RFS Failed as Endpoint in Adjuvant Immunotherapy Trials

July 31, 2023


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: aotto@mdedge.com.

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