Curtailing the High Rate of Late-Stage Attrition of Investigational Therapeutics Against Unprecedented Targets in Patients with Lung and Other Malignancies

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Abstract
A greater understanding of the pathogenesis and biology of cancer coupled with major advances in biotechnology has resulted in the identification of rationally designed, target-based (RDTB) anticancer therapeutics, ushering in new therapeutic opportunities and high expectations for the future as well as developmental challenges. Because these agents appear to principally target malignant cells, it is expected that they will produce less toxicity at clinically effective doses than nonspecific cytotoxic agents, but their target requirements are likely to be much more stringent. The innate complexity of the networks that contain elements targeted by these agents also decreases the probability that any single therapeutic manipulation will result in robust clinical activity and success when used alone, particularly in patients with solid malignancies that have multiple relevant signaling aberrations. In contrast, proof of principle and robust antitumor activity may be most efficiently demonstrated in nonrandomized evaluations involving tumors that are principally driven by aberrations of the specific target. The predominant therapeutic manifestation of RDTB agents in preclinical studies is due to decreased tumor growth rates and will likely be similar in the clinic; however, such manifestations are not readily detectable and quantifiable using nonrandomized clinical evaluations. To curtail the increasing rate of late-stage attrition of RDTB agents, which, if maintained, will stymie progress in cancer therapy, the design of initial nonrandomized evaluations, particularly the selection of tumors and patients, must be guided by the principal biological features of the agents. Next, evaluations, some of which must be randomized, can be performed in a wide range of tumor types, depending on the presence and relevance of the target. To validate the concept of RDTB therapeutics and to realize their full potential, radically different development, evaluation, and regulatory paradigms must be adopted.