Evaluation of classical clinical endpoints as surrogates for overall survival in patients treated with immune checkpoint blockers: a systematic review and meta-analysis

J Cancer Res Clin Oncol. 2018 Nov;144(11):2245-2261. doi: 10.1007/s00432-018-2738-x. Epub 2018 Aug 21.

Abstract

Purpose: Classical clinical endpoints [e.g., objective response rate (ORR), disease control rate (DCR), and progression-free survival (PFS)] may not be appropriate for immune checkpoint blockers (ICBs). We evaluated correlations between these endpoints and overall survival (OS) for surrogacy.

Methods: Randomized controlled trials (RCTs) of solid tumors patients treated with ICBs published between 01/2005 and 03/2017, and congress proceedings (2014-2016) were included. Arm-level analyses measured 6-month PFS rate to predict 18-month OS rate. Comparison-level analyses measured ORR odds ratio (OR), DCR OR, and 6-month PFS hazard ratio (HR) to predict OS HR. A pooled analysis for single-agent ICBs and ICBs plus chemotherapy vs chemotherapy was conducted. Studies of single-agent ICBs vs chemotherapy were separately analyzed.

Results: 27 RCTs involving 61 treatment arms and 10,300 patients were included. Arm-level analysis showed higher 6- or 9-month PFS rates predicted better 18-month OS rates for ICB arms and/or chemotherapy arms. ICB arms had a higher average OS rate vs chemotherapy for all PFS rates. Comparison-level analysis showed a nonsignificant/weak correlation between ORR OR (adjusted R2 = - 0.069; P = 0.866) or DCR OR (adjusted R2 = 0.271; P = 0.107) and OS HR. PFS HR correlated weakly with OS HR in the pooled (adjusted R2 = 0.366; P = 0.005) and single-agent (adjusted R2 = 0.452; P = 0.005) ICB studies. Six-month PFS HR was highly predictive of OS HR for single-agent ICBs (adjusted R2 = 0.907; P < 0.001), but weakly predictive in the pooled analysis (adjusted R2 = 0.333; P = 0.023).

Conclusions: PFS was an imperfect surrogate for OS. Predictive value of 6-month PFS HR for OS HR in the single-agent ICB analysis requires further exploration.

Keywords: Cytotoxic T-lymphocyte-associated antigen-4; Immune checkpoint blockers; Programmed cell death ligand-1; Programmed cell death-1; Solid tumors; Surrogate endpoint.

Publication types

  • Meta-Analysis
  • Review
  • Systematic Review

MeSH terms

  • Antineoplastic Agents / immunology
  • Antineoplastic Agents / therapeutic use*
  • Endpoint Determination / methods*
  • Humans
  • Molecular Targeted Therapy / methods*
  • Neoplasms / drug therapy*
  • Neoplasms / immunology
  • Neoplasms / metabolism
  • Randomized Controlled Trials as Topic
  • Survival Analysis

Substances

  • Antineoplastic Agents

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