2009 David I. Quinn MBBS (Hons) PhD FRACP Associate Professor of - PowerPoint PPT Presentation

Genitourinary Cancer Update 2009 David I. Quinn MBBS (Hons) PhD FRACP Associate Professor of Medicine Chief, Section of GU Medical Oncology Division of Cancer Medicine & Blood Diseases Medical Director, Norris Cancer Hospital & Clinics Co-Leader, Genitourinary Cancer Program Kenneth J. Norris Comprehensive Cancer Center Keck School of Medicine University of Southern California Dr. Quinn has received honoraria and served on advisory boards for Glaxo Smith Kline and Genentech

Learning Objectives After reading and reviewing this material, the participant should be better able to: • List the major potentially practice changing presentations in the filed of GU cancer from ASCO 2009 – Assess their merit – As applicable applied their content to clinical practice • Understand the implications of material presented that may impact clinical practice in GU oncology in the coming years • Recognize that Dr. Quinn has a somewhat obtuse and off-beat sense of humor

Genitourinary Cancers - Best of ASCO 2009: Key abstracts Rini, B. Bevacizumab plus Interferon-alpha versus Interferon-alpha monotherapy in Patients with Metastatic Renal Cell Carcinoma: Results of Overall Survival for CALGB 90206 #5019 Escudier, B. Final results of the phase III, randomised, double-blind AVOREN trial of first-line bevacizumab + interferon- α2a in metastatic renal cell carcinoma. #5020 Sternberg, C. A randomized, double-blind phase III study of Pazopanib in treatment-naive and cytokine-pretreated patients with advanced renal cell carcinoma #5021 Scher, H. Antitumor activity of MDV3100 in a Phase 1-2 study of Castration-Resistant Prostate Cancer. #5011 In addition, we will look at the following abstracts in some detail 5018 – bevacizumab with Cisplatin and Gemcitabine in TCC AUA 1408 – Sipuleucel in CRPC

ASCO 2009: Renal Cell Cancer Highlights Bevacizumab adds to RR, PFS & toxicity from Interferon- α OS, cost benefit analyses inconclusive #5019, 5020, 5112 Pazopanib - doubles PFS in RCC compared to placebo … #5021, 5110 VEGF TKi de ja vu? Real advance or just another choice? ..And there are more in the pipeline for next year: AV-951, BAY 73-4506, ABT-869, Axitinib #5032, 5033, 5036 Neoadjuvant VEGF pathway therapy: beautiful science, but warts in practice #5004, 5096 Predicting toxicity from VEGF TKIs #5005, 5006, 5045; Predictors of outcome: CA9 , #5003 ; Chr 9p #5090 ; More data on Papillary RCC #5091, 5092, 5103, 5146, e16020 New therapies? Combination targeted therapy – mTORi + VEGF ligand blockade may work #5039, 5104; S1, oral modulated fluoropyrimidine, activity in Japanese pts #5100, Perifosine, Akt inhibitor – modest activity #5034, 5101

Survival by the Memorial Sloan-Kettering Cancer Center Risk Factor Model 1.0 Risk factors associated with worse prognosis • KPS <80 0.9 • Low serum hemoglobin (13 g/dL/11.5 g/dL: M/F) • High corrected calcium (10 mg/dL) 0.8 • High LDH (300 U/L) 0.7 • Time from Dx to IFN- <1 yr Proportion surviving 0 risk factors (164 patients, 30 alive) 0.6 1 or 2 risk factors (348 patients, 23 alive) 3, 4, or 5 risk factors (144 patients, 1 alive) 0.5 0.4 0.3 0.2 0.1 0.0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Motzer RJ et al. J Clin Oncol . 2002 ;20:289- Years following systemic therapy 296; Lam JS, et al. J Urol. 2005; 173:1853- 1862.

RCC: Role of VHL, HIFs and Growth Factors in Disease Progression Paracrine Function Pericyte RAS RAF MEK ERK Autocrine Function Tumor cell VHL HIF-1  HIF-1  p38MAPK RAS Paracrine HIF-1  RAF Function PI3K MEK RAS Endothelial HIF-1  mTOR/Akt ERK RAF cell MEK VEGF EGF VEGF ERK EGF PDGF PDGF EGF VEGF PDGF

Treatment options for RCC have been revolutionized in a short period of time… Bevazucimab + IFN 5,6 ? Everolimus 7 ? High dose Temsirolimus 4 interleukin-2 1 Pazopanib? Sorafenib 2 Sunitinib 3 Axitinib? 1992-2005 2005 2006 2007 2008 2009 ...but this rapid change has left many unanswered questions, including the optimal Interferon-  sequence of therapy 1.Fyfe G et al. J Clin Oncol 13:688-696 , 1995 2.Escudier B et al. N Engl J Med 356:125-134,2007 3.Motzer RJ et al. N Engl J Med 356:115-124,2007 4.Hudes G et al. N Engl J Med 356:2271-2281 2007 5. Escudier B et al. Lancet 370:2103-211, 2007 6. Rini BI et al. J Clin Oncol epud Oct, 2008 7. Motzer RJ et al. Lancet 372:449-456 2008

Final Overall Survival 1.0 Sunitinib (n=375) Median: 26.4 months 0.9 (95% CI: 23.0 - 32.9) Overall Survival Probability IFN-  (n=375) 0.8 Median: 21.8 months (95% CI: 17.9 - 26.9) 0.7 0.6 0.5 0.4 0.3 Total Death 0.2 Hazard Ratio = 0.821 Sunitinib 190 (95% CI: 0.673 - 1.001) 0.1 IFN-  p =0.051 (Log-rank) 200 0 0 3 6 9 12 15 18 21 24 27 30 33 36 Time (months) nDeath/nRisk Sunit 375 44 / 326 38 / 283 48 / 229 42 / 180 14 / 61 4 / 2 nDeath/nRisk IFN-  15 / 53 375 61 / 295 46 / 242 52 / 187 25 / 149 1 / 1 Figlin R et al. , ASCO 2008, abstract #5024 8

TARGET: Preplanned Secondary Analysis OS Data With Placebo Patients Censored 100 Sorafenib (n=451) = 17.8 months Placebo (n=452) = 14.3 months OS (% patients) HR (sorafenib/placebo) = 0.78 75 95% CI: 0.62 – 0.97 P =0.0287* 50 25 0 0 4 8 12 16 20 24 28 32 36 40 Time From Randomization (months) Approximate start of crossover is 30 June 2005. * Statistically significant: O’Brien– Fleming threshold for statistical significance =0.037. Adapted from Bukowski RM et al. Presented at ASCO Annual Meeting; June 1-5, 2007; Chicago, IL.

Bevacizumab + IFN-  : Phase 3 Trials in mRCC Patient population Clear-cell mRCC BO17705 (Roche) CALGB 90206 N=638 N=700 Randomization Randomization IFN-  IFN-  IFN-  9.0 MU TIW 9.0 MU TIW 9.0 MU TIW + + Bevacizumab Placebo 10 mg/kg d 1,15 d 1, 15 Studies powered to detect increase in median survival >13.0 – 17.0 months Escudier B et al. Lancet 370: 2103-11, 2007.

Progression-free survival (investigator assessed) 1.0 0.9 HR=0.63, p<0.0001 0.8 Probability of being Median progression-free survival: progression-free 0.7 Bevacizumab + IFN = 10.2 months 0.6 Placebo + IFN = 5.4 months 0.5 0.4 0.3 0.2 0.1 5.4 10.2 0 0 6 12 18 24 Time (months) Number of patients at risk Placebo + IFN 322 137 59 15 0 Bevacizumab + IFN 327 196 107 18 0 Escudier B et al. Lancet 370:2103-211, 2007

Bevacizumab plus Interferon-alpha versus Interferon-alpha Monotherapy in Patients with Metastatic Renal Cell Carcinoma: Results of Overall Survival for CALGB 90206 Abstract 5019 Brian I. Rini 1 , Susan Halabi 2,3 , Jonathan E. Rosenberg 4 , Walter M. Stadler 5 , Daniel A.Vaena 6 , James N. Atkins 7 , Joel Picus 8 , Piotr Czaykowski 9 , Janice Dutcher 10 and Eric J. Small 4 1. Cleveland Clinic Taussig Cancer Institute, Cleveland, OH 2. Department of Biostatistics / Bioinformatics, Duke University Medical Center, Durham, NC 3. CALGB Statistical Center, Durham, NC 4. University of California San Francisco, San Francisco, CA 5. University of Chicago Medical Center, Chicago, IL 6. University of Iowa, Iowa City, IA 7. Southeast Cancer Control Consortium Inc. 8. Washington University, St. Louis, MO 9. University of Manitoba, Winnipeg, Manitoba; NCI Canada, Kingston, ON, Canada 10. New York Medical College, NY, NY; Eastern Cooperative Oncology Group, Boston, MA

Final Overall Survival by Treatment Arm: CALBG 90206 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) 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

Frequency of selected grade 3 or 4 AEs 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%

Conclusions (Rini) • 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

Final overall survival from phase III, randomised, double- blind AVOREN trial of first-line bevacizumab + interferon-  2a in metastatic renal cell carcinoma Abstract 5020 1.0 IFN + Bevacizumab (n=327) IFN + placebo (n=322) 0.8 HR=0.86 (95% CI: 0.72 – 1.04) Probability of survival p=0.1291 (stratified*) 0.6 0.4 0.2 *Stratified by Motzer score and region 23.3 21.3 0 0 6 12 18 24 30 36 42 Time (months) Escudier B, Bellmunt J, Negrier S, Bajetta E, Melichar B, Bracarda S, Ravaud A, Golding S, Jethwa S on behalf of the AVOREN investigators, ASCO 2009