1. Targeting tyrosine- kinase receptors: pitfalls and benefits Massimo Di Maio Unità Sperimentazioni Cliniche Istituto Nazionale Tumori Fondazione “G.Pascale”, Napoli dimaiomax@libero.it Roma, 22 febbraio 2013

2. 1)effective systemic therapy against metastases is lacking; 2)this malignancy must be regarded as a priority for studies in tumor biology and development of novel, mechanism- driven therapies; 3)randomized trials are essential to evaluate promising new agents or combinations. 10 years ago….

3. Evidence based medicine: the pyramid of evidence Ho P M et al. Circulation 2008;118:1675-1684 Large randomized controlled trials

4. A randomized trial (in order to have many benefits and a few pitfalls ) should be: 1.Scientifically relevant 2.Methodologically correct 3.Ethically acceptable

5. AuthorAgentSettingPts PFS (months) OS (months) Primary endpoint Motzer (NEJM, 2007) ( J Clin Oncol 2009) Sunitinib vs IFN 1 st line750 11.0 vs 5.0 (HR 0.44, 95%CI 0.32-0.54) 26.4 vs 21.8 (HR 0.82, 95%CI 0.67-1.00) PFS Escudier (NEJM, 2007) (J Clin Oncol 2009) Sorafenib vs Placebo 2 nd line903 5.5 vs 2.8 (HR 0.44, 95%CI 0.35-0.55) 17.8 vs 15.2 (HR 0.88, 95%CI 0.74-1.04) OS Escudier (Lancet, 2007 J Clin Oncol 2010) Bevacizumab + IFN vs placebo+IFN 1 st line649 10.2 vs 5.4 (HR 0.63, 95%CI 0.52-0.75) 23.3 vs 21.3 (HR 0.86, 95%CI 0.72-1.04) OS Rini (J Clin Oncol, 2008 J Clin Oncol 2010) Bevacizumab + IFN vs IFN 1 st line732 8.5 vs 5.2 (HR 0.72, 95%CI 0.61-0.83) 18.3 vs 17.4 (HR 0.86, 95%CI 0.73-1.01) OS Hudes (NEJM, 2007) Temsirolimus vs IFN (vs TEMSR+IFN) 1 st line626 5.5 vs 3.1 (HR not reported) 10.9 vs 7.3 (HR 0.73, 95%CI 0.58-0.92) OS Motzer (Lancet, 2008) (Cancer, 2010) Everolimus vs placebo 2 nd line410 4.0 vs 1.9 (HR 0.30, 95%CI 0.22-0.40) 14.8 vs 14.4 (HR 0.87, P=0.162) PFS Sternberg (J Clin Oncol, 2010) Eur J Cancer 2013) Pazopanib vs placebo 1 st or 2 nd line 435 9.2 vs 4.2 (HR 0.46, 95%CI 0.34-0.62) 22.9 vs 20.5 (HR 0.91, 95%CI 0.71-1.16) PFS Motzer (ESMO 2012) Pazopanib vs sunitinib 1 st line1110 8.4 vs 9.5 (HR 1.05, 95%CI 0.90-1.22) 28.4 vs 29.3 (HR 0.91, 95%CI 0.76-1.08) PFS (non- inferiority) Main randomized phase III trials (with drugs currently avaialble in clinical practice)

6. The modern concept of evidence based medicine Haynes RB et al, BMJ 2002; 324: 1350

7. Treatment options for patients with advanced RCC Appropriateness evaluation RAND/University of California-Los Angeles Appropriateness Method 2006: –132 treatment options in 3 clinical scenarios 2012: –575 treatment options in 34 clinical scenarios Halbert RJ et al, Cancer 2006; 107: 2375-2383 Gore ME et al, Eur J Cancer 2012; 48:1038-1047

8. Treatment options for patients with advanced RCC Appropriateness evaluation

10. Some methodological issues The choice of endpoint in RCTs Comparison among different options The need for “strategy” trials

11. Christopher W Ryan Evolving standards of care in advanced RCC Systemic therapies in advanced RCC: current status ASCO meeting 2010

13. “Overall survival is considered the most reliable cancer endpoint, and when studies can be conducted to adequately assess survival, it is usually the preferred endpoint.” Guidance for industry Clinical trials endpoints for the approval of cancer drugs FDA, May 2007 ?

14. EndpointsAdvantagesDisadvantages Overall survival Clinical benefit for regular approval Universally accepted direct measure of benefit Easily measured Precisely measured Blinding not essential May involve larger studies May be affected by crossover or sequential therapy Guidance for industry Clinical trials endpoints for the approval of cancer drugs FDA, May 2007

15. EndpointsAdvantagesDisadvantages Progression-free survival Surrogate for accelerated approval or regular approval* Smaller sample size and shorter follow-up Not affected by crossover or subsequent therapies Not precisely measured; subject to assessment bias, particularly in open label studies Frequent radiological or other assessments, balanced among treatment arms Blinding preferred Blinded review recommended *Adequacy as a surrogate endpoint is highly dependent upon other factors such as effect size, effect duration, and benefits of other available therapy. Guidance for industry Clinical trials endpoints for the approval of cancer drugs FDA, May 2007

16. Crossover of experimental treatment 1 st line Standard arm Experimental arm PD Time 2 nd line(s) with crossover 2 nd line(s) Overall survival 1 st line 2 nd line(s)

17. Broglio KR, Berry DA. J Natl Cancer Inst 2009; 101: 1642-1649

18. “For clinical trials with a PFS benefit, lack of statistical significance in OS does not imply lack of improvement in OS, especially for diseases with long survival post-progression (SPP) OS is a reasonable endpoint when SPP is short but is too high a bar when median SPP is long” Broglio KR, Berry DA. J Natl Cancer Inst 2009; 101: 1642-1649

19. PFS as endpoint in cancer trials Richard Pazdur, M.D., director of the FDA Office of Oncology Drug Products, acknowledges that PFS requires a more nuanced risk–benefit analysis than OS does, but he says that sometimes PFS is an appropriate endpoint for registration trials. “A lot of it has to do with magnitude, magnitude, magnitude,” he said in an interview. “Just demonstrating a statistically significant difference in PFS is not enough. It has to be clinically meaningful.” Tuma R, J Natl Cancer Inst 2009

20. Motzer et al, N Engl J Med 356:115-24, 2007 Sunitinib: progression-free survival Magnitude of benefit

21. Blagoev KB et al, Cell Reports 3: 277-281, 2013

22. Motzer et al, J Clin Oncol 27: 3584-3590, 2009 Sunitinib vs IFN: overall survival

23. Blagoev KB et al, Cell Reports 3: 277-281, 2013

24. Some methodological issues The choice of endpoint in RCTs Comparison among different options The need for “strategy” trials

25. SunitinibBevacizumab TemsirolimusPazopanib

26. There are no direct comparative data to allow an accurate estimation of the differences between available treatments for 1st-line treatment of advanced RCC. In the absence of direct comparative data, indirect comparisons based in particular on the individual safety profiles can guide the clinical choice among different agents […]. There may be other factors such as route of administration and other preferences that will play a role. European Medicines Agency CHMP assessment report Procedure No. EMEA/H/C/001141 Before COMPARZ….

27. Eisen, ASCO 2012 Oral abstract session ? Weakness of indirect comparisons…

28. Mills EJ et al, BMC Cancer 2009 Weakness of indirect comparisons…

29. ? Mills EJ et al, BMC Cancer 2009

30. A direct comparison… Motzer, ESMO 2012

31. Statistical Analysis Plan PFS non-inferiority demonstrated if upper bound of 95% CI for HR<1.25 –Cox proportional hazard analysis adjusted for stratification factors –By independent review 631 PFS events needed for 80% power Planned enrollment of 1100 patients Motzer, ESMO 2012

32. Primary Endpoint: Progression-free Survival (independent review) Pazopanib Sunitinib NMedian PFS (95% CI) Pazopanib5578.4 mo (8.3, 10.9) Sunitinib5539.5 mo (8.3, 11.1) HR (95% CI ) = 1.047 (0.898,1.220) Motzer, ESMO 2012

33. Interim Analysis of Overall Survival Pazopanib Sunitinib NMedian OS (95% CI) Pazopanib55728.4 mos (26.2, 35.6) Sunitinib55329.3 mos (25.3, 32.5) HR (95% CI ) = 0.908 (0.762,1.082) P-value = 0.275 Motzer, ESMO 2012

34. How to integrate different endpoints: efficacy and QoL WorseEqualBetter Relevant QoL not of interest QoL not of interest (?) QoL Shorter No change Longer Survival

35. QoL as endpoint in RCTs: some methodological issues How to handle missing data? –Risk of bias: non-responding patients are those who feel ill Which timing of QoL administration? –Timing is relevant, especially if treatments have different schedules How to interpret the relevance of differences? –“Minimum clinically relevant difference”

36. Park MH et al, Value in Health 15:933-939, 2012 (n=485: 140 cancer patients, 60 family members, 39 medical oncologist, 34 oncology nurse, 133 general nurse, 79 pharmacist)

37. Park MH et al, Value in Health 15:933-939, 2012 (n=485: 140 cancer patients, 60 family members, 39 medical oncologist, 34 oncology nurse, 133 general nurse, 79 pharmacist)

38. Some methodological issues The choice of endpoint in RCTs Comparison among different options The need for “strategy” trials

39. The need for trials comparing different treatment sequences Currently approved drugs allow different treatment sequences However, to date, we have no solid evidence to prefer one sequence or another

40. A -> B -> C -> D C -> A -> B -> D A -> C -> B B -> A -> C…. A -> B -> D C -> D -> A -> B D -> A -> C -> B B -> A -> D…..

41. The real limitation of PFS as an endpoint … is not its utility in avoiding “dilution” related to crossover; …is not its intrinsic relevance, given that the magnitude of benefit is sufficiently large; …the real limitation is that we are focused on the single line of treatment, and we consider all that happens beyond progression no more than a confounding factor…

42. Registrative trialsPost-registrative trials Approach“Explanatory”“Pragmatic” ComparisonNew drug vs. comparator “acceptable” for regulatory agencies Comparison between sequences - strategies Inclusion criteria RestrictiveLarge, more similar to clinical practice EndpointPFSOverall survival

43. Thanks for your attention! Massimo Di Maio Unità Sperimentazioni Cliniche Istituto Nazionale Tumori Fondazione “G.Pascale”, Napoli dimaiomax@libero.it Roma, 22 febbraio 2013