Rigorousness of Phase III trials for lung cancer may be declining

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1. Phase III trials for advanced non-small-cell lung cancer (NSCLC) over the last three decades have been increasingly using progression-free survival (PFS) rather than overall survival as a primary endpoint.

2. The threshold for declaring clinical relevance for positive outcomes is decreasing.

Evidence rating level: 2 (Good)

Study Rundown: Advanced NSCLC is an extremely aggressive form of cancer with poor outcomes, and thus has been the subject of many clinical trials over the past several decades. Though many new agents have been developed, overall outcomes remain poor. The purpose of this literature review was to evaluate changes in the design and interpretation of randomized trials on NSCLC over the last three decades. After analyzing 203 trials, the authors found that sample sizes, the use of PFS as a primary outcome rather than overall survival, and the number of trials reporting a positive outcome has increased over time. The latter findings were attributed to studies recommending new agents based on statistically non-significant positive trends or benefit in secondary outcomes like toxicity. Based on these findings, the authors suggested that while statistical power has increased, the standards for judging clinical benefit of new therapies are falling. As a result, the cost-benefit of large phase III trials may be decreasing, and that clearer guidelines for clinically relevant outcomes may need to be established.

Click to read the article in JCO

In-Depth [retrospective literature review]: The authors conducted a literature search for all phase III randomized controlled clinical trials of systemic therapy for NSCLC through Pubmed and professional oncology society guidelines. Eligible studies were phase III, evaluated systemic therapy only, focused on advanced NSCLC, and were conducted between 1980 and 2010. Studies were designated as positive if the authors explicitly recommended the new treatment for clinical use or for further evaluation. Other extracted data included publication date, size, primary and secondary outcomes, trial outcome, statistical significance, and the magnitude of clinical benefit in terms of the primary outcome. A total of 203 trials were ultimately included. Overall survival was still the most common primary end point measured, but from 1980 to 2010, the use of progression free survival increased significantly (none from 1980-1990, 13% in 2001-2010, P = 0.002). The proportion of trials reporting a positive outcome without meeting their primary statistical end points increased from 30% in 1980-1990 to 53% in 2001-2010, P < 0.001. Sample size increased significantly (P < 0.001). Furthermore, trends toward decreasing magnitude of survival gain (P = 0.11) were seen.

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