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  • 1. ASCO 2012Genito-Urinary cancers Bertrand TOMBAL, MD, PhD Cliniques universitaires Saint-Luc Bruxelles
  • 2.  Prostate Kidney And what’s left…. Very few academic trials Many pharma sponsor “updated” trials or post-marketing trials. “If you can convince, confuse”
  • 3.  Prostate Kidney And what’s left….
  • 4. Steve, 72 y.o, PSA 375 ng/ml, multiple bone metastases, T/degarelix 120/80 mg 18 mm + 6 m. 13 mmCourtesy of B.Tombal and F. Lecouvet, CUSL, UCL, Brussels
  • 5. In conclusion, IAD is currentlywidely offered to patients withPCa in various clinical settings,and its status should no longer beregarded as investigational (LE: 2).
  • 6. Calais da Silva(1) Klotz(2) Salonen((3)) Loc. adv. (70%) Loc. adv (50%) Stage Rising PSA Metastatic (30%) Metastatic (50%) N enrolled 766 852 N randomized 626 1386 554 Progression IAD/CAD N 127/107 0.80 HR 0.81 1,08 (0.67-0.98, (95% CI, p) (0.63–1.05, 0.11) (0.90-1.29, 0.43) 0.024) Death IAD/CAD N 169/170 268/256 186/206 OS (years) 8.8/9.1 3.7/3.8 HR 0.99 1.02 1,15 (0.94-1.40) (95% CI, p) (0.80–1.23, 0,84) 0.86-1.21;0.009 0.17 Death/PCa Increase IAD Increase IAD1. SEUG/EORTC, Eur Urol. 2009 Jun;55(6):1269-77.2. NCIC CTG PR.7. J Clin Oncol 29: 2011 (suppl 7; abstr 3)3. Finnprostate study VII, J Urol. 2012 Jun;187(6):2074-81.
  • 7. Intermittent (IAD) versus continuous androgen deprivation (CAD) in hormone sensitive metastatic prostate cancer (HSM1PC) patients (pts): Results of S9346 (INT-0162), an international phase III trial. Hussain et al., J Clin Oncol 30, 2012 (suppl; abstr 4) 3040 hormone naïve M1 PCa pts with performance status (PS) 0-2, PSA ≥ 5 ng/ml were treated with 7 months (m) of goserelin + bicalutamide. 1535 pts achieving PSA ≤4 ng/ml on m 6 and 7 were randomized to CAD or IAD. Primary objective: To assess if OS with IAD is non-inferior to CAD Median FUp 10 y.Characteristic of the patients at randomization IAD (770) CAD (765) Age (yrs) Median (range) 70 (39,97) 70 (39,92) Disease extent Extensive 49% 47% Minimal 51% 53% Visceral disease 7.1% 6.3% Bone Pain Present 28% 28% Gleason score ≥8 27% 27%
  • 8. Overall survival 10 years survival rateHR (IAD/CAD) = 1.09 (95% CI 0.95, 1.24).
  • 9. Steve, 72 y.o, PSA 375 ng/ml, multiple bone metastases, T/goserelin + CPA 6 wks. + 6 m.Courtesy of B.Tombal and F. Lecouvet, CUSL, UCL, Brussels
  • 10. Neoadjuvant androgen pathway suppression prior to prostatectomy. Elahe A. Mostaghel al., J Clin Oncol 30, 2012 (suppl; abstr 4520) 35men with localized PCa treated for 3 months prior to prostatectomy with  Goserelin (G), and 5α-reductase inhibiteur dustasteride (D) 3.5 mg QD, antiandrogen bicalutamide (B) 50 mg QD, and androgen synthesis inhibitor ketoconazole (K) 200 mg TID
  • 11. Neoadjuvant androgen pathway suppression prior to prostatectomy. Elahe A. Mostaghel al., J Clin Oncol 30, 2012 (suppl; abstr 4520) testosterone DHTTreatment ng/g (SD) nM ng/g (SD) nMUntreated 0.21 (0.08) 0.7 4.38 (0.99) 15G+B 0.07 (0.08) 0.3 0.92 (0.49) 3.2G+D 0.32 (0.17) 1.1 0.02 (0.02) 0.06G+B+D 0.33 (0.23) 1.1 0.04 (0.07) 0.15G+B+D+K 0.24 (0.23) 0.8 0.02 (0.02) 0.08
  • 12. Neoadjuvant androgen pathway suppression prior to prostatectomy. Elahe A. Mostaghel al., J Clin Oncol 30, 2012 (suppl; abstr 4520) G+B G+D G+B+D G+B+D+KNadir PSA < 0.2 71% 27% 90% 77%Pathologic responseCR 0 0 10% 8%Near CR (≤ 0.2cc) 0 18% 20% 23%
  • 13. From Ryan and Tindall, J Clin Oncol 29:3651-3658. 2011
  • 14. Effect of neoadjuvant abiraterone acetate (AA) plus leuprolide acetate (LHRHa) on PSA, pathological complete response (pCR), and near pCR in localized high-risk prostate cancer (LHRPC): Results of a randomized phase II study. ME Taplin al., J Clin Oncol 30, 2012 (suppl; abstr 4521) 58 men ≥ 3 positive biopsies and Gleason ≥ 7 (4+3), T3, PSA ≥ 20 ng/mL or PSA velocity > 2 ng/mL/year. First 12 wks randomized to LHRHa or LHRHa/AA/prednisone (P) 5mg qd. After 12 wks and a PBx 12 more wks of LHRHa/AA/P followed by RP
  • 15. Effect of neoadjuvant abiraterone acetate (AA) plus leuprolide acetate(LHRHa) on PSA, pathological complete response (pCR), and near pCRin localized high-risk prostate cancer (LHRPC): Results of a randomizedphase II study.ME Taplin al., J Clin Oncol 30, 2012 (suppl; abstr 4521) 12 wks AA/ 24 wks AA/ p 24 wks LHRHa 24 wks LHRHa Pathological CR 4% 10% 0.6120 Near CR 11% 24% 0.2992 (≤5mm) pT3 59% 48% Positive nodes 11% 28%
  • 16. Identifying the best candidate for radical prostatectomy among patients with high-risk prostate cancer. Briganti A, et al. Predict consortium. Eur Urol. 2012 Mar;61(3):584-92. “Very high-risk cancers localized to the prostate are rarely cured by prostatectomy alone,” Dr. Taplin said. “Therapies that combine surgery with older androgen-inhibiting drugs have not historically improved outcomes. This unmet need has given rise to efforts to develop new drugs capable of more completely reducing androgen levels within the prostate tumors
  • 17. Available options in CRCP COU-AA-302 Docetaxel (Abiraterone) Abiraterone acetate +P PREVAIL Cabazitaxel (enzalutamide) Enzalutamide (MDV3100) Metastasis SymptomsCRPC 67000+ Sipuleucel-T alpharadin-T
  • 18. Available options in CRCP Increase in Relative Hazard ratio median reduction in (95% CI; P-value) survival risk of death 0.65 Abiraterone/P vs. placebo/P1 3.9 months 35% (0.540.77; P<0.001) 0.63† MDV3100 vs. placebo 2* 4.8 months 37% (P<0.0001) Docetaxel(q3w)/P vs. 0.76 2.4 months 24% Mitoxantrone/P3 (0.620.94; P=0.009) 0.70 Cabazitaxel/P vs. mitoxantrone/P4 2.8 months 30% (0.590.83; P<0.0001) 0.78 Sipuleucel T vs. placebo5 4.1 months 22% (0.61 to 0.98; P:0.03) 0.70 Alpharadin vs. placebo6 2.8 months 31% (0.55-0.88; P:0.00185)P: prednisone1. de Bono, et al. N Engl J Med 2011;364:1995–2005; 2. Medivation Press Release AFFIRM 3rd November 2011; study stopped early followingfavourable interim results 95 % CI not stated; 3. Tannock, et al. N Engl J Med 2004;2351:1502–12; 4. de Bono, et al. Lancet 2010; 76:1147–545; 5. Kantoff, et al. N Engl J Med 2010;363:411–22; 6. Bayer Press Release ALSYMPCA 24th September 2011
  • 19. Interim analysis (IA) results of COU-AA-302, a randomized, phase III study of abiraterone acetate (AA) in chemotherapy-naive patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). Ryan et al., J Clin Oncol 30, 2012 (suppl; abstr LBA4518) Efficacy endpointsPatients AA 1000 mg daily RANDOMIZED 1:1 Co-primaryProgressive chemo- Prednisone 5 mg BID  rPFS by central review (Actual= 546)naïve CRCP patients  OSN=1088 SecondaryAsymptomatic or mildly  Time to opiate usedsymptomatic Placebo daily  Time to Prednisone 5 mg BID chemotherapy (Actual= 542)  Time to ECOG-PS deterioration  TTPPPhase 3 multicenter, randomized, double-blind, placebo-controlled studyconducted at 151 sites in 12 countries: USA, Europe, Australia, CanadaStratification by ECOG performance status 0 vs 1
  • 20. COU-AA-302 Statistical Plan Overall Assumption rPFS OS α 0.01 0.04 Power 91% 85% HR 0.67 0.80 Expected events 378 773 Planned OS Analysis 1Q10 2Q10 3Q10 4Q10 1Q11 2Q11 3Q11 4Q11 1Q12 2Q12 3Q12 4Q12 IA1 IA2 IA3 (~15% OS Events) (40% OS Events) (55% OS events) 116 Events 311 Events 425 Events  < 0.0001  = 0.0005  = 0.0034 IA = interim analysis. Ho, HR=1.0.Ryan et al. ASCO 2012; Abstract LBA4518 (Oral Presentation)
  • 21. AA +P Placebo + P Population characteristics (n=546) (n=542) Median age, years (range) 71(44-95) 70 (44-90) Median time from initial diagnosis 5.5 5.1 Median PSA (ng/ml) 42.0 37.7 Median alkaline phosphatase (IU/L) 93.0 90.0 Median hemoglobin (g/dl) 13.0 13.1 Gleason ≥8 at initial diagnosis 53.9% 50.0% Extent of disease Bone metastases 83% 80% > 10 bone metastases 48% 47% Soft tissue or nodes 49.1% 50% Pain (BPI short form) 0-1 66% 64% 2-3 32% 33%Ryan et al., J Clin Oncol 30, 2012 (suppl; abstr LBA4518)
  • 22. Ryan et al., J Clin Oncol 30, 2012 (suppl; abstr LBA4518)
  • 23. Ryan et al., J Clin Oncol 30, 2012 (suppl; abstr LBA4518)
  • 24. Other secondary endpoints AA +P Placebo + P Median Median HR(95%CI) p (months) (months) 0.69 (0.57- Time to opiate use NR 23.7 0.0001 0.0.83) Time to chemotherapy 0.58 (0.49- 25.2 16.8 <0.0001 initiation 0.69) Time to ECOG PS 0.82 (0.71- 12.3 10.9 0.0053 deterioration 0.94) 0.49 (0.42- Time to PSA progression 11.1 5.6 <0.0001 0.57)Ryan et al., J Clin Oncol 30, 2012 (suppl; abstr LBA4518)
  • 25. Subsequent therapies AA +P Placebo + P (n=546) (n=542) N(%) N(%) No. with selected subsequent 242 (44.3) 327 (60.3) therapy for CRPC Docetaxel 207 (37.9 287 (53.0) Cabazitaxel 45 (8.2) 53 (9.6) Ketoconazole 39 (7.1) 63 (11.6) Sipuleucel-T 27 (4.9) 24 (4.4) Abiraterone acetate 26 (4.8) 54 (10.0)Ryan et al., J Clin Oncol 30, 2012 (suppl; abstr LBA4518)
  • 26. Serologic and clinical responses AA +P Placebo + P (n=546) (n=542) RR(95%CI) p N(%) N(%) PSA decline ≥50% 62% 24% NA <0.0001 N=220 N=218 2.273 RECIST defined objective 36% (1.591- < 0.0001 response 3.247) Complete response 11% 4% Partial response 25% 12% Stable disease 61% 39% Progressive disease 2% 15%Ryan et al., J Clin Oncol 30, 2012 (suppl; abstr LBA4518)
  • 27. Side-Effects AA +P Placebo + P (n=546) (n=542) % % All grades Grade 3/4 All gardes Gradde 3/4 Fatigue 39 2 34 2 Fluid retention 28 0.7 24 1.7 Hypokalemia 17 2 13 2 Hypertension 22 4 13 3 Cardiac disorders 19 6 16 3 Atrial fibrillation 4 1.3 5 0.9 ALT increased 12 5.4 5 0.8 AST increased 11 3 5 0.9Ryan et al., J Clin Oncol 30, 2012 (suppl; abstr LBA4518)
  • 28. Abiraterone pre-chemotherapy,a true paradigm shift ?  Using PFS in Prostate Cancer  A risky IDMC decision  What about the overall results
  • 29. Prerequisites for accepting PSA as a validco-primaryClearly defined and specified in advance YESCapable of being ascertained as completely as YESpossibleMeasured in the same way for all subjects YESCapable of unbiased assessment YESReflect tangible clinical benefit? Unknown
  • 30. COU-AA-302 Statistical Plan Price You Pay: Biased Estimate of Clinical Benefit
  • 31. Adrenals androgens inhibitor Patient % > 50% PSA Duration Total Drug s response (months) (n) Ketoconazole (400 mg tid) + Small et al., 19971 50 63 3.5 hydrocortisone Ketoconazole (400 mg tid) + Small et al.,19972 20 55 8.5 hydrocortisone + AAW Ketoconazole (400 mg tid) + Small et al., 20043 128 27 8.6 hydrocortisone + AAW Ketoconazole (200 mg tid) + Harris et al, 20024 28 46 7.5 hydrocortisone Ketoconazole (400 mg tid) + Millikan et al., 20015 45 31 NA hydrocortisone + AAW Ketoconazole (400 mg tid) + dutasteride Taplin et al., 20096 57 56 20 (0,5 mg sid) + hydrocortisone Ryan et al., 2012 Abiraterone AA + P 546 62% 11,1 % PSA response: % of patients achieving 50% decrease in PSA; AAW = anti-androgen withdrawal1) J Urol. 1997 157(4):1204-7; 2) Cancer 1997 80(9):1755-9; 3) JCO 2004 22(6):1025-33; 4) J Urol. 2002168(2):542-5; 5) Urol Oncol. 2001 6(3):111-115; 6) Clin Cancer Res. 2009 15(22):7099-105: 7) JNCI 199486(3):222-7; 8) Anticancer Drugs 2004 15(9):843-7.
  • 32. Available options in CRCP Increase in Relative Hazard ratio median reduction in (95% CI; P-value) survival risk of death 0.65 Abiraterone/P vs. placebo/P1 3.9 months 35% (0.540.77; P<0.001) 0.63† MDV3100 vs. placebo 2* 4.8 months 37% (P<0.0001) 0.76 Docetaxel(q3w)/P vs. Mitoxantrone/P3 2.4 months 24% (0.620.94; P=0.009) 0.70 Cabazitaxel/P vs. mitoxantrone/P4 2.8 months 30% (0.590.83; P<0.0001) 0.78 Sipuleucel T vs. placebo5 4.1 months 22% (0.61 to 0.98; P:0.03) 0.70 Alpharadin vs. placebo6 2.8 months 31% (0.55-0.88; P:0.00185) 0,75 Abiraterone + P vs.P ? NR in AA 25% (0.61-0.93); P 0.0097P: prednisone1. de Bono, et al. N Engl J Med 2011;364:1995–2005; 2. Medivation Press Release AFFIRM 3rd November 2011; study stopped early followingfavourable interim results 95 % CI not stated; 3. Tannock, et al. N Engl J Med 2004;2351:1502–12; 4. de Bono, et al. Lancet 2010; 76:1147–545; 5. Kantoff, et al. N Engl J Med 2010;363:411–22; 6. Bayer Press Release ALSYMPCA 24th September 2011
  • 33. Primary, secondary, and quality-of-life endpoint results from the phase IIIAFFIRM study of MDV3100, an androgen receptor signaling inhibitor.J. de Bono et al., J Clin Oncol 30, 2012 (suppl; abstr 4519)
  • 34. Primary, secondary, and quality-of-life endpoint results from the phase III AFFIRM study of MDV3100, an androgen receptor signaling inhibitor. J. de Bono et al., J Clin Oncol 30, 2012 (suppl; abstr 4519)Quality of life response by FACT-P
  • 35. Side effects of interest All grades Grade ≥ 3 MDV3100 Placebo MDV3100 PlaceboFatigue 33.6 29.1 6.3 6.3Cardiac disorders 6.1 7.5 0.9 0.9Myocardial infarction 0.3 0.5 0.3 0.3LFT abnormalities 1.0 1.5 0.4 0.4Seizure 0.6 0.0 0.6 0.6
  • 36. Primary, secondary, and quality-of-life endpoint results from the phase IIIAFFIRM study of MDV3100, an androgen receptor signaling inhibitor.J. de Bono et al., J Clin Oncol 30, 2012 (suppl; abstr 4519)
  • 37.  Prostate Kidney And what’s left….
  • 38. New agent timelines pazopanib(6) Sorafenib(1) Sunitinib(2) Everolimus(4) 2005 2006 2007 2008 2009 2010 2011 20012 Axitinib) temsirolimus(3) Bevacizumab +Ifα(5)1. Motzer RJ, et al. N Engl J Med. 2007;356(2):115-124. 3. Hudes G, et al. N Engl J Med. 2007;356(22):2271-2281. 4. Escudier B, et al. Lancet.2007;370(9605):2103-2211. 5. Rini BI, et al. J Clin Oncol. 2008;26(33):5422-5428. 6. Motzer RJ, et al. Lancet. 2008;372(9637):449-456. 7.Sternberg CN, et al. J Clin Oncol. 2010;28(6):1061-1068.
  • 39. Results 1st line targeted therapies Median PFS Median OS Agent N ORR(%) months months 47 vs. 12 11,0 vs. 5 26,4 vs. 21,8 Sunitinib vs. INFα(1,2) 750 P< 0,001 P< 0,001 P=0.051 8,6 vs. 4.8 5,5 vs. 3,1 10,9 vs. 7,1 Temsirolimus vs. INFα(3) 626 NS P<0,0001 P=0,008 INFα 19,8 31 vs. 13 10,2 vs 5,4 Bevacizumab + INFα vs. INFα(4) 649 B/INFα NR P= 0,0001 P=0,0001 P 0,0267 26 vs. 13 8,5 vs. 5,2 Bevacizumab + INFα vs. INFα(5) 732 NR P<0,0001 P<0,0001 5,7 vs 5,6 Sorafenib vs INFα(6) 189 5 vs. 9 NR P=0,504 30 vs. 3 9,2 vs 4,2 21,1 vs. 18,7 Pazopanib vs. placebo 435 P<0,001 P<0,001 P 0,021. Motzer RJ et al. NEJM 2007; 2 Motzer RJ et al. JCO 2007; 3. Hudes et al. NEJM 2007; 4. Escudier et al.Lancet 2007; 5. Rini et al. JCO 2008; Escudier et al. JCO 2006; Sternberg C JCO 2010
  • 40. Results 2nd line targeted therapies Median PFS Median OS Agent ORR(%) months months 10 vs. 2 5,5 vs. 2,8 Sorafenib vs. placebo(1) 17,8 vs 15,2 P< 0,001 P< 0,001 5 vs. 0 4,9 vs. 1,9 Everolimus vs. placebo(2) 14,8 vs. 14,4 NS P<0,0001 6,7 vs. 4,7 Axitinib vs. sorafenib(3) P < 0.0011. B. Escudier et al., NEJM 2007; 2. RJ Motzer et al., The Lancet2008 3 BI Rini et al., The Lancet 2011
  • 41. New agent timelines pazopanib(6) Sorafenib(1) Sunitinib(2) Everolimus(4) tivozanib 2005 2006 2007 2008 2009 2010 2011 20012 Axitinib) temsirolimus(3) Bevacizumab +Ifα(5)1. Motzer RJ, et al. N Engl J Med. 2007;356(2):115-124. 3. Hudes G, et al. N Engl J Med. 2007;356(22):2271-2281. 4. Escudier B, et al. Lancet.2007;370(9605):2103-2211. 5. Rini BI, et al. J Clin Oncol. 2008;26(33):5422-5428. 6. Motzer RJ, et al. Lancet. 2008;372(9637):449-456. 7.Sternberg CN, et al. J Clin Oncol. 2010;28(6):1061-1068.
  • 42. Tivozanib versus sorafenib as initial targeted therapy for patients with advanced renal cell carcinoma: Results from a phase III randomized, open-label, multicenter trial. R. Motzer et al., J Clin Oncol 30, 2012 (suppl; abstr 4501) Key eligibility criteria  Advanced RCC Tivozanib 1.5 mg/day po RANDOMIZED 1:1  Clear cell histology 3 weeks on/1 week off  Measurable disease N=260  Prior nephrectomy  0-1 prior therapy but no VGEF or mTOR Sorafenib 400mg po bid therapy Continuous  ECOG PS 0-1 N=257TIVO-1 Phase 3 superiority of tivozanib vs. sorafenib as first-line targeted therapyfor mRCC
  • 43. PFS assessmentMedian PFS (95%CI) Tivozanib (n=260) Sorafenib (n=257) HR pIndependen 11.9 9.1 0.797 0.042t (9.3-14.7) (7.3-9.5) 14.7 9.6Investigator 0.722 0.003 (10.4-16.6) (9.0-11.0) Tivozanib (n=260) Sorafenib (n=257) Best overall response, % Complete response 1 1 Partial response 32 23 Stable disease 52 65 Progressive disease 13 7 ORR 33 23 95%CI 27-39 18-29 p 0,014
  • 44. Treatment emergent AEs Tivozanib (n=259,%) Sorafenib (n=257,%) All grade Grade 3(4) All grade Grade 3(4) Hypertension 44 24(2) 34 17(<1) Diarrhea 22 2 32 6 Dysphonia 21 0 5 0 Fatigue 18 5 16 4 Weight loss 17 <1 20 3 Asthenia 15 4(<1) 16 3 Hand-foot S. 13 2 54 17 Back pain 14 3 7 2 Nausea 11 <1 8 <1 Dyspnea 10 2 8 2 Decrease appetite 10 <1 9 <1 Alopecia 2 0 21 0
  • 45. Cardiac safety analysis for a phase III trial of sunitinib (SU) or sorafenib (SO) or placebo (PLC) in patients (pts) with resected renal cell carcinoma (RCC). NB Haas et al., J Clin Oncol 30, 2012 (suppl; abstr 4500)ECOG 2805 (ASSURE) Stratify Arm A Sunitinib daily R Risk by TNM for 4 of 6 weeks for 1 E N Stage/Grade year R G E Intermediate Risk Non- A Metastatic I P High Risk N Kidney S H Histologic Cancer D Arm B Sorafenib T R SubtypeThat meets O daily continuously R E Clear cell radiologic M for 1 year A C Non-clear cell criteria to Ibe clinically T T Performance Z  T1bNany I O status(resectable) E O M SurgeryM0 disease Arm C Placebo N Y Daily Open vs 1 laparoscopic continuously for 1 year
  • 46.  To determine if patients treated with sunitinib or sorafenib experience clinically significant decreases in left ventricular ejection fraction. Primary endpoint of interest was LVEF decline within 6 months, defined as LVEF below the institutional lower limit of normal, where the drop is at least 16% from baseline. MUGA MUGA MUGA MUGA Treatment with Sorafenib, Sunitinib or Placebo 12 mo 3 mo 6 mo Randomization End of study MUGA Completion of therapy
  • 47. Frequency of clinically significant congestiveheart failure (CHF) Timepoint Sunitinib Sorafenib Placebo 2 Months - 1 (16%) - 3 Months 6 (16 to 21%) 1 (21%) 2 (19 & 32%) 4 Months 2 (23 & 24%) - - 6 Months 1 (18%) 5 (16 to 19%, 37%) 3 (17 to 19%) Pts Assessed 397 394 502 Events 9 7 5 Rate 2.3% 1.8% 1.0% 90% CI 1.2 – 3.9% 0.8 – 3.3% 0.4 – 2.1%
  • 48. Patients with Other Events Other LVEF events defined as one of the following: LVEF decline >=16% occurring after 6 months, or a grade 2 or 3 left ventricular systolic or diastolic dysfunction reported via AdEERS or on a case report form Type of Event Sunitinib Sorafenib Placebo LVEF decline >=16% 5 2 3 Grade 2 LV Event 5 6 8 Grade 3 LV Event 2 3 - Pts Assessed 510 507 572 Events (Combined) 21 18 16 Rate 4.3% 5.3% 3.7% 90% CI 2.8 – 5.9% 2.3 – 5.2% 1.8 – 4.2%
  • 49. Axitinib for first-line metastatic renal cell carcinoma (mRCC): Overallefficacy and pharmacokinetic (PK) analyses from a randomized phase IIstudy.B.Rini et al., J Clin Oncol 30, 2012 (suppl; abstr 4503)
  • 50. Axitinib for first-line metastatic renal cell carcinoma (mRCC): Overall efficacy and pharmacokinetic (PK) analyses from a randomized phase II study. B.Rini et al., J Clin Oncol 30, 2012 (suppl; abstr 4503) Primary objective To compare the objective response rate (ORR) in patients receiving axitinib plus dose titration (Arm A) vs. axitinib plus placebo (Arm B)80% power to detect ≥ 25% improvement in ORR Secondary objectives  Progression-free survival  Axitinib plasma pharmacokinetics  Blood pressure measurements …
  • 51. Clinical Efficacy of Axitinib for First- line Metastatic RCC Arm C Arm A+B Total Not eligible for Eligible for (n=213) dose titration dose titration (n=91) (n=112) mPFS (months) 14.5 16.4 14.5 (95% CI) (11.5-17.4) (11.0-19-0) (11.0-19.3) ORR 48% 59% 43% (95%CI) (41%-55%) (49%-70%) (34%-53%)
  • 52. Patient preference between pazopanib (Paz) and sunitinib (Sun): Results of a randomized double-blind, placebo-controlled, cross-over study in patients with metastatic renal cell carcinoma (mRCC)—PISCES study, NCT 01064310. B.Escudier et al., J Clin Oncol 30, 2012 (suppl; abstr CRA4502) Pazopanib Sunitinib 800 mg once daily, 50 mg 4/2, 10 weeks 10 weeks Patient choice Randomisation of treatment to progression n=169 Sunitinib Pazopanib 50 mg 4/2, 800 mg once daily, 10 weeks 10 weeks Period 1 2-week washout Period 2 Off study Double-blind 0 10 Time (weeks) 12 22 1:1 randomisation, Patients on sunitinib received placebo during 2-week ‘off- period’
  • 53. Assessment: Questionnaire time points1 Period 1 Washout Period 2 Pazopanib Sunitinib Placebo Sunitinib Sunitinib Placebo Sunitinib Pazopanib Weeks0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Patient preference: End of study EQ-5D: Baseline, washout, end of study FACIT-Fatigue: Every 2 weeks SQLQ: Every 2 weeks
  • 54. Primary endpoint: Patient preference for studytreatments (Primary analysis population) 1 100 90% CI (for difference): 37.0-61.5; p<0.001 90 80 70 Patients (%) 60 70% 50 (n=80) 40 30 20 8% 10 22% (n=9) (n=25) 0 Preferred pazopanib Preferred sunitinib No preference
  • 55. Most common adverse events (>10%; cont’d) 1 Adverse event Pazopanib (n=153) Sunitinib (n=148) All grades Grade 3 Grade 4 All grades Grade 3 Grade 4 Hair colour changes 17% 0 0 14% 0 0 Mucosal inflammation 16% 0 0 22% 1% 0 Rash 8% <1% 0 11% 0 0 Dysgeusia 16% 0 0 27% 0 0 Headache 14% <1% 0 11% 0 0 Hypertension 23% 8% 0 26%) 9% 0 Epistaxis 5% 0 0 11% <1% 0 Decreased appetite 20% 0 0 19% <1% 0 • Compared with sunitinib, pazopanib was associated with a lower incidence of asthenia, stomatitis and hand-foot syndrome, and a greater incidence of diarrhoea Note: The electronic case report form collected relationship to IP without distinguishing which treatment period the adverse event (AE) was related to. An AE which spanned more than one period was considered to be an AE for the period during which the AE increased in grade. There is only one label for relationship for the whole event. As such, it is not always possible to determine which period treatment the AE was related to.1. GSK data on file.
  • 56. Which reasons influenced their choice?1 Better quality of life Less fatigue Less taste change Less mucositis/stomatitis Less nausea/vomiting Pazopanib preferred (n=80) Less hand-foot syndrome Sunitinib preferred (n=25) Better appetite Less stomach pain Less diarrhoea Other Less hair colour change 0 10 20 30 40 50 60 70 Number of patients1. Escudier B, et al. ASCO 2012 oral presentation; abstract 4502.
  • 57. Patient preference, a key driver of treatmentchoice ?  Assumption of equivalent efficacy  Continuous vs. intermittent treatment
  • 58.  Prostate Kidney And what’s left….