ASCO GU Oncology 2009 Robert Dreicer, M.D., M.S., FACP Chair Dept - PowerPoint PPT Presentation

ASCO GU Oncology 2009 Robert Dreicer, M.D., M.S., FACP Chair Dept of Solid Tumor Oncology Taussig Cancer Institute Professor of Medicine Cleveland Clinic Lerner College of Medicine

Phase III CALGB 90206 Trial: Study Design (abstract LBA5019) Inclusion Criteria IFN-  /Bevacizumab (n=369) • mRCC with component of R IFN-  9 MU s.c. 3x/week clear cell histology A Bevacizumab 10 mg/kg IV q2w • Measurable or evaluable N disease D Exclusion Criteria O • Prior systemic therapy M • Evidence of CNS I IFN-  (n=363) metastases Z IFN-  9 MU s.c. 3x/week Stratification: E • Nephrectomy status (n = 732) • MSKCC risk group • Primary objective: OS • Secondary objectives: PFS, ORR, and safety Rini et al. J Clin Oncol 2009; 27(suppl):239s

Frequency of selected grade 3 or 4 AEs LBA5019 Bevacizumab + IFN IFN Adverse event (n=366) (n=352) Any grade 3/4 adverse event 79% 61% Fatigue/asthenia/malaise 37% 30% Anorexia 17% 8% Proteinuria 15% <1% Hypertension 11% 0% Hemorrhage 2% <1% Venous thromboembolism 2% 1% Gastrointestinal perforation <1% 0% Arterial ischemia 1% 0%

Objective Response Bev + IFN (n=325) IFN (n=314) Overall Response rate 25.5% 13.1% [95% CI = 20.9-30.6] [95% CI = 9.5-17.3] CR 3.7% 1.9% PR 23.4% 12.7% p < 0.0001 Duration of response 11.9 months 9.7 months [95% CI = 8.3 – 14.8] [95% CI = 7.6 – 19.8] p = 0.362 Note: patients with measurable disease only LBA5019

Kaplan-Meier Overall Survival by Treatment Arm Kaplan-Meier Overall Survival Curves by Treatment Arm 1.0 IFN BEV/IFN Overall Survival (probability) 0.8 Stratified log-rank p=0.069 ---- BEV/IFN: Median OS 18.3 months 0.6 IFN: Median OS 17.4 months 0.4 0.2 0.0 0 6 12 18 24 30 36 42 48 54 60 Time(months) LBA5019 Number of Patients at Risk IFN 363 286 221 177 148 118 98 64 37 10 1 BEV/IFN 369 314 242 190 160 139 116 94 42 17 2

Median OS (months) according to treatment arm and subsequent therapy ( LBA5019) Bevacizumab + Interferon Total Stratified HR (unstratified log-rank Interferon p comparing arms) Received 2 nd -line 31.4 26.8 28.2 0.80 (p=0.079) therapy (p=0.055) (n=408) Did not receive 2 nd - 13.1 9.1 10.2 0.82 line therapy (p=0.059) (p=0.108) (n=324) Total 18.3 17.4 18.1 0.86 (p=0.097) (p=0.069)

Authors Conclusions LBA5019 Overall survival is greater in patients with metastatic clear cell RCC  receiving bevacizumab plus interferon as initial systemic therapy compared to interferon alone, but does not meet pre-defined criteria for significance Although the favorable effect of bevacizumab plus IFN on OS is  preserved regardless of subsequent treatment, the most robust OS is achieved in patients with favorable underlying disease biology who are able to receive subsequent therapy The combination of bevacizumab and IFN as initial therapy in  metastatic RCC patients results in a significantly greater progression-free survival and objective response rate versus IFNA monotherapy Toxicity is greater in the combination therapy arm, including more  fatigue, anorexia, hypertension and proteinuria

Phase III AVOREN Trial: Study design IFN-  2a/Bevacizumab (n=327) R IFN-  9 MIU s.c. 3x/week* A Bevacizumab 10 mg/kg IV q2w Nephrectomized patients N until progression with advanced RCC D O M Stratification: I IFN-  /placebo (n=322) Country Z IFN-  9 MIU s.c. 3x/week* MSKCC risk group E placebo 10 mg/kg IV q2w until progression (n = 649) *Dose reduction allowed • Primary objective: OS • Secondary objectives: PFS, TTP, TTF, ORR, and safety • Median follow-up: 22 months Escudier et al. J Clin Oncol 2009; 27(suppl):239s (abstract 5020).

Phase III AVOREN Trial : Final OS results IFN+placebo IFN+bev Log rank HR P Value (n=322) (n=327) Median OS (months) Unstratified .3360 NR NR 0.91 (0.76-1.10) Stratified 21.3 23.3 0.86 (0.72-1.04) .1291 Median OS after censoring patients at 20.8 23.3 0.84 (0.70-1.02) .0766 time of crossover (months)  Multiple Cox regression analysis for OS: − HR 0.78 (0.63-0.96); P = .0219  OS not affected by reduction of IFN dose: − OS 26 months with reduced-dose IFN and 23.3 months with standard IFN Escudier et al. J Clin Oncol 2009; 27(suppl):239s (abstract 5020) ).

Phase III AVOREN trial of interferon alpha plus bevacizumab or placebo in nephrectomized advanced RCC: Final OS results N Median OS (months) Post-protocol HR IFN+plac vs. therapy IFN+placebo IFN+bev IFN+bev Subsequent TKI 120 vs. 113 33.6 38.6 0.80 (0.56-1.13) Subsequent 92 vs. 83 39.7 43.6 0.88 (0.58-1.35) sunitinib Subsequent 50 vs. 60 30.7 38.6 0.73 (0.44-1.20) sorafenib  Subgroup analysis demonstrated similar benefit regardless of age, Motzer score, baseline VEGF levels, and number of metastatic sites  However, patients without liver metastases demonstrated significant OS benefit from the addition of bevacizumab (27.5 vs. 21.4 months, HR 0.76; P = .0155) Escudier et al. J Clin Oncol 2009; 27(suppl):239s (abstract 5020)

Phase III study of pazopanib in treatment-naïve or cytokine-pretreated advanced RCC Eligibility: 2:1 • Locally advanced or R metastatic RCC Pazopanib 800mg qd A • Clear cell histology (n = 290) N • Treatment naive or D failure of 1 prior O cytokine therapy M Placebo* I Stratification: (n = 145) Z ECOG PS E Prior nephrectomy Rx naive (n=233) vs. 1 (n = 435) *Option to crossover via an cytokine failure (n=202) open label study at progression • Primary objective: PFS • Secondary objectives: OS, ORR, duration of response, safety, health-related QOL Sternberg et al. J Clin Oncol 2009; 27(suppl):240s (abstract 5021)

Phase III study of pazopanib in treatment-naïve or cytokine-pretreated advanced RCC: Efficacy placebo pazopanib Patient population HR P Value (n=290) (n=145) ORR (%) Overall population 3 30 NR NR Treatment-naïve* 4 32 NR NR Cytokine- pretreated† 3 29 NR NR Median PFS (months) 4.2 9.2 Overall population 0.46 (0.34-0.62) <.0000001 2.8 11.1 Treatment-naïve* 0.40 (0.27-0.60) <.0000001 Cytokine- pretreated† 4.2 7.4 0.54 (0.35-0.84) <.001 .02‡ Median OS (months) 18.7 21.1 0.73 (0.47-1.12) * n = 78 for placebo and 155 for pazopanib; † n = 67 for placebo and 135 for pazopanib ‡ one -sided P value  48% of patients on placebo arm received pazopanib at disease progression Sternberg et al. J Clin Oncol 2009; 27(suppl):240s (abstract 5021).

Phase III study of pazopanib in treatment-naïve or cytokine-pretreated advanced RCC: Safety placebo pazopanib Grade 3/4 Adverse Events (n=145) (%) (n=290) (%) Hypertension <1 4 Diarrhea <1 4 Anorexia <1 2 Vomiting 2 3 Fatigue 2 2 Asthenia 0 3 Hemorrhage 0 2 ALT abnormalities 1 12 AST abnormalities <1 8 ALT = alanine transferase; AST = aspartate aminotransferase  4% of pts in the pazopanib arm and 3% in the placebo arm experienced grade 5 adverse events Sternberg et al. J Clin Oncol 2009; 27(suppl):240s (abstract 5021)

RCC Treatment Algorithm: 2009 Setting Patients Therapy Other Options (≥ level 2) (level 1) Good or Sunitinib HD IL-2 Intermediate risk Untreated Bevacizumab + Sorafenib IFN Clinical trial Observation Poor risk Temsirolimus Sunitinib Clinical trial Cytokine- Sorafenib Sunitinib refractory Pazopanib Bevacizumab VEGF-R Everolimus Sunitinib refractory Clinical trial Sorafenib mTOR-refractory Clinical trial Clinical trial *Adapted from M Atkins, ASCO 2006 & R Bukowski ASCO 2007

Randomized Trial of p53 Targeted Adjuvant Therapy for Patients with Organ- Confined Node-Negative Urothelial Bladder Cancer Abstract 5017 Walter M. Stadler, Seth P. Lerner, Susan Groshen, John P. Stein † , Ellenie Tuazon, David Quinn, Donald G. Skinner, Derek Raghavan, David Esrig, Gary Steinberg, David Wood, Laurence Klotz, Craig Hall, Richard Cote † Deceased

p53 Status May be Prognostic Probability of Not p53 negative( n=142) Recurring p53 positive( n=101) p< 0.001 Years from Cystectomy Esrig, et al NEJM 1994; 1259-64

STUDY DESIGN Radical Cystectomy (P1, P2a, P2b, NO, MO) Registration - Consent to p53 Analysis and Randomized Trial IHC, p53 Wild type IHC, p53 Altered ( ≤ 10% nuclear +) (>10% nuclear +) Consent for Consent for Randomization Re- Randomization Not Re- Confirmed Confirmed Observ. Arm III MVAC x 3 Observ. Observ. Arm I Arm II Arm IV Abstract 5017

Overall Survival: MVAC vs. Observation (Arm 2) 1.00 Observed (n=56) Estimated Probability of 0.90 0.80 0.70 Survival MVAC (n=58) 0.60 0.50 0.40 p=0.75 0.30 0.20 0.10 0.00 0 12 24 36 48 60 72 84 96 108 120 132 Months Since Randomization Abstract 5017

Authors Conclusions  Unable to confirm prognostic value of p53  Centrally performed IHC may not be analytically valid  Stage migration led to better than expected outcomes  Preliminary data based on too small of a cohort  p53 mutation and pathway analysis pending  Unable to confirm predictive value of p53  See above  Randomization challenges led to underpowered trial Abstract 5017

A Multicenter Study of Cisplatin, Gemcitabine and bevacizumab As First Line Therapy for Metastatic Urothelial Cancer: Hoosier Oncology Group Protocol GU04-75 ABSTRACT 5018 N. M. Hahn, W. M. Stadler, R. T. Zon, D. Waterhouse, J. Picus, S. Nattam, C. S. Johnson, S. M. Perkins, M. J. Waddell, C. J. Sweeney