Howard L Kaufman1,2, Lawrence H Schwartz3, William N William4,5, Mario Sznol6, Kyle Fahrbach7, Yingxin Xu7,8, Eric Masson9,10, Andrea Vergara-Silva11,12. 1. Massachusetts General Hospital, 55 Fruit St Gray 730, Boston, MA, USA. howardkaufman6@gmail.com. 2. Replimune Inc., 18 Commerce Way, Woburn, MA, 01801, USA. howardkaufman6@gmail.com. 3. Columbia University College of Physicians and Surgeons, New York Presbyterian Hospital, 622 W 168th St, New York, NY, USA. 4. MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, USA. 5. Centro Oncológico BP, a Beneficência Portuguesa de São Paulo, São Paulo, Brazil. 6. Yale School of Medicine, 333 Cedar St, New Haven, CT, USA. 7. Evidera, 7101 Wisconsin Ave, Suite 1400, Bethesda, MD, USA. 8. Regeneron Pharmaceuticals Inc., 777 Old Saw Mill River Rd, Tarrytown, NY, USA. 9. AstraZeneca, 35 Gatehouse Dr, Waltham, MA, USA. 10. Biogen, 225 Binney St, Cambridge, MA, USA. 11. AstraZeneca, One MedImmune Way, Gaithersburg, MD, USA. 12. Ayala Pharmaceuticals, 1313 N. Market Str, Suite 5100, Wilmington, DE, USA.
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.
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 tumorspatients 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.
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