A key aim of early clinical development for new cancer treatments is to detect the potential for efficacy early and to identify a safe therapeutic dose to take forward to phase II. Because of this need, researchers have sought to build mathematical models linking initial radiologic tumor response, often assessed after 6 to 8 weeks of treatment, with overall survival. However, there has been mixed success of this approach in the literature. We argue that evolutionary selection pressure should be considered to interpret these early efficacy signals and so optimize cancer therapy.