The relationship between rash, tumour KRAS mutation status and clinical and quality of life outcomes in patients with advanced colorectal cancer treated with cetuximab in the NCIC CTG/AGITG CO.17.
BACKGROUND
The NCIC CTG/AGITG CO.17 trial demonstrated that cetuximab monotherapy improved overall and progression-free survival (OS and PFS) in patients previously treated for advanced colorectal cancer. A strong relationship was observed between benefit from cetuximab and development of rash. In this analysis, the association of rash and benefit from cetuximab is explored and presented by KRAS mutation status.


METHODS
Rash was graded by NCI CTC 2.0 criteria. Landmark analysis was performed by excluding patients who died or dropped out within 28 days and then grouping by worst grade of rash experienced by day 28. Multivariate Cox models were conducted separately for patients with KRAS wild-type (WT) tumours and KRAS mutated (MUT) tumours. CO.17 primary outcome was OS.


RESULTS
Development of grade 2 + rash on cetuximab was associated with a trend towards increased OS (HR 0.61 with 95% CI 0.36-1.02 and p = 0.06) and PFS (HR 0.68 with 95% CI 0.45-1.03 and p = 0.07) as compared to grade 0/1 rash in patients with WT tumours. In patients with WT tumours on cetuximab both grade 0/1 and grade 2 + rash were associated with increased PFS (HR 0.57 95% CI 0.38-0.86; p = 0.008; and HR 0.32 95% CI 0.21-0.49; p < 0.0001) respectively, in comparison with best supportive care (BSC). Only development of grade 2 + rash on cetuximab was associated with increased OS (HR 0.52 with 95% CI 0.34-0.80 and p = 0.003) in comparison with BSC. No significant difference was found in OS or PFS among patients on cetuximab with MUT tumours with either rash grade as compared to BSC. No consistent trend was observed for the association of severity of rash and quality of life (QoL).


CONCLUSIONS
As all patients with WT tumours benefitted to some extent from cetuximab regardless of the grade of rash, grade of rash was not a useful predictive marker.
National Health and Medical Research Council Clinical Trials Centre, University of Sydney , Sydney, New South Wales , Australia.
Dirkje W
DW
Sommeijer
Christos S
CS
Karapetis
John R
JR
Zalcberg
Dongsheng
D
Tu
Derek J
DJ
Jonker
John
J
Simes
Niall
N
Tebbutt
Desmond
D
Yip
Timothy J
TJ
Price
Chris J
CJ
O'Callaghan
D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000068818:Cetuximab; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D018572:Disease-Free Survival; D005076:Exanthema / Q000139:chemically induced* / Q000235:genetics; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D011788:Quality of Life; D016896:Treatment Outcome; D018631:ras Proteins / Q000235:genetics*
D061067:Antibodies, Monoclonal, Humanized; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D000068818:Cetuximab