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U.S. Food and Drug Administration

U.S. Food and Drug Administration. Notice: Archived Document The content in this document is provided on the FDA’s website for reference purposes only. It was current when produced, but is no longer maintained and may be outdated. . Colorectal Cancer Endpoints Workshop November 12, 2003.

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U.S. Food and Drug Administration

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  1. U.S. Food and Drug Administration Notice: Archived Document The content in this document is provided on the FDA’s website for reference purposes only. It was current when produced, but is no longer maintained and may be outdated.

  2. Colorectal Cancer Endpoints WorkshopNovember 12, 2003 A Case for Time to Tumor Progression as a Clinical Benefit Endpoint in the First-line Therapy of Metastatic Colorectal Cancer Langdon L Miller, MD Chief Medical Officer PTC Therapeutics Gary L Elfring, MS Statistical Consultant Pfizer Corporation

  3. Acknowledgements Pfizer Corporation Sumant Ramachandra, MDGroup LeaderUS Medical Oncology Gabriela Gruia, MD Full-Development Team Leader Camptosar®

  4. Premise (1) An objective, non-survival clinical benefit endpoint is needed as the basis for full regulatory approval of new therapies for metastatic colorectal cancer

  5. Why the Need Now?

  6. An Increasing Number of Treatments Has Added Therapeutic Complexity 7 Cituximab (Erbitux)* 6 Bevacizumab (Avastin)* Oxaliplatin (Eloxatin) 5 Capecitabine (Xeloda) 4 Drugs Available Irinotecan/CPT-11 (Camptosar) 3 Leucovorin (Leucovorin) 2 5-fluorouracil (Adrucil) 1 0 1960 1965 1970 1975 1980 1985 1990 1995 2000 2005 Year *Not yet FDA approved

  7. An Increasing Number of TherapiesHas Prolonged Survival 19 mo 20 16 mo 15 13 mo Median Survival 10 5 0 5-FU/LV (capecitabine) 5-FU/LV (capecitabine) 5-FU/LV (capecitabine) CPT-11 CPT-11 Oxaliplatin FDA-Approved Therapies Saltz LB et al. Proc Amer Soc Clin Oncol 19:#938, 2000; Tournigand C et al. Proc Amer Soc Clin Oncol 20:#494, 2001Grothey A et al. Proc Amer Soc Clin Oncol 20:#496, 2001; Goldberg RM et al. Proc Amer Soc Clin Oncol 22:#1009, 2003

  8. Multiple Therapies • Confound relationship between early tumor control effects and long-term survival effects • Disconnect early tumor control effects and long-term survival effects • Reduce likelihood that survival benefit will be seen

  9. Subsequent Therapies Confound Relationship Between Early Tumor Control and Overall Survival 13 A 4 9 Tumor Control HR = 1.75Survival HR = 1.23 16 A+B 4 3 9 7 Original Therapy (A) 16 New Therapy (B) AB 4 3 9 Tumor Control HR = 1.75Survival HR = 1.00 16 A+B 9 7 Palliative Care 16 A+C 7 9 Tumor Control HR = 1.00Survival HR = 1.14 19 A+BC 7 3 9 Alternative Therapy (C) Is B inefficacious? Treatments Is A+B more efficacious than A+C? 0 5 10 15 20 25 30 Time (mo)

  10. Subsequent Therapies Disconnect Early Tumor Control and Long-Term Survival Later Therapy Later Therapy 13 A 4 9 Tumor Control HR = 1.75Survival HR = 1.23 9 mo 16 A+B 7 9 Original Therapy New Therapy 9 mo Later Therapy 18 mo Palliative Care 21 ACDE 4 3 3 3 9 Tumor Control HR = 1.75Survival HR = 1.14 18 mo 25 A+BCDE 7 3 3 3 9 Treatments 0 5 10 15 20 25 30 Time (mo)

  11. Prolonged Survival • Increases sample sizes • Prolongs accrual time • Delays time until final analysis • Increases costs

  12. Sample Size Requirements for a Study Increase Superiority Survival Study

  13. Sample Size Requirements for a Study Increase Non-inferiority Survival Study

  14. Time to Accrue Sufficient Number of Patients Increases Survival Study

  15. Time to Acquisition of Mature Data is Prolonged Survival Study

  16. Cost to Conduct A Study Increases Survival Study

  17. Implications for Evaluation of Survival as the Primary Measure of Clinical Benefit • Value of survival as an endpoint is reduced • Development in colorectal cancer takes on added risk, time, and expense • Conduct of noninferiority studies or multiple studies becomes impractical • NDA submissions are delayed • Antitumor therapies may not be studied

  18. Why Not Evaluate Symptom Control Instead?

  19. Issues with Symptom Control • Symptom severity is subjective • Disparate types of symptoms in metastatic colorectal cancer complicate interpretation • Fatigue vs pain vs anorexia vs dyspnea vs ascites • Symptoms are not uniformly present at diagnosis and are often not severe • Treatment and disease may induce the same symptoms (eg, nausea, diarrhea) • Relevant symptoms may be missed

  20. Baseline Symptoms in Patients with Untreated Metastatic Colorectal Cancer Combined EORTC QLQ C-30 from all patients with baseline data enrolled in Data from Saltz et al. N Engl J Med 343:905, 2000 and Douillard et al. Lancet 355:1041, 2000

  21. Issues with Symptom Control • Instruments may be insensitive to important changes in tumor size

  22. Subjective Measures of Quality of Life May Not Change Despite Objective Tumor Shrinkage Response Rates p<0.005 p<0.001 50 50 39 35 40 40 30 30 % % 22 21 20 20 10 10 0 0 CPT-11 5-FU/LV 5-FU/LV CPT-11 5-FU/LV 5-FU/LV EORTC QLQ C-30 Global Health Status Better Better P=NS P=NS 20 20 15 15 10 10 5 5 Mean Change (se) Mean Change (se) 0 0 -5 -5 CPT-11/5-FU/LV CPT-11/5-FU/LV -10 -10 5-FU/LV 5-FU/LV -15 -15 -20 -20 Worse Worse 0 4 8 12 16 20 24 28 32 0 4 8 12 16 20 24 28 32 Weeks Weeks Data from Saltz et al. N Engl J Med 343:905, 2000 and Douillard et al. Lancet 355:1041, 2000

  23. Issues with Symptom Control • Symptom progression analyses are often not useful because symptom progression usually occurs after tumor progression (when patient is off study)

  24. Weight Loss Most Often Occurs after Tumor Progression 1 N=1015 0.9 0.8 0.7 0.6 Weight Loss 5% 0.5 Probability 0.4 0.3 0.2 Time to Tumor Progression 0.1 0 0 10 20 30 40 Months *Definitive weight loss (last time weight was <5% from baseline)Data from Saltz et al. N Engl J Med 343:905, 2000 and Douillard et al. Lancet 355:1041, 2000

  25. Declines in Functional Scores Most Often Occur After Tumor Progression 1 N800 0.9 0.8 Physical Functioning 0.7 Cognitive Functioning 0.6 Social Functioning 0.5 Probability Role Functioning 0.4 Emotional Functioning 0.3 Global Health 0.2 Time to Tumor Progression 0.1 0 0 10 20 30 40 Months *Definitive EORTC QLQ C-30 score worsening (last time score was no worse than baseline)Data from Saltz et al. N Engl J Med 343:905, 2000 and Douillard et al. Lancet 355:1041, 2000

  26. Declines in Symptom Scores Most Often Occur After Tumor Progression 1 N800 0.9 0.8 Nausea/Vomiting 0.7 Diarrhea Pain 0.6 Dyspnea 0.5 Probability Appetite Loss 0.4 Fatigue 0.3 0.2 Time to Tumor Progression 0.1 0 0 10 20 30 40 Months *Definitive EORTC QLQ C-30 score worsening (last time score was no worse than baseline)Data from Saltz et al. N Engl J Med 343:905, 2000 and Douillard et al. Lancet 355:1041, 2000

  27. Symptom Progression When Patient is Off Study and is Receiving Second-Line Therapy Confounds Interpretation of Results Baseline No PD PD No PD No PD Discontinuation due to tumor progression Worsened symptoms; decline in weight and functional status CPT-11/5-FU/LV Oxali/5-FU/LV 0 3 6 9 12 Months CT scans

  28. Implications for Evaluation of Symptoms as the Primary Measure of Clinical Benefit • Problems with complexity, subjectivity, reliability, and interpretability make study design and analysis difficult • Development in colorectal cancer takes on added risk and expense • Antitumor therapies may not be studied

  29. Premise (2) Time to tumor progression (TTP) offers an objective, reliable, and practical alternative to survival and symptom-control endpoints • * Time from randomization to the first of either objective tumor progression or death (where tumor progression is a >20% increase in sum of longest dimensions of measured tumors from nadir or the appearance of 1 new tumor [RECIST])

  30. Why Consider TTP as an Endpoint?

  31. Time to Tumor Progression • Represents the most common cause of treatment failure • Incorporates the value of time • Offers direct assessment of disease burden that logically correlates with symptom progression and survival

  32. Tumor Progression is the Most Common Cause of Treatment Failure in Patients with Metastatic Colorectal Cancer Combined data from all treated patients who discontinued therapy. Data from Saltz et al. N Engl J Med 343:905, 2000 and Douillard et al. Lancet 355:1041, 2000

  33. By Incorporating the Value of Time, TTP Better Categorizes Tumor Control Than Response Rate Response Status Response Stable Disease Progressive Disease 80 70 PD at 6 wks PD at 18 wks 60 PD at 54 wks 50 Total Target Tumor Length (cm) 40 30 20 10 0 0 6 12 18 24 30 36 42 48 54 Time (weeks)

  34. It’s Only Logical That Halting Tumor Progression is Clinically Beneficial . . . . . . . . . . PrimaryDiagnosis MetastaticCarcinoma Adenoma Cancer Burden over Time Healthy

  35. It’s Only Logical That Halting Tumor Progression is Clinically Beneficial . . . . . . . . . . PrimaryDiagnosis MetastaticCarcinoma Adenoma Cancer Burden over Time Healthy Symptoms None None Fatigue, Fatigue, anorexia obstruction pain, dyspnea, DVT ascites, obstruction Survival Decades Decade Years Months

  36. Time to Tumor Progression • Correlates with survival in metastatic colorectal cancer

  37. Changes in Median Endpoint Values Suggest that TTP Appears to Correlate with Survival 3 mo 3 mo 13 CPT-11 4 9 N=1068 13 5-FU/LV 4 9 16 CPT-11/5-FU/LV 7 9 0 5 10 15 20 Time (mo) Equation: y = ax + b Data from Saltz et al. N Engl J Med 343:905, 2000 and Douillard et al. Lancet 355:1041, 2000

  38. Changes in Median Endpoint Values Suggest Hypothetical Equation Correlating TTP with Survival 13 CPT-11 4 9 N=1068 13 5-FU/LV 4 9 3 mo 3 mo 16 CPT-11/5-FU/LV 7 9 0 5 10 15 20 Time (mo) Equation: Survival = 1TTP + 9 mo Data from Saltz et al. N Engl J Med 343:905, 2000 and Douillard et al. Lancet 355:1041, 2000

  39. Both Hypothetical and Actual Equation Correlate TTP with Survival Hypothetical equation: Survival = 1TTP + 9 mo N=1068 Actual equation: Survival = 1.17TTP + 8.33 mo; r=.56 30 25 20 Survival (mo) 15 10 5 0 0 2 4 6 8 10 12 14 16 Time to Tumor Progression (mo) Data from Saltz et al. N Engl J Med 343:905, 2000 and Douillard et al. Lancet 355:1041, 2000

  40. One-One TTP-Survival Relationship is Constant Independent of Treatment, Performance Status, or LDH Data from Saltz et al. N Engl J Med 343:905, 2000 and Douillard et al. Lancet 355:1041, 2000

  41. TTP Correlation with Survival 30 25 N=1068 20 Median Survival (mo)  95% CI 15 10 5 0 0-9 9-15 15-21 21-27 27-33 33-39 39-51 >51 n=321 n=170 n=135 n=116 n=73 n=96 n=99 n=58 TTP (wks) *TTP assessed at 6-week intervals through Week 36 and then at 12-week intervalsData from Saltz et al. N Engl J Med 343:905, 2000 and Douillard et al. Lancet 355:1041, 2000

  42. TTP is Highly Correlated with Survival in Cox Regression Analysis Data from Saltz et al. N Engl J Med 343:905, 2000 and Douillard et al. Lancet 355:1041, 2000

  43. Results Are Corroborated by a Publication Analysis of Correlation Between TTP and Survival* Louvet C et al. Cancer 91:2033, 2000

  44. Time to Tumor Progression • Provides a direct reflection of drug activity • Is not confounded by subsequent (eg, 2nd-line) therapies • Offers utility as an endpoint in non-inferiority trials

  45. TTP Provides an Accurate and Direct Reflection of Drug Activity, Unaffected by Subsequent Therapies Original Therapy (A) New Therapy (B) Palliative Care Alternative Therapy (C) 13 A 4 9 Tumor Control HR = 1.75Survival HR = 1.23 16 A+B 4 3 9 7 16 AB 4 3 9 Tumor Control HR = 1.75Survival HR = 1.00 Treatments 16 A+B 9 7 16 A+C 7 9 Tumor Control HR = 1.00Survival HR = 1.14 19 A+BC 7 3 9 0 5 10 15 20 25 30 Time (mo)

  46. Time to Tumor Progression • Reduces sample sizes • Shortens accrual time • Speeds time until final analysis • Decrease costs • Makes first-line development in colorectal cancer practical

  47. Sample Size Requirements for a Study Superiority TTP Study

  48. Sample Size Requirements for a Study Non-inferiority TTP Study

  49. Time to Accrue Sufficient Number of Patients TTP Study

  50. Time to Acquisition of Mature Data TTP Study

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