Recurrence-free survival (RFS) is not a strong surrogate for overall survival in randomized trials of adjuvant immunotherapy for cancer.
FDA approvals in the adjuvant setting for cancer immunotherapy are increasingly based on trials that use RFS as a surrogate endpoint for overall survival, largely because such a design allows for smaller, speedier trials.
To test the validity of using RFS as a surrogate for overall survival in this setting, investigators conducted a meta-analysis of 15 phase 2 and 3 randomized controlled trials (RCTs) of adjuvant CTLA4 and anti-PD1/L1 blockers for melanoma, non–small cell lung cancer, renal cell cancer, and other tumors.
The team used weighted regression at the arm and trial levels to assess the efficacy of RFS as a surrogate for overall survival.
The strength of the association was quantified by weighted coefficients of determination (R2), with a strong correlation considered to be R2 of 0.7 or higher.
If there were strong correlations at both the arm and trial levels, RFS would be considered a robust surrogate endpoint for overall survival; however, if one of the correlations at the arm or trial level was not strong, RFS would not be considered a surrogate endpoint for overall survival.
At the arm level, moderate and strong associations were observed between 2-year RFS and 3-year overall survival (R2, 0.58) and between 3-year RFS and 5-year overall survival (R2, 0.72; 95% CI, 0.38 – 1.00).
At the trial level, a moderate association was observed between effect of treatment on RFS and overall survival (R2, 0.63).
The findings were confirmed in several sensitivity analyses that were based on different trial phases, experimental arms, cancer types, and treatment strategies.
"Our meta-analysis failed to find a significantly strong association between RFS and OS in RCTs of adjuvant immunotherapy," the authors concluded. "RFS should not be used as a surrogate endpoint for OS in this clinical context." Instead, the finding indicates that overall survival is "the ideal primary endpoint" in this setting.
The study, led by Yuanfang Li, PhD, of Sun Yat-sen University Cancer Center in Guangzhou, China, was published June 30 in the Journal of the National Cancer Institute.
Correlations were calculated from a relatively limited number of RCTs that involved different types of cancer, and overall survival data were not fully mature in some of the trials.
The analysis did not include patient-level data.
The work was funded by the National Natural Science Foundation of China and others.
The investigators had no disclosures.
M. Alexander Otto is a physician assistant with a master’s degree in medical science and a journalism degree from Newhouse. He is an award-winning medical journalist who worked for several major news outlets before joining Medscape. Alex is also an MIT Knight Science Journalism fellow. Email: firstname.lastname@example.org.
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Cite this: RFS Failed as Endpoint in Adjuvant Immunotherapy Trials - Medscape - Jul 31, 2023.