2008Mar09 CSPOR CRC NSAS-BC02 DFS Disease Free Survival CSPOR-BC NPO NPO / Validity Time-to- Reliability Reproducibility QALY Intra-rater reliability Inter-rater reliability Sensitivity Feasibility IPSS IPSS =0.08 =0.54. 1997;88:1013-20. 1
IPSS DCCT DCCT Provided by Dr. John Lachin 2
PFS Progresson Free Survival reliabile valid NSCLC * PFS QOL ALS QC *Yothers JCO 2007; 25: 5153-4. PFSOS OS PFS OS PFS PFS Freidlin et al. JCO 2007; 25: 2122-6 PFS PFS Time-to- PFS attrition PFS 2 PD QALY USA FDA. Guidance for industry clinical trial endpoints for 2! the approval of cancer drugs and biologics. 2007May Time-to-event 100 Overall survival (All randomized) OS Overall Survival TTP Time to Progression PD PD 50 PFS Progression Free Survival PD HR = 0.68 [0.52-0.87] TTF Time to Treatment Failure p = 0.0024 (stratified log-rank test) DFS Disease Free Survival 2 RFS Recurrence Free Survival RFI Recurrence Free Interval Overall survival (%) Median follow-up : 3 yrs 3-year OS - S-1 80.5% - Surgery alone 70.1% 0 0 1 2 3 4 5 (years) No. at risk S-1 Surgery alone 529 530 518 508 390 372 207 176 55 53 Gastrointestinal Cancers Symposium (ASCO-GI), Jan. 19-21, 2007, Orlando, FL 3
Time-to-event Kaplan-Meier product-limit Kaplan-Meier 5 MST Median Survival Time (2 death1 death1 censor1 death1 10 9 8 7 6 1 1(1-1/10) 1(1-1/10)(1-1/9) 1(1-1/10)(1-1/9)(1-1/7) Hinotsu, Akaza, Ohashi and Kotake(1999), Cancer 86:1818-26 Late-phase FDA Johnson et al. JCO 21:1404-11, 2003 1990 200211 71 FDA QOL 1992 RRTTP DFS TTF QOL Johnson et al. JCO 21:1404-11, 2003 1990 200211 Johnson et al. JCO 21:1404-11, 2003 1990 200211 57 18 refractory CR RR 26 DFS RR 10 CML RR+ 9 refractory RR+TTP 7 4 DFS 2 FDA TTP 1 2 2 CCR 1 1 4
RR Time-to-event Johnson et al. JCO 21:1404-11, 2003 1990 200211 DFS: SRE 3 Pamidronate,Zoledronate Mitoxantrone* CML Busulfan Tamoxifen TTP: Paclitaxel BleomycinTalc* Tamoxifen* DCIS Tamoxifen CDDP Amifostine* OS PFS DFS Hudis et al. JCO 2007; 25: 2127-32 Hudis et al. JCO 2007; 25: 2127-32 DCIS Punt et al. JNCI 2007; 99:998-1003 Punt et al. JNCI 2007; 99:998-1003 52 OS 8 DFS 5
Allegra et al. JCO 2007; 25: 3572-5 Time to Failure of Strategy? Time-to- QALY Oxaliplatin PFS Tme to Failure of Strategy(TFS) 1 TFS FDA July 21, 2004 Three Month Change in PSA as a Surrogate Endpoint for surrogate endpoint Mortality in Advanced Hormone-Refractory Prostate Cancer: Data From Southwest Oncology Group Study 99-16 QOL OS PFS * Patrick A. Burch, M.D. OS PFS 7, Graham F. Greene, M.D. 8, Mitchell C. Benson, M.D., 1 OS DFS Eric J. Small, M.D. 9, Derek Raghavan, M.D., Ph.D, 10 E. David PSA *Buyse Burzykowski et al. Evaluation of Surrogate Endpoints, Springer, 2005. Prostate cancer endpoints workshop Daniel P. Petrylak, M.D. 1, Donna Ankerst, Catherine M. Tangen, Dr.PH. 2, Maha A. Hussain, M.D. 3, Primo N. Lara Jr., M.D. 4, Jeffrey A. Jones, M.D. 5, Mary Ellen Taplin, M.D. 6, Crawford, M.D. 11 1Columbia University, New York, NY 2 Southwest Oncology Group Statistical Center, Seattle, WA 3 University of Michigan Comprehensive Cancer Center, Ann Arbor, MI 4 University of California, Davis, Sacramento, CA 5 Baylor College of Medicine, Houston, TX 6 University of Massachusetts Medical Center, Worcester, MA 7 Mayo Clinic, Rochester, MN 8 University of Arkansas for Medical Science, Little Rock, AR 9 University of California San Francisco Cancer Center, San Francisco, CA 10 Cleveland Clinic Foundation, Cleveland, OH 11 University of Colorado Health Science Center, Denver, CO Schema Criterion 1a: Survival by Treatment R D/E* Docetaxel 60 mg/m 2 IV D2 every 21 days Estramustine 280 mg po TID, D1-5 Premedication: Dexamethasone 20 mg PO TID starting evening of D1 M/P Mitoxantrone 12 mg/m 2 IV every 21 days Prednisone 5 mg po BID continuously 100% 80% 60% 40% 20% Median At Risk Deaths in Months D + E 261 162 18 M + P 268 182 16 P =.02 *Per protocol amendment January 15, 2001: Coumadin 2 mg PO daily + ASA 325 mg PO daily was added Docetaxel and mitoxantrone doses could be increased to 70 mg/m 2 and 14 mg/m 2, respectively, if no grade 3 or 4 toxicities were seen in cycle 1 0% 0 12 24 36 48 Months After Registration 6
Criterion 1b: Survival by Surrogate Criterion 1c: Survival by Treatment and Surrogate 100% 80% 60% no 50% dec 50% dec At Risk 291 238 P <.0001 Deaths 214 130 Median in Months 14 21 100% 80% 60% D + E, no 50% dec D + E, 50% dec M + P, no 50% dec M + P, 50% dec At Risk 99 162 192 76 P <.0001 Deaths 71 91 143 39 Median in Months 15 21 14 21 40% 40% 20% 20% 0% 0 12 24 36 48 Months After Registration 0% 0 12 24 36 48 Months After Registration NSCLC 191 146 TTP vs Johnson et al. Lancet Oncology 2006; 7: 741-6. NSCLC 191 146 TTP vs Johnson et al. Lancet Oncology 2006; 7: 741-6. OS 1 39 1 10 3 Tang et al. JCO 2007; 25: 4562-8. Buyse et al. JCO 2007; 25: 5218-24. OS PFS 0.99 0.94-1.00 0.74 0.44-1.00 PFS 6 OS 12 0.94 0.87-1.00 3 OS PFS 0.54 0.34-0.74 PFS 20 OS 11% 7-15% PFSOS 6 PFS 57% 12 OS 52% 7
18 ) Sargent et al. JCO 2007; 25: 4569-74. 3 DFS 5 Sargent et al.(jco 2005) 18 20898 3 DFS 2 DFS5 3 DFS5OS III 0.92(0.85-0.95), II 0.70 0.44-0.80 Time-to- QALY AZTAIDS Volberding, et al. NEJM 1990;322:941-9 AZT QOL Lenderking, et al. NEJM 1994;330:738-43 QOL adjusted-life year QALY QALY AZT 8