Improved endpoints for cancer immunotherapy trials.
Unlike chemotherapy, which acts directly on the tumor, cancer immunotherapies exert their effects on the immune system and demonstrate new kinetics that involve building a cellular immune response, followed by changes in tumor burden or patient survival. Thus, adequate design and evaluation of some immunotherapy clinical trials require a new development paradigm that includes reconsideration of established endpoints. Between 2004 and 2009, several initiatives facilitated by the Cancer Immunotherapy Consortium of the Cancer Research Institute and partner organizations systematically evaluated an immunotherapy-focused clinical development paradigm and created the principles for redefining trial endpoints. On this basis, a body of clinical and laboratory data was generated that supports three novel endpoint recommendations. First, cellular immune response assays generate highly variable results. Assay harmonization in multicenter trials may minimize variability and help to establish cellular immune response as a reproducible biomarker, thus allowing investigation of its relationship with clinical outcomes. Second, immunotherapy may induce novel patterns of antitumor response not captured by Response Evaluation Criteria in Solid Tumors or World Health Organization criteria. New immune-related response criteria were defined to more comprehensively capture all response patterns. Third, delayed separation of Kaplan-Meier curves in randomized immunotherapy trials can affect results. Altered statistical models describing hazard ratios as a function of time and recognizing differences before and after separation of curves may allow improved planning of phase III trials. These recommendations may improve our tools for cancer immunotherapy trials and may offer a more realistic and useful model for clinical investigation.
Hoos
Axel
A
Cancer Immunotherapy Consortium of the Cancer Research Institute, New York, NY, USA. axel.hoos@bms.com
Eggermont
Alexander M M
AM
Janetzki
Sylvia
S
Hodi
F Stephen
FS
Ibrahim
Ramy
R
Anderson
Aparna
A
Humphrey
Rachel
R
Blumenstein
Brent
B
Old
Lloyd
L
Wolchok
Jedd
J
D014408:Biomarkers, Tumor / Q000378:metabolism*; D019496:Cancer Vaccines / Q000627:therapeutic use*; D002986:Clinical Trials as Topic / Q000592:standards* / Q000639:trends; D006801:Humans; D007111:Immunity, Cellular; D007167:Immunotherapy / Q000379:methods* / Q000592:standards / Q000639:trends; D053208:Kaplan-Meier Estimate; D015233:Models, Statistical; D015337:Multicenter Studies as Topic / Q000592:standards; D009369:Neoplasms / Q000276:immunology* / Q000628:therapy*; D017063:Outcome Assessment, Health Care; D016032:Randomized Controlled Trials as Topic / Q000592:standards; D013997:Time Factors; D016896:Treatment Outcome
D014408:Biomarkers, Tumor; D019496:Cancer Vaccines
Eur J Cancer. 2009 Jan;45(2):228-47
19097774
Immunity. 2009 Oct 16;31(4):527-8
19833080
Cancer Immunol Immunother. 2008 Mar;57(3):285-8
17721782
J Clin Oncol. 2008 Feb 20;26(6):955-62
18281670
J Natl Cancer Inst. 2007 Oct 3;99(19):1455-61
17895472
Curr Opin Immunol. 2006 Apr;18(2):206-13
16464564
Lancet Oncol. 2010 Feb;11(2):155-64
20004617
J Natl Cancer Inst. 2000 Feb 2;92(3):205-16
10655437
J Clin Oncol. 2005 Dec 10;23(35):9008-21
16061912
Int J Cancer. 2005 Nov 20;117(4):596-604
15945101
J Natl Cancer Inst. 2006 Sep 20;98(18):1292-301
16985248
Cancer Immunol Immunother. 2009 Oct;58(10):1701-13
19259668
Proc Natl Acad Sci U S A. 2008 Feb 26;105(8):3005-10
18287062
Nat Rev Cancer. 2006 May;6(5):409-14
16633367
Eur J Cancer. 2009 May;45(8):1424-31
19167214
J Clin Oncol. 2006 Jul 1;24(19):3089-94
16809734
Cancer Immunol Immunother. 2010 Apr;59(4):609-18
19894047
J Immunother. 2007 Jan;30(1):1-15
17198079
Nat Rev Cancer. 2009 Sep;9(9):675-81
19701243
J Natl Cancer Inst. 2008 Sep 17;100(18):1280-1
18780859
Nat Med. 2004 Sep;10(9):909-15
15340416
Nat Rev Cancer. 2007 Feb;7(2):95-106
17251916
Int J Cancer. 2001 Nov;94(4):531-9
11745440
N Engl J Med. 2010 Aug 19;363(8):711-23
20525992
Gene Ther. 2005 Oct;12 Suppl 1:S131-8
16231045
Vaccine. 2007 Sep 27;25 Suppl 2:B97-B109
17916465
Nat Clin Pract Oncol. 2008 Sep;5(9):557-61
18665147
Biometrics. 1988 Mar;44(1):229-41
3358991
Clin Cancer Res. 2009 Sep 1;15(17):5591-8
19671877
J Clin Oncol. 2002 Apr 15;20(8):2067-75
11956267
J Immunother. 2002 Mar-Apr;25(2):97-138
12074049
J Immunother. 2005 Jan-Feb;28(1):63-72
15614046
Int Rev Immunol. 2003 May-Aug;22(3-4):283-319
12745643
Stat Med. 1997 Mar 30;16(6):695-704
9131757
Cancer Immunol Immunother. 2008 Mar;57(3):289-302
17721783
J Clin Oncol. 2003 Jun 15;21(12):2415-32
12805342
N Engl J Med. 2008 Jun 19;358(25):2704-15
18565863
J Clin Oncol. 2010 Mar 1;28(7):1099-105
20100959
Lancet. 2008 Jul 12;372(9633):145-54
18602688
J Clin Oncol. 2010 Mar 1;28(7):1085-7
20100956
Cancer Immunol Immunother. 2008 Mar;57(3):303-15
17721781
J Natl Cancer Inst. 2006 Sep 20;98(18):1263-5
16985240
Clin Cancer Res. 2009 Dec 1;15(23):7412-20
19934295