Chapter 1 - Definition: Translational and Personalised Medicine, Biomarkers, Pharmacodynamics
Surrogate endpoints or biomarkers are often used as an intermediate readout of treatment effect at a point in time earlier than the clinical endpoint of interest. Surrogate markers are typically assessed in situations where there is a long time course to an event that is clinically meaningful, such as survival. For example, pathological complete response (pCR) and progression-free survival (PFS) are often used as surrogate markers for overall survival in breast cancer clinical trials. However, it is important to note that surrogate markers such as pCR and PFS may not always correlate with overall survival, as was shown for bevacizumab in metastatic breast cancer, where a PFS benefit did not translate to improved overall survival.
Another surrogate endpoint is treatment-related toxicity, which is used in monitoring chemotherapy drugs and targeted agents. One example with drugs that affect cell proliferation is myelosuppression. For example, the depth of myelosuppression that occurs with drugs that affect cell proliferation is reflective of the drug’s antiproliferative effect, and thus may serve as an early indicator of anti-tumour activity, before radiological response is seen. Another example is hyperglycaemia that is observed with phosphoinositide 3-kinase (PI3K) inhibitors. This is thought to be a mechanism-based toxicity, as the alpha subunit of PI3K has an important role in insulin signalling, and thus it may be potentially used as a surrogate marker of target inhibition.