1. The Ever-Changing Landscape Daniel Heng MD MPH FRCPC University of Calgary

2. Outline  Staging  Genetics behind RCC  Treatment of metastatic disease Case Prognostic Factors Mechanisms of Resistance  Cytoreductive nephrectomy

3. Staging Cohen et al NEJM 2004

5. VHL Von Hippel Lindau Courtesy sppider.cchmc.org & www.bme.jhu.edu HIF1a Ub Proteosome Degradation Of HIF1a

6. VHL Von Hippel Lindau HIF1a Transcription of Genes Associated with Angiogenesis and Proliferation

7. Angiogenesis and Proliferation AngiogenesisCell ProliferationEndothelial Stabilization VEGF VEGFR TGFa/B/ EGFR PDGF PDGFR Cohen et al NEJM 2005

8. Von Hippel Lindau  75-80% of sporadic clear cell RCCs have VHL defect: Frameshift / truncation mutation Deletion Promoter methylation Cohen et al NEJM 2005 PromoterVon Hippel Lindau Gene Transcription CH 3

9. Targeted Therapies: The Revolution Courtesy AZ

10. Targeted Therapy in mRCC  VEGF inhibitors Sunitinib Sorafenib Bevacizumab Pazopanib Axitinib  mTOR inhibitors Temsirolimus Everolimus

11. Targets and Inhibitors Rini et al JCO 2005, 2009

12. Treatment of mRCC: 2011 SettingPatientsTherapy (level 1 evidence) Other Options (>level 1 evidence) UntreatedGood or intermediate risk Sunitinib Bevacizumab+IFN Pazopanib HD IL-2 Sorafenib Clinical Trial Observation Poor riskTemsirolimusSunitinib Clinical Trial Second-lineCytokine refractory Axitinib Sorafenib Sunitinib Bevacizumab+IFN Prior VEGFAxitinib Everolimus Clinical Trial Targeted therapy not previously used

13. Case I: JN 60F otherwise healthy Had abdominal discomfort so abdominal ultrasound was ordered 7x5 cm central mass in right kidney incidentally detected pT3a N0 M0 clear cell renal cell carcinoma resected by laparoscopic right radical nephrectomy Staging CT scans revealed no other metastases

14. Case I: JN  Standard of care would be CT scans of the abdomen and pelvis with chest x-ray every 6 months for first 2 years yearly thereafter  Because of 50% chance of recurrence, was offered adjuvant clinical trial REC2 clinical trial ○ One year of sunitinib, sorafenib, or placebo

15. Case I: JN  Consented to ASSURE clinical trial Had no side effects whatsoever … was she on placebo? 6 month CT scan clear 12 month CT scan ○ Multiple pulmonary metastases bilaterally max 2 cm ○ Liver metastases

16. Case I: JN

17.  She now has metastatic disease  Her calcium, LDH, neutrophils, platelets are within normal range, ECOG 0  Her hemoglobin is low at 100 What is her Prognostic Category? 1) Favorable risk – median OS 44 months 2) Intermediate risk – median OS 21 months 3) Poor risk – median OS 8 months

18. Intl mRCC Database Consortium: Independent Predictors of Poor OS Heng et al JCO 2009

19. Prognostic Factors If patient has 0 factors: Favorable Prognosis If patient has 1-2 factors: Intermediate Prognosis If patient has 3-6 factors: Poor Prognosis

20. Overall Survival in the New Era Favorable: 0 factors (mOS 44 mos) Intermediate: 1-2 factors (mOS 21 mos) Poor: 3-6 factors (mOS 8 mos) p<0.0001 Heng et al ASCO 2011

21. Case I: JN  She has intermediate risk criteria due to anemia What first line targeted therapy would you choose? 1)Sunitinib 2)Temsirolimus 3)Everolimus 4)Interferon 5)High dose IL-2

22. Sunitinib PFS Motzer et al NEJM 2007

23. Pazopanib PFS Sternberg et al..J Clin Oncol 2010; 28: 1061-1068.

24. Bevacizumab+IFN  AVOREN Phase III Trial Met clear cell RCC Treatment naive IFN-α2b SC IFN-α2b SC + Bevacizumab IV Progression free survival benefit (10.2 vs. 5.4 months p<0.0001) No OS benefit due to crossover

25. Temsirolimus Overall Survival Benefit TEMSR vs IFN log rank p=0.0069 PFS 3.7 vs. 1.9 months mOS 10.9 vs. 7.3 months Hudes et al NEJM 2007

26. Escudier et al NEJM 2007 Sorafenib PFS

27. Treatment of mRCC: 2011 SettingPatientsTherapy (level 1 evidence) Other Options (>level 1 evidence) UntreatedGood or intermediate risk Sunitinib Bevacizumab+IFN Pazopanib HD IL-2 Sorafenib Clinical Trial Observation Poor riskTemsirolimusSunitinib Clinical Trial Second-lineCytokine refractory Axitinib Sorafenib Sunitinib Bevacizumab+IFN Prior VEGFAxitinib Everolimus Clinical Trial Targeted therapy not previously used

28. Case I: JN She chooses to be on sunitinib She is dosed at the standard 50 mg 4 weeks on and 2 weeks off Her baseline assessments included – CT scan of the chest, abdomen, pelvis – Bone scan (normal) – CBC, liver function tests, creatinine, baseline TSH – MUGA/echo only in patients with prior history of cardiac disease or significant risk factors

29. Case I: JN She is followed with CT scans every 3 months (every 2 cycles) – 3 month CT: 19% tumor reduction – 6 month CT: stable disease from previous – 9 month CT: stable disease from previous At 11 months: – She develops significant anemia (Hb 88) – She is tired, symptomatic of anemia – Had syncopal episode – She requires a transfusion of 2 units PRBC

30. Case I: JN Sunitinib was held for 4 weeks but counts did not recover, required blood transfusions every 3 days Became neutropenic despite not being on any drug Considered bone marrow infiltration of RCC – Bone marrow biopsy could not confirm this (sampling error) – Decided that this was progressive disease and needed new line of therapy

31. Mechanisms of Resistance

32. 1) Angiogenic redundancy – PDGF, FGF, PIGF 2) Intratumoral hypoxia induces redundancy factors Grepin R et al J Oncology 2010

33. Mechanisms of Resistance 3) Natural selection of more invasive tumor cells Grepin R et al J Oncology 2010

34. Mechanisms of Resistance 4) Recruitment of bone marrow derived proangiogenic and inflammatory cells – IL-6, GCSF recruitment 5) Targeted endothelial cells can recruit pericytes to protect them and release PDGF 6) Vessel cooption: smaller, new tumors develop around normal blood vessels Grepin R et al J Oncology 2010

35. Everolimus: Progression-Free Survival Central Radiology Review Motzer R, Escudier B, Oudard S et al. LBA 5026 ASCO 2008. Patients at Risk Everolimus 272132 47 8 2 0 0 Placebo 13832 41 0 0 0 100 80 60 40 20 0 024 6 810 12 Probability, % Hazard ratio = 0.30 95% CI [0.22, 0.40] Median PFS Everolimus: 4.0 mo Placebo: 1.9 mo Log rank P value <0.001 RAD001 (n=272) Placebo (n=138) Months

36. Axitinib Progression-free Survival (IRC Assessment) IRC = Independent Review Committee 361256202145966438201010 3622241571005128126310 Subjects at risk, n Axitinib Sorafenib 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0246810 Time (months) P<0.0001 (log-rank) Stratified HR 0.665 (95% CI 0.544–0.812) 1214161820 Axitinib Sorafenib mPFS, mo 95% CI 6.7 4.7 6.3–8.6 4.6–5.6 Progression-Free Survival (probability) Rini et al ASCO 2011

37. Treatment of mRCC: 2011 SettingPatientsTherapy (level 1 evidence) Other Options (>level 1 evidence) UntreatedGood or intermediate risk Sunitinib Bevacizumab+IFN Pazopanib HD IL-2 Sorafenib Clinical Trial Observation Poor riskTemsirolimusSunitinib Clinical Trial Second-lineCytokine refractory Axitinib Sorafenib Sunitinib Bevacizumab+IFN Prior VEGFAxitinib Everolimus Clinical Trial Targeted therapy not previously used

38. Case I: JN Began Everolimus 10mg/kg – No longer required transfusions – Feeling much better – Minimal side effects – Monitored with CT scans and Hb every 3 months 3 month CT: stable disease, Hb 135 – 6 months: symptomatic anemia again, Hb 88 Did not recover with everolimus cessation Required transfusions every 3 days Deemed to have progressive disease

39. Case I: JN What third-line targeted therapy would you choose? 1)Sunitinib 2)Temsirolimus 3)Everolimus 4)Interferon 5)High dose IL-2 6)Pazopanib 7)Bevacizumab+IFN 8)Clinical Trial

40. Case I: JN Patient chooses pazopanib as she had third party insurance Monitored patient with CT scans every 3 months – 3 months: 18% decrease – 6 months: slowly progressive liver disease, lungs stable (15% increase) – 9 months: progressive disease in liver (20% increase)

41. Case I: JN  Screening for clinical trial of BMS PD-1 inhibitor  Still slightly anemic

42. Lessons Learned  Targeted therapy extended her life significantly “Thank you, this time last year I thought I wouldn’t be here anymore”  Progression can come in different ways and not just on CT scans  Third line therapy is therapy that you haven’t used before, if available

44. Background  Two prospective randomized trials 1,2 with metastatic RCC showed that the addition of cytoreductive nephrectomy (CN) improves overall survival (OS) as compared to interferon-alpha (IFN-a) alone (13.6 months vs. 7.8 months; Hazard ratio=0.69, p=0.001)  IFN-a is a historic standard of care.  Patients were enrolled between 1991-1998.  The role of debulking nephrectomy in the era of novel VEGF-targeted agents remains poorly defined. 1. Flanigan RC et al. N Eng J Med. 2001;345:1655. 2. Mickisch GH et al. Lancet. 2001;358:966

45. RCC Consortium Database  Consecutive 645 patients with median follow up 25 months.  Metastatic RCC, any histology.  Treated with anti-VEGF agents: ○ Sunitinib ○ Sorafenib ○ Bevacizumab  No prior VEGF-targeted agents.  Data collected using uniform data collection software and standardized definitions.  Excluded N=331 (s/p nephrectomy, but not cytoreductive).

46. Overall Survival on Univariable Analysis mOS: 19.8 vs. 9.4 months Hazard Ratio:0.44 (95% CI: 0.32-0.59) p<0.001

47. Cytoreductive Nephrectomy  Cytoreductive nephrectomy in era of targeted therapy may produce superior OS when adjusted for known prognostic factors Adjusted Hazard Ratio 0.68 (95% CI: 0.46, 0.99) Choueiri et al J Urol 2011

48. The impact of cytoreductive nephrectomy by risk groups 1  Favorable risk group (N=23): 22/23 underwent CN  Intermediate risk group (N=143): HR: 0.46 (95% CI: 0.27-0.78, p=0.004)  Poor risk group (N=117): HR: 0.67 (95% CI: 0.44-1.01, p=0.056) 1. Heng et al. JCO 2009; 27: 5794-9

49. Cytoreductive Nephrectomy by KPS -KPS>80: 23.9 vs. 14.5 months, p=0.003 -KPS<80: 10.1 vs. 6 months, p=0.077

50. Cytoreductive Nephrectomy  Cytoreductive Nephrectomy (CN) is independently associated with an improved overall survival in metastatic RCC patients treated with VEGF-targeted agents  Cytoreductive nephrectomy in era of targeted therapy may produce superior OS when adjusted for known prognostic factors  The benefit seems to be marginal in patients in the poor-risk group/poor KPS  Prospective clinical trials in progress Choueiri et al J Urol 2011

51. Case II: LL  65M Asian Male  Metastatic RCC to lungs (4 cm) and mediastinal lymph nodes (2 cm)  Prior nephrectomy for clear cell renal cell carcinoma 1.5 years ago  ECOG 0  Normal Ca, LDH, Hb, Platelet, Neutrophil counts

52. Case II: LL  Patient chose sunitinib  Initiated 50 mg PO 4 weeks on/ 2 weeks off Severe mucositis and anal ulcerations after 2 wks Severe fatigue, pancytopenia Stopped cycle early and gave 4 week break  Dose reduced to 37.5 4 weeks on/ 2 weeks off Mucositis, hand foot syndrome, pancytopenia Was able to finish whole cycle but very difficult

53. Case II: LL  Managed hand foot syndrome with moisturizing urea-based creams  Magic mouth wash for mucositis  Transfused red blood cells and platelets and tolerated neutropenia for now  CT scan: 80% reduction in tumor volume!

54. Case II: LL  Continued 37.5 mg 4/2 Stopped 2 weeks early because of mucositis, fatigue, hand foot syndrome despite maximal side effect management. Wanted to quit.  Started 25 mg 4/2 Tolerated 4 weeks but hand foot syndrome, fatigue, and diarrhea Managed diarrhea with BRAT diet, imodium Was able to finish cycle. Wanted to quit.

55. Case II: LL  Sunitinib now dosed 25 2/1 Really liked the dosing schedule and has been maintained on it  CT scan: lung lesions almost non- existent and largest mediastinal lymph node was 1.2 cm  Excellent response!

56. Case II: LL BEFOREAFTER

57. Lessons Learned Toxicities should be managed to maximum tolerated dose Asian patients may not tolerate the drug as well but should still continue with same dose reduction schedule – Only in very frail, elderly patients do I start dose reduced at 37.5 4/2 Individualized dosing is possible to maintain drug exposure as long as possible

58. Conclusions  mRCC Treatment Revolution VEGF inhibitors mTOR inhibitors Clinical trials are important to find new drugs  Cytoreductive nephrectomy may be helpful in certain patients  Our patients are living much longer than they used to … progress!!