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Miernik Katarzyna (Arcana Institute, Cracow, Poland), Czarny-Ozga Ilona (Arcana Institute, Cracow, Poland), Walczak Jacek (Arcana Institute, Cracow, Poland)
Assessment of Quality and Clinical Significance of Endpoints in Cancer Immunotherapy
Journal of Health Policy and Outcomes Research, 2015, nr 2, s. 45-67, tab., bibliogr. 52 poz.
Słowa kluczowe
Leczenie, Choroby nowotworowe, Leki
Medical treatment, Cancer, Drugs
This review describes available immunotherapeutic agents approved for the treatment of prostate cancer (sipuleucel-T), advanced melanoma (ipilimumab, pembrolizumab, nivolumab) and NSCLC (nivoluamb) and underline that their specific mechanism of action require to use appropriate endpoints for the efficacy evaluation. The FDA and EMA guidelines on endpoints in clinical trials indicate the use of overall survival as a primary endpoints. However, there is a trend for using the time-to-event endpoints for drug approval since 1990. Oncological clinical trials utilize apart from OS also the endpoints based on tumor assessment - e.g. progression-free survival, disease-free survival or response rate. This review presents the differences in mechanism of actions between standard chemotherapy and immunotherapy which imply the significant differences in the kinetic of response and long-term effects. The WHO and RECIST response criteria were developed to estimate the effect of cytotoxic drugs on cancer and the new patterns of response observed after treatment with immunotherapeutic agents indicate the need for adopting novel criteria in the evaluation of tumor responses. The performed review of pivotal clinical trials assessing the efficacy of immunotherapy showed that the most commonly evaluated endpoints were: OS, PFS and RR. Prolonged survival with concomitant lack of benefit in PFS was explained by the need for applying irRC for evaluation of the efficacy of immunotherapeutic agents beyond the classical measurement. It could be concluded that trial design which takes into account disease characteristics and immunotherapeutic agents' mechanism of action is the key to define appropriate endpoints and proper evaluation of the efficacy(original abstract)
Pełny tekst
  1. Parish CR. Cancer immunotherapy: The past, the present and the future. Immunol. Cell Biol. 2003; 81: 106-113
  2. Mellman I., Coukos G., Dranoff G. Cancer immunotherapy comes of age. Nature 2011;480: 480-489
  3. Finn OJ. Cancer immunology. N. Engl. J. Med. 2008; 358: 2704-15
  4. Blank CU., Hooijkaas AI., Haanen JB., Schumacher TN. Combination of targeted therapy and immunotherapy in melanoma. Cancer Immunol. Immunother. 2011; 60: 1359-1371
  5. Blank CU. The perspective of immunotherapy: new molecules and new mechanisms of action in immune modulation. Curr. Opin. Oncol. 2014; 26: 204-214
  6. FDA website - data on approval of ipilimumab [Cited: 07.12.2015] Available from:
  7. FDA website - data on approval of nivolumab [Cited: 07.12.2015] Available from:
  8. FDA website - data on approval of pembrolizumab [Cited: 07.12.2015] Available from:
  9. FDA website - data on approval of nivolumab - lung cancer [Cited: 07.12.2015] Available from:
  10. FDA website - data on approval of sipuleucel-T [Cited: 07.12.2015] Available from:
  11. EMA website - data on approval of ipilimumab [Cited: 07.12.2015] Available from:
  12. EMA website - data on approval of nivolumab [Cited: 07.12.2015] Available from:
  13. EMA website - data on approval of pembrolizumab [Cited: 07.12.2015] Available from:
  14. EMA website - data on approval of nivolumab - lung [Cited: 07.12.2015] Available from:
  15. EMA website - data on approval of sipuleucel-T [Cited: 07.12.2015] Available from:
  16. EMA website - data on withdrawal of sipuleucel-T [Cited: 07.12.2015] Available from:
  17. Dranitsaris G., Cohen RB., Acton G., Keltner L., Price M., Amir E., Podack ER., Schreiber TH. Statistical Considerations in Clinical Trial Design of Immunotherapeutic Cancer Agents. J. Immunother. 2015; 38: 259-266
  18. Pardoll DW. The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 2012; 12: 252-264
  19. Wolchok JD., Hoos A., O'Day S., et al. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin. Cancer Res. 2009; 15: 7412-7420
  20. Brahmer JR., Hammers H., Lipson EJ. Nivolumab: targeting PD-1 to bolster antitumor immunity. Future Oncol. 2015; 11: 1307-1326
  21. Biomarkers Definition Working Group: Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin. Pharmacol. Ther. 2001; 69: 89-95
  22. EMA. Guideline on the evaluation of anticancer medicinal products in man. EMA/CHMP/205/95/Rev.4 [Cited: 07.12.2015] Available from:
  23. FDA. Guidelines for Industry Clinical Trials Endpoints for the Approval of Cancer Drugs and Biologics. [Cited: 07.12.2015] Available from:
  24. Wilson M.K., Karakasis K., Oza A.M.: Outcomes and endpoints in trials of cancer treatment: the past, present, and future. Lancet Oncol. 2015;16:e32-e42
  25. McCain J.A.: The ongoing evolution of endpoints in oncology. [Cited: 07.12.2015] Available from:
  26. Wilson MK., Collyar D., Chingos DT., et al. Outcomes and endpoints in trials: bridging the divide. Lancet Oncol. 2015;16: e43-e52
  27. Ribas A., Hersey P., Middleton MR., Gogas H., Flaherty KT., Sondak VK., Kirkwood JM. New Challenges in Endpoints for Drug Development in Advanced Melanoma. Clin. Cancer Res. 2012; 18: 336-341
  28. Ribas A., Chmielowski B., Glaspy JA. Do we need a different set of response assessment criteria for tumor immunotherapy? Clin. Cancer Res. 2009; 15: 7116-7118
  29. Hoos A., Britten CM., Huber C., O'Donnell-Tormey J. A methodological framework to enhance the clinical success of cancer immunotherapy. Nat. Biotechnol. 2011; 29: 867-870
  30. Schadendorf D., Hodi FS., Robert C. et al. Pooled Analysis of Long-Term Survival Data From Phase II and Phase III Trials of Ipilimumab in Unresectable or Metastatic Melanoma. J. Clin. Oncol. 2015; 33: 1889-1894
  31. Hoos A., Eggermont MM., Janetzki S. et al. Improved endpoints for cancer immunotherapy trials. J. Natl. Cancer Inst. 2010; 102: 1388-1397
  32. Di Giacomo AM., Danielli R., Guidoboni M., et al. Therapeutic efficacy of ipilimumab, an anti-CTLA-4 monoclonal antibody, in patients with metastatic melanoma unresponsive to prior systemic treatments: clinical and immunological evidence from three patients cases. Cancer Immunol. Immunother. 2009; 58: 1297-1306
  33. Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting results of cancer treatment. Cancer. 1981;47: 207-214
  34. Eisenhauer EA., Therasse P., Bogaerts J. et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur. J. Cancer. 2009; 45: 228-247
  35. Johnson P., Greiner W., Al-Dakkak I., Wagner S. Which metrics are appropriate to describe the value of new cancer therapies? Biomed. Res. Int. 2015; 2015: 865101
  36. Hodi FS., O'Day SJ., McDermott DF. et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 2010; 363: 711-723
  37. Robert C., Thomas L., Bondarenko I. et al.: Ipilimumab plus Dacarbazine for Previously Untreated Metastatic Melanoma. N. Engl. J. Med. 2011; 364:2517-2526
  38. Brahmer JR., Drake CG., Wollner I., et al. Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J. Clin. Oncol. 2010; 28: 3167-3175
  39. Topalian SL., Hodi FS., Brahmer JR. et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N. Engl. J. Med. 2012; 366: 2443-2454
  40. Topalian SL., Sznol M., McDermott DF. et al. Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. J. Clin. Oncol. 2014; 32: 1020-1030
  41. Robert C, Long GV, Brady B., et al. Nivolumab in previously untreated melanoma without BRAF mutation. N. Engl. J. Med. 2015; 372: 320-330
  42. Weber JS., D'Angelo SP., Minor D. et al. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2015; 16: 375-384
  43. Brahmer J., Reckamp KL., Baas P. et al. Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. N. Engl. J. Med. 2015; 373: 123-135
  44. Ribas A., Puzanov I., Dummer R. et al. Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol. 2015; 16: 908-918
  45. Robert C., Schachter J., Long GV. et al. Pembrolizumab versus Ipilimumab in Advanced Melanoma. Engl. J. Med. 2015; 372: 2521-2532
  46. Hamid O., Robert C., Daud A. et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N. Engl. J. Med. 2013; 369: 134-144
  47. Robert C., Ribas A., Wolchok JD. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet. 2014; 384: 1109-1117
  48. Larkin J., Hodi FS., Wolchok JD. Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. Engl. J. Med. 2015; 373: 1270-1271
  49. Postow M., Chesney J., Pavlick AC. et al. Nivolumab and Ipilimumab versus Ipilimumab in Untreated Melanoma. N. Engl. J. Med. 2015; 372: 2006-2017
  50. Higano CS., Schellhammer PF., Small EJ. et al. Integrated data from 2 randomized, double-blind, placebo-controlled, phase 3 trials of active cellular immunotherapy with sipuleucel-T in advanced prostate cancer. Cancer. 2009; 115: 3670-3679
  51. Kantoff PW., Higano CS., Shore ND., et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N. Engl. J. Med. 2010; 363: 411-422
  52. Small EJ., Schellhammer PF., Higano CS. Placebo-controlled phase III trial of immunologic therapy with sipuleucel-T (APC8015) in patients with metastatic, asymptomatic hormone refractory prostate cancer. J. Clin. Oncol. 2006; 24: 3089-3094
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