1. Advances in Treatment of Renal Cell Carcinoma: Evolving Role of mTOR Inhibitors Gary R. Hudes MD Fox Chase Cancer Center Philadelphia, PA

2. Targeted Therapies for Treatment of Advanced RCC Bevacizumab +/- Interferon Sorafenib Sunitinib Temsirolimus Everolimus Others in development –Axitinib –Pazopanib

3. IL-2 Highly Effective in Subset of Patients In meta-analysis (N=255)1 –Overall response rate (ORR) = 15% –Complete response (CR) rate = 7% –Median response duration, 54 mo (3 to >131) Duration among patients with CR, >80 mo –Median OS, 16.3 mo 5- to 10-yr survival rate, 10%–20% –Grade 3/4 toxicities with high-dose IL-2 Hypotension (36%); malaise (21%); nausea/vomiting (13%); oliguria (12%); CNS orientation (10%) –Patient selection: most responders have clear cell RCC, high tumor carbonic anhydrase IX 1. Fisher RJ et al. J Sci Am. 2000;6(S1):55 2. Yang JC et al. J Clin Oncol. 2003;21(16):3127

4. Sunitinib vs IFN-  in First-Line RCC: Phase III Trial Sunitinib 50 mg PO qd for 4 wk then 2 wk off for repeated 6-wk cycles (n=375) IFN-  9 MU SC 3×/wk (n=375) Patients with untreated metastatic RCC (N=750) Stratified based on performance status, LDH level, prior nephrectomy OutcomeSunitinib IFN-  P value ORR,* %398<.000001 Median PFS,* mo 115<.000001 Median OS, mo26.421.8.051 HR (95% CI) 0.821 (0.673 – 1.001) Figlin RA et al. J Clin Oncol. 2008;26. Abstract 5024 *By independent review

5. Bevacizumab + IFN-  vs IFN-  in First-Line RCC: Phase III Trials IFN-  + bevacizumab IFN  -2a 9 MIU SC 3×/wk + bevacizumab 10 mg/kg q 2 wk IFN-  9 MIU SC 3×/wk (+ placebo on AVOREN trial) Patients with untreated metastatic RCC Outcome AVOREN 1 (N=649)CALGB 90206 2 (N=732) IFN-  + Bevacizumab (n=327) IFN-  + Placebo (n=322) P value IFN-  + Bevacizumab (n=369) IFN-  (n=363)P value ORR, %3113.000125.513.1<.0001 Median PFS, %10.25.4.0001 8.55.2<.0001 HR (95% CI) 0.63 (0.52–0.75) 0.71 (0.61–0.83) 1. Escudier B et al. Lancet. 2007;370(9605):2103 2. Rini BI et al. J Clin Oncol. 2008;26(33):5422 CALGB = Cancer And Leukemia Group B

6. Temsirolimus in Poor-Risk, Untreated Metastatic RCC: Phase III Outcome IFN-  TEM TEM + IFN-  Median OS, mo7.310.98.4 Median PFS, mo 1.93.83.7 ORR, %4.88.68.1 Clinical benefit,* %15.532.1 † 28.1 ‡ *Clinical benefit = CR + PR + SD for ≥24 wk † P<.001 vs IFN-  ‡ P=.002 vs IFN-  Temsirolimus 25 mg IV qiw (n=209) IFN-  3–18 MU SC tiw (n=207) Patients with previously untreated, poor prognosis, mRCC (N=626) Temsirolimus 15 mg IV qw + IFN-  6 MU SC tiw (n=210) Hudes G et al. N Engl J Med. 2007;356(22):2271 SD = stable disease

7. Temsirolimus in Poor-Risk, Untreated Metastatic RCC: Phase III Hudes G et al. N Engl J Med. 2007;356(22):2271 Time (mo) OS Probability of Survival Temsirolimus IFN Combination 1.00 0.75 0.50 0.25 0.00 0 510 15 20 25 30 No. at Risk IFN20712680421530 Temsirolimus209159110561930 Combination21013593501772

8. Poor-Risk Features for Eligibility in Phase III Temsirolimus Trial Minimum of 3 of 6 poor-risk features required –Lactose dehydrogenase: >1.5 x upper limit of normal –Hemoglobin: < lower limit of normal –Corrected calcium: >10 mg/dL –Time from RCC diagnosis to randomization: <1 year –Karnofsky performance status: 60-70 –Metastases in multiple organs Hudes G et al. N Engl J Med. 2007;356:2271.

9. Efficacy of Targeted Agents After First-Line Cytokines 1. Escudier B et al. N Engl J Med. 2007;356(2):125 2. Bukowski RM et al. J Clin Oncol. 2007;25(18S). Abstract 5023 3. Rosenberg JE et al. J Clin Oncol. 2007;25(18S). Abstract 5095 4. Yang JC et al. N Engl J Med. 2003;349(5):427 ParameterSorafenib 1 Sunitinib 3 Bevacizumab 4 Dose400 mg BID50 mg/day 4 wk on/2 wk off 10 mg/kg IV q 2 wk Trial designPhase IIIPhase II*Phase II No. of patients receiving targeted agent 45116839 ORR, %104510 Median PFS, mo5.58.44.8 Median OS, mo17.8 2 19.9NR *Pooled data from 2 trials NR = not reported

10. Efficacy of Other Sequential Targeted Agent Strategies 1st-Line Therapy  2nd-Line Therapy Study DesignEfficacy Outcomes Antiangiogenic therapy  Sunitinib (n = 16) or Sorafenib (n = 14) 1 Retrospective ORR 56% with sunitinib, 7% with sorafenib Median TTP 10.4 mos Sorafenib  Sunitinib (n = 51) 2 RetrospectivePR 15%; SD 51% Sunitinib  Sorafenib (n = 51) 2 RetrospectivePR 9%; SD 55% Bevacizumab  Sunitinib (N = 61) 3 ProspectivePR 23%; SD 59%; tumor shrinkage 52% VEGF-targeted therapy  Temsirolimus (N = 15) 4 RetrospectiveSD 33%; PD 20%; too early to assess 47% 1. Tamaskar I et al. J Urol. 2008;179:81. 2. Sablin MP et al. J Clin Oncol. 2007;25(18S):5038. 3. George DJ et al. J Clin Oncol. 2007;25(18S):5035. 4. Wood L et al. ASCO 2008 Genitourinary Cancers Symposium. Abstract 353. PD = progressive disease

11. Everolimus After First-Line Targeted Agents (Phase III) Everolimus 10 mg PO qd + best supportive care (n=277) Placebo + best supportive care (n=139) Patients with metastatic RCC progressing on VEGFR TKI (N=416) Stratified based on no. of prior TKIs and MSKCC risk group OutcomeEverolimusPlaceboP value ORR, %20— SD, %6732— Median PFS, mo4.91.9<.001 HR (95% CI)0.33 (0.25–0.43) Median OS,* mo14.814.4.177 HR (95% CI)0.87 (0.65–1.17) Crossover allowed upon disease progression Kay A et al. Presented by Motzer at: ASCO Genitourinary Cancers Symposium. February 26-28, 2009; Orlando, FL. Abstract 278 *112 of 139 placebo-treatment patients crossed over to everolimus

12. RCC Treatment Algorithm: 2008 RegimenSettingTherapyOptions Treatment-naive patient MSK risk: good or intermediate Sunitinib Bevacizumab + IFN-α High-dose IL-2 MSK risk: poorTemsirolimusSunitinib Treatment-refractory patient (≥ 2nd-line) Cytokine refractorySorafenibSunitinib Bevacizumab Refractory to VEGF/VEGFR inhibitors EverolimusSequential TKIs or VEGF inhibitor Bukowski RM. Presented at: 43rd ASCO Annual Meeting. June 1-5, 2007; Chicago, IL. Adapted from M Atkins mTOR = mammalian target of rapamycin; TKI = tyrosine kinase inhibitor; VEGF = vascular endothelial growth factor; VEGFR = vascular endothelial growth factor receptor

13. Case 1

14. Case 1: July 2008 61-yr-old man presents with abdominal bloating and right upper quadrant abdominal pain KPS is 90, CBC is normal, creatinine and liver functions are within normal range Ultrasound right abdomen: large right renal mass CT imaging: –~17 cm right renal mass with IVC thrombus –Multiple bilateral lung lesions –Bilateral adrenal masses –Retroperitoneal adenopathy Bone scan, Brain MRI both negative KPS = Karnofsky Performance Status

15. Patient Chart: July 20, 2008 Patient undergoes right radical nephrectomy and IVC tumor thrombectomy/IVC resection Pathology: –17 cm clear cell RCC, Furhman grade 4 –Tumor invades Gerota’s fascia, right renal vein, and IVC –Right hilar and paraaortic lymph nodes contain metastatic tumor –pT3bN1M1, stage IV

16. Patient Chart: September, 2008 Post-operative evaluation: –KPS = 90. –Hgb, LDH, Calcium normal; –Post-op CT imaging shows increasing pulmonary, adrenal, and mediastinal and retroperitoneal nodal metastases

17. What treatment do you recommend? High-dose IL-2 Sunitinib Sorafenib Bevacizumab + Interferon alpha Temsirolimus Observation until symptoms of metastatic disease develop

18. Patient Chart: September 9, 2008 Patient starts sunitinib, 50 mg daily, 4/2 schedule –AEs: Grade 1 fatigue and anorexia –Best Response: Stable disease He is followed with serial CT imaging with stable disease until 3/09 –Progression of lung, pleural, adrenal, and nodal metastases after week 30 sunitinib

19. Case 1 Sept 2008, Pre-sunitinib May 2009, week 30 sunitinib

20. What treatment do you recommend after the patient’s tumor progresses on sunitinib? High-dose IL-2 Sorafenib Bevacizumab + Interferon alpha Temsirolimus Everolimus Clinical trial of a new agent

21. Patient Chart, June 2009 Patient begins everolimus, 10 mg PO daily –AEs: diarrhea, stomatitis, fatigue all gr 1 –Triglyceride and cholesterol elevations, gr 1; Anemia gr 2 CT imaging after 8 weeks: –Stable disease, with some reduction of pulmonary and retroperitoneal node metastases –Bilateral interstial “ground glass” infiltrates –Pulmonary function tests DLCO 90% predicted Resting Room Air O 2 Sat = 94%

22. Case 1 May 2009 Pre-everolimusJuly 2009, Week 8 everolimus

23. Case 1 May 2009 Pre-everolimus July 2009, Week 8 everolimus

24. What do you recommend for a patient with asymptomatic everolimus-related pneumonitis? Continue everolimus at present dose Continue everolimus at reduced dose Continue everolimus at present dose, with addition of prednisone Discontinue everolimus and begin temsirolimus Discontinue everolimus and begin sorafenib

25. Case 2

26. Case 2: March 2006 64-yr-old woman presents with fever of unknown etiology KPS is 90, Phys Exam negative for peripheral adenopathy, organomegaly, or abdominal mass Diagnostic Evaluation: –CBC and chemistries normal –CT abdomen: 7.5 cm right renal mass and right renal hilar adenopathy –CT chest – no metastatic disease –Bone scan: normal KPS = Karnofsky Performance Status

27. Patient Chart: April 2006 Patient undergoes right radical nephrectomy and retroperitoneal tumor debulking –Stage T2N2M0 –Histology: Clear cell carcinoma with papillary features –Grade: Fuhrman 4

28. Patient Chart, Sept 2006 New symptoms of abdominal tightness and low back pain; KPS = 70 Physical findings: –Decreased breath sounds right lung base –Abdomen distended; ascites present Lab Data: –Wbc 3.9, Hgb 11.5, platelets 259,000, creat 1.2, Calcium 9.7, LDH 629 (normal to 618 IU/L) –Cytology (ascites): postive CT chest/abdomen: –Retroperitoneal and mesenteric adenopathy –Tumor on surface of right diaphragm –Ascites, right pleural effusion

29. Prognostic Group Modified MSKCC prognostic factors in patients with no prior systemic therapy:* –Karnofsky PS – 70 –Time from diagnosis to need for systemic therapy < 1yr –LDH > 1.5 x ULN –Hemoglobin < ULN –Corrected serum calcium > 10mg/dL –Multiple organ sites of metastatic disease Presence of 3 or more factors places patient in the poor prognosis group *Mekhail TM et al, J Clin Oncol, 2005;23:832-41

30. What therapy would you recommend for a patient with metastatic renal cell carcinoma and 3 or more adverse prognostic factors? High dose IL-2 Bevacizumab + Interferon Sorafenib Sunitinib Temsirolimus

31. Patient Chart: Sept 2006 Paracentesis performed to relieve distention and pain Patient begins temsirolimus 25 mg IV weekly Best Response: Stable disease x 24 weeks –KPS improved, back pain resolved –20% reduction in size of retroperitoneal lymph nodes –Decrease in ascites Adverse Effects: –Grade 1 fatigue, stomatits, and skin rash –Grade 2 hyperglycemia, grade 1 anemia

32. Safety of Targeted Agents in First-Line RCC AgentMost Common Grade 3/4 Adverse Events Sunitinib 1 Hypertension (8%); fatigue (7%); hand-foot syndrome (5%); diarrhea (5%); vomiting (4%); asthenia (4%) † Bevacizumab 2 Fatigue (37%); anorexia (17%); hypertension (10%); dyspnea (9%); nausea (7%) Temsirolimus 3 Asthenia (11%); dyspnea (9%); infection (5%); pain (5%) IFN-  (vs temsirolimus) 3 Asthenia (26%); dyspnea (6%); infection (4%); fever (4%); back pain (4%) 1. Motzer RJ et al. N Engl J Med. 2007;356:115. 2. Rini BI et al. J Clin Oncol. 2008;26:5422. 3. Hudes G et al. N Engl J Med. 2007;356:2271. † All grade 3; no grade 4 AEs observed in >1% of patients receiving sunitinib

33. Safety of Targeted Agents in First-Line RCC Agent Most Common Grade 3/4 Laboratory Abnormalities Sunitinib 1 Increased lipase (16%); neutropenia (12%); lymphopenia (12%); increased uric acid (12%); thrombocytopenia (8%); leukopenia (5%); hypophosphatemia (5%); increased amylase (5%) Bevacizumab 2 Proteinuria (15%); neutropenia (9%); anemia (4%) Temsirolimus 3 Anemia (20%); hyperglycemia (11%); hyperlipidemia (3%) IFN-  (vs temsirolimus) 3 Anemia (22%); neutropenia (7%); leukopenia (5%); increased aspartate aminotransferase (4%) 1. Motzer RJ et al. N Engl J Med. 2007;356:115. 2. Rini BI et al. J Clin Oncol. 2008;26:5422. 3. Hudes G et al. N Engl J Med. 2007;356:2271. † All grade 3; no grade 4 AEs observed in >1% of patients receiving sunitinib

34. Planned Phase II Study of Bevacizumab, Sorafenib, and Temsirolimus in mRCC (ECOG 2804 “BeST” Trial) 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 Bevacizumab IV over 30 – 90 min days 1–15 + Temsirolimus IV over 30 min days 1, 8, 15, 22 Bevacizumab IV over 30–90 min days 1 – 15 Primary end point: PFS *Expected enrollment (N=360*) + Sorafenib bid PO, days 1–28 Bevacizumab IV over 30–90 min days 1 – 15 + Sorafenib PO bid, days 1–28 Temsirolimus IV over 30 min days 1, 8, 15, 22 RANDOMIZATIONRANDOMIZATION Available at: http://www.clinicaltrial.gov/ct2/show/NCT00378703?term=bevacizumab+and+sorafenib+and+temsirolimus&rank=1. Accessed June 12, 2009

35. Advances in Treatment of Renal Cell Carcinoma: Evolving Role of mTOR Inhibitors Gary R. Hudes MD Fox Chase Cancer Center Philadelphia, PA