May 29, 2014 6 Comments
When asked to define what constituted pornography in his 1964 Supreme Court decision (Jacobellis versus Ohio 1964) Justice Potter Stewart stated, “I know it when I see it.” When I reviewed an article on the changing landscape of clinical trials in non-small cell lung cancer (NSCLC) (Shifting patterns in the interpretation of phase 3 clinical trial outcomes in advanced non-small cell lung cancer: The bar is dropping, Sacher A. G. et al, J Clin Oncol May 10, 2014), Justice Stewart came to mind.
The authors selected 203 NSCLC trials from a total of 245 studies conducted between 1980 and 2010. They compared how often the studies met their endpoints with how often the study authors’ called the results “positive.” Among the findings, it seems that earlier studies (before the year 2000) were geared for overall survival, while later studies (after 2000) overwhelmingly favored progression free survival. Although patient survivals changed little, the number of trials reported as successful increased dramatically.
Progression-free survival measures how long it takes for a patient to fail treatment. That is, for the disease to worsen on therapy. Its use increased after 2000 when Docetaxel, for the first time, provided a survival advantage in recurrent disease.
The FDA’s willingness to accept progression-free survival for drug approval was originally based on their expectation that the benefit would be “substantial and robust” but they did not define the term. One group has suggested that improvements should be of the magnitude of 50 percent. Another went even further suggesting a doubling of the survival advantage.
Unfortunately, the trend has been just the opposite. Trials from the 1980s on average gave a 3.9 month improvement, which fell to a meager 0.9 months after 2000.
What are patients and their physicians to make of these trends? First, the large clinical trials, that are so common today, are much more likely to achieve significance. The troubling corollary is that statistical significance is not the same as clinical relevance. The “publish or perish” climate, combined with the skyrocketing cost of drug development has placed inordinate demands upon investigators and their sponsors to achieve “positive results.” Fearing failure, many pharmaceutical companies sponsor “safe” trials that provide incremental advances but few breakthroughs.
Meaningful advances in oncology are generally quite evident. The first use of Interferon alpha for the treatment of hairy cell leukemia provided a response rate of 100 percent and earned a lead article in the New England Journal of Medicine (NEJM) with only seven patients!
Similarly the 57 percent response rate for Crizotinib in ALK positive lung cancer required only 82 patients for a place in the NEJM. Unfortunately, the failure of contemporary investigators to identify more “paradigm changing therapies” has forced many to lower the bar.
The clear solution to the problem is the better selection of candidates for therapy. Despite advances in molecular biopsy a paucity of truly effective companion diagnostics exist. Outside of EGFR, ALK, and ROS-1, it is anybody’s guess how to manage the vast majority of non-small cell lung cancer patients.
While we expand our armamentarium and develop better companion diagnostics, today we can apply measures of cellular response (as found in an EVA-PCD assay)
that capture all of operative mechanisms of sensitivity for all classes of drugs. While it is not always possible to know why a patient will respond, it is possible to know that they will respond. In the words of Judge Stewart, when it comes to a responsive lung cancer patient “I know it when I see it.”