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Progression-Free Survival as a Surrogate for Overall Survival in Clinical Trials of Targeted Therapy in Advanced Solid Tumors

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Abstract

Over the past 15 years, targeted therapy has revolutionized the systemic treatment of cancer. In parallel, there has been a growing debate on the choice of end points in clinical trials in oncology. This debate basically hinges on the choice between overall survival (OS) and progression-free survival (PFS). PFS is advantageous because it is measured earlier than OS, requires a smaller sample size than OS to achieve the desired power, and is not influenced by cross-over. On the other hand, PFS is prone to measurement error and bias, and may not capture the entire treatment effect on the outcomes of most interest to patients with an incurable disease: a prolonged survival and improved quality of life. Therefore, how can we choose between two imperfect end points? The answer to this question would certainly be made easier if PFS could be demonstrated to be a valid surrogate for OS. The validation of a surrogate end point is best made using individual-patient data (IPD) from randomized trials, which allows for standardized assessments of the patient-level and the trial-level correlations between surrogate and final end points. Proper IPD meta-analytical evaluations for targeted agents have still been rare, and to our knowledge only three studies on this topic are currently available in the metastatic setting: one in breast cancer, one in colorectal cancer and one in lung cancer. Although these three studies suffer from limitations inherent to the availability of IPD and the design of the original clinical trials, they have not been able to validate PFS as surrogate for OS, because only modest correlations were found between these two end points, both at the patient and at the trial level. Even if properly conducted surrogate-endpoint evaluations have thus far been unsuccessful, these evaluations are a step in the right direction and can be expected to be applied on a much larger scale in the era of data sharing of clinical trials.

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References

  1. Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001;344(11):783–92.

    Article  CAS  PubMed  Google Scholar 

  2. Coiffier B, Lepage E, Briere J, Herbrecht R, Tilly H, Bouabdallah R, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med. 2002;346(4):235–42.

    Article  CAS  PubMed  Google Scholar 

  3. Demetri GD, von Mehren M, Blanke CD, Van den Abbeele AD, Eisenberg B, Roberts PJ, et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med. 2002;347(7):472–80.

    Article  CAS  PubMed  Google Scholar 

  4. O’Brien SG, Guilhot F, Larson RA, Gathmann I, Baccarani M, Cervantes F, et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2003;348(11):994–1004.

    Article  PubMed  Google Scholar 

  5. Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361(10):947–57.

    Article  CAS  PubMed  Google Scholar 

  6. Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364(26):2507–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Shaw AT, Kim DW, Nakagawa K, Seto T, Crino L, Ahn MJ, et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med. 2013;368(25):2385–94.

    Article  CAS  PubMed  Google Scholar 

  8. Burzykowski T, Buyse M, Piccart-Gebhart MJ, Sledge G, Carmichael J, Luck HJ, et al. Evaluation of tumor response, disease control, progression-free survival, and time to progression as potential surrogate end points in metastatic breast cancer. J Clin Oncol. 2008;26(12):1987–92.

    Article  CAS  PubMed  Google Scholar 

  9. Buyse M, Burzykowski T, Carroll K, Michiels S, Sargent DJ, Miller LL, et al. Progression-free survival is a surrogate for survival in advanced colorectal cancer. J Clin Oncol. 2007;25(33):5218–24.

    Article  CAS  PubMed  Google Scholar 

  10. Fukuoka M, Wu YL, Thongprasert S, Sunpaweravong P, Leong SS, Sriuranpong V, et al. Biomarker analyses and final overall survival results from a phase III, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small-cell lung cancer in Asia (IPASS). J Clin Oncol. 2011;29(21):2866–74.

    Article  CAS  PubMed  Google Scholar 

  11. Solomon BJ, Mok T, Kim DW, Wu YL, Nakagawa K, Mekhail T, et al. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med. 2014;371(23):2167–77.

    Article  PubMed  Google Scholar 

  12. Pilotto S, Carbognin L, Karachaliou N, Garassino M, Cuppone F, Petraglia S, et al. Moving towards a customized approach for drug development: lessons from clinical trials with immune checkpoint inhibitors in lung cancer. Transl Lung Cancer Res. 2015;4(6):704–12.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Johnson JR, Temple R. Food and drug administration requirements for approval of new anticancer drugs. Cancer Treat Rep. 1985;69(10):1155–9.

    CAS  PubMed  Google Scholar 

  14. Saad ED, Buyse M. Statistical controversies in clinical research: end points other than overall survival are vital for regulatory approval of anticancer agents. Ann Oncol. 2016;27(3):373–8.

    Article  CAS  PubMed  Google Scholar 

  15. Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E, et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012;13(3):239–46.

    Article  CAS  PubMed  Google Scholar 

  16. Buyse M, Molenberghs G, Burzykowski T, Renard D, Geys H. The validation of surrogate endpoints in meta-analyses of randomized experiments. Biostatistics. 2000;1(1):49–67.

    Article  CAS  PubMed  Google Scholar 

  17. Ciani O, Davis S, Tappenden P, Garside R, Stein K, Cantrell A, et al. Validation of surrogate endpoints in advanced solid tumors: systematic review of statistical methods, results, and implications for policy makers. Int J Technol Assess Health Care. 2014;30(3):312–24.

    Article  PubMed  Google Scholar 

  18. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228–47.

    Article  CAS  PubMed  Google Scholar 

  19. US Department of Health and Human Services. Food and Drug Administration. Center for Drug Evaluation and Research. Center for Biologics Evaluation and Research. Guidance for industry: clinical trial endpoints for the approval of cancer drugs and biologics. Available at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071590.pdf. Accessed 16 Aug 2016.

  20. European Medicines Agency. Committee for Medicinal Products for Human Use (CHMP). Appendix 1 to the Guideline on the Evaluation of Anticancer Medicinal Products in Man (CHMP/ewp/205/95 rev.3). Methodological considerations for using progression-free survival (PFS) as primary endpoint in confirmatory trials for registration. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/12/WC500017736.pdf. Accessed 16 Aug 2016.

  21. Biomarkers Definitions Working Group. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther. 2001;69(3):89–95.

    Article  Google Scholar 

  22. De Gruttola VG, Clax P, DeMets DL, Downing GJ, Ellenberg SS, Friedman L, et al. Considerations in the evaluation of surrogate endpoints in clinical trials. summary of a National Institutes of Health workshop. Control Clin Trials. 2001;22(5):485–502.

    Article  PubMed  Google Scholar 

  23. Buyse M, Molenberghs G, Paoletti X, Oba K, Alonso A, Van der Elst W, et al. Statistical evaluation of surrogate endpoints with examples from cancer clinical trials. Biom J Biometrische Zeitschrift. 2016;58(1):104–32.

    Article  PubMed  Google Scholar 

  24. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human use. ICH Harmonised Tripartite Guideline. Statistical principles for clinical trials. Federal Register 63, No. 179, 49583. Available at: http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E9/Step4/E9_Guideline.pdf. Accessed 18 Aug 2016.

  25. Prentice RL. Surrogate endpoints in clinical trials: definition and operational criteria. Stat Med. 1989;8(4):431–40.

    Article  CAS  PubMed  Google Scholar 

  26. Vanderweele TJ. Surrogate measures and consistent surrogates. Biometrics. 2013;69(3):561–9.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Fleming TR, DeMets DL. Surrogate end points in clinical trials: are we being misled? Ann Intern Med. 1996;125(7):605–13.

    Article  CAS  PubMed  Google Scholar 

  28. Shi Q, de Gramont A, Grothey A, Zalcberg J, Chibaudel B, Schmoll HJ, et al. Individual patient data analysis of progression-free survival versus overall survival as a first-line end point for metastatic colorectal cancer in modern randomized trials: findings from the analysis and research in cancers of the digestive system database. J Clin Oncol. 2015;33(1):22–8.

    Article  PubMed  Google Scholar 

  29. Laporte S, Squifflet P, Baroux N, Fossella F, Georgoulias V, Pujol JL, et al. Prediction of survival benefits from progression-free survival benefits in advanced non-small-cell lung cancer: evidence from a meta-analysis of 2334 patients from 5 randomised trials. BMJ Open. 2013;3(3).

  30. Foster NR, Renfro LA, Schild SE, Redman MW, Wang XF, Dahlberg SE, et al. Multitrial evaluation of progression-free survival as a surrogate end point for overall survival in first-line extensive-stage small-cell lung cancer. J Thorac Oncol. 2015;10(7):1099–106.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Mauguen A, Pignon JP, Burdett S, Domerg C, Fisher D, Paulus R, et al. Surrogate endpoints for overall survival in chemotherapy and radiotherapy trials in operable and locally advanced lung cancer: a re-analysis of meta-analyses of individual patients’ data. Lancet Oncol. 2013;14(7):619–26.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Michiels S, Le Maitre A, Buyse M, Burzykowski T, Maillard E, Bogaerts J, et al. Surrogate endpoints for overall survival in locally advanced head and neck cancer: meta-analyses of individual patient data. Lancet Oncol. 2009;10(4):341–50.

    Article  PubMed  Google Scholar 

  33. Paoletti X, Oba K, Bang YJ, Bleiberg H, Boku N, Bouche O, et al. Progression-free survival as a surrogate for overall survival in advanced/recurrent gastric cancer trials: a meta-analysis. J Natl Cancer Inst. 2013;105(21):1667–70.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Rotolo F, Pignon JP, Bourhis J, et al. Surrogate endpoints for overall survival in loco-regionally advanced nasopharyngeal carcinoma: an individual patient data meta-analysis. J Natl Cancer Inst. 2016;109(4):pii:djw239.

  35. Buyse M, Michiels S, Squifflet P, Lucchesi KJ, Hellstrand K, Brune ML, et al. Leukemia-free survival as a surrogate end point for overall survival in the evaluation of maintenance therapy for patients with acute myeloid leukemia in complete remission. Haematologica. 2011;96(8):1106–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Sridhara R, Johnson JR, Justice R, Keegan P, Chakravarty A, Pazdur R. Review of oncology and hematology drug product approvals at the US Food and Drug Administration between July 2005 and December 2007. J Natl Cancer Inst. 2010;102(4):230–43.

    Article  PubMed  Google Scholar 

  37. Nair A, Lemery SJ, Yang J, Marathe A, Zhao L, Zhao H, et al. FDA approval summary: lenvatinib for progressive, radio-iodine-refractory differentiated thyroid cancer. Clin Cancer Res. 2015;21(23):5205–8.

    Article  CAS  PubMed  Google Scholar 

  38. Kazandjian D, Blumenthal GM, Chen HY, He K, Patel M, Justice R, et al. FDA approval summary: crizotinib for the treatment of metastatic non-small cell lung cancer with anaplastic lymphoma kinase rearrangements. Oncologist. 2014;19(10):e5–11.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Khozin S, Blumenthal GM, Jiang X, He K, Boyd K, Murgo A, et al. U.S. Food and Drug Administration approval summary: erlotinib for the first-line treatment of metastatic non-small cell lung cancer with epidermal growth factor receptor exon 19 deletions or exon 21 (L858R) substitution mutations. Oncologist. 2014;19(7):774–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Blumenthal GM, Cortazar P, Zhang JJ, Tang S, Sridhara R, Murgo A, et al. FDA approval summary: sunitinib for the treatment of progressive well-differentiated locally advanced or metastatic pancreatic neuroendocrine tumors. Oncologist. 2012;17(8):1108–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Halabi S, Rini B, Escudier B, Stadler WM, Small EJ. Progression-free survival as a surrogate endpoint of overall survival in patients with metastatic renal cell carcinoma. Cancer. 2014;120(1):52–60.

    Article  CAS  PubMed  Google Scholar 

  42. Zabor EC, Heller G, Schwartz LH, Chapman PB. Correlating surrogate endpoints with overall survival at the individual patient level in BRAFV600E-mutated metastatic melanoma patients treated with vemurafenib. Clin Cancer Res. 2016;22(6):1341–7.

    Article  CAS  PubMed  Google Scholar 

  43. Michiels S, Pugliano L, Marguet S, Grun D, Barinoff J, Cameron D, et al. Progression-free survival as surrogate end point for overall survival in clinical trials of HER2-targeted agents in HER2-positive metastatic breast cancer. Ann Oncol. 2016;27(6):1029–34.

    Article  CAS  PubMed  Google Scholar 

  44. Alonso A, Van der Elst W, Molenberghs G, Buyse M, Burzykowski T. On the relationship between the causal-inference and meta-analytic paradigms for the validation of surrogate endpoints. Biometrics. 2015;71(1):15–24.

    Article  PubMed  Google Scholar 

  45. Prasad V, Kim C, Burotto M, Vandross A. The strength of association between surrogate end points and survival in oncology: a systematic review of trial-level meta-analyses. JAMA Intern Med. 2015;175(8):1389–98.

    Article  PubMed  Google Scholar 

  46. Buyse M. Contributions of meta-analyses based on individual patient data to therapeutic progress in colorectal cancer. Int J Clin Oncol. 2009;14(2):95–101.

    Article  PubMed  Google Scholar 

  47. Christakis DA, Zimmerman FJ. Rethinking reanalysis. JAMA. 2013;310(23):2499–500.

    Article  CAS  PubMed  Google Scholar 

  48. Strom BL, Buyse M, Hughes J, Knoppers BM. Data sharing, year 1—access to data from industry-sponsored clinical trials. N Engl J Med. 2014;371(22):2052–4.

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Service de Biostatistique et d’Epidémiologie, Gustave Roussy, B2M RDC, 114 rue Edouard Vaillant, 94805, Villejuif Cedex, France

    Stefan Michiels

  2. Université Paris-Saclay, Université Paris-Sud, UVSQ, CESP, INSERM U1018, 94805, Villejuif, France

    Stefan Michiels

  3. Ligue Nationale Contre le Cancer Meta-Analysis Platform, Gustave Roussy, 94805, Villejuif, France

    Stefan Michiels

  4. International Drug Development Institute (IDDI), Louvain-la-Neuve, Belgium

    Everardo D. Saad

  5. Interuniversity Institute for Biostatistics and Statistical Bioinformatics (I-BioStat), Hasselt University, Hasselt, Belgium

    Marc Buyse

  6. International Drug Development Institute (IDDI), San Francisco, CA, USA

    Marc Buyse

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  1. Stefan Michiels
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  2. Everardo D. Saad
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  3. Marc Buyse
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Correspondence to Stefan Michiels.

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Ligue Nationale Contre le Cancer.

Disclosure

Dr. Michiels declares no conflict of interest. Dr. Buyse report being employed by and holding stock in the International Drug Development Institute, and Dr. Saad reports being employed by the International Drug Development Institute.

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Michiels, S., Saad, E.D. & Buyse, M. Progression-Free Survival as a Surrogate for Overall Survival in Clinical Trials of Targeted Therapy in Advanced Solid Tumors. Drugs 77, 713–719 (2017). https://doi.org/10.1007/s40265-017-0728-y

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  • DOI: https://doi.org/10.1007/s40265-017-0728-y

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