Predictive Value of Radiological Response, Pathological Response and Relapse-Free Survival for Overall Survival in Neoadjuvant Immunotherapy Trials: Meta-Analyses of Individual Patient Data

Abstract

Background: An increasing number of clinical trials are being conducted exploring the efficacy of neoadjuvant immune checkpoint inhibitors. Surrogate endpoints for overall survival (OS) are urgently needed.

Methods: Phase II or III trials of neoadjuvant immunotherapy that reported data on OS and surrogate endpoints were identified from January 1, 2000, to November 20, 2021. Individual patient data were requested from corresponding authors or extracted from eligible trials. At the individual level, associations between radiological and pathological response and OS were measured by the Cox model and quantified by hazard ratio (HR). C-statistic was used to quantify the predictive performance of radiological and pathological response for OS. The coefficient of determination (R2) between RFS and OS was evaluated by a bivariate survival model.

Results: Thirteen trials reporting 534 patients were included. ORR correlated with improved OS (3-years OS: 87.4% versus 72.0% for ORR versus non-ORR, respectively; HR, 0.37, 95% CI, 0.18-0.77). The HRs for OS in patients achieving MPR and pCR were 0.25 (95% CI, 0.11-0.55) and 0.15 (95% CI, 0.05-0.50). The survival benefit maintained after adjusting tumor type. C-statistics of ORR, MPR and pCR were 0.62, 0.64 and 0.62, respectively. The strength of association between RFS and OS was strong (R 2  = 0.89, 95% CI, 0.79-0.95).

Conclusions: The findings of this meta-analysis suggest that ORR, MPR, pCR and RFS are valid predictors for OS when using neoadjuvant immune checkpoint inhibitors. Moreover, MPR, pCR and RFS may be the most optimal surrogates for OS.

Note:
Funding Information: This work was supported by the grants of the National Key R&D Program of China (2017YFC1309001), Guangzhou Science and Technology Plan Projects (Health Medical Collaborative Innovation Program of Guangzhou; 201803040019), National Natural Science Foundation of China (82103586,81730072, 81672407, 81872001, 81902411 and 81772589).

Conflict of Interests: The authors declare that they have no competing interests.

Keywords: neoadjuvant, immune checkpoint inhibitor, surrogate, overall survival