Increased industry funding and reliance on PFS as endpoint biggest shifts in mCRC trials since 1980

SAN FRANCISCO – None of the phase III randomized controlled trials in metastatic colorectal cancer conducted during 1980-1989 used progression-free survival as their endpoint, whereas approximately 40% of those conducted during 2010-2014 did, according to an analysis reported at the 2015 Gastrointestinal Cancers Symposium, sponsored by the American Society of Clinical Oncology.

Investigators led by Dr. Sunil Parimi, a fellow at the Tom Baker Cancer Centre, University of Calgary, Alberta, studied the characteristics of 192 phase III randomized controlled trials in metastatic colorectal cancer (mCRC) conducted between 1980 and 2014 and reported in an abstract or published article. To assess temporal trends, they split the trials into decades.

Susan London/Frontline Medical News

The use of overall survival as an endpoint peaked at 35% of trials in 2000-2009 and fell thereafter. None of the trials conducted in the first decade used progression-free survival (PFS) as their endpoint, whereas approximately 40% of those conducted in 2010-2014 did.

This trend “is one of the most surprising and interesting changes to me that has occurred over the decades,” Dr. Parimi commented in an interview. “Before, we used to use hard endpoints such as overall survival and quality of life, especially from the metastatic standpoint, and now that’s gradually started to taper off and surrogate endpoints have started to take the lead, progression-free survival in particular.”

Its use has likely contributed to increases in the proportions of trials meeting their primary endpoint (from 11% to 42%) and reporting in their conclusions that their results were positive (from 33% to 53%), “either warranting further study or endorsing a drug to be used in the general population,” he added.

Yet, PFS has not been validated as a surrogate for overall survival in this context, according to Dr. Parimi. “It is definitely still controversial whether or not we are looking at the outcomes that really matter in the mCRC population, or is it just something that’s more attainable,” he elaborated. “The proponents of it would say, it’s more difficult to find overall survival with later-line therapy, with cross-over trial designs, which are all new advents. So that’s why, partially at least, there is more of a dependence on progression-free survival as an endpoint.”

The proportion of trials relying on industry funding rose from 1990 onward, from roughly 10% to 60%. There were also increases during the study period in the median number of agents used in investigational arms (from 1.5 to 2.5) and in the share of trials evaluating targeted therapies (from 0% to 68%), Dr. Parimi reported in a poster session.

The proportion of the trials that were published more than doubled, going from 39% of those conducted during 1980-1989 to 82% of those conducted during 2000-2014.

A variety of factors may be contributing to the observed trends, he speculated. “It’s pressure from various angles that’s driving people to come up with a positive study, quote unquote, regardless of what the outcome is. The intention behind doing this study was just to raise awareness of what the shifts are and then subsequently, we can debate the ramifications or the implications of those shifts.”

Although median progression-free and overall survival on the trials increased during the study period, the absolute magnitude of benefit derived from the investigational therapy relative to the control therapy did not increase significantly, hovering at about a 1-month gain for each endpoint across decades.

“The improvements that we make are always small amounts – there have not been any big explosions,” Dr. Parimi commented. “There are a number of reasons why that may be. But maybe it’s because we have come up with so many therapeutics, and so much research has been put into this already that we just are not making those dramatic findings.”

The study’s results have important implications when it comes to allocation of research funding, according to Dr. Parimi, who disclosed that he had no relevant conflicts of interest.

“I think that if we did fewer studies that had a higher standard of efficacy or outcome, we’d save more money on the drug-development process, and we could shift it to areas where it was truly needed. And I actually think that we can accelerate drug development in that way, as opposed to coming out with multiple bodies of literature that disperse the amount of funds that we use for different projects, and drugs which may or may not have true hard-outcome benefits, at least in the eyes of many,” he concluded. “So if we can allow for that paradigm shift, or maybe rather go back to that, fewer trials with more quality would definitely be advantageous.”

SAN FRANCISCO – None of the phase III randomized controlled trials in metastatic colorectal cancer conducted during 1980-1989 used progression-free survival as their endpoint, whereas approximately 40% of those conducted during 2010-2014 did, according to an analysis reported at the 2015 Gastrointestinal Cancers Symposium, sponsored by the American Society of Clinical Oncology.

Investigators led by Dr. Sunil Parimi, a fellow at the Tom Baker Cancer Centre, University of Calgary, Alberta, studied the characteristics of 192 phase III randomized controlled trials in metastatic colorectal cancer (mCRC) conducted between 1980 and 2014 and reported in an abstract or published article. To assess temporal trends, they split the trials into decades.

Susan London/Frontline Medical News

The use of overall survival as an endpoint peaked at 35% of trials in 2000-2009 and fell thereafter. None of the trials conducted in the first decade used progression-free survival (PFS) as their endpoint, whereas approximately 40% of those conducted in 2010-2014 did.

This trend “is one of the most surprising and interesting changes to me that has occurred over the decades,” Dr. Parimi commented in an interview. “Before, we used to use hard endpoints such as overall survival and quality of life, especially from the metastatic standpoint, and now that’s gradually started to taper off and surrogate endpoints have started to take the lead, progression-free survival in particular.”

Its use has likely contributed to increases in the proportions of trials meeting their primary endpoint (from 11% to 42%) and reporting in their conclusions that their results were positive (from 33% to 53%), “either warranting further study or endorsing a drug to be used in the general population,” he added.

Yet, PFS has not been validated as a surrogate for overall survival in this context, according to Dr. Parimi. “It is definitely still controversial whether or not we are looking at the outcomes that really matter in the mCRC population, or is it just something that’s more attainable,” he elaborated. “The proponents of it would say, it’s more difficult to find overall survival with later-line therapy, with cross-over trial designs, which are all new advents. So that’s why, partially at least, there is more of a dependence on progression-free survival as an endpoint.”

The proportion of trials relying on industry funding rose from 1990 onward, from roughly 10% to 60%. There were also increases during the study period in the median number of agents used in investigational arms (from 1.5 to 2.5) and in the share of trials evaluating targeted therapies (from 0% to 68%), Dr. Parimi reported in a poster session.

The proportion of the trials that were published more than doubled, going from 39% of those conducted during 1980-1989 to 82% of those conducted during 2000-2014.

A variety of factors may be contributing to the observed trends, he speculated. “It’s pressure from various angles that’s driving people to come up with a positive study, quote unquote, regardless of what the outcome is. The intention behind doing this study was just to raise awareness of what the shifts are and then subsequently, we can debate the ramifications or the implications of those shifts.”

Although median progression-free and overall survival on the trials increased during the study period, the absolute magnitude of benefit derived from the investigational therapy relative to the control therapy did not increase significantly, hovering at about a 1-month gain for each endpoint across decades.

“The improvements that we make are always small amounts – there have not been any big explosions,” Dr. Parimi commented. “There are a number of reasons why that may be. But maybe it’s because we have come up with so many therapeutics, and so much research has been put into this already that we just are not making those dramatic findings.”

The study’s results have important implications when it comes to allocation of research funding, according to Dr. Parimi, who disclosed that he had no relevant conflicts of interest.

“I think that if we did fewer studies that had a higher standard of efficacy or outcome, we’d save more money on the drug-development process, and we could shift it to areas where it was truly needed. And I actually think that we can accelerate drug development in that way, as opposed to coming out with multiple bodies of literature that disperse the amount of funds that we use for different projects, and drugs which may or may not have true hard-outcome benefits, at least in the eyes of many,” he concluded. “So if we can allow for that paradigm shift, or maybe rather go back to that, fewer trials with more quality would definitely be advantageous.”

SAN FRANCISCO – None of the phase III randomized controlled trials in metastatic colorectal cancer conducted during 1980-1989 used progression-free survival as their endpoint, whereas approximately 40% of those conducted during 2010-2014 did, according to an analysis reported at the 2015 Gastrointestinal Cancers Symposium, sponsored by the American Society of Clinical Oncology.

Investigators led by Dr. Sunil Parimi, a fellow at the Tom Baker Cancer Centre, University of Calgary, Alberta, studied the characteristics of 192 phase III randomized controlled trials in metastatic colorectal cancer (mCRC) conducted between 1980 and 2014 and reported in an abstract or published article. To assess temporal trends, they split the trials into decades.

Susan London/Frontline Medical News

The use of overall survival as an endpoint peaked at 35% of trials in 2000-2009 and fell thereafter. None of the trials conducted in the first decade used progression-free survival (PFS) as their endpoint, whereas approximately 40% of those conducted in 2010-2014 did.

This trend “is one of the most surprising and interesting changes to me that has occurred over the decades,” Dr. Parimi commented in an interview. “Before, we used to use hard endpoints such as overall survival and quality of life, especially from the metastatic standpoint, and now that’s gradually started to taper off and surrogate endpoints have started to take the lead, progression-free survival in particular.”

Its use has likely contributed to increases in the proportions of trials meeting their primary endpoint (from 11% to 42%) and reporting in their conclusions that their results were positive (from 33% to 53%), “either warranting further study or endorsing a drug to be used in the general population,” he added.

Yet, PFS has not been validated as a surrogate for overall survival in this context, according to Dr. Parimi. “It is definitely still controversial whether or not we are looking at the outcomes that really matter in the mCRC population, or is it just something that’s more attainable,” he elaborated. “The proponents of it would say, it’s more difficult to find overall survival with later-line therapy, with cross-over trial designs, which are all new advents. So that’s why, partially at least, there is more of a dependence on progression-free survival as an endpoint.”

The proportion of trials relying on industry funding rose from 1990 onward, from roughly 10% to 60%. There were also increases during the study period in the median number of agents used in investigational arms (from 1.5 to 2.5) and in the share of trials evaluating targeted therapies (from 0% to 68%), Dr. Parimi reported in a poster session.

The proportion of the trials that were published more than doubled, going from 39% of those conducted during 1980-1989 to 82% of those conducted during 2000-2014.

A variety of factors may be contributing to the observed trends, he speculated. “It’s pressure from various angles that’s driving people to come up with a positive study, quote unquote, regardless of what the outcome is. The intention behind doing this study was just to raise awareness of what the shifts are and then subsequently, we can debate the ramifications or the implications of those shifts.”

Although median progression-free and overall survival on the trials increased during the study period, the absolute magnitude of benefit derived from the investigational therapy relative to the control therapy did not increase significantly, hovering at about a 1-month gain for each endpoint across decades.

“The improvements that we make are always small amounts – there have not been any big explosions,” Dr. Parimi commented. “There are a number of reasons why that may be. But maybe it’s because we have come up with so many therapeutics, and so much research has been put into this already that we just are not making those dramatic findings.”

The study’s results have important implications when it comes to allocation of research funding, according to Dr. Parimi, who disclosed that he had no relevant conflicts of interest.

“I think that if we did fewer studies that had a higher standard of efficacy or outcome, we’d save more money on the drug-development process, and we could shift it to areas where it was truly needed. And I actually think that we can accelerate drug development in that way, as opposed to coming out with multiple bodies of literature that disperse the amount of funds that we use for different projects, and drugs which may or may not have true hard-outcome benefits, at least in the eyes of many,” he concluded. “So if we can allow for that paradigm shift, or maybe rather go back to that, fewer trials with more quality would definitely be advantageous.”