A Randomized, Phase II Study of Concurrent Radiotherapy and Oxaliplatin, Capecitabine With or Without Cetuximab in Rectal Cancer Tumor Stratified by KRAS Mutation Status.
Aims: The primary aim of this study is to estimate the pathological complete response rate
following neoadjuvant radiotherapy with concurrent capecitabine and oxaliplatin (CAPOX),
with or without cetuximab based on the KRAS mutation status in rectal cancer.
Hypothesis: Cetuximab, a monoclonal antibody targeted against the EGF receptor, is active in
metastatic colorectal cancer and a radio-sensitizer. In colorectal cancer, the presence of
KRAS mutation has been associated with the absence of response to cetuximab. We hypothesise
that the addition of cetuximab to CAPOX concurrent with neoadjuvant radiotherapy only
benefited patients whose tumours do not have the KRAS mutation and therefore, personalizing
cetuximab therapy based on tumour KRAS mutation status may yield a higher pathological
Methods: This study employed a standard 2-stage Phase II design to evaluate the efficacy and
tolerability of two neoadjuvant chemoradiotherapy regimens. The assignment of the
neoadjuvant chemotherapy will be determined by the KRAS mutation status of the tumor.
Subjects with KRAS mutation will receive CAPOX. Subjects with no KRAS mutation will be
randomized to receive CAPOX +/- cetuximab.Definitive surgery is scheduled for 6-8 weeks
after the completion of chemoradiotherapy. Surgical management will be a sphincter
preservation approach whenever possible, using the total mesorectal excision technique.After
the operation, pathologic evaluation of the surgical specimen will be performed.
Significance:In this proof-of-concept study, we aim to demonstrate that using an enriched
patient cohort to test our hypothesis that the addition of cetuximab will yield a higher
pathological response rate in KRAS mutation-negative rectal cancer. This approach can
potentially identify a subset of patients that may benefit from cetuximab and spare those
who may not benefit from unnecessary treatment toxicities and costs. Our study will help to
prioritise novel targeted agents for a smaller, faster, and less expensive confirmatory
phase III trials.
Allocation: Randomized, Endpoint Classification: Efficacy Study, Primary Purpose: Treatment
Wei Peng Yong, MRCP, MB ChB
National University Hospital, Singapore
Singapore: Health Sciences Authority