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SAN DIEGO -- Most cancer drugs granted accelerated approval by the FDA have not demonstrated a benefit in overall survival (OS) or quality of life within 5 years, according to a cohort study presented here.

Of 46 cancer drug-indication pairs that received accelerated approval from 2013 to 2017, 43% demonstrated a clinical benefit in confirmatory trials, reported Edward Scheffer Cliff, MBBS, MPH, of Brigham and Women's Hospital and Harvard Medical School in Boston, during a press briefing at the American Association for Cancer Research annual meeting.

Of note, 63% (29 drugs) were converted to regular approval, 22% were withdrawn, and 15% were ongoing after a median of 6.3 years. Among drug-indication pairs that were converted to regular approval from 2013 to 2023, less than half were based on a pivotal trial or trials demonstrating an improvement in OS, Cliff and team detailed in .

Among the 29 indications that were converted to regular approval, 69% showed clinical benefit: 24% showed improvements in both OS and quality of life, 24% improved OS without demonstrating a quality-of-life benefit, and 21% improved quality of life without improving OS. The other 31% were converted without showing benefits in OS or quality of life in confirmatory trials.

The researchers noted that "despite its origins in HIV treatment, accelerated approval is now most common in oncology, with approximately one-third of all oncology drug approvals using the pathway and more than 80% of all accelerated approvals being granted for cancer therapies."

In his presentation, Cliff said that "the FDA should ensure that manufacturers run confirmatory trials powered to robustly assess clinically meaningful endpoints, and physicians should consider -- and communicate to their patients -- a residual uncertainty of clinical benefit when they offer a novel therapy to their patients."

Cliff and colleagues also reported that the time from accelerated approval to projected confirmatory trial completion increased from 3.4 years in 2013 to 4.5 years in 2017. For the withdrawn indications, duration from accelerated approval to withdrawal decreased from 9.9 years to 3.6 years. For the 29 converted indications, duration from accelerated approval to conversion to regular approval increased from 1.6 years to 3.6 years.

The authors also conducted an analysis of 66 drug-indication pairs that received accelerated approval and were either converted to regular approval (48) or withdrawn (18) between 2013 and 2023.

Of those 48, 18 had the same indication for accelerated and regular approval, 18 included an earlier line of therapy, eight were broadened without moving to an earlier line of therapy, three were narrowed, and one was changed in an alternate way.

Cliff reported that most of these conversions to regular approval relied on measures other than OS:

• 40% were converted based on OS
• 44% on progression-free survival
• 10% on response rate plus duration of response
• 4% on response rate
• 2% despite a negative confirmatory trial

Shivaani Kummar, MD, of Oregon Health & Science University in Portland, who moderated the press briefing, said that as a practicing oncologist she welcomes the possibility that her patients can get more rapid access to novel therapies through the accelerated approval process, but that "once you do that, it's hard to do confirmatory trials because patients won't accept some other treatment and [oncologists are hesitant] to randomize patients to something else."

Cliff suggested that one way of addressing that problem would be to ensure that confirmatory trials are "recently or reasonably accrued at the time of accelerated approval."

For this study, Cliff and colleagues identified 129 cancer drug-indication pairs that received accelerated approval from January 2013 to July 2023. They looked at accelerated approvals with more than 5 years of follow-up (approved through December 2017), which included 46 indications, of which 52% were original indications and 48% were supplemental.

Forty-one percent of drugs had preapproval pivotal trials with response rate as the primary endpoint, with a mean response rate of 50.6%, and 46% used response rate with duration of response, with a mean response rate of 40.7% and average median duration of response of 10.1 months. Progression-free survival was used in 9% of trials, and OS and complete remission rate were each the primary endpoint for one accelerated approval.

Cliff and team acknowledged that the study had several limitations, including the fact that they only looked at confirmatory trial data to evaluate the clinical benefit of cancer indications for accelerated approvals, and that subsequent or larger trials in the same trial population could provide evidence of clinical benefit. In addition, seven drugs were still awaiting confirmatory trial results -- drugs that may eventually show clinical benefit.

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