Drug Development for Chronic Cancers: Time to Think Differently?

As the treatments for epithelial cancers have inched forward, the chronic management of patients with high performance status has become a common problem in the practice of oncology. This conundrum is clearly illustrated by the excellent, yet negative, randomized trial by Colombo et al that accompanies this editorial. This large, well-designed clinical trial tested another modestly active agent, patupilone, in comparison with pegylated liposomal doxorubicin (PLD) in patients with platinum-resistant ovarian cancer. Sadly, this study did not meet its prespecified superiority end point, namely an overall survival improvement compared with the use of PLD. What drug development lessons can be learned from yet another trial that fails to meet its designed superiority outcome? There are several potential points for consideration by solid tumor oncologists and gynecologic oncologists as we design strategies to incrementally improve the lives of patients with cancer until we find the rare breakthroughs that will irrefutably extend patient survival. First, we need to acknowledge that the barriers for achieving major advances are formidable. Previously treated solid tumors have been selected in a devilishly Darwinian crucible of genetic instability, heterogeneity, and mutagenic primary therapy. Drug-resistant cancers tend to be broadly refractory to additional agents, regardless of mechanism. Platinum-resistant tumor response rates to topotecan, PLD, and trabectedin are all half of what would be expected in the untreated or platinum-sensitive patient groups. Without a predictive biomarker to enrich for patients who are likely to benefit, many nonresponders will be present in both arms of a randomized trial in platinum-resistant ovarian cancer, making it difficult to detect small but potentially important signs of clinical benefit. This low response rate and the brief duration of improvement combine to dictate very large and costly sample sizes. Yet even adequately sized superiority trials like that of Colombo et al are likely to fail. Table 1 details the recent phase III randomized trials in platinum-refractory ovarian cancer. From these trials, performed over more than a decade, it is apparent that classic chemotherapy development has hit a glass ceiling in platinum-resistant ovarian cancer. One must conclude that inferiority is a real possibility in these trials (because the approved drugs have reproducible, modest effects), therapeutic equivalence is an optimistic outcome, and superiority to current treatment is a distant, unlikely achievement. New superiority trials with classic chemotherapy must be regarded like third Hollywood marriages: a “triumph of hope over experience.” Second, our models for predicting success are unreliable. The phase II experience that led to this phase III trial is not yet published but is described as a single-arm, nonrandomized study. These modestly sized, nonrandomized trials are treacherous guides and have increasingly been criticized for their lack of predictive power. The reliability of single-arm, phase II trials is undermined by undefined patient selection factors and the wide variability that is caused by the