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Response, PFS or OS – what is the best endpoint in advanced colorectal cancer? Marc Buyse

Response, PFS or OS – what is the best endpoint in advanced colorectal cancer? Marc Buyse IDDI, Louvain-la-Neuve & Hasselt University marc.buyse@iddi.com. POSSIBLE ENDPOINTS. Overall survival (OS) Progression-free (PFS) Tumor response (ORR) Biomarkers (including tumor measurements).

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Response, PFS or OS – what is the best endpoint in advanced colorectal cancer? Marc Buyse

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  1. Response, PFS or OS – what is the best endpoint in advanced colorectal cancer? Marc Buyse IDDI, Louvain-la-Neuve & Hasselt University marc.buyse@iddi.com

  2. POSSIBLE ENDPOINTS • Overall survival (OS) • Progression-free (PFS) • Tumor response (ORR) • Biomarkers (including tumor measurements)

  3. Requirements for idealendpointIN TRIALS Ideal endpoint in clinical trialsshould • capture all clinically relevant events • be easy to measure • have little opportunity for ascertainment bias • be observed as early as possible • be observed in as many patients as possible • be statistically sensitive to real treatment benefits

  4. CONSIDERATIONS FOR ENDPOINTS

  5. Reasons for better sensitivity of PFS as compared with OS • Larger number of events at same follow-up time • PFS less affected by competing risks (especially in elderly populations) • PFS unaffected by effective rescue therapies and successive treatment lines • Attenuation of treatment effect on OS vs. PFS

  6. PFS Median gain 4 months • Assumptions: • Median PFS = 12 months in control group • Median PFS = 16 months in experimental group • HR = .75 (25% riskreduction)

  7. OS Median gain 4 months • Assumptions: • Median OS = 24 months in control group • Median OS = 28 months in experimental group • HR = .86 (14% riskreduction)

  8. Samplesizes • To have 80% power of detecting HR = .75, 380 events are required

  9. Samplesizes • To have 80% power of detecting HR = .75, 380 events are required • To have 80% power of detecting HR = .86, 1,380deaths are required

  10. SECOND-LINE TREATMENTS • OS is confounded by treatments received on progression • Reintroduction of same treatment (e.g. oxaliplatin) • Cross-overs in randomized trials • Other approved second-line treatments • Experimental agents • Paradoxically, the better a new treatment, the less likely an OS benefit Ref: de Gramont et al, JCO 2007; 25: 3224.

  11. OXALIPLATIN REINTRODUCTION Ref: de Gramont et al, JCO 2007; 25: 3224.

  12. POST-PROGRESSION SURVIVAL (PPS) Ref: Broglio and Berry, JNCI 2009;101:1642.

  13. POWER FOR OS AS A FUNCTION OF SPP Ref: Broglio and Berry, JNCI 2009;101:1642.

  14. POWER FOR OS AS A FUNCTION OF SPP Ref: Broglio and Berry, JNCI 2009;101:1642.

  15. POWER FOR OS AS A FUNCTION OF SPP Ref: Broglio and Berry, JNCI 2009;101:1642.

  16. The exquisitesensitivity of biomarkerS Phase II trial of Interleukin-2 + a viral suspension of a recombinant vaccinia vector containing the sequence coding for the human MUC1 antigen 21 patients with elevated PSAafter prostatectomy and histological documentation of MUC1 antigen expression Weekly schedule Three-weekly schedule

  17. « CLINICAL » OUTCOMES vs. BIOMARKER Protocol-defined “clinical” outcomes • PSA response rate* • Duration of PSA response • Time to PSA progression • Biomarker • PSA measurements over time • * PSA decreased to < 4 ng/ml or to < 50% of baselinelevelfor at least 4 weeks

  18. PSA MEASUREMENTS OVER TIME

  19. MODELLING OF PSA MEASUREMENTS • Model contains the following terms: • Randomized treatment (Weekly or Three-weekly) • Time • Period (pre- vs. post-treatment) • Interactions

  20. MODELLING OF PSA MEASUREMENTS

  21. MODELLING OF PSA MEASUREMENTS • Treatment had an overall effect

  22. MODELLING OF PSA MEASUREMENTS • Weekly schedule had a more pronounced effect on PSA levels

  23. MODELLING OF PSA MEASUREMENTS • There were no pre-treatment differences in PSA levels between the two schedules (as expected)

  24. MODELLING OF PSA MEASUREMENTS • The weekly schedule had a significantly larger effect on PSA levels as compared with the three-weekly schedule

  25. MODELLING OF PSA MEASUREMENTS • Phase II trials shouldberandomized and use biomarkersratherthan ORR, PFS or OS • Interim analyses of phase III trials could use biomarkers • But: • Validation trials are required to show thatbiomarkers are predictive of clinicalefficacy

  26. CONCLUSION : OS IS NO LONGER A USEFUL ORAPPROPRIATE PRIMARY ENDPOINT FOR TRIALS • Differences in OS unlikely with active further Rx lines • PFS arguably neither meaningful nor reliable • Therefore: • Search for biomarkers (including tumor measurements) • Perform quantitative analyses of statistical surrogacy • Revisit assumption of proportional hazards • Why use a single endpoint ?!

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