Outcomes of patients with advanced cancer and KRAS mutations in phase I clinical trials. Oncotarget 2014 Oct 15;5(19):8937-46
Date
10/15/2014Pubmed ID
25313136Pubmed Central ID
PMC4253408DOI
10.18632/oncotarget.2339Scopus ID
2-s2.0-84910088551 (requires institutional sign-in at Scopus site) 6 CitationsAbstract
BACKGROUND: KRAS mutation is common in human cancer. We assessed the clinical factors, including type of KRAS mutation and treatment, of patients with advanced cancer and tumor KRAS mutations and their association with treatment outcomes.
METHODS: Patients referred to the Phase I Clinic for treatment who underwent testing for KRAS mutations were analyzed.
RESULTS: Of 1,781 patients, 365 (21%) had a KRAS mutation. The G12D mutation was the most common mutation (29%). PIK3CA mutations were found in 24% and 10% of patients with and without KRAS mutations (p<0.0001). Of 223 patients with a KRAS mutation who were evaluable for response, 56 were treated with a MEK inhibitor-containing therapy and 167 with other therapies. The clinical benefit (partial response and stable disease lasting ≥6 months) rates were 23% and 9%, respectively, for the MEK inhibitor versus other therapies (p=0.005). The median progression-free survival (PFS) was 3.3 and 2.2 months, respectively (p=0.09). The respective median overall survival was 8.4 and 7.0 months (p=0.38). Of 66 patients with a KRAS mutation and additional alterations, higher rates of clinical benefit (p=0.04), PFS (p=0.045), and overall survival (p=0.02) were noted in patients treated with MEK inhibitor-containing therapy (n=9) compared to those treated with targeted therapy matched to the additional alterations (n=24) or other therapy (n=33).
CONCLUSIONS: MEK inhibitors in patients with KRAS-mutated advanced cancer were associated with higher clinical benefit rates compared to other therapies. Therapeutic strategies that include MEK inhibitors or novel agents combined with other targeted therapies or chemotherapy need further investigation.
Author List
Said R, Ye Y, Falchook GS, Janku F, Naing A, Zinner R, Blumenschein GR Jr, Fu S, Hong DS, Piha-Paul SA, Wheler JJ, Kurzrock R, Palmer GA, Aldape K, Hess KR, Tsimberidou AMAuthor
Razelle Kurzrock MD Center Associate Director, Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AdolescentAdult
Aged
Aged, 80 and over
Antineoplastic Combined Chemotherapy Protocols
Child
Child, Preschool
Class I Phosphatidylinositol 3-Kinases
Disease-Free Survival
Female
Humans
MAP Kinase Kinase 1
Male
Middle Aged
Mutation
Neoplasms
Phosphatidylinositol 3-Kinases
Protein Kinase Inhibitors
Proto-Oncogene Proteins
Proto-Oncogene Proteins p21(ras)
Retrospective Studies
Treatment Outcome
Young Adult
ras Proteins
