Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
The time to progression ratio for phase II trials of personalized medicine Marc Buyse, ScD IDDI, Louvain-la-Neuve, and I-BioStat, Hasselt University, Belgium [email protected] Outline • Definition of TTPR • TTPR in gastro-intestinal stromal tumors • TTPR to design a trial in advanced colorectal cancer • TTPR for trials of personalized medicine • Tentative conclusions The TTP ratio (TTPR) Start of Rx for advanced disease TTP1 TTP2 TTP3 Rx1 Rx2 Rx3 First progression Second progression TTPR = TTP2 / TTP1 … Death Use of TTPR Cytostatics are not expected to induce tumor shrinkage, but it is hoped that they can stabilize the tumor (delay progression). For second-line therapies, the « time to progression ratio » (or « growth modulation index »), is defined as TTPR = TTP2 / TTP1 Given the natural history of most tumors, TTPR generally does not exceed 1 (i.e. TTP2 tends to be shorter than TTP1). Von Hoff suggested that TTPR > 1.33 reflects activity of the second-line therapy. Ref: Mick et al. Controlled Clinical Trials 21:343-59, 2000. TTPR-based designs : second-line treatment only Start of Rx for advanced disease TTP1 TTP2 Rx1 Rx2 First progression, entry on trial Second progression TTPR-based designs : two lines of treatment Start of Rx for advanced disease, entry on trial TTP1 TTP2 Rx1 Rx2 First progression Second progression TTPR when doubling dose of imatinib for progressing gastro-intestinal stromal tumors Proportion of patients with TTPR > 1.33 after cross-over from 400 mg to 800 mg of imatinib daily, broken down by response to 400mg Partial response 2/3 (67%) Stable disease 13/36 (36%) Progressive disease 12/72 (17%) All patients Ref: Zalcberg et al, Eur J Cancer 41:1751-7, 2005. 27/110 (25%) Trial comparing two imatinib doses in patients with gastro-intestinal stromal tumors R 181 * 400 mg imatinib daily 196 * 800 mg imatinib daily * Nr of patients with adequate DNA for KIT genotype analysis Ref: Debiec-Rychter et al, Eur J Cancer 42:1093-1103, 2006. Cumulative incidence of response by KIT mutation Ref: Debiec-Rychter et al, Eur J Cancer 42:1093-1103, 2006. TTPR after cross-over by KIT mutation Proportion of patients with TTPR > 1.25 after cross-over from 400 mg to 800 mg Exon 11 mutation (N=248) 83% Exon 9 mutation (N=58) 57% Wild type (N=52) P= 0.0017 7% Ref: Debiec-Rychter et al, Eur J Cancer 42:1093-1103, 2006. P= 0.0012 Trial comparing two chemotherapy sequences in patients with advanced colorectal tumors R 109 FOLFIRI – FOLFOX 111 FOLFOX – FOLFIRI Primary endpoint = Time to second progression (TTP1 + TTP2) Secondary endpoints = TTP1, TTP2, survival Ref: Tournigand et al, J Clin Oncol 22:229-37, 2004. 1.0 Distribution of TTPR in advanced colorectal cancer Patients Events 137 0.6 0.4 0.2 0.0 Probability 0.8 147 0 0.4 0.8 2 3 TTP Ratio 4 5 6 1.0 Distribution of TTPR in advanced colorectal cancer Patients Events 137 0.6 0.2 0.4 of the patients had a TTPR > 0.5 0.0 50% Probability 0.8 147 0 0.4 0.8 0.5 2 3 TTP Ratio 4 5 6 1.0 Distribution of TTPR in advanced colorectal cancer Patients Events 137 0.6 of the patients had a TTPR > 0.8 0.4 Probability 0.8 147 0.0 0.2 33% 0 0.4 0.8 0.8 2 3 TTP Ratio 4 5 6 1.0 Distribution of TTPR in advanced colorectal cancer Patients Events 137 0.6 of the patients had a TTPR > 1 0.4 Probability 0.8 147 0.0 0.2 25% 0 0.4 0.8 1 2 3 TTP Ratio 4 5 6 1.0 Distribution of TTPR in advanced colorectal cancer Patients Events 137 0.6 0.4 0.2 20% of the patients had a TTPR > 1.25 0.0 Probability 0.8 147 0 0.4 0.8 1.25 2 3 TTP Ratio 4 5 6 TTPR – test of hypothesis A possible null hypothesis is: H0: TTPR = TTP2 / TTP1 HR0 versus the alternative hypothesis: HA: TTPR = TTP2 / TTP1 > HR0 1.0 Test of hypothesis in advanced colorectal cancer Patients Events 137 0.2 0.4 0.6 H0 : TTPR ≤ 0.75 0.0 50% Probability 0.8 147 0 0.4 0.8 0.75 2 3 TTP Ratio 4 5 6 A sign test statistic For the ith patient, let ri be equal to +1 if TTP2 > TTP1 HR0 –1 if TTP2 TTP1 HR0 and TTP2 is uncensored The test statistic (equivalent to a sign test statistic) X² = (i ri)² / i ri² has a ² distribution with 1 d.f. Ref: Mick et al. Controlled Clinical Trials 21:343-59, 2000. A sign test statistic HR0 = 0.7 = 0.05 Correlation = 0.7 90% 85% 80% Ref: Mick et al. Controlled Clinical Trials 21:343-59, 2000. A sign test statistic HR0 = 0.7 = 0.05 Correlation = 0.5 Ref: Mick et al. Controlled Clinical Trials 21:343-59, 2000. A sign test statistic HR0 = 0.7 = 0.05 Correlation = 0.3 Ref: Mick et al. Controlled Clinical Trials 21:343-59, 2000. TTP1 vs. TTP2 in advanced colorectal cancer R² = 0.03 TTP1 vs. TTP2 in advanced colorectal cancer Statistics for correlated survival times In the absence of censoring, TTP1 and TTP2 can be compared using a paired t-test or a non-parametric test for paired observations. If TTP2 is censored, TTP1 and TTP2 are paired survival times. The ordinary rank test statistics (e.g. logrank or Gehan-Wilcoxon) can be used with variance corrected to account for the correlation between TTP1 and TTP2. Ref: Jung, Lifetime Data Analysis 5:67-79, 1999. TTPR – another test of hypothesis Let p be the proportion of patients for whom TTPR > HR0. A possible null hypothesis is: H 0 : p p0 versus the alternative hypothesis: HA: p > p0 which leads to Flemings’ one-stage or Simon’ two-stage designs. 1.0 Tests of hypothesis in advanced colorectal cancer Patients Events 137 0.6 0.4 0.2 22% H0 : p0 ≤ 22% 0.0 Probability 0.8 147 0 0.4 0.8 1.33 2 3 TTP Ratio 4 5 6 Trial of molecular profiling TTP1 TTP2 At least two prior therapies for advanced disease, no further therapy available Molecular profiling of tumor biopsy by IHC, FISH or micro-array to identify target Last progression, entry on trial Progression on targeted therapy Ref: Von Hoff, AACR 100th Annual Meeting, Denver, CO, April 18-22, 2009. Trial of molecular profiling Trial designed to test p0 (proportion of patients with TTPR > 1.3): H0: p p0 = 15% Primary analysis: proportion of patients with TTPR > 1.3: 18 / 66 (27%, 95% C.I. 17% - 38%, P = 0.007) Breast Colorectal Ovarian Others 8 / 18 (44%) 4 / 11 (36%) 1 / 5 (20%) 5 / 32 (16%) Ref: Von Hoff, AACR 100th Annual Meeting, Denver, CO, April 18-22, 2009. Trial of molecular profiling Promising results, and amongst the 18 patients with TTPR > 1.3, none would have received same drug through plysician’s choice. However, • Is TTPR > 1.3 good enough? • Trial was not randomized, therefore no evidence that physician’s choice could have yielded similar results • Only 66 patients of 106 could have molecular profiling Trial designs using TTPR – pros and cons + Test time to progression rather than response; hence well suited to test cytostatic agents + Patients serve as their own control, a desirable feature to control between-patient variability + Efficient if substantial correlation between TTP1 and TTP2 - Choice of appropriate value for HR0 - TTP1 difficult to estimate retrospectively, and potentially biased downwards if standard first-line treatment included in design and new agent is promising - Inefficient if poor correlation between TTP1 and TTP2