Caution needed when using PFS as an OS surrogate in immunotherapy trials
medwireNews: In phase II and III trials of oncologic immunotherapeutic agents, treatment effect sizes are on average larger for progression-free survival (PFS) than for overall survival (OS), find researchers who question the value of using PFS as a surrogate for OS in such trials.
They write in the Journal of Clinical Oncology: “In the absence of objective, clinically relevant outcome data, caution should be taken in interpreting treatment effects that are based solely on data for surrogate outcomes, such as PFS for OS, because as our study highlights, there are some important differences between surrogate and final outcome measures.
“Given the rapidly developing therapeutics in oncologic research, the assessment of both types of outcomes (ie, OS and PFS) is essential for clinical and policy decision making.”
Investigator Agnes Dechartres (INSERM U1153, Paris, France) and collaborators identified 51 trials (76% phase III, 24% phase II) assessing 14 immunotherapeutic drugs approved by the US Food and Drug Administration (FDA), for which results were available on ClinicalTrials.gov. All included trials reported on both PFS and OS.
They evaluated the differences in outcome measures by calculating a ratio of hazard ratios (rHR) and found that on average treatment effect sizes were 17% greater for PFS than for OS (rHR=0.83).
And in almost half (45%) of the included trials, treatment with the immunotherapeutic agent was associated with a statistically significant improvement in PFS, but not OS.
The discrepancy between PFS and OS was especially pronounced for certain drugs, such as obinutuzumab (rHR=0.21), bevacizumab (rHR=0.75), rituximab (rHR=0.79), and ramucirumab (rHR=0.82), whereas the treatment effect sizes did not differ for other drugs, including alemtuzumab (rHR=0.94), cetuximab (rHR=0.96), ipilimumab (rHR=0.95), and trastuzumab (rHR=0.96).
“Our results raise particular concerns for some of these drugs because their FDA approval was based on PFS benefits, with no benefits seen in the final outcome OS,” comment Dechartres et al.
They also evaluated surrogacy metrics – such as the coefficient of determination (R2) – and found consistent results. The R2 was low, at 38%, indicating that “only 38% of the variability in the OS effect could be explained by the variability in the PFS effect,” say the study authors.
“These results suggest that PFS cannot be considered a good surrogate for OS when investigating immunotherapy drugs,” they write, emphasizing that “[c]aution must be taken when interpreting PFS in the absence of OS data.”
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