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Raising the bar of efficacy in cancer therapeutics

Raising the bar of efficacy in cancer therapeutics. Alberto Sobrero Ospedale San Martino Genova, Italy. Today’s topic : size of benefit in phase III clinical trials on advanced solid tumors. Clinically worthwhile Clinically relevant ( efficacy-effectiveness ) Vs

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Raising the bar of efficacy in cancer therapeutics

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  1. Raising the bar of efficacy in cancer therapeutics Alberto Sobrero Ospedale San Martino Genova, Italy

  2. Today’stopic: size of benefit in phase III clinical trials on advancedsolidtumors • ClinicallyworthwhileClinicallyrelevant (efficacy-effectiveness) Vs • Statisticallysignificant NOT • Adjuvantsetting • Type of endpoint • Ways of summarizing benefit • Cost , price, reimbursement

  3. Size of benefit (target delta) : a compromise • plausible to achieve • worthwhile if achieved

  4. Target delta: HR • 0.5 meansdoubling of the benefit vs control • 48 months • 0.66 means 50% increment of the benefit vs control • 46 months • 0.80 means 25% increment of the benefit vs control 45 months fantastic very good hmm…

  5. 15 pivotal R phase III registration trials, 9 biologics , 8 cancer types median HR PFS .57 OS .73 median absolute gain 2.7 months 2.0 months …hmm… Very good / fantastic Sobrero and Bruzzi , JCO 2009

  6. The 3 problems HR vs absolute delta low target HR in trial design target HR in trial design vs p value in trial analysis and interpretation.

  7. PROBLEM 1: ABSOLUTE GAIN Increase in median OS for different HR as a function of prognosis MST Increase in median values as a function of HR In control 0.9 0.8 0.7 0.6 0.5 0.4 6 .6 1.5 2 4 6 9 Clinically worthwhile relative delta is a function of prognosis Both HR AND absolute gain must be considered 24 2.6 6 10 16 24 36 worthless worthwhile Unrealistic

  8. PROBLEM 2. ‘ LOW PROFILE’Typical phase III trial design in advanced cancer (PFS 6 mo) • Delta 25% i.e. HR = .75 • Median delta = 1.8 mo • Power 90% • N = 800 • Cost = 100 M If we get this , is this really clinically worthwhile? Be more corageous : raise the bar

  9. PROBLEM 3: INCONSISTENCY DESIGN CONDUCT ANALYSIS REPORT INTERPRET. Define target delta…………....target delta is ignored and... p value becomes the focus…

  10. Problem 3 : INCONSISTENCY H1 H0 NEG POS POS POSITIVE ( median gain 25 days) HR 0.4 0.5 0.6 0.7 0.8 0.9 1.0

  11. ‘Statistically positive’ trials with deltas lower than those pre-specified in the protocol AUTHOR DRUG TUMOR predefined reported p HR HR value Johnstone 09 lapatinib breast 0.64 0.71 0.019 Jonker 07 cetuximab colon 0.74 0.77 0.001 Moore 07 erlotinib pancreas 0.75 0.82 0.038 Llovet 08 sorafenib liver 0.6 0.69 0.001 Escudier 07 sorafenib renal 0.67 0.72 0.02 modified from Ocana A. JNCI,2011

  12. The solutions: raising the bar above the minimum clinically worthwhile effect • Maintainingtoday’sstatisticalthinking • Change H1: Shootatlarger, clinicallyworthwhileeffect

  13. Proposal maintaining today’s classical stat thinking: raise the bar, change H1 New H1 H1 H0 • Co-development • Predictive markers • Adjuvant setting NEG LIMBO ? POS POS HR 0.4 0.5 0.6 0.7 0.8 0.9 1.0

  14. The pros of raising the bar • POP agents off market  credibility / uniformity • Smaller trials  reduced costs, more rapid clinical devel. • Trials on selected patients selective approval

  15. The contras of raising the bar • Increased statistical uncertainty • Missing cumulative effect of incrementalists • Cost and devel. time vs RISK  fewer agents • Less funding to clinical and translational research

  16. The solutions: the two ways of raising the bar above the minimum clinically worthwhile effect • Maintainingtoday’sstatisticalthinking • Change H1: Shootatlarger, clinicallyworthwhileeffect • Changingtoday’sstatisticalthinking • Change H0: shootatrejectinganythinginferior to a minimumclinicallyworthwhileeffect

  17. Proposal changing today’s classical statistical thinking: change H0 New H1 New H0, MCWE H1 H0 NEG NEG LIMBO NEG POS HR 0.4 0.5 0.6 0.7 0.8 0.9 1.0

  18. The limbo level MCWE, new H0 APPROVE Consider increasing Sample size • Co-development • Predictive markers • Adjuvant setting H0 Further studies only if non toxic low cost LIMBO LIMBO APPROVE HR 0.4 0.5 0.6 0.7 0.8 0.9 1.0

  19. Pros and cons of changing H0 PROS CONS Identification of MCWE difficult Size of trials ( ifeffectclose to MCWE) • Forces to reason in terms of relevance, not stat. significance • Statistical uncertainty not increased • Promotes adaptive designs

  20. CONCLUSIONS • Raise the bar ( H1 or H0 ) shooting at deltas larger than MCWE • Consistency:design vs analysis-interpretation  less emphasis on p values, more on HR AND absolute gains.

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