You are here

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)

Heinz-Josef Lenz, Fang-Shu Ou, Alan P. Venook, Howard S. Hochster, Donna Niedzwiecki, Richard M. Goldberg, et al.

J Clin Oncol 35, 2017 (suppl; abstr 3511)

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:

CALGB 80405 was a randomized Ph3 trial showing no OS or PFS difference in mCRC pts treated with Bevacizumab (BV) or Cetuximab (Cet) in the first line. A Nanostring platform was used to determine the CMS classification of 392 KRAS wt (codon 12 and 13) primary tumors and correlated it with OS and PFS in patients enrolled in 80405.

Methods:

CMS for 392 of 431tumors were defined using a custom CRC Nanostring panel (39 CMS classification not possible). Stratified Cox proportional hazard model was used to evaluate the effect of CMS classification stratified by prior radiation, prior chemotherapy, adjusting for age, sex, race, primary in place, liver met only, and sidedness.

Results:

We found CMS1 (14%), CMS2 (47%), CMS3 (2%), CMS4 (29%), NonConsensus (8%). Results are shown in Table 1. Patients with CMS1 who received BV had significantly longer OS than those who received Cet (HR 0.47, 95% CI [0.24, 0.92]). Patients with CMS2 who received BV tended to have shorter OS than those who received Cet (HR 1.41, CI [0.95, 2.08]).

Conclusions:

Our data suggest that CMS is associated with OS and PFS in first line therapy in mCRC patients. Preliminary data suggest that certain CMS may be associated with efficacy of Bev and Cet based chemotherapy. CMS classification should be explored as a stratification factor in future trials. Support: U10CA180821, U10CA180830, U10CA180882 Clinical trial information: NCT00265850

 

CMS 
Classification

OS (mths)


PFS (mths)


Overall


   

Overall


   

Events/N

Median (95% 
C.I.)

BV
Median (95% 
C.I.)

Cet
Median (95% 
C.I.)

Events/N

Median (95% 
C.I.)

BV
Median (95% 
C.I.)

Cet
Median (95% 
C.I.)

CMS 1

40/55

17.0

20.4

11.7

45/55

6.5

7.0

6.0

(11.3-27.8)

(11.3-NE)

(10.6-27.8)

(5.4-10.6)

(5.7-15.9)

(3.9-14.4)

CMS 2

131/183

39.7

36.8

41.2

169/183

13.3

12.9

14.9

(35.3-43.1)

(33.6-43.1)

(37.2-54.4)

(12.4-14.9)

(10.2-14.8)

(12.9-19.4)

CMS 4

92/114

23.7

26.7

20.0

106/114

9.6

9.9

9.5

(18.8-29.5)

(19.3-36.9)

(16.4-31.0)

(8.4-11.1)

(9.0-11.6)

(7.6-11.8)

                 

Logrank P-Value

 

0.003

0.115

<0.001

 

<0.001

0.113

0.003

Adjusted P-Value

 

0.022

0.596

0.005

 

0.011

0.228

0.005

P-Value for interaction 
(between CMS and BV/Cet)

0.042

---

---

 

0.224

---

---

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