Setting the bar for therapeutic trials in non-small-cell lung cancer: how low can we go?

Despite the progress achieved in the early diagnosis and treatment of lung cancer over the last 40 years, more than 220,000 US citizens will receive a lung cancer diagnosis in 2014, the vast majority of whom will die as a result of their disease within a few months. Fortunately, the pace of discovery has quickened and produced greater insight into lung cancer biology, which in turn has yielded new potential therapeutic targets. In fact, today there are more than 120 drugs in development for lung cancer, in contrast with just 25 years ago, when thoracic oncologists were limited to fewer than a dozen chemotherapy agents to treat advanced disease. However, getting these newer drugs to the clinic as quickly as possible is a daunting task that has elicited much debate pertaining to the design and interpretation of phase III clinical trials. To investigate how the design and interpretation of clinical trials conducted in advanced non–small-cell lung cancer (NSCLC) may have changed over time, Sacher et al undertook a review of all phase III therapeutic studies performed between 1980 and 2010. In the article that accompanies this editorial, each of the 203 unique clinical trials evaluated by Sacher et al was assessed for its design, primary outcome, reported statistical difference, and the magnitude of survival benefit. For the purposes of their analysis, a trial was deemed to be “positive” if the authors of the original report “recommended the new treatment arm be adopted” on any basis or if “further study” of the experimental arm was recommended. In addition, if the authors of the original report “explicitly stated that the study agent was either equal in efficacy or noninferior to the control arm,” Sacher et al classified the study as “asserting noninferiority. ” Several noteworthy trends were identified in this three-decade retrospective analysis. First, the number of advanced NSCLC phase III trials increased from 32 in the 1980s to more than 100 studies executed between 2001 and 2010. Second, sample size increased over time from a median enrollment of approximately 150 to more than 400 participants per study. Third, there was a change in the make-up of therapeutic strategies under investigation, from primarily multiagent triplet chemotherapy regimens in the 1980s to mainly doublet chemotherapy regimens in the 1990s, and most recently, to an increase in the number of trials (approximately one in five studies) involving targeted therapies in the 2000s. Fourth, coincident with the change in therapeutic strategies, there was a shift in primary trial end point from an exclusive use of overall survival (OS) in the 1980s and 1990s to more frequent use of progression-free-survival (PFS) after 2000. Fifth, a statistically significant trend toward more positive interpretations of trial results was noted after 2000, compared with the decades 1980 through 2000, although the fraction of studies meeting their preplanned primary statistical end point remained essentially unchanged. Finally, over time, the magnitude of survival benefit deemed “clinically relevant” progressively diminished, from a median of 3.9 months in the 1980s to just 0.9 months after 2000 (P .001). Interestingly, only before 1990 were studies deemed to be “negative” on the basis of an insignificant magnitude of survival benefit, despite statistical significance. Sacher et al suggest their data “raise questions regarding the design and interpretation of phase III trials in NSCLC. ” In reflecting on these trends, it seems doubtful that many oncologists or victims of lung cancer would lament the increase in the overall number of NSCLC phase III trials, given the magnitude of this public health problem. Relatedly, the increase in sample size can be viewed as a welcome development that represents a positive response to previous criticisms regarding lack of adequate power required to detect clinically meaningful survival differences in the National Cancer Institute–sponsored trials that were conducted between 1973 and 1994. Likewise, the shift away from exclusive chemotherapy-based therapeutic questions toward more trials of targeted therapies undoubtedly reflects advances in our knowledge of tumor biology and the investigation of new, less toxic cytotoxic and targeted therapies (eg, pemetrexed, erlotinib, and crizotinib). None of these developments seems particularly problematic. By contrast, the shift toward PFS as a preferred primary end point in NSCLC clinical trials is more controversial. The motivation to use PFS as a preferred end point, as opposed to OS, stems in part from an understandable desire to reduce the duration and cost of cancer clinical trials. However, unlike colon cancer, for instance, a surprisingly small amount of data supports the role of PFS as a surrogate for OS in advanced lung cancer trials. Recently, Laporte et al attempted to settle this deficit by way of a meta-analysis using individual patient data derived from five randomized trials that compared front-line docetaxel-based chemotherapy with vinorelbine-based chemotherapy. Unfortunately, the results of this analysis offered at best only modest support for using PFS in lieu of OS, at least in the conventional chemotherapy setting, leading some thoracic oncology experts to urge continued use of OS as the preferred primary end point in future lung cancer trials. However, in circumstances in which active drugs are available for recurrent or progressive disease, as is now the case with NSCLC, PFS is viewed by some experts as an appropriate primary JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 32 NUMBER 14 MAY 1