The Validity of Surrogate Endpoints in Sub Groups of Metastatic Colorectal Cancer Patients Defined by Treatment Class and KRAS Status.
Background and Aim: Findings from the literature suggest that the validity of surrogate endpoints in metastatic colorectal cancer (mCRC) may depend on a treatments' mechanism of action. We explore this and the impact of Kirsten rat sarcoma (KRAS) status on surrogacy patterns in mCRC.
Methods: A systematic review was undertaken to identify randomized controlled trials (RCTs) for pharmacological therapies in mCRC. Bayesian meta-analytic methods for surrogate endpoint evaluation were used to evaluate surrogate relationships across all RCTs, by KRAS status and treatment class. Surrogate endpoints explored were progression free survival (PFS) as a surrogate endpoint for overall survival (OS), and tumour response (TR) as a surrogate for PFS and OS.
Results: 66 RCTs were identified from the systematic review. PFS showed a strong surrogate relationship with OS across all data and in subgroups by KRAS status. The relationship appeared stronger within individual treatment classes compared to the overall analysis. The TR-PFS and TR-OS relationships were found to be weak overall but stronger within the Epidermal Growth Factor Receptor + Chemotherapy (EGFR + Chemo) treatment class; both overall and in the wild type (WT) patients for TR-PFS, but not in patients with the mutant (MT) KRAS status where data were limited.
Conclusions: PFS appeared to be a good surrogate endpoint for OS. TR showed a moderate surrogate relationship with PFS and OS for the EGFR + Chemo treatment class. There was some evidence of impact of the mechanism of action on the strength of the surrogacy patterns in mCRC, but little evidence of the impact of KRAS status on the validity of surrogate endpoints.
Heather Poad was funded by MRC IMPACT. (Medical Research Council, Integrated Midlands Partnership for Biomedical Training in Complex Disease, grant number: MR/N013913/1). Sylwia Bujkiewicz was funded by MRC Methodology Research Panel grant (MR/T025166/1). Lorna Wheaton was funded by a National Institute for Health Research (NIHR) Pre-doctoral Fellowship [NIHR301013]. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. The funding bodies played no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript. Sam Khan is funded by a NIHR ACL in Medical Oncology post. The APC was funded by the UKRI open access block grant provided to the University of Leicester.
CitationPoad, H.; Khan, S.; Wheaton, L.; Thomas, A.; Sweeting, M.; Bujkiewicz, S. The Validity of Surrogate Endpoints in Sub Groups of Metastatic Colorectal Cancer Patients Defined by Treatment Class and KRAS Status. Cancers 2022, 14, 5391. https://doi.org/10.3390/ cancers14215391
Author affiliationDepartment of Health Sciences
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