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Shifting Patterns in Phase III Trial Interpretation

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Shifting Patterns in the Interpretation of Phase III Clinical Trial Outcomes in Advanced Non–Small-Cell Lung Cancer: The Bar Is Dropping

Adrian G. Sacher, Lisa W. Le and Natasha B. Leighl

Princess Margaret Cancer Centre/University Health Network, University of Toronto, Toronto, Ontario, Canada.

Corresponding author: Natasha B. Leighl, MD, MMSc, Department of Biostatistics, Division of Medical Oncology/Hematology, Princess Margaret Cancer Centre/University Health Network, University of Toronto, 610 University Ave, 5-105, Toronto, Ontario, Canada M5G 2M9; e-mail: Natasha.Leighl@uhn.ca



Despite multiple trials of new agents in advanced non–small-cell lung cancer (NSCLC), outcomes remain poor. This study explores how the design and interpretation of randomized trials in advanced NSCLC has changed over time.


Phase III randomized controlled trials of systemic therapy for advanced NSCLC between 1980 and 2010 were identified, and their primary end point, outcome, statistical significance, and conclusions were recorded.


Of 245 trials identified, 203 were eligible for study inclusion. Although overall survival remains the most common primary end point of phase III trials, more trials from the last decade have used progression-free survival instead (none in 1980 to 1990, 13% in 2001 to 2010; P = .002). The percentage of trials meeting their primary statistical end points remained stable over time; however, the percentage of trials reporting a positive outcome without meeting that end point increased (30% in 1980 to 1990, 53% in 2001 to 2010; P < .001). A trend toward decreasing magnitude of survival gain in positive trials was seen over time (3.9 months in 1980 to 1990, 2.5 months in 2001 to 2010; P = .11), with a concomitant increase in the sample size of clinical trials over the same time period (median: 152 patients in 1980 to 1990, 413 in 2001 to 2010; P < .001). Only studies predating 1990 reported negative results as a result of insufficient magnitude of survival benefit despite statistical significance.


A significant shift has occurred over the past three decades in the design and interpretation of phase III trials in advanced NSCLC. The use of survival as the primary measure of benefit is declining, as is the magnitude of benefit deemed clinically relevant.

J Clin Oncol 32.

http://jco.ascopubs.org/content/early/2 ... l.pdf+html

Progression-Free Survival: Meaningful or Simply Measurable?


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Robert A. Nagourney, M.D.

When asked to define what constituted xxxography 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 functional cytometric assays) 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.”

Are the reports on Nivolumab as treatment for NSLC cause for near term hope or to be viewed with restraint. The drug appears to have been fast tracked, but reports have gone from relatively optimistic to less so in the last year or so.

Bristol-Myers Squibb statistical data:

http://web1.pharmiweb.com/PressReleases ... 4f9rBtOUc8

Positive report in BusinessWeek Oct 2013:

http://www.businessweek.com/ap/2013-10- ... ancer-drug

More restrained report in Business Week May 15, 2014:

http://www.businessweek.com/ap/2014-05- ... study-data

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Quality of life (QoL) and symptom benefit should be accepted by clinicians and regulators as additional coprimary endpoints in clinical trials of chemotherapies for platinum-resistant and refractory ovarian cancer, according to a group of experts.

These measures are "the most important aims of treatment" in these patients because improvements in overall and progression-free survival (OS and PFS) have hit a ceiling in trial after trial of chemotherapies, say Michael Friedlander, MD, and colleagues from the Prince of Wales Hospital, in New South Wales, Australia. The group published a letter on May 13 in the Journal of Clinical Oncology.

The conventions of OS and PFS should remain in place in trials but be supplemented by these "other meaningful ways to measure treatment benefit," they say.

The letter writers are responding to a recent study and accompanying editorial published in the journal that related to 2 chemotherapies being compared in a phase 3 trial in this patient population (J Clin Oncol. 2013;30:3841-3847). In the trial, patupilone and liposomal doxorubicin produce the same PFS (3.7 months median) and a comparable OS (13.2 vs 12.7 months).

In short, Dr. Friedlander and his colleagues believe that palliative chemotherapy should be also evaluated for improvement in quality of life and symptoms and that those measures should count in the drug approval process.

There needs to more than one "route to registration of new agents," they say about the need for regulatory changes.

Agreed, said David Spriggs, MD, of Memorial Sloan-Kettering Cancer Center, in New York City. He served as the editorialist on the study of patupilone vs liposomal doxorubicin and, in turn, responded to the Australian letter about his essay and the trial.

"It is essential," Dr. Spriggs writes, that "comfort, function and quality of life have a place in the commercialization pathway."

Both he and the Australians believe that "today's development process seems excessively focused on duration of life."

Patients with recurrent ovarian cancer…are incurable with today's therapies.

"Patients with recurrent ovarian cancer (platinum-sensitive or resistant) are incurable with today's therapies," he writes, adding that life expectancy is 12 to 18 months.

The problem of poor prognosis is not limited to ovarian cancer, adds Dr. Spriggs. "In these settings…a patient's goal is to enjoy a comfortable and highly enjoyable life for as long as possible," he says.

But accommodating QoL as a primary endpoint in a drug approval trial "has historically been quite difficult," Dr. Spriggs adds. "This is a reflection of the fact that QoL can be slippery when reduced to practice."

Dr. Friedlander and colleagues report that there is a major clinical trial under way (Gynecologic Cancer Intergroup Symptom Benefit Trial) that is seeking to "validate an instrument to measure symptom benefit that can be applied to clinical trials." The trial is also seeking to identify subsets of patients who are most likely to benefit from palliative chemotherapy.

The authors have disclosed no relevant financial relationships.

Citation: New Endpoints Proposed for Chemotherapy in Ovarian Cancer. Medscape. Jun 18, 2013.

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"These measures are 'the most important aims of treatment' in these patients because improvements in overall and progression-free survival (OS and PFS) have hit a ceiling in trial after trial of chemotherapies,"

I personally think this is scandalous. What they are saying is that they are coming up with any drugs which are any better than the drugs that they have been using all along. So big Pharma has no new drugs to sell. So they change the goal line. Or, more accurately, they lower the bar. Progression free survival and overall survival are hard objective endpoints. Quality of life is totally squishy and unobjective. So future clinical trials in cancer are going to be designed and scored by psychologists. Patients should never ever let them get away with this. Their feet should be held close to the fire. Shame on them.

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