Most therapies tested in phase 3 cancer trials fail to confer meaningful survival benefit

ByRyan Lawrence

More than 80% of therapies tested in phase 3 oncology trials did not demonstrate clinically meaningful benefit in extending survival, according to results of a study published in JNCCN — Journal of the National Comprehensive Cancer Network.

In quantifying the number of false-positive, false-negative and true-negative trial results, investigators called for better solutions in applying more stringent statistical criteria to phase 2 trials and rethinking the process for moving a new therapy to phase 3 testing.

Phase 3 trials and overall survival. — Data derived from Shen C, et al. *J Natl* *Compr* *Canc* *Netw*. 2021;doi:10.6004/jnccn.2020.7690.

“In particular, collecting trial data from early phases and analyzing those data together with phase 3 data are important to achieve a better understanding of the problem. More research is needed in this regard,” Changyu Shen, PhD, associate professor at Harvard Medical School at the time of this study, told Healio.

Changyu Shen

Shen and colleagues analyzed summary data of 187 OS and 216 progression-related survival (PRS) endpoints for 362 industry-sponsored, randomized, phase 3 superiority oncology trials conducted from 2008 to 2017. The trials, predominantly two-arm studies of an intervention drug compared with a control treatment, were largely in lung, breast, gastrointestinal, and hematologic cancers.

Results showed that of the 56 OS endpoints that achieved statistical significance, the true efficacy of experimental therapies did not reach the projected effect size in 33 cases (58.4% false-positives). Additionally, among 131 OS endpoints that did not achieve statistical significance, the true efficacy of experimental therapies reached the projected effect size in one case (0.9% false-negatives). There were 34 (24.5%) false-positives and three (4.2%) false-negatives among PRS endpoints.

Use of more stringent statistical criteria in determining which therapies advance to phase III trials is likely to be a solution, Shen told Healio.

“This strategy would increase the proportion of truly effective therapies [among those] that are advanced to phase 3 trials, subsequently reducing false-positives and true negatives and improving trial success rate,” Shen and colleagues wrote. “Ultimately, this is the strategy that can potentially reduce unnecessary health care expenditures and, most important, improve patient outcomes.”

Shen added that 87% of industry-sponsored phase 3 clinical trials during the last decade were “testing therapies that did not achieve meaningful clinical benefit in prolonging survival.”

“This is higher than we expected,” he told Healio.

The clinical trial pipeline in oncology must be efficient and accurate in order to sustain the rate of innovation in cancer therapeutics, in addition to ensuring patients have access to effective yet affordable therapies, he said in a National Comprehensive Cancer Network press release.

“Our work shows that in the past 10 years, this has not been the case,” he said. “And it shows that reducing false-positive errors by imposing [a] more stringent statistical threshold in phase 3 trials is not likely to be practically feasible.”