Evaluating overall survival improvement as a cancer clinical trials end point is time-consuming and costly, but traditional radiographic measurements of tumours might not accurately reflect clinical benefit due to confounding factors
Molecular imaging aims to augment traditional radiographic measurements by differentiating malignant from normal tissues in order to better capture biological or molecular responses to therapy
Circulating tumour factors, such as proteins, DNA, and cells, hold great promise as early predictors of therapeutic response and disease recurrence
Tumour-derived factors present in the circulation might also enable early detection of molecular resistance markers and provide information on tumour heterogeneity
Pharmacodynamic biomarkers evaluate the biological, molecular, and functional effects of a drug on its target, potentially offering insights into mechanisms of action of new compounds and/or validating new targets
Validation of specific biomarkers requires their broad inclusion in clinical trials for assessment of performance
In cancer-drug development, a number of different end points have been used to establish efficacy and support regulatory approval, such as overall survival, progression-free survival (PFS), and radiographic response rate. However, these traditional end points have important limitations. For example, in lung cancer clinical trials, evaluating overall survival end points is a protracted process and these end points are most reliable when crossover to the investigational therapy is not permitted. Furthermore, although radiographic surrogate end points, such as PFS and response rate, generally correlate with clinical benefit in the setting of cytotoxic chemotherapy and molecular targeted therapies, novel immunotherapies might have atypical response kinetics, which confounds radiographic interpretation. In this Review, we discuss the need to develop alternative or surrogate end points for lung cancer clinical trials, and focus on several new biomarkers that could serve as surrogate end points, including functional imaging biomarkers, circulating factors (tumour proteins, DNA, and cells), and pharmacodynamic tumour markers. By enabling the size, duration, and complexity of cancer trials to be reduced, biomarker end points hold the promise to accelerate drug development and improve patient outcomes.
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We thank Dr Phil Lavori for helpful discussions surrounding statistical implications of biomarker-driven clinical trials. The work of J.F.G. is funded in part by the NIH National Cancer Institute (Grant: C06CA059267). The work of A.T.S. is funded in part by the NIH National Cancer Institute (Grant: R01CA164273).
J.W.N. has received grants for research support from ArQule, Boehringer–Ingelheim, Merck and Roche/Genentech, and has acted as a consultant for Clovis Oncology. J.F.G. has acted as a consultant for Boehringer–Ingelheim, Jounce Therapeutics and Kyowa Hakko Kirin. A.T.S. has acted as a consultant for Ariad, Chugai, Genentech, Ignyta, Novartis and Pfizer, and has received honouraria for speaking for Novartis, Pfizer and Roche.
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Neal, J., Gainor, J. & Shaw, A. Developing biomarker-specific end points in lung cancer clinical trials. Nat Rev Clin Oncol 12, 135–146 (2015). https://doi.org/10.1038/nrclinonc.2014.222
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