1 / 57

Emerging Options for Treatment of Metastatic Kidney Cancer

Emerging Options for Treatment of Metastatic Kidney Cancer. Robert J. Motzer MD Attending Physician Memorial Sloan-Kettering Cancer Center Professor of Medicine Weil Medical College of Cornell University New York, NY. Expert Review Clinical Application of Evolving Treatment Paradigms.

dimaia
Download Presentation

Emerging Options for Treatment of Metastatic Kidney Cancer

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript


  1. Emerging Options for Treatment of Metastatic Kidney Cancer Robert J. Motzer MD Attending Physician Memorial Sloan-Kettering Cancer Center Professor of Medicine Weil Medical College of Cornell University New York, NY Expert Review Clinical Application of Evolving Treatment Paradigms

  2. Renal Cell Carcinoma (RCC) RCC is the most common cancer of the kidney1,2 Current analyses estimate more than 50,000 new cases and 13,000 deaths in the United States in 20073,4 Recurrence develops in approximately 40% of patients with localized tumors5 Approximately 30% of patients with RCC present with metastatic disease1 5-year survival rate for patients with metastatic RCC is <10%6 Motzer RJ, et al. N Engl J Med. 2007;356:115-124; 2. Parkin DM, et al. CA Cancer J Clin. 2005;55:74-108; 3. Pickle LW, et al. CA Cancer J Clin. 2007;57:30-42; 4. Jemal A, et al. Ca Cancer J Clin. 2007;57:43-66; 5. Lam JS, et al. World J Urol. 2005;23:202-212; 6. Motzer RJ, et al. N Engl J Med.1996;335:865-875

  3. Treatment of Advanced/Metastatic RCC RCC is highly resistant to chemotherapy Cytokines have response rates of 5% to 20% and median OS of 12 months but their use is limited by toxicity1,2 Therapies targeted to VEGF and PDGF receptors are the new standard of care (e.g., sunitinib and sorafenib)1,3 VEGF = Vascular endothelial growth factor; PDGF = Platelet-derived epithelial growth factor.1. Motzer RJ, et al. N Engl J Med. 2007;356:115-124; 2. Hutson TE, et al. Clin Genitourin Cancer Suppl.2006;5(Suppl 1):S31-S39; 3. Escudier B, et al. N Engl J Med. 2007;356:125-134.

  4. RCC MSKCC Risk Model 1.0 0.8 0.6 0.4 0.2 0 0 risk factors = favorable risk 1/2 risk factors = intermediate risk 3–5 risk factors = poor risk Proportion Surviving Median Survival 30 months 14 months 5 months 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Years From Start of Interferon-α Therapy Motzer R et al. J Clin Oncol 2002;20:289–296.Reprinted with permission from the American Society of Clinical Oncology.

  5. Clear Cell RCC: VHL Gene Mutation E2 CUL2 VHL complex disrupted Rbx1 Elongin C Elongin B VHL protein Β-domain Mutant α-domain HIFα accumulation PDGF VEGF Glut1 DeVita. Cancer: Principles and Practice of Oncology. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins. 2005;1826.

  6. RCC Cancer BiologyVHL-HIF Pathway Targets of Agents E2 CUL2 Rbx1 Elongin C Elongin B VHL protein Β-domain Mutant α-domain HIFα accumulation Temsirolimus Everolimus mTOR Bevacizumab VEGF Trap VEGF PDGF TGFα PDGFR KDR EGFR Erlotinib, gefitinib, lapatinib Sorafenib, sunitinib axitinib, pazopanib, AZD2171 Sorafenib, sunitinib axitinib, pazopanib DeVita. Cancer: Principles and Practice of Oncology. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins. 2005;1826; Atkins. ASCO. 2006 Plenary session.

  7. mTOR Pathway Growth factors PI-3 kinase Extracellular membrane PTEN loss PI-3K/Akt activation PTEN Akt mTOR Temsirolimus Everolimus S6K 4EBP1 Translation Cell proliferation Cell division Angiogenesis Rini. J Clin Oncol. 2005;23:1028, adapted with permission from the American Society of Clinical Oncology; Patel. Br J Cancer. 2006;94:614; Motzer. J Clin Oncol. 2006;24:5601.

  8. Treatment Naïve mRCC Patients • First-line therapy - no prior systemic treatment • Series of phase 3 trials - comparator arm interferon (IFN)-a • Agents investigated: • Sunitinib • Temsirolimus • Bevacizumab • Sorafenib (phase 2)

  9. Patient CharacteristicsRecent Randomized Trials in Advanced RCC 1. Motzer R, et al., N Engl J Med 2007, 356:115-124. 2. Hudes G, et al. N Engl J Med 2007;356:2271−2281. 2. Escudier et al. Lancet 2007;370:2103−1211. 3. Szczylik C, et al. ASCO 2007.

  10. Sunitinib vs. InterferonStudy Design Eligibility Criteria • ≥18 years of age • mRCC • Clear cell histology • No prior systemic treatment • Measurable disease by RECIST • ECOG PS of 0 or 1 • Adequate organ function Sunitinib 50 mg PO daily on 4/2 schedule (n=375) (N=750) RANDOM I Z A T I ON IFN-a 3 MU sc tiw 1st week, 6 MU sc tiw 2nd week, 9 MU sc tiw 3rd week thereafter (n=375) Motzer et al. N Engl J Med 2007;356:115–124.

  11. Study Endpoints Progression-free survival (PFS) 90% power to detect a 35% improvement Primary endpoint met atthe pre-planned Interim Analysis 2 Overall survival (OS) 85% power to detect a 35.7% improvement 390 events required for the final analysis Response rate, safety, patient-reported outcomes Primary Endpoint Secondary Endpoints Figlin et al. Abstract 5024, ASCO 2008.

  12. Best Response *Sunitinib vs. IFN-: P<0.000001 ASCO-2007 Update. Motzer et al. N Engl J Med 2007;356:115–124.

  13. Progression Free Survival (Independent Central Review) 1.0 0.9 Sunitinib Median: 11.0 months (95% CI:10.7-13.4) 0.8 0.7 IFN-aMedian: 5.1 months(95% CI:3.9-5.6) 0.6 0.5 0.4 0.3 0.2 0.1 0.0 PFS probability Hazard Ratio=0.53895% CI (0.439, 0.658) P<0.000001 0 5 10 15 20 25 30 Time (months) No. at Risk Sunitinib: 375 240 156 54 10 1 IFN-α: 375 124 46 15 4 0 Motzer et al. N Engl J Med 2007;356:115–124.

  14. Sunitinib vs. IFN- in First-line mRCC PFS by MSKCC Risk Status Motzer et al. Abstract 5024, ASCO 2007.

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

  16. Post-study Treatments *P<0.0001 Figlin et al. Abstract 5024, ASCO 2008.

  17. Overall Survival Analyses *Stratification factors: ECOG PS, LDH, and nephrectomy. Figlin et al. Abstract 5024, ASCO 2008.

  18. Overall Survival Multivariate Analysis* *Treatment comparisons controlling for baseline factors simultaneously from Cox model. Figlin et al. Abstract 5024, ASCO 2008.

  19. Sunitinib vs. IFN- in First-line mRCC Adverse Events Motzer et al. submitted for publication

  20. Treatment Naïve RCCPoor-risk Patients Clinical criteria to define a poor risk population (previously treated vs. untreated) are available Use in a clinical trial setting and/or to determine therapy is reasonable Validation and development of an international risk classification is underway It is unclear whether this group of patients can be defined biologically

  21. Temsirolimus (CCI-779)Phase III Trial in Poor Risk RCC* IFN 3MU-18MU (n=207) CR + PR – 7% CR + PR + SD‡ – 29% Med. OS 7.3 months§ Randomize† • 3/6 Poor Risk • Features • LDH>1.5xULN • Hgb < LLN • Ca++ (cor) >10 • KPS <70% • DFI <1 year • Multiple sites of metastases • Metastatic RCC • (N=626) TEM 25mg QW (n=209) CR + PR – 9% CR + PR + SD – 46% Med. OS 10.9 months§ IFN 6MU + TEM 15mg QW(n=210) CR + PR – 11% CR + PR + SD – 41% Med. OS 8.4 months *Modified MSK poor risk; †Stratification by Country and Nephrectomy status ‡SD  16 weeks; §P=0.0069 Hudes et al. ASCO, 2006.

  22. Temsirolimus ± IFN-αMaximum Percent Reduction in Tumor Measurement* 200 100 0 –100 Change from baseline (%) 44% 67% 77% IFN TEMSR IFN + TEMSR Patients *Investigator assessed measurements

  23. Temsirolimus ± IFN-aOverall Survival by Treatment 1.0 0.8 0.6 0.4 0.2 0 Survival distribution function Arm 2: Temsirolimus Arm 1: IFN Arm 3: IFN + Temsirolimus 0 5 10 15 20 25 30 35 Time to death

  24. Temsirolimus vs. IFN-aSecondary End Points †Based on log-rank test stratified by prior nephrectomy and region. ‡Based on Cox proportional hazard model stratified by prior nephrectomy and region. #Based on Cochran-Mantel-Haenszel test stratified by prior nephrectomy and region. **CR, PR, or SD for ≥24 weeks. Independent assessment. 1Hudes et al. N Engl J Med 2007;356:2271–2281.

  25. Temsirolimus Phase III Trial Percent (%) of Patients with Selected Adverse Events All Grades and Grade 3–4

  26. Temsirolimus Phase III Trial (cont’d) Percent Patients with Laboratory AbnormalitiesAll Grades and Grade 3–4

  27. Phase III Trial Temsirolimus vs. IFN-αSubset Analyses 1. HR : hazard ratio; 2 MSK prognostic groups Dutcher et al. ASCO, 2007.

  28. BevacizumabPhase III Trials in RCC Patient Population: Metastatic Clear Cell Ca No Prior Systemic Therapy CALGB 90206 N = 732 BO17705 (AVOREN) N = 649 Randomize Randomize IFN- 9.0 MU TIW + Bevacizumab 10 mg/kg d1,15 IFN-α 9.0 MU TIW + Bevacizumab 10 mg/kg d1,15 IFN-α 9.0 MU TIW + Placebo IFN- 9.0 MU TIW 1Rini, B: letter to CALGB, 7/9/07; 2Escudier et al. Lancet 2007;370:2103−1211.

  29. PFS in Evaluable PatientsAVOREN and CALGB 90206 5.2 8.5 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 Median PFS: Bevacizumab + IFN-a2a (n=327) = 10.2 months Placebo + IFN-a2a (n=322) = 5.4 months Probability of being progression-free Bevacizumab + IFN-a2b (n=369) = 8.5 months Placebo + IFN-a2b (n=363) = 5.2 months 5.4 10.2 0 6 12 18 24 30 36 42 48 Time (months) Escudier et al. Lancet 2007;370:2103−1211. Rini, et al. JCO in press

  30. AVORENPFS by MSKCC Risk Status* Risk factors associated with shorter survival are low hemoglobin, high corrected calcium, high LDH, poor performance status, and an interval of <1 yr from diagnosis to treatment. *Escudier, et al. Lancet. 2007;370:2103-2111.

  31. AVOREN and CALGB 90206Selected Grade 3/4 Adverse Events

  32. AVOREN Trial Interim Analysis of Overall Survival (251 of 450 Scheduled Events) 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 Probability of survival HR=0.75 (95% CI: 0.58–0.97), p<0.0267* Median overall survival: Bevacizumab + IFN = NR† Placebo + IFN = 19.8 months 19.8 0 6 12 18 24 30 Time (months) Number ofpatients at risk Placebo + IFN 322 262 176 53 1 0 Bevacizumab+ IFN 327 275 197 60 2 0 *Stratified by Motzer score and region category; unstratified analysis HR=0.79, p=0.067;prespecified level of significance P=0.0056 †Not reached

  33. Selected Serious Adverse Events (Grade 3/4) Associated With Sunitinib, Bevacizumab and Temsirolimus *Poor risk patients – stratified according to modified MSKCC criteria plus number of metastatic sites 1. Motzer RJ, et al. N Engl J Med 2007;356:115–124; 2. Escudier B, et al. Lancet 2007;370:2103–2111; 3. Hudes G, et al. N Engl J Med 2007;356:2271−2281; 4. Escudier B, et al. N Engl J Med 2007;356:125−134.

  34. Phase IISorafenib vs. IFN-α in Treatment Naïve Advanced RCC Period 1 Period 2 • Randomization • 1:1 • N=189 • Stratification • MSKCC prognostic score Eligibility Criteria • Clear-cell histology • No prior systemic therapy • ECOG PS of 0 or 1 • All MSKCC risk groups Sorafenib400 mg bid n=97 Sorafenib 600 mg bid n=44 • PrimaryEnd Point • PFS Disease progression IFN-a 9 MU tiw n=92 Sorafenib 400 mg bid n=50 End Points (Investigator Assessment) Szczylik et al. J Clin Oncol 2007;25(suppl):5025, abstract.

  35. Sorafenib vs. IFN-a in Treatment Naïve mRCC Patients: PFS 100 80 60 40 20 0 Median PFS (121 events/189 patients) Sorafenib = 5.7 months IFN = 5.6 months Hazard Ratio = 0.883 p = 0.504 (log-rank test) Progression-Free Survival (% patients) 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Time From Randomization (months) Adapted from Szczylik C et al. Presented at ASCO Annual Meeting;June 1-5, 2007; Chicago, IL.

  36. Treatment Refractory mRCC Patients Refractory to cytokines Refractory to non-cytokine regimens Refractory to angiogenesis inhibitors

  37. Treatment Approaches in Renal CancerGlobal Evaluation Trial(TARGETs) Sorafenib400 mg bid ORR 10% SD 74% PFS 5.5 mo • Eligibility criteria • Histologically/cytologically confirmed, unresectable and/or metastatic disease • Clear cell histology • Measurable disease • Failed one prior systemic therapy in last 8 months • ECOG PS 0 or 1 • Good organ function • No brain metastasis • Poor-risk MSKCC group excluded (1:1) Randomization n~905 • Major end points • PFS (α=0.01) • OS (α=0.04) Placebo* ORR 2% SD 53% PFS 2.8 mo • Stratification • MSKCC criteria • Country Secondary end point: ORR *Crossover - initiated 6/05 Escudier et al. Presented at: ECCO 13 – the European Cancer Conference, October 30-November 3, 2005; Paris, France. Abstract 794.

  38. Sorafenib in Second-Line mRCC: PFS Benefit* Sorafenib 1.00 Placebo Censored observation Median PFS Sorafenib=5.9 months Placebo=2.8 months HR=0.51 P<0.001 0.75 Proportion of Patients Progression Free 0.50 0.25 0 0 2 4 6 8 10 12 14 16 18 20 Time From Randomization (months) *Based on investigator assessment. Escudier. N Engl J Med. 2007;356:124.

  39. Phase III TARGETs Trial: Response and Maximum Percent Reduction in Tumor Measurement* Placebo Best response Sorafenib Best response 100 80 60 40 20 0 –20 –40 –60 –80 –100 Maximum Percent Reduction inTumor Measurement 50 100 150 200 250 50 100 150 200 250 Patient number Patient number 20% 74% PR – 0% SD – 55% PR – 2% SD – 78% *Independently assessed measurements available for 574 patients.

  40. TARGETsFinal OS Analyses TARGET: Per-protocol OS Analysis at 561 deaths TARGET: Preplanned Secondary Analysis† OS Data for Placebo Patients Censored 1.00 0.75 0.50 0.25 0.00 1.00 0.75 0.50 0.25 0.00 • 216/452 placebo recipients crossed over to sorafenib • 615 of all drug taken on placebo arm was sorafenib Sorafenib (N=451) Placebo (N=452) Proportion of patients surviving Proportion of patients surviving Sorafenib Placebo HR=0.88* CI: 0.74–1.04 HR (sor/pla)=0.78* 95% CI: 0.62–0.97 p=0.0287* 0 4 8 12 16 20 24 28 32 36 40 0 4 8 12 16 20 24 28 32 36 40 Months for randomization Months for randomization Summary OS: Sorafenib Placebo Final Analysis (9/06) 17.8 mos 15.2 mos Censored Analysis (6/05) 17.8 mos 14.3 mos *Non-significant (P=0.146); †Planned analysis prior to unblinding of the OS data; O’Brien-Fleming threshold for statistical significance a=0.037 Bukowski et al. ASCO, 2007.

  41. Phase II Evaluation of Sunitinib in mRCC Two Independent, Single-arm, Multicenter, Phase II Trials (Trial 014: N=63; Trial 1006: N=106)1,2 Continue sunitinib treatment unless progression or intolerability Patients with advanced disease and failure of prior cytokine therapy Sunitinib 4 weeks on, 2 week off (4/2) Dosing schedule Sunitinib Sunitinib 50 mg/day* *Dose reduction permitted(to 37.5 mg/day and then to 25 mg/day). 1. Motzer RJ, et al. J Clin Oncol 2006;24:16–24. 2. Motzer RJ, et al. JAMA 2006;295:2516–2524

  42. Sunitinib: Phase II Efficacy • Sunitinib has been studied in two Phase II trials in cytokine-refractory patients with advanced RCC Motzer et al. JAMA 2006N=106 Motzer et al. JCO 2006N=63 • Motzer RJ, Michaelson MD, Redman BG, et al. Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. Journal of Clinical Oncology 2006;24:16–24. • Motzer RJ, Rini BI, Bukowski RM, et al. Sunitinib in Patients with metastatic renal cell carcinoma. Journal of the American Medical Association 2006;295:2516–2524.

  43. Everolimus (RAD001) in mRCC Everolimus is an oral agent that is an inhibitor of mTOR Responses were observed in previously treated and untreated metastatic RCC patients1 Phase III trial was initiated in patients who progressed on VEGFR TKI therapy 1. Jac et al. ASCO, 2007. Abstract 5107.

  44. Phase III Trial of Everolimus vs. Placebo Everolimus vs. Placebo Primary endpoint: PFS Secondary endpoints: OS, safety, response,patient-reported outcomes • Eligibility criteria: • Metastatic RCC with clear cell histology • Measurable disease • Refractory to TKIs – sunitinib and/or sorafenib • Prior bevacizumab and cytokines permitted • Stratify by: • MSKCC risk group (favorable vs. intermediate vs. poor) RANDOMI ZE Everolimus 10 mg/day p.o. BSC Placebo 10 mg/day p.o. BSC 2:1 Study Design (n = 410) Motzer. ASCO, 2008. Abstract LBA5026.

  45. Phase III Trial of Everolimus vs. Placebo Efficacy/Results *Central review †81% of the patients receiving placebo crossed over at progression Abbreviation: NR = not reported Motzer. ASCO, 2008. Abstract LBA5026.

  46. RECORD 1 TrialPFS in Everolimus and Placebo Patients Independent Review Investigator Assessment Hazard ratio = 0.30 95% CI [0.22, 0.40] Median PFS Everolimus: 4.0 moPlacebo: 1.9 mo P<0.001 Hazard ratio = 0.31 95% CI [0.23, 0.41] Median PFS Everolimus: 4.6 moPlacebo: 1.8 mo p<0.001 100 80 60 40 20 0 100 80 60 40 20 0 Everolimus (n = 272) Placebo (n = 138) Everolimus (n = 272) Placebo (n = 138) Probability (%) Probability (%) 0 2 4 6 8 10 12 0 2 4 6 8 10 12 Months Months Motzer et al. ASCO, 2008.

  47. RECORD 1 Trial Maximum % Change in Target Lesions and ORR* Everolimus Placebo 100% 75% 50% 25% 0% –25% –50% –75% –100% NE = not evaluable *Central Radiology Review

  48. Phase III Trial of Everolimus vs. Placebo Grade 3/4 Adverse Events Motzer. ASCO, 2008. Abstract LBA5026.

  49. Reported Phase II/III Datafor Clear Cell RCC Therapy *MSKCC risk status Atkins et al. ASCO 2006 Plenary session; Figlin et al. Clin Adv Hematol Oncol 2007;5:35; Escudier et al. Drugs 2007;67:1257; Cho et al. Clin Cancer Res 2007;13:761s; Atkins et al. Clin Cancer Res 2005;11:3714. Motzer et al. Abstract LBA5026, ASCO 2008

  50. Investigational Agents Rini. ASCO. 2005 (abstr 4509); Hutson. ASCO. 2007 (abstr 5031); Sridhar. ASCO. 2008 (abstr 5047); Jac. ASCO. 2008 (abstr 5113); Ravaud. ASCO. 2006 (abstr 4502); Huang. ASCO. 2008 (abstr 5053).

More Related