Abstract
An article in a recent edition of Current Oncology explored the validation of progression-free survival (pfs) as an endpoint in clinical trials of antineoplastic agents for metastatic colorectal cancer, metastatic renal cell carcinoma, and ovarian cancer. The support for pfs as a surrogate endpoint for overall survival (os) was elucidated. As with the aforementioned tumour types, advanced non-small-cell lung cancer (nsclc) has seen a rise in active agents since the year 2000. Those agents range from improved cytotoxics such as pemetrexed, to targeted therapies such as tyrosine kinase inhibitors of the epidermal growth factor receptor and agents that target the EML4-ALK gene mutation. More recently, it has also become apparent that histology plays an important role in the response to and outcomes of treatment. With the therapeutic options for patients with advanced nsclc increasing, concerns are being raised that the efficacy of drugs measured by os may be diluted in clinical trials, thereby underestimating their true clinical benefit. That possibility, together with the need to have efficacious drugs available to patients earlier, has resulted in the search for a surrogate to the os endpoint in advanced nsclc. The present article follows up the recent article on pfs as a surrogate. Although advances in identifying pfs as a valid surrogate endpoint for os have been made in other tumour types, in advanced nsclc, such surrogacy has not been formally validated. Until it has, os should remain the primary endpoint of clinical trials in advanced nsclc.
Highlights
Lung cancer is the leading cause of cancer death among men and women in North America[1]
With the therapeutic options for patients with advanced nsclc increasing, there are concerns that the efficacy of drugs measured by os may be diluted in clinical trials, thereby underestimating their true clinical benefit
Among all randomized controlled trials of systemic therapy in nsclc, breast cancer, and colorectal cancer published in five major journals from 1974 to 2009, the proportion of trials with pfs as the primary endpoint increased from 0% (1975–1984) to 20% (2005–2009)[9]
Summary
Lung cancer is the leading cause of cancer death among men and women in North America[1]. Measuring os as an endpoint in clinical trials requires large patient numbers and increased length of follow-up, potentially delaying the approval of new agents. Marginal differences in pfs observed between study arms might be a result of differences in subjective assessments of progression and might not represent clinically meaningful improvement, such as improvement of qol or performance status. Despite those limitations, the use of pfs as a primary endpoint in clinical trials is increasing. Among all randomized controlled trials of systemic therapy in nsclc, breast cancer, and colorectal cancer published in five major journals from 1974 to 2009, the proportion of trials with pfs as the primary endpoint increased from 0% (1975–1984) to 20% (2005–2009)[9]. A review of anticancer drug product approvals by the U.S Food and Drug Administration (fda) between 2005 and 2007 found that 17% of drug approvals for new indications (9 of 53) were based on trials with pfs endpoints[11]
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