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Journal of Cancer Research and Clinical Oncology

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Open Access 01-11-2018 | Original Article – Clinical Oncology

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

Authors: Howard L. Kaufman, Lawrence H. Schwartz, William N. William Jr, Mario Sznol, Kyle Fahrbach, Yingxin Xu, Eric Masson, Andrea Vergara-Silva

Published in: Journal of Cancer Research and Clinical Oncology | Issue 11/2018

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.

AstraZeneca Pharmaceuticals LP (2017) Imfinzi™ (durvalumab) injection, for intravenous use [prescribing information]. AstraZeneca Pharmaceuticals LP, Wilmington

Bellmunt J et al (2017) Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med 376:1015–1026. https://doi.org/10.1056/NEJMoa1613683 CrossRefPubMedPubMedCentral

Blumenthal GM et al (2017) Milestone analyses of immune checkpoint inhibitors, targeted therapy, and conventional therapy in metastatic non-small cell lung cancer trials: a meta-analysis. JAMA Oncol 3:e171029. https://doi.org/10.1001/jamaoncol.2017.1029 CrossRefPubMedPubMedCentral

Booth CM, Eisenhauer EA (2012) Progression-free survival: meaningful or simply measurable? J Clin Oncol 30:1030–1033. https://doi.org/10.1200/JCO.2011.38.7571 CrossRefPubMed

Borghaei H et al (2015) Nivolumab versus docetaxel in advanced nonsquamous non–small-cell lung cancer. N Engl J Med 373:1627–1639. https://doi.org/10.1056/NEJMoa1507643 CrossRefPubMedPubMedCentral

Brahmer J et al (2015) Nivolumab versus docetaxel in advanced squamous-cell non-small-cell Lung Cancer. N Engl J Med 373:123–135. https://doi.org/10.1056/NEJMoa1504627 CrossRefPubMedPubMedCentral

Bristol‐Myers Squibb (2013) Yervoy prescribing information. Princeton, NJ. https://packageinserts.bms.com/pi/pi_yervoy.pdf

Bristol‐Myers Squibb (2017) Opdivo prescribing information. Princeton, NJ. https://packageinserts.bms.com/pi/pi_opdivo.pdf

Checkpoint Inhibitors Spur Changes in Trial Design (2017) Cancer Discov 7:1209–1210. https://doi.org/10.1158/2159-8290.CD-ND2017-006 CrossRef

Chesney J et al (2016) 1108PD: interim safety and efficacy of a randomized (1:1), open-label phase 2 study of talimogene laherparepvec (T) and ipilimumab (I) vs I alone in unresected, stage IIIB-IV melanoma. Ann Oncol 27:vi380–vi381CrossRef

Eisenhauer E et al (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45:228–247. https://doi.org/10.1016/j.ejca.2008.10.026 CrossRefPubMed

Escudier B et al (2017) LBA5CheckMate 214: Efficacy and safety of nivolumab + ipilimumab (N + I) v sunitinib (S) for treatment-naïve advanced or metastatic renal cell carcinoma (mRCC), including IMDC risk and PD-L1 expression subgroups. Ann Oncol. https://doi.org/10.1093/annonc/mdx440.029 CrossRef

Fehrenbacher L et al (2016) Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. Lancet 387:1837–1846. https://doi.org/10.1016/S0140-6736(16)00587-0 CrossRefPubMed

Ferris RL et al (2016) Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med. https://doi.org/10.1056/NEJMoa1602252 CrossRefPubMedPubMedCentral

Flaherty KT et al (2014) Surrogate endpoints for overall survival in metastatic melanoma: a meta-analysis of randomised controlled trials. Lancet Oncol 15:297–304. https://doi.org/10.1016/S1470-2045(14)70007-5 CrossRefPubMedPubMedCentral

Foster NR et al (2011) Tumor response and progression-free survival as potential surrogate endpoints for overall survival in extensive stage small-cell lung cancer. Cancer 117:1262–1271. https://doi.org/10.1002/cncr.25526 CrossRefPubMed

Gatzemeier U et al (2000) Phase III comparative study of high-dose cisplatin versus a combination of paclitaxel and cisplatin in patients with advanced non-small-cell lung cancer. J Clin Oncol 18:3390–3399. https://doi.org/10.1200/jco.2000.18.19.3390 CrossRefPubMed

Genentech (2017) Tecentriq prescribing information. Genentech, South San Francisco

Guyot P, Ades AE, Ouwens MJ, Welton NJ (2012) Enhanced secondary analysis of survival data: reconstructing the data from published Kaplan–Meier survival curves. BMC Med Res Methodol 12:9. https://doi.org/10.1186/1471-2288-12-9 CrossRefPubMedPubMedCentral

Hamid O et al (2011) A prospective phase II trial exploring the association between tumor microenvironment biomarkers and clinical activity of ipilimumab in advanced melanoma. J Transl Med 9:204. https://doi.org/10.1186/1479-5876-9-204 CrossRefPubMedPubMedCentral

Hamid O et al (2016) 1107O: final overall survival for KEYNOTE-002: pembrolizumab (pembro) versus investigator-choice chemotherapy (chemo) for ipilimumab (ipi)-refractory melanoma. Ann Oncol 27:vi379–vi380CrossRef

Herbst RS et al (2016) Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet 387:1540–1550. https://doi.org/10.1016/S0140-6736(15)01281-7 CrossRefPubMed

Hersh EM et al (2011) A phase II multicenter study of ipilimumab with or without dacarbazine in chemotherapy-naive patients with advanced melanoma. Invest New Drugs 29:489–498. https://doi.org/10.1007/s10637-009-9376-8 CrossRefPubMed

Hodi FS et al (2014) Ipilimumab plus sargramostim vs ipilimumab alone for treatment of metastatic melanoma: a randomized clinical trial. JAMA 312:1744–1753. https://doi.org/10.1001/jama.2014.13943 CrossRefPubMedPubMedCentral

Hodi FS et al (2016a) Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial. Lancet Oncol 17:1558–1568. https://doi.org/10.1016/S1470-2045(16)30366-7 CrossRefPubMedPubMedCentral

Hodi FS et al (2016b) Evaluation of immune-related response criteria and RECIST v1. 1 in patients with advanced melanoma treated with pembrolizumab. J Clin Oncol 34:1510–1517. https://doi.org/10.1200/JCO.2015.64.0391 CrossRefPubMedPubMedCentral

Hoyle MW, Henley W (2011) Improved curve fits to summary survival data: application to economic evaluation of health technologies. BMC Med Res Methodol 11:139. https://doi.org/10.1186/1471-2288-11-139 CrossRefPubMedPubMedCentral

Johnson JR, Williams G, Pazdur R (2003) End points and United States Food and Drug Administration approval of oncology drugs. J Clin Oncol 21:1404–1411. https://doi.org/10.1200/JCO.2003.08.072 CrossRefPubMed

Kaufman HL et al (2017) Durable response rate as an endpoint in cancer immunotherapy: insights from oncolytic virus clinical trials. J Immunother Cancer 5:72. https://doi.org/10.1186/s40425-017-0276-8 CrossRefPubMedPubMedCentral

Kemp R, Prasad V (2017) Surrogate endpoints in oncology: when are they acceptable for regulatory and clinical decisions, and are they currently overused? BMC Med 15:134. https://doi.org/10.1186/s12916-017-0902-9 CrossRefPubMedPubMedCentral

Langer CJ et al (2016) Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol 17:1497–1508. https://doi.org/10.1016/S1470-2045(16)30498-3 CrossRefPubMedPubMedCentral

Lynch TJ et al (2012) Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in stage IIIB/IV non-small-cell lung cancer: results from a randomized, double-blind, multicenter phase II study. J Clin Oncol 30:2046–2054. https://doi.org/10.1200/JCO.2011.38.4032 CrossRefPubMed

Maio M et al (2015) Five-year survival rates for treatment-naive patients with advanced melanoma who received ipilimumab plus dacarbazine in a phase III trial. J Clin Oncol 33:1191–1196. https://doi.org/10.1200/JCO.2014.56.6018 CrossRefPubMedPubMedCentral

Merck and Company Inc (2017) Keytruda prescribing information. Whitehouse Station, NJ. https://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf

Motzer RJ et al (2015) Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med 373:1803–1813. https://doi.org/10.1056/NEJMoa1510665 CrossRefPubMedPubMedCentral

Nishino M, Giobbie-Hurder A, Gargano M, Suda M, Ramaiya NH, Hodi FS (2013) Developing a common language for tumor response to immunotherapy: immune-related response criteria using unidimensional measurements. Clin Cancer Res 19:3936–3943. https://doi.org/10.1158/1078-0432.CCR-13-0895 CrossRefPubMedPubMedCentral

Pfizer (2017) Bavencio prescribing information. New York, NY

Prasad V, Kim C, Burotto M, Vandross A (2015) The strength of association between surrogate end points and survival in oncology: a systematic review of trial-level meta-analyses. JAMA Intern Med 175:1389–1398. https://doi.org/10.1001/jamainternmed.2015.2829 CrossRefPubMed

Reck M et al (2016) Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. https://doi.org/10.1056/NEJMoa1606774 CrossRefPubMed

Ribas A et al (2013) Phase III randomized clinical trial comparing tremelimumab with standard-of-care chemotherapy in patients with advanced melanoma. J Clin Oncol 31:616–622. https://doi.org/10.1200/JCO.2012.44.6112 CrossRefPubMedPubMedCentral

Rittmeyer A et al (2017) Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet. https://doi.org/10.1016/S0140-6736(16)32517-X CrossRefPubMed

Robert C et al (2011) Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 364:2517–2526. https://doi.org/10.1056/NEJMoa1104621 CrossRefPubMed

Robert C et al (2015a) Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med 372:320–330. https://doi.org/10.1056/NEJMoa1412082 CrossRefPubMed

Robert C et al (2015b) Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med 372:2521–2532. https://doi.org/10.1056/NEJMoa1503093 CrossRefPubMed

Rosenberg JE et al (2016) 784P: nivolumab monotherapy in metastatic urothelial cancer (mUC): updated efficacy by subgroups and safety results from the CheckMate 032 study. Ann Oncol 27:vi271CrossRef

Seymour L et al (2017) iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics. Lancet Oncol 18:e143–e152. https://doi.org/10.1016/S1470-2045(17)30074-8 CrossRefPubMedPubMedCentral

Sharma P et al (2016) O3: efficacy and safety of nivolumab plus ipilimumab in metastatic urothelial carcinoma: first results from the phase I/II CheckMate 032 study. J Immunother Cancer 4:225

Smith DA et al (2016) Updated survival and biomarker analyses of a randomized phase II study of atezolizumab vs docetaxel in 2L/3L NSCLC (POPLAR). J Clin Oncol 34 (suppl 15; abstr 9028; poster 351)CrossRef

Socinski M et al (2016) LBA7_PR: CheckMate 026: a phase 3 trial of nivolumab vs investigator’s choice (IC) of platinum-based doublet chemotherapy (PT-DC) as first-line therapy for stage iv/recurrent programmed death ligand 1 (PD-L1)–positive NSCLC. Ann Oncol 27:vi588

Spigel DR et al (2015) A phase III study (CheckMate 017) of nivolumab (Anti-Programmed Death-1) vs docetaxel in previously treated advanced or metastatic squamous (SQ) cell non-small cell lung cancer (NSCLC). J Clin Oncol 33 (Suppl 15; abstr 8009)

Thompson JA et al (2012) Ipilimumab in treatment-naive and previously treated patients with metastatic melanoma: retrospective analysis of efficacy and safety data from a phase II trial. J Immunother 35:73–77. https://doi.org/10.1097/CJI.0b013e31823735d6 CrossRefPubMed

Weber J et al (2009) A randomized, double-blind, placebo-controlled, phase II study comparing the tolerability and efficacy of ipilimumab administered with or without prophylactic budesonide in patients with unresectable stage III or IV melanoma. Clin Cancer Res 15:5591–5598. https://doi.org/10.1158/1078-0432.CCR-09-1024 CrossRefPubMed

Weber J et al (2016a) Overall survival in patients with advanced melanoma (MEL) who received nivolumab (NIVO) vs investigator’s choice chemotherapy (ICC) in the phase 3 CheckMate 037 trial. Pigment Cell Melanoma Res 30:150

Weber JS et al (2016b) Sequential administration of nivolumab and ipilimumab with a planned switch in patients with advanced melanoma (CheckMate 064): an open-label, randomised, phase 2 trial. Lancet Oncol 17:943–955. https://doi.org/10.1016/S1470-2045(16)30126-7 CrossRefPubMedPubMedCentral

Wolchok JD et al (2009) Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res 15:7412–7420. https://doi.org/10.1158/1078-0432.CCR-09-1624 CrossRefPubMed

Wolchok JD et al (2010) Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study. Lancet Oncol 11:155–164. https://doi.org/10.1016/S1470-2045(09)70334-1 CrossRefPubMed

(2005) Validity of surrogate endpoints in Oncology executive summary of rapid report A10-05, Version 1.1. In: Institute for quality and efficiency in health care: executive summaries. Cologne, Germany

Title: Evaluation of classical clinical endpoints as surrogates for overall survival in patients treated with immune checkpoint blockers: a systematic review and meta-analysis
Authors: Howard L. Kaufman
Lawrence H. Schwartz
William N. William Jr
Mario Sznol
Kyle Fahrbach
Yingxin Xu
Eric Masson
Andrea Vergara-Silva
Publication date: 01-11-2018
Publisher: Springer Berlin Heidelberg
Published in: Journal of Cancer Research and Clinical Oncology / Issue 11/2018
Print ISSN: 0171-5216
Electronic ISSN: 1432-1335
DOI: https://doi.org/10.1007/s00432-018-2738-x

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