Defining actionable mutations for oncology therapeutic development.
Genomic profiling of tumours in patients in clinical trials enables rapid testing of multiple hypotheses to confirm which genomic events determine likely responder groups for targeted agents. A key challenge of this new capability is defining which specific genomic events should be classified as 'actionable' (that is, potentially responsive to a targeted therapy), especially when looking for early indications of patient subgroups likely to be responsive to new drugs. This Opinion article discusses some of the different approaches being taken in early clinical development to define actionable mutations, and describes our strategy to address this challenge in early-stage exploratory clinical trials.
Oncology IMED, AstraZeneca, Darwin Building, Cambridge Science Park, Cambridge CB4 0WG, UK.
T Hedley
TH
Carr
Oncology IMED, AstraZeneca, Darwin Building, Cambridge Science Park, Cambridge CB4 0WG, UK.
Robert
R
McEwen
Oncology IMED, AstraZeneca, Waltham, Massachusetts 02451, USA.
Brian
B
Dougherty
Oncology IMED, AstraZeneca, Waltham, Massachusetts 02451, USA.
Justin H
JH
Johnson
Oncology IMED, AstraZeneca, Waltham, Massachusetts 02451, USA.
Jonathan R
JR
Dry
Oncology IMED, AstraZeneca, Waltham, Massachusetts 02451, USA.
Zhongwu
Z
Lai
Oncology IMED, AstraZeneca, Alderley Park, Macclesfield SK10 4TG, UK.
Zara
Z
Ghazoui
Oncology IMED, AstraZeneca, Waltham, Massachusetts 02451, USA.
Naomi M
NM
Laing
Oncology IMED, AstraZeneca, Alderley Park, Macclesfield SK10 4TG, UK.
Darren R
DR
Hodgson
Oncology IMED, AstraZeneca, Alderley Park, Macclesfield SK10 4TG, UK.
Francisco
F
Cruzalegui
Oncology IMED, AstraZeneca, Darwin Building, Cambridge Science Park, Cambridge CB4 0WG, UK.
Simon J
SJ
Hollingsworth
Oncology IMED, AstraZeneca, Waltham, Massachusetts 02451, USA.
J Carl
JC
Barrett
D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics; D009154:Mutation; D011720:Pyrazoles / Q000627:therapeutic use; D011743:Pyrimidines / Q000627:therapeutic use; D011744:Pyrimidinones; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
D011720:Pyrazoles; D011743:Pyrimidines; D011744:Pyrimidinones; D016159:Tumor Suppressor Protein p53; C549567:adavosertib