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Highlights in the Managment of Urogenital Cancer

Highlights in the Managment of Urogenital Cancer. Future directions for targeted therapies in advanced renal cell cancer Alessandro Morabito Unità Sperimentazioni Cliniche Istituto Nazionale Tumori di Napoli. Roma, 10 maggio 2008. The past…. IL-2, interferon. Advances in last years.

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Highlights in the Managment of Urogenital Cancer

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  1. Highlights in the Managment of Urogenital Cancer Future directions for targeted therapies in advanced renal cell cancer Alessandro Morabito Unità Sperimentazioni Cliniche Istituto Nazionale Tumori di Napoli Roma, 10 maggio 2008

  2. The past… IL-2, interferon

  3. Advances in last years • In understanding the biology and genetics of renal cell carcinoma • Availability of novel targeted approaches for the treatment of metastatic RCC

  4. New target-based agents Erlotinib Cetuximab Bevacizumab Temsirolimus Everolimus Sunitinib Sorafenib Brugarolas, NEJM 2007

  5. Target-based agents: results of phase III trials * No statistically significant according to O’Brien-Fleming

  6. The present…: an embarrassment of riches ?

  7. Therapeutic algoritm

  8. Future directions ?

  9. Targeted therapies: challenges and future directions • Combination therapy • New schedules • Sequential strategies • Role of cytokines • New agents • Predictive biomarkers • Adjuvant and neo-adjuvant therapy

  10. Targeted therapies: challenges and future directions • Combination therapy • New schedules • Sequential strategies • Role of cytokines • New agents • Predictive biomarkers • Adjuvant and neo-adjuvant therapy

  11. Combination therapy • What is the actual goal of therapy with combination of target based agents? • What are the targets we want to direct therapy toward? • How does one develop a rationale to proceed into the clinic with combination therapy?

  12. Goal of combination therapy • To increase the degree of the antitumor effects of single agents • To induce more complete responses impeding the onset of refractory disease • To overcome the resistance that develops with single-agent therapy

  13. Alternative end points for agents that are not expected to cause a major tumor regression… Morabito A, Ann Oncol 2006

  14. Phase II design for targeted agents is similar to that of cytotoxics • Objective response seems to be a useful end-point and it is predictive for success of the drug • Agents with high response rates tended to have high non-progression rates • Renal cell carcinoma is the exception to this…

  15. Non PD rates...

  16. Targets for RCC therapy • VHL or HIF mediated pathways • VEGF • VEGF receptors • EGFR • mTOR • PDGF • Non-VHL-mediated pathways • Raf kinase • Phosphatidylinositol 3-kinase • Akt • Nuclear factor B

  17. Rationale combinations of targeted therapies • Horizontal blockade • Numerous target molecules downstream from HIF- are inhibited • Vertical blockade • The same pathway is targeted at two or more different levels

  18. Targets generally in different cell types (tumor, endothelial, pericyte) Inhibition by multiple specific agents or by multitargeted agents To prevent cancer cell proliferation, promote apoptosis, ablate angiogenesis Horizontal blockade Sosman JA, Clin Cancer Res 2007

  19. Horizontal blockade of VEGF and EGFR pathways • Elevated levels of TGF- in RCC • TGF- is a growth factor for RCC independent of stroma • Elevated expression of VEGF has been considered to be a mechanism for acquired resistance to EGFR blockade • Inhibition of EGFR results in suppression of VEGF expression in laboratory models Bevacizumab Sunitinib Sorafenib Erlotinib Gefitinib

  20. Single agent bevacizumab: 10% objective responses Poor results with single-agent treatment against EGFR Combination of bevacizumab and erlotinib: results of a phase 2 study (positive…) Bevacizumab Sunitinib Sorafenib Erlotinib Gefitinib Hainsworth JD, J Clin Oncol 2005

  21. Combination of bevacizumab and erlotinib: results of a randomized phase 2 study (negative…!) Bukowski, J Clin Oncol 2007

  22. Horizontal blockade of VEGF and EGFR pathways:other combinations Bevacizumab Sunitinib Sorafenib Erlotinib Gefitinib *Patel, ASCO 2007 **Ryan, Genitourinary Cancer Symposium 2008

  23. The same pathway is targeted at two or more different levels Vertical blockade could overcome an aspect of resistance that may develop through feedback mechanisms (ie.  VEGF levels in response to blocking VEGFR) Vertical blockade Temsirolimus Everolimus Bevacizumab Sunitinib Sorafenib Sosman JA, Clin Cancer Res 2007

  24. Vertical blockade of VEGF pathway Temsirolimus Everolimus Bevacizumab Sunitinib Sorafenib *Feldman DR, ASCO 2007 **Sosman JA, ASCO 2006

  25. Vertical blockade of VEGF pathway Temsirolimus Everolimus Bevacizumab Sunitinib Sorafenib *Patnaik A, ASCO 2007 **Rosenberg JE, Genitourinary Cancer Symposium 2008

  26. Vertical blockade of VEGF pathway Temsirolimus Everolimus Bevacizumab Sunitinib Sorafenib *Merchan JR, ASCO 2007; ** Zafar Y, ASCO 2006; *** Bendell JC, ASCO 2007

  27. Phase II Study of Bevacizumab, Sorafenib, and Temsirolimus in mRCC (ECOG 2804 “BeST” Trial) + Temsirolimus i.v. over 30 min d1, d8, d15, d22 Sorafenib p.o. b.i.d., d1−28 • Eligibility criteria • Confirmed clear cell RCC • Measurable metastatic disease • <25% of any other histology (papillary, chromophobe, or oncocytic) • Primary or metastatic lesion • Not curable by standard radiotherapy or surgery • Prior nephrectomy • No more than 1 prior regimen containing vaccine- or cytokine-based immunotherapy • No prior antiangiogenic therapy, bevacizumab or mTOR inhibitors Bevacizumab i.v. over 30−90 min d1−15 + Bevacizumab 10 i.v. over 30−90 min d1-15 Temsirolimus 25 i.v over 30 min d1, d8, d15, d22 (N=360) RANDOM I s A T I ON + Bevacizumab 5 i.v. over 30−90 min d1−15 Sorafenib 200 b.i.d. p.o., d1−28 Primary endpoint: PFS Start Date:  September 2007; recruiting NCT00378703. www.clinicaltrials.gov.

  28. SABRE-R: Phase II Study of Sunitinib With or Without Bevacizumab as First-line Therapy in mRCC (USA) Sunitinib 50 mg p.o. o.d. 4/2 schedule + (n=50) • Eligibility criteria • Histologically confirmed mRCC • Measurable disease by RECIST • ECOG PS of 0 or 1 • Prior nephrectomy • No prior systemic or adjuvant therapy • Adequately controlled hypertension Placebo (N=100) RANDOM I S A T I ON + Sunitinib 50 mg p.o. o.d. 4/2 schedule Bevacizumab 10 mg/kg i.v. q2w (n=50) Primary endpoint: PFS and safety Secondary end points: ORR, duration of response, TTP, OS NCT00491738. www.clinicaltrials.gov. Start Date:  August 2007; recruiting

  29. Phase II Open-label Study of Bevacizumab plus Temsirolimus for First-line Treatment of mRCC Bevacizumab 10 mg/kg every 2 weeks + temsirolimus25 mg/week (n=80) Sunitinib 50 mg/day4/2 schedule • Eligibility criteria • Metastatic RCC • No prior systemic treatment • ECOG PS ≤2 (n=40) (N=160) RANDOM I S A T I ON Bevacizumab 10 mg/kg every 2 weeks + IFN-a 9 MU q.i.w. (n=40) Primary endpoint: PFS at 48 weeks Secondary endpoints: ORR, response duration, OS, QoL, safety PIs: Escudier and Negrier

  30. Targeted therapies: challenges and future directions • Combination therapy • New schedules • Sequential strategies • Role of cytokines • New agents • Predictive biomarkers • Adjuvant and neo-adjuvant therapy

  31. New schedules • Dose escalation of Sorafenib* • Phase 2 study of intra-patient dose escalation of sorafenib, up to 800 mg BID • 91% of pts escalated to 1200 mg or 1600 mg per day • OR: 52% • Continuous daily administration of Sunitinib** • 107 pts, refractory to cytokines, randomized in a phase 2 study (morning vs evening) • Manageable safety profile • OR: 19% and SD: 40% * Amato RJ, ASCO 2007 ** Srinivas S, ASCO 2007

  32. Renal EFFECT: Phase II Trial of Sunitinib CD vs the 4/2 Schedule in First-line mRCC Sunitinib 50 mg p.o. daily on 4/2 schedule • Eligibility criteria • Advanced RCC • Clear-cell histology • Measurable disease • No prior systemic therapy • No brain metastasis (N=282) RANDOM I S A T I ON Sunitinib 37.5 mg p.o. continuous daily Primary end point: TTP Secondary end points: safety and tolerability, ORR, OS, QOL NCT00267748. www.clinicaltrials.gov. Start Date:  December 2005; recruiting

  33. Targeted therapies: challenges and future directions • Combination therapy • New schedules • Sequential strategies • Role of cytokines • New agents • Predictive biomarkers • Adjuvant and neo-adjuvant therapy

  34. Sequencial strategies • Is there a role? • TKIs have antitumor activity in RCC pts previously treated with antiangiogenic therapy • Which agent? • Type of anti-angiogenic therapy received does not predict response to subsequent therapy • Is there an optimal sequence? • Current data support use of sequential TKIs; prospective studies in progress will define efficacy and toxicity

  35. Sequential TKIs in advanced RCC: retrospective analyses Tamaskar et al. ASCO 2006; Escudier et al. ASCO 2007

  36. (n=60) (n=60) (n=60) (n=60) START: Randomised Phase II Sequential Two-agent Assessment in RCC Therapy (Proposed) Temsirolimus (n=120) Sunitinib R • Eligibility criteria • mRCC of any type • PS 0/1 • No brain mets • No prior systemic therapy Bevacizumab (N=240) Progression RANDOM I S A T I ON Sunitinib (n=120) Bevacizumab R Temsirolimus • Stratification: • Clear cell vs non–clear cell • Prior nephrectomy (yes/no) • PS (0/1) Objectives: Estimate TTP1 and ORR with each drug (first-line setting) Estimate TTP2 and ORR with each drug (second-line setting) Estimate and rank TTP1 + TTP2 for each sequence

  37. Randomised Phase III Study of Temsirolimus vs Sorafenib as second-line Therapy in mRCC Temsirolimus 25 mg i.v. +Best supportive care • Eligibility criteria • Metastatic clear cell RCC • Measurable disease • Failed sunitinib • Karnofsky PS ≥70% • ≥1 measurable lesion by RECIST • No prior mTOR inhibitors • No brain metastases N=440 RANDOM I S A T I ON Sorafenib +Best supportive care Primary end point: PFS Secondary end points: OS, ORR, QoL, Safety Start Date:  July 2007; recruiting Expected Completion Date:  October 2010 NCT00474786. www.clinicaltrials.gov

  38. MD Anderson: Study Proposal

  39. Targeted therapies: challenges and future directions • Combination therapy • New schedules • Sequential strategies • Role of cytokines • New agents • Predictive biomarkers • Adjuvant and neo-adjuvant therapy

  40. Role of cytokines • VEGF has been shown to suppress immune function by: • blocking maturation of myeloid cells into mature dendritic cells • inducing the immature myeloid cells to suppress normal T-cell responses • Anti-VEGF therapy may reverse these immunosuppressive effects

  41. Interferon and…. bevacizumab Bukowski RM, Berlin 2008

  42. Interferon and…. VEGFR inhibitors *Bracarda S,Genitourinary Cancer Symposium 2008; **Gollob J, ASCO 2006; ***Ryan W, ASCO 2006 § Kondagunta GV, ASCO 2007

  43. IL-2 and…bevacizumab *Tamaskar IR, Genitourinary Cancer Symposium 2008; Buti S, ASCO 2007

  44. Targeted therapies: challenges and future directions • Combination therapy • New schedules • Sequential strategies • Role of cytokines • New agents • Predictive biomarkers • Adjuvant and neo-adjuvant therapy

  45. New agents • VEGFR inhibitors • Axitinib • AZD2171 • Pazopanib • Everolimus (RAD001) • Integrin inhibition • M200 (volociximab) • Akt/MAP kinase inhibition • Perifosine • Tie 2 inhibition • AMG 386 • C-Met inhibition • ARQ 197 • XL880

  46. New VEGFR inhibitors in RCC *Rini BI, ASCO 2007; **Sridhar SS; ASCO 2007; ***Hutson TE, ASCO 2007

  47. Everolimus: Phase III in RCC (RECORD-1 study) • Oral inhibitor of mTOR • Patients with metastatic RCC and PD after receiving sunitinib and/or sorafenib • Stratified by number of prior treatments and MSKCC risk criteria (favourable vs intermediate vs poor) • The trial was stopped after a planned interim results showed significantly better progression-free survival with everolimus….Complete results will be presented at ASCO 2008 Everolimus 10 mg/d+ BSC N=362 2 : 1 RAD001 : Placebo Placebo + BSC NCT00410124. www.clinicaltrials.gov

  48. Everolimus? The next algorithm…?

  49. Targeted therapies: challenges and future directions • Combination therapy • New schedules • Sequential strategies • Role of cytokines • New agents • Predictive biomarkers • Adjuvant and neo-adjuvant therapy

  50. Predictive biomarkers • Serum/plasma markers: • VEGF • sVEGFR • Tissue/cells: • HIF expression • VHL gene mutation

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