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2012 GU Cancers Symposium

2012 GU Cancers Symposium . San Francisco, CA February 2-4, 2012. Jerry M. Maniate MD, M.Ed, FRCPC Assistant Professor, Department of Medicine University of Toronto Dr. H. James Watt Hematology/Oncology Clinic Service of Hematology/Oncology Director of Medical Education

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2012 GU Cancers Symposium

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  1. 2012 GU Cancers Symposium • San Francisco, CA • February 2-4, 2012 Jerry M. Maniate MD, M.Ed, FRCPC Assistant Professor, Department of Medicine University of Toronto Dr. H. James Watt Hematology/Oncology Clinic Service of Hematology/Oncology Director of Medical Education St. Joseph’s Health Centre

  2. Objectives • In the next 30 minutes...

  3. Outline • Prostate Cancer • Bone Targeted Therapy • Renal Cell Cancer

  4. Highlights of GUCA Symposium • 2500 attendees • 284 Prostate cancer abstracts • 136 Renal cell carcinoma abstracts

  5. Novel Targets & Novel Agents

  6. MDV3100 • Specific inhibitor of androgen receptor • No known effect on androgen production • Preclinical: anti-proliferative activity on prostate cancer cells that harbour amplification of AR Scher, Lancet 2010; 375: 1437 Scher, JCO, March 1, 2006

  7. MDV3100 • Progression measured as rising PSA • Improved OS post-docetaxel • Median OS: 18.4 mths vs. • Not hormone resistant but rather castrate resistant due to drive of AR signaling Scher, Lancet 2010; 375: 1437 Scher, JCO, March 1, 2006

  8. Post-chemotherapy: failed docetaxel MDV3100 160 mg po OD Placebo Primary EP: Overall Survival Secondary EP: Radiographic PFS Time to first SRE Time to PSA progression Circulating tumour cell count conversion rate AFFIRM Study. Scher HI et al. JCO 30, 2012 (suppl 5; abstract LBA1)

  9. AFFIRM Study • N = 1199 pts (800 vs. 399) • Balanced demographics / disease characteristics • 520 death events reached • Independent Drug Monitoring Committee (IDMC) concluded that the trial be stopped, unblinded and that the patients on placebo be offered the test agent

  10. Post-chemotherapy: failed docetaxel MDV3100 160 mg po OD Placebo 18.4 mths 13.6 mths p<0.001 Median OS PFS Time to PSA progression Safety TO FOLLOW AFFIRM Study. Scher HI et al. JCO 30, 2012 (suppl 5; abstract LBA1)

  11. AFFIRM Study • Survival benefit observed across subgroups vs. placebo • Median duration of Tx: 8.3 vs. 3.0 mths • Tumour response on imaging • No difference in adverse events • No myelosuppression • 0.6% had seizures (5 pts: 2 with brain mets, 2 had lidocaine for biopsies)

  12. PREVAIL Study • Asymptomatic or minimally symptomatic men with metastatic PrCa who are chemotherapy naive

  13. Bone Targeted Therapy

  14. Radium-223 Chloride • ALSYMPCA Study

  15. ALSYMPCA Study • Radium-223 acts as a calcium mimic • Integrated into bone • Alpha emitter that provides localized effect • Induces dsDNA breaks in adjacent tumour cells • Short penetration • Phase 2: Nilsson, Lancet Onco GUCA 2012, Abstract 8

  16. ALSYMPCA Study • Phase 3: post-docetaxel and docetaxel ineligible • BSC ± Radium-223 • 6 injections at 4-wk intervals • N = 541 (radium) vs. 268 (placebo) • No cytotoxic chemotherapy • Primary EP: OS • Secondary EP: QoL, safety

  17. ALSYMPCA Study • Planned interim analysis at 320 deaths • Balanced baseline characteristics • Results: • OS: 14.0 mths vs. 11 mths (stat sig) • No routine imaging unlike DEN & Zometa studies

  18. ALSYMPCA Study • SRE: include spinal cord compression, pathologic fractures • Reduced risk for SCC with Radium-223 vs. placebo • A/E: • Modest increase in neutropenia but only 2% • Very well tolerated

  19. Bone Protection in MetCRPC • Can we prolong bone metastases free survival? • Fracture prevention? • Should we place patients on bone protective agent? • Zoledronate vs. Denosumab? • What is the optimal scheduling? • Individualization of options?

  20. Bone Protection in MetCRPC • Considerations for individualization: • Poor dentition • Convenience: IV vs. SC • Renal dysfunction • Side effects • Cost and co-payments • Are these agents necessary when other agents are being used?

  21. Renal Cell Carcinoma

  22. RCC in the Vulnerable Patient • Comorbidity Scores

  23. RCC & Comorbidity Scores • Accounting for comorbidities is important for clinical prognosis • SEER Registry (1995- 2007 data) • 1155 people with T1a N0 M0, well-differentiated • At 10 years: • 4% mortality for RCC causes • 51% from non-RCC causes

  24. Competing Risks • What diseases did the patient have before the cancer diagnosis? • Which ones are relevant?

  25. Charlson Comorbidity Index • Developed by fitting a statistical model to evaluate predictors of mortality

  26. Developed by fitting a statistical model to evaluate predictors of mortality • As CCI score increases, the mortality rate increases

  27. Charlson Comorbidity Index • 203 older pts with cancer • Little or no correlation between comorbidty (CCI or Cumulative Illness Rating Scale - Geriatrics) and functional status (ECOG or ADLs) • An assessment of comorbid medical conditions can provide information that is independent of patient’s functional status. Thus need to assess both. J Clin Oncol. 1998;16(4):1582

  28. Charlson Comorbidity Index • CAUTIONS: • **Other measures may be more appropriate • Nomograms are statistical models that can be used to predict outcomes, and are visual representations of the model • Be careful of extrapolation to unusual values

  29. Metastatic RCC • When to treat? • What are the deciding factors for when to start systemic therapy?

  30. Metastatic RCC: Goal • Delay as long as possible a patient from reaching a lethal tumour burden while maintaining QoL • RCC is an inherently diverse disease with a diverse biology

  31. Who can we observe? • Good performance status • Low volume • Slow growing • Asymptomatic

  32. When should we start? • Increased pace of disease • New organ sites • Symptoms from disease • MD / patient anxiety

  33. Therapy in mRCC • Advantages: • Reduction in tumour burden • Delay worsening of disease • Relatively convenient, oral therapy • Disadvantages: • Chronic therapy • Chronic toxicity

  34. Sunitinib in Elderly Pts with mRCC • Pooled data analysis of 1059 pts • 65% (689 pts): Sunitinib 50 mg/d (4wks on, 2wks off) • 35% (370 pts): continuous OD dosing • 1st line setting: 74% (783 pts) • 2nd line setting: 26% (276 pts) Hutson TE et al. J Clin Oncol. 29: 2011 (suppl; abstract 4604)

  35. Sunitinib in Elderly Pts with mRCC • Median PFS: 9.0 vs. 10.9 mths (p=0.0830) • Median OS: 23.3 vs. 23.7 mths (p=0.5441) • No difference when age taken • Overall tolerability is similar • In younger pts: increased HFS, chest pain Hutson TE et al. J Clin Oncol. 29: 2011 (suppl; abstract 4604)

  36. Ph.3 AXIS Trial for mRCC • What is the effect of prior first-line treatment duration and axitinib dose titration on axitinib efficacy? • Axitinib: potent and selective 2nd-gen VEGFR-I (VEGFR-1, -2, and -3) Rini BI et al. GUCA Symp 2012; abstract 354

  37. Axitinib • Potent and selective second-generation inhibitor of VEGFR-1, -2, and -3 • If no toxicity > grade 2 and BP <150/90 mmHg without anti-HTN meds for >2 wks ➜ increase axitinib to 7mg po BID and then to 10 mg po BID Rini BI et al. GUCA Symp 2012; abstract 354

  38. AXIS Trial Second Line mRCC (clear cell) Axitinib 5 mg po BID Sorafenib 400 mg po BID 6.7 mths 4.7 mths Median PFS p<0.0001 6.6 mths At least one total daily dose > 10mg N =132 pts 8.3 mths At least one total daily dose ≤ 10mg N = 227 pts Rini BI et al. GUCA Symp 2012; abstract 354

  39. AXIS Trial Second Line mRCC (clear cell) Axitinib 5 mg po BID Sorafenib 400 mg po BID 6.7 mths 4.7 mths Median PFS p<0.0001 N =194 pts (53.7%) N =195 pts (53.9%) Prior Sunitinib ≥9mths 6.3 mths Prior Sunitinib <9mths 4.5 mths Rini BI et al. GUCA Symp 2012; abstract 354

  40. Foretinib • Oral multi-kinase inhibitor targeting MET, VEGF, RON, AXL and TIE-2 receptors • Activating mutations and/or amplifications in MET in papillary RCC Choueiri TK et al. GUCA Symp 2012; abstract 355

  41. Locally adv. or met papillary RCC Intermittent arm Foretinib 240 mg/d on day 1-5 of every 14 days 37 pts Daily dose arm Foretinib 80 mg/d 37 pts ORR 13.5% PFS 9.3 mths 1-yr OS 70% Median OS not reached Choueiri TK et al. GUCA Symp 2012; abstract 355

  42. Locally adv. or met papillary RCC Intermittent arm Foretinib 240 mg/d on day 1-5 of every 14 days 37 pts Daily dose arm Foretinib 80 mg/d 37 pts ORR 13.5% PFS 9.3 mths 1-yr OS 70% Median OS not reached Choueiri TK et al. GUCA Symp 2012; abstract 355

  43. Foretinib: Toxicity • Grade 3/4: • Fatigue 6.8% • HTN 50% • Diarrhea 6.8% • Non-fatal pulmonary embolism: 11% • No sig diff between the 2 cohorts in efficacy or safety

  44. Summary • Prostate Cancer • Bone Targeted Therapy • Renal Cell Cancer

  45. Questions • maniaj@stjoe.on.ca

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