The hazards of endpoints.

The article by Hoos et al. (1) in this issue of the Journal makes three recommendations about endpoints in immunotherapy trials: 1) cellular immune response assays are highly variable and require standardization; 2) immunotherapies may evince unusual patterns of antitumor response and therefore require different endpoints; and 3) immunotherapy may have a delayed benefit on survival, which requires a different approach to achieving statistical power in clinical trials. All three recommendations are important and indeed are worthy of consideration in oncology more generally. I will expand on the authors' points, focusing on the importance of immune response, biomarkers, and tumor response and progression. Historically, cancer drug development has been remarkably inefficient. Suppose we were to use the same approach in developing agricultural products, for example, corn varieties. We start with many genetically distinct varieties of corn. In the first phase of development, we would plant seeds from each variety and spray the sprouting plants with pesticide. We would drop from further development those varieties that seem adversely affected. In the next phase, we would plant seeds from those varieties still under consideration and pull up the stalks 8 weeks later to weigh the ears. Small ear varieties would be discarded. In the next phase, 14 weeks after planting, we assess the sugar content of the kernels, discarding those with low concentrations. Then, we would consider har-diness and so on. We'd probably end up with lousy corn and we'd wonder if we had discarded a better overall variety along the way. One problem with this approach to choosing corn varieties is that we would have failed to address the relationships among the various effects. Another is that we would have failed to observe the effects of all the variables at maturity. But the biggest problem is the staccato learning process. Each experiment was a discrete unit rather than one part of a continual learning process in which the answers to relevant questions got stronger over time. In the clinical development of cancer drugs, we consider toxicity early on, then antitumor effect (or immunologic effect or other biomarker effect), and then clinical effect. We fail to assess and relate these effects over the patients' follow-up, and we fail to associate them with the primary clinical endpoint in a longitudinal fashion. We must address the entire patient, including the patient's course of disease over time. Especially important are tumor burden and factors that …