

Results:

CMS classification could be determined in 385 specimens available from the ITT population (n = 592). In this KRAS exon 2 wt population (n = 385), frequencies were: CMS1 (10.4%), CMS2 (36.6%), CMS3 (11.7%), CMS4 (29.1%), non-consensus (12.2%). In RAS wt (n = 315), frequencies were: CMS1 (11.1%), CMS2 (38.1%), CMS3 (9.5%), CMS4 (29.5%), non-consensus (11.7%). Independent of the treatment, CMS was a strong prognosticator for ORR (p = 0.023), PFS (p < 0.001) and OS (p < 0.001). For data on CMS and treatment efficacy in the RAS wt population see the following table.

Conclusions:

CMS classification is prognostic for mCRC. The survival benefit in RAS wt previously observed for FOLFIRI cetuximab vs. FOLFIRI bevacizumab is not significantly different across CMS groups, although there are trends when comparing OS HR between categories with CMS4 showing the best HR.

 

 

Median PFS (months)


Median OS (months)


events

All

FOLFIRI

FOLFIRI

p*

events

All

FOLFIRI

FOLFIRI

p*

Cetuximab

Bevacizumab

HR

Cetuximab

Bevacizumab

HR

CMS 1

33/35

6.1

5.1

6.7

0.83

32/35

13.1

20.3

11.0

0.28

(3.2-9.1)

(0.2-10.1)

(3.9-9.4)

1.08

(6.7-19.4)

(8.4-32.3)

(5.1-16.8)

0.68

CMS 2

93/117

12.3

12.2

12.4

0.54

64/117

31.9

38.3

30.8

0.40

(10.9-13.7)

(9.5-14.9)

(10.9-13.8)

1.14

(25.1-38.8)

(27.5-49.2)

(26.7-34.8)

0.80

CMS 3

27/30

7.6

7.3

10.0

0.76

20/30

18.7

16.6

18.7

0.60

(4.0-11.2)

(6.2-8.4)

(4.2-15.7)

0.90

(11.9-25.4)

(NE-41.2)

(12.7-25.6)

0.77

CMS 4

81/93

9.9

10.5

9.7

0.07

56/93

25.3

41.3

22.3

0.016

(9.0-10.9)

(6.9-14.1)

(8.8-10.6)

0.67

(19.8-30.3)

(19.2-63.4)

(15.9-28.8)

0.53

                       

*p = logrank test , HR = Hazard ratio

All content © 2017 American Society of Clinical Oncology. All rights reserved.