Overall survival (OS) and disease-free progression (PFS) are two important indicators for evaluating the therapeutic effect of patients with non-small cell lung cancer. OS is the gold standard for clinical research endpoints. PFS is a surrogate indicator, which is susceptible to bias. Whether PFS can replace OS has always been a controversial topic. Dr. Natasha B. Leighl of the University of Toronto and his colleagues reviewed 200 clinical trials related to non-small cell lung cancer and found that fewer and fewer trials have OS as the primary endpoint.

Research points:

140324 Although overall survival is still the most common main evaluation indicator in phase III trials of new drugs for advanced non-small cell lung cancer, more and more trials have begun to use progression-free survival as the main evaluation indicator in the past decade.

Only trials earlier than 1990 would interpret the test results as negative due to insufficient survival (no statistical difference).

Dr. Natasha B. Leighl of the University of Toronto and his colleagues reviewed 200 articles and found that with the improvement of clinically relevant technology, in clinical trials of advanced lung cancer, overall survival is less and less used as the primary endpoint of the trial.

Before 2000, almost all phase III trials of advanced non-small cell lung cancer used survival as the main evaluation index. However, from 2001 to 2010, 19% of Phase III trials began to use other evaluation indicators instead of overall survival (compared with previous decades, P<0.001), and the most frequently used was progression-free survival ( 13%). Dr. Natasha B. Leighl of the University of Toronto and his colleagues report in the Journal of Clinical Oncology.

From 1990 to 2010, the proportion of trials using progression-free survival as the main evaluation indicator rose from 0% to 13%, they noted. The proportion of trials that meet the prescribed main evaluation indicators has remained unchanged, but the proportion of positive test results has increased. The authors write that although trials with overall survival as the main evaluation indicator have declined over time, there is no significant difference in this change.

They concluded that these findings raise questions about the design and interpretation of phase III trials for advanced non-small cell lung cancer. The purpose of this multi-phase clinical trial is to concentrate resources on promising drugs, and to eliminate toxic or least effective drugs at each stage. Our results suggest that we are gradually not good at accomplishing this task in advanced non-small cell lung cancer trials.

Clinical trials of advanced non-small cell lung cancer have produced first-line and second-line chemotherapy and targeted therapy drugs for patients after chemotherapy failure. However, the authors pointed out that the effects of these treatments were mediocre.

As pharmaceutical companies and the oncology community increase interest in non-small cell lung cancer, trial design and interpretation are changing. They continued. These changes include the choice of primary and secondary evaluation indicators, statistical power and sample size.

We advocate the use of progression-free survival as the main evaluation indicator, because more and more patients will switch to other treatment options after the disease progresses, and there are more and more treatment options. Although the US Food and Drug Administration has accepted the progression-free survival of patients with advanced non-small cell lung cancer as the main evaluation indicator for drug approval, everyone has not yet begun to do so.

Opponents who use progression-free survival as the main evaluation index question the subjectivity of evaluation and its relationship with clinically relevant results. Progression-free survival and other new evaluation indicators have aroused debate on the definition of clinically meaningful benefits.

In addition to changes in the design of clinical trials, the interpretation of these trials will also change. The authors said. There have been reports that although the efficacy of a new treatment is extremely limited or suspicious, more and more researchers are willing to interpret these results as positive.

Research Introduction:

In order to inform the discussion, Leighl and his colleagues wrote a literature review to examine the changes in the design and interpretation of advanced non-small cell lung cancer phase III trials over the past 30 years.

Initially, the authors identified 248 experimental studies published between 1980 and 2010. Excluding trials that did not meet systemic treatment criteria, the analysis included 203 independent studies: 32 published in the 1980s, 53 published in the 1990s, and 118 published in the last decade.

The size of the test sample ranged from 152 in the first ten years (median) to 413 in 2001-2010 (P<0.001). In the 1980s, triple therapy was the mainstay, and in the 1990s, dual therapy was the mainstay. In the last decade, there have been evaluations of targeted therapy. <>

The authors evaluate the changes in test interpretation by evaluating the statistical significance and the characteristics of statistically significant positive or negative results.

In the past 30 years, the proportion of trials with a significant improvement has remained relatively stable, about 30%. However, the percentage of test results that were positive (although the main evaluation indicators were not significantly improved) increased from 30% in the 1980s to 53% from 2001 to 2010.

Twenty-four trials were considered positive due to improvements in secondary evaluation indicators, 26 trials asserted that they were not inferior to (other drugs) in the absence of non-inferior trial design, and 9 trials were based on the numbers of the primary endpoint indicators Tend to require further testing.

Finally, the authors examined the extent to which patients benefited based on the definition of significantly improved survival. In 60 trials that reported a significant increase in survival, the median increase in survival between 1981 and 1990 was 3.9 months, and between 1991 and 2000, the median increase in survival was 2.4 months. In the last ten years, the median increase in survival is 2.5 months.

An analysis of all trials that reported positive results found that survival increased by 3.9 months during the first decade, survival increased by 2.0 months during the second decade, and survival increased between 2001 and 2010 0.9 months.

Our findings confirm the changes in the design of the Phase III trial for advanced non-small cell lung cancer, the authors concluded. In the past 30 years, although the sample size has been expanded, statistical power has been improved, and the design level has been improved, the obstacles to judging the clinical efficacy of new lung cancer drugs seem to be diminishing.

Original source:

http://www.medpagetoday.com/HematologyOncology/LungCancer/44584

Published literature:

Adrian G. Sacher, Lisa W. Le and Natasha B. Leighl .ShiftingPatterns in the Interpretation of Phase III Clinical Trial Outcomes in AdvancedNon--Small-Cell Lung Cancer: The Bar Is Dropping. JCO March 3, 2014,doi:10.1200/JCO .2013.52.7804