The document discusses renal cancer (kidney cancer) and advances in its treatment. It describes several targeted drugs that have improved outcomes for metastatic renal cell carcinoma (mRCC) compared to previous immunotherapy options. Drugs include tyrosine kinase inhibitors like sunitinib, sorafenib, pazopanib and axitinib as well as the mTOR inhibitor temsirolimus. Clinical trials have established these as standard first and second line options depending on a patient's risk level and prior treatment history. Ongoing research focuses on optimizing treatment sequencing and identifying biomarkers to guide more personalized therapy selection.

1. RENAL CANCER: state of the art Giovanni Luca Ceresoli Thoracic and GU Oncology Unit Humanitas Gavazzeni Clinic – Bergamo, Italy 27/10/2011 - 29/10/2011, Amman, Jordan 3rd EASO Masterclass in Clinical Oncology

2. Survival by the MSKCC Risk Factor Model (n=463) Motzer, JCO 2002 Time From Start of IFN -  (years) Proportion Surviving 0 2 16 14 13 11 9 5 4 3 6 15 12 10 8 7 6 MSKCC Criteria : Favorable : 0 risk factors present Intermediate : 1 or 2 risk factors Poor : 3 or more risk factors 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0

3. Molecular Pathways in RCC

4. Progress in the Treatment of RCC IFN- α and high-dose IL-2 1980s 1995 1999 2004 2005/2006 2007 2009/2011 High-dose IL-2 IFN- α shows improved survival vs. hormonal therapy Sorafenib Sunitinib Temsirolimus, Bevacizumab + IFN Everolimus “ orphan” disease “ overcrowded”disease 8 RCTs; 7 drugs Pazopanib, Axitinib

5. mRCC: available drugs ANTI-VEGF LIGANDS TKIs mTOR INHIBITORS Bevacizumab Sorafenib Sunitinib Pazopanib (Axitinib) Temsirolimus Everolimus

6. Licensed Targeted Agents for mRCC * treatment-naive pts; ** pretreated pts 10.9 vs 7.3 P=0.0069 5.5 vs 3.1 P<0.0001 8.6 vs 4.8 NS 626 Temsirolimus vs IFN- a 18.3 vs 17.4 P=0.069 8.4 vs 4.9 P<0.0001 26 vs 13 P<0.0001 732 Bevacizumab + IFN- a vs IFN- a (CALGB) 14.8 vs 14.4 P=0.177 4.9 vs 1.9 P<0.001 1 vs 0 – 410 Everolimus vs Placebo Agent n ORR (%) Median PFS (months) Median OS (months) Sunitinib vs IFN- a 750 31 vs 6 P<0.000001 11 vs 5 P<0.001 26.4 vs 21.8 P=0.0510 Bevacizumab + IFN- a vs IFN- a (AVOREN) 649 31 vs 13 P=0.0001 10.4 vs 5.5 P<0.0001 23.3 vs 21.3 P=0.1291 Sorafenib vs Placebo 903 10 vs 2 P<0.001 5.5 vs 2.8 P<0.000001 17.8 vs 14.3 P=0.0287 Pazopanib vs Placebo 435 30 vs 3 P<0.001 11.1 vs 2.8* 7.4 vs 4.2** P<0.0001 22.9 vs 20.5 P=0.224

7. Ljungberg B et al. Eur Urol 2010; 58:398-406 Treatment Risk or prior treatment Recommended agent First line Low- or intermediate-risk Sunitinib Bevacizumab plus IFN-a Pazopanib High-risk Temsirolimus Second line Prior cytokine therapy Sorafenib Pazopanib Prior VEGFR therapy Everolimus Prior mTOR inhibitor therapy Clinical trials

8. FIRST-LINE TREATMENT (Low or intermediate risk) RR: 30-31%, mPFS 10.4-11 mos, mOS 22.9-26.4 mos * AVOREN study; ** Results in treatment-naive pts only good: 39% intermediate: 55% poor: 3% good: 29% intermediate: 56% poor: 8% good: 38% intermediate: 56% poor: 6% Prognostic groups Agent n ORR (%) Median PFS (months) Median OS (months) Sunitinib vs IFN- a 750 31 vs 6 P<0.000001 11 vs 5 P<0.001 26.4 vs 21.8 P=0.0510 Bevacizumab + IFN- a vs IFN- a* 649 31 vs 13 P=0.0001 10.4 vs 5.5 P<0.0001 23.3 vs 21.3 P=0.1291 Pazopanib vs Placebo 233 (435) 30 vs 3 P<0.001 11.1 vs 2.8** P<0.0001 22.9 vs 20.5 P=0.224

9. FIRST-LINE TREATMENT (Poor risk) Minimum of 3 poor-risk features required : LDH >1.5 X upper limit of normal Hemoglobin <lower limit of normal Corrected calcium >10 mg/dL Time from diagnosis to first treatment <1 yr Karnofsky performance status 60-70 Multiple organ site of metastasis MODIFIED POOR RISK CRITERIA intermediate: 31% poor: 69% Prognostic groups 10.9 vs 7.3 P=0.0069 5.5 vs 3.1 P<0.0001 8.6 vs 4.8 NS 626 Temsirolimus vs IFN- a Agent n ORR (%) Median PFS (months) Median OS (months)

10. SECOND-LINE TREATMENT EAU Guidelines 2010 * Everolimus was as effective after 1 TKI, as it was after both; ** in CK pretreated pts 14.8 vs 14.4 P=0.177 4.9 vs 1.9 P<0.001 2 vs 0 – 410 Everolimus vs Placebo Agent n ORR (%) Median PFS (mos) Median OS (mos) Sorafenib vs Placebo 903 10 vs 2 P<0.001 5.5 vs 2.8 P<0.000001 17.8 vs 14.3 P=0.0287 Pazopanib vs Placebo 202 (435) 30 vs 3 P<0.001 7.4 vs 4.2** P<0.0001 22.9 vs 20.5 P=0.224 Treatment Risk or prior treatment Recommended agent Second line Prior cytokine therapy Sorafenib Pazopanib Prior VEGFR therapy Everolimus Prior mTOR inhibitor therapy Clinical trials

11. Phase III study of axitinib vs sorafenib as second-line therapy for mRCC (AXIS trial) Stratification Prior regimen ECOG PS (0 vs 1) Sorafenib 400 mg BID Eligibility criteria Histologically confirmed mRCC with clear cell component Failure of prior first-line regimen containing ≥1 of: Sunitinib Bevacizumab + IFN- α Temsirolimus Cytokine(s ) N=723 Primary endpoint: PFS Secondary endpoints: OS, ORR, duration of response, safety, QoL Rini et al. ASCO 2011 RANDOM I S A T I ON Axitinib 5 mg BID Independent Review Committee

12. AXIS: Progression-Free Survival Time (months) Progression-Free Survival (probability) 0 2 4 6 8 0.0 0.5 0.9 1.0 10 12 14 16 18 20 Axitinib Sorafenib 6.7 4.7 6.3-8.6 4.6-5.6 P <0.0001 (log-rank) Stratified HR 0.665 (95% CI 0.544-0.812) mPFS, mo 95% CI 0.8 0.7 0.6 0.4 0.3 0.2 0.1 Rini et al. ASCO 2011

13. AXIS trial: Adverse Events Rini et al. ASCO 2011 Sorafenib (%) Axitinib (%) 32 32 51 12 8 17 22 32 29 53 All Grade 4 13 27 15 19 24 32 39 40 55 All Grade 0 0 Alopecia 4 <1 Rash 16 5 HFS <1 1 Stomatitis 0 <1 Hypothyroidism 1 3 Vomiting 1 3 Nausea 5 11 Fatigue 11 16 Hypertension 7 11 Diarrhea Grade 3/4 Grade 3/4 Event

14. Phase II results: RR27%, mPFS 11.8 mos; in clear cell mRCC who had undergone nephrectomy: RR 32%, mPFS 14.8 mos (Bhargava et al., ASCO 2010). Good toxicity profile.

15. Molecular targets of anti-angiogenic agents VEGFR-1 VEGFR-2 VEGFR-3 PDGFR-ß PDGFR-α c-Kit Flt-3 Anti-angiogenesis Bevacizumab Different activities against multiple kinase targets may result in differing efficacy and toxicity profiles VEGF-A VEGF-B VEGF-C VEGF-D VEGF-E Pazopanib 1 Sorafenib 2 Raf Sunitinib 3

16. Pazopanib 32 Sorafenib 25 Sunitinib 54 1. Kumar et al . Br J Cancer 2009; doi: 10.1038/sj.bjc.6605366. Figure adapted from Karaman et al. Nat Biotechnol 2008;26:127–32. Kinases inhibited with IC 50 <1 μ M Targeted therapies ??? Red circles: targeted kinases; larger cycles indicate higher affinity binding.

17. At 8.0 nM, pazopanib inhibits VEGFR-2 and c-Kit At 51.0 nM, sunitinib inhibits VEGFR-2 , VEGFR-3, PDGFR-α, PDGFR-β, c-Kit and Flt-3 1. Kumar et al . Br J Cancer 2009; doi: 10.1038/sj.bjc.6605366; 2. Karaman et al. Nat Biotechnol 2008;26:127–32. Different affinity for different drugs and kinases Flt-3 and c-Kit are expressed on haematopoietic stem cells and precursor cells. They are critical regulators in the proliferation and differentiation of haematopoietic progenitor cells.

18. Grade 3/4 (%) Adverse Events NR* *NR= Not reported in prescribing information or source reference NR* 1 2 3

19. Lab Abnormalities Pazopanib (N=586) Sunitinib (N=375) Sorafenib (N=451) All Grades Grade 3/4 All Grades Grade 3/4 All Grades Grade 3/4 ALT increased, % 52 10 46 3 NA NA AST increased, % 54 7 52 2 NA NA Tot.bilirubin increased, % 35 2 19 1 NA NA Anemia, % 24 2 71 3 44 2 Neutropenia, % 31 2 72 12 18 5 Thrombocytopenia, % 30 2 65 8 12 1

20. Phase III non-inferiority trial of pazopanib vs sunitinib in first-line metastatic RCC (COMPARZ) www.clinicaltrials.gov (NCT00720941) Pazopanib 800 mg/day Sunitinib 50 mg/day (Schedule 4/2) Primary endpoint: PFS Secondary endpoints: OS, ORR, time to response, duration of response, safety, QoL N=876 Eligibility criteria: Locally advanced or mRCC with clear-cell histology No prior systemic therapy for advanced or mRCC Measurable disease by RECIST Karnofsky PS ≥70% RANDOM I S E NON-INFERIORITY TRIAL

21. Treatment choice in RCC: unmet needs We do not cure the patient: CR with current 1-st line treatment < 1%. Untargeted use of targeted therapy (arbitrary or registration criteria rather than scientific rationale).

22. Advanced RCC: factors influencing treatment DISEASE-RELATED FACTORS Prognostic scores (MSKCC, Heng, French) Tumor burden Number and sites of metastases PATIENT-RELATED FACTORS Age Performance status Comorbidity HISTOLOGIC SUBTYPE Clear cell carcinoma Non-clear cell carcinoma TREATMENT STATUS Treatment na ïve Treatment refractory: cytokines, TKIs, mTOR inhibitors BIOLOGICAL FACTORS Tumor-related Patient-related (genetic/pharmacogenomic factors)

23. RCC: non-clear cell histology RCC is a collection of different types of tumors, each with a specific genetic, histological and clinical pattern. Clear cell (75-85%) Papillary (Type I + II) (12-14%) Chromophobic (4-6%) Oncocytic (2-4%) Collecting duct (1%) VHL C-met FH Proximal nephron Distal nephron No standard treatment, consider TKIs

24. Survival by the MSKCC Risk Factor Model (n=463) Motzer, JCO 2002 Time From Start of IFN -  (years) Proportion Surviving 0 2 16 14 13 11 9 5 4 3 6 15 12 10 8 7 6 MSKCC Criteria : Favorable : 0 risk factors present Intermediate : 1 or 2 risk factors Poor : 3 or more risk factors 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0

25. Prognostic Factors (1 st line): Heng Model Adverse prognostic factors Overall survival probability according to risk group Heng, JCO 2009 Overall survival probability N = 645 pts >ULN Platelets >ULN Neutrophils >ULN Calcium <LLN Hemoglobin < 1 year Time from dx < 80 KPS 9.4 months Poor 3 to 6 28.5 months Intermediate 1-2 37 months Favorable 0

26. Heng et al., ASCO 2010 Prognostic Factors (2 nd line): Heng Model

27. Clinical practice PS 0 PS 1 PS > 1 Good risk Intermediate risk Poor risk “ 90% of poor risk patients are PS 2-3” (B. Escudier, Warszawa 2011)

28. When Should we Treat? A Three Stage Treatment Scheme Rini BJ Proc ASCO 2008, Kirchner H Expert Rev Anticancer Ther, 2010

29. Any role for observation alone in mRCC ? SYMPTOMATIC PATIENTS should be treated. In ASYMPTOMATIC PATIENTS several factors should be considered: RATE OF PROGRESSION & FUHRMAN GRADE; NUMBER AND SITES OF METASTASES; PATIENT STATUS: AGE, PS, COMORBIDITIES, PATIENT WISHES. Information on treatment: chronic, mostly no cure, change in quality of life.

30. Different scenarios for second-line therapy Primary refractory disease Progression after initial control (long PFS) Progression after initial control (short PFS) Intolerance Progression on reduced doses due to toxicity Indolent vs aggressive progression Site-specific progression (brain, bone, liver) These clinical scenarios are likely driven by different biology Guidelines seem very simple, but…

31. Why thinking to sequences? Irrespective of the agents used in 1 st line, 75-80% of advanced RCC patients will obtain a clinically significant benefit: 84% with Sunitinib 1 77% with Bevacizumab + IFN 2 68% with Pazopanib (including 1 st and 2 nd line patients) 3 . Furthermore, with few exceptions, combinations of molecularly targeted agents proved to be too toxic (and too costly...). 1. Motzer et al. NEJM 2007; 2. Escudier et al. Lancet 2007; Sternberg et al. J Clin Oncol 2010

32. SWITCH: Phase III sequential study of sorafenib and sunitinib Sorafenib 400 mg BID Sunitinib 50 mg/day (Schedule 4/2) Discontinuation (due to progressive disease/toxicity) Study being conducted in Germany RANDOM I SA T I ON Eligibility mRCC with all histologies Stratification ECOG PS 0 or 1 No prior systemic therapy for advanced or mRCC Primary endpoints: overall PFS Secondary endpoints: total time to progression, OS, disease control rate and cardiotoxicity N=540 www.clinicaltrials.gov (NCT00732914) Sunitinib 50 mg/day (Schedule 4/2) Sorafenib 400 mg BID

33. RECORD-3: Phase II sequential study of sunitinib and everolimus Everolimus 10 mg/day Sunitinib 50 mg/day (Schedule 4/2) Eligibility Patients with advanced RCC Stratification Karnofsky performance status ≥70% No prior systemic therapy for advanced or mRCC Discontinuation (due to progressive disease/toxicity) RANDOM I SA T I ON Primary endpoints: first PFS Secondary endpoints: second PFS, ORR, duration of response, patient-reported outcomes, OS www.clinicaltrials.gov (NCT00903175) Everolimus 10 mg/day Sunitinib 50 mg/day (Schedule 4/2) N=390

34. TKI–TKI–mTOR or TKI–mTOR–TKI? We do know that Everolimus is as effective after 1 TKI, as it is after both TKI/VEGF inhibitor 2 mTOR inhibitor TKI/VEGF inhibitor 1 mTOR inhibitor ? TKI/VEGF inhibitor

35. Porta C, et al. EJMCO 2010 Sequential treatment PRIMARY REFRACTORY PATIENTS (20%)

36. RCC and the elderly RCC is primarily a disease of the elderly. The median age of first diagnosis of RCC is approximately 65 years , and over 25% of newly diagnosed patients are older than 75 years 2 1. Eisen T. J Natl Cancer Inst. 2008; 100:1454-1463. 2. National Cancer Institute SEER Database. Cancer: Renal and kidney pelvis. 2009 0 Rate per 100,000 20 50 40 <1 Age at Diagnosis (Years) 70 60 30 10 1-4 5-9 10-14 15-19 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 65-69 70-74 75-79 80-84 85+ 60-64

37. Clinical benefit with sorafenib in elderly patients Eisen T, et al. J Natl Cancer Inst. 2008 Patients <70 (n=381) Patients ≥70 (n=70) Disease control rate (%) 84 84 Median PFS (months) 5.6 6.1 EU-ARCCS 1 NA-ARCCS 2 All Patients (N=1150) Patients ≥ 70 (n=265) Patients < 70 (N=1891) Patients ≥ 70 (n=537) Disease control rate* (%) 85 86 84 83

38. Elderly pts in TARGET trial Two-fold increase of PFS with sorafenib vs placebo ≥ 70 = 6.1 months HR = 0.43; 95% CI = 0.26–0.69 <70 = 5.6 months HR = 0.55; 95% CI = 0.47–0.66 80 0 1 Survival distribution function Placebo <70 years (n=407) 0.75 0.50 0.25 Placebo ≥70 years (n=45) 70 60 50 40 30 20 10 0 Sorafenib ≥70 years (n=70) Sorafenib <70 years (n=381) Eisen T, et al. J Natl Cancer Inst. 2008

39. Advanced RCC: factors influencing treatment BIOLOGICAL FACTORS Tumor-related Patient-related (genetic/pharmacogenomic factors)

40. VEGF baseline levels are PROGNOSTIC, NOT PREDICTIVE Bukowski, ASCO 2007 Lara, ASCO 2010

41. Correlation of sVEGFR-2 with PFS and tumor response Hutson et al . J Clin Oncol 2008;26(15S):Abstract 5046 and oral presentation. PAZOPANIB

42. Multiple markers: PAZOPANIB Multiplatform analysis of plasma Cytokines and Angiogenic Factors (CAFs) Tran et al., ASCO 2010

43. Association of IL8 Polymorphism with OS ( P = 0.003) PAZOPANIB Xu et al., JCO 2011 Pts with the wild type AA genotype had twice as long mOS than pts who had the variant TT genotype.

44. Association of FGFR2 Polymorphism with OS ( P = 0.01) PAZOPANIB Xu et al., JCO 2011 Patients with the wild type CC genotype had significantly prolonged median OS compared with patients with the variant TT genotype.

45. Development of Resistance; Angiogenic Escape VEGF No angiogenesis Hypoxia Cancer cells VEGF inhibitors Early Phase: Response to Anti-VEGF Treatment Endothelial Cell VEGF PIGF Second wave of angiogenesis Cancer cells Endothelial Cell FGF, IL8 and other factors Late Phase: Escape to Anti-VEGF Treatment HIF HIF VEGF inhibitors Casanovas et al. Cancer Cell, 2005

46. Biological factors Limitations Retrospective exploratory analyses Not corrected for multivariate analysis Next steps Confirm findings in independent datasets Address whether they are predictive or prognostic markers

47. Conclusions In the last 5 years, anti-angiogenic treatments (TKIs) have change the therapeutic scenario of mRCC, with a clear improvement in patient outcome . As multiple treatment options are now available for mRCC patients, an understanding of how to utilize this group of agents is required. The use of various clinical features allows a rational approach to therapy selection: histologic subtype, prior treatment status, prognostic group, co-mordid diseases (age). Further refinement of therapy selection is required and will require further biologic information as well as comparative randomized trials .

49. Role of Cytoreductive Nephrectomy (CN) Demonstrated in the era of citokines Suspected, but not demonstrated in the era of TKIs Ongoing randomized trials: CARMENA, SURTIME In clinical practice CN if: PS 0-1; Primary tumor majority of tumor bulk; Symptomatic primary tumor.

50. Cytoreductive Nephrectomy: Phase III CARMENA Trial Untreated patients with mRCC and primary in place (N = 576) Nephrectomy followed by sunitinib Sunitinib alone Sponsor: French NCI Primary endpoint: DFS

51. Cytoreductive Nephrectomy: Phase III SURTIME Trial Untreated patients with mRCC and primary in place (N = 458) Nephrectomy Sunitinib Sponsor: EORTC Sunitinib Nephrectomy Primary endpoint: DFS

52. AMG 386 + Sorafenib in mRCC RCC a highly angiogenic disease Targeting both VEGF and non-VEGF angiogenic pathways may enhance antitumor effects Angiopoietins (Ang1, Ang2) involved in vascular remodeling via Tie2 interactions AMG 386 : first-in-class recombinant peptide-Fc fusion protein (ie, peptibody) Selectively neutralizes Ang1 and Ang2 interactions with Tie2 Rini BI, et al. ASCO GU 2011. Abstract 309.

53. Phase II Trial of AMG 386 + Sorafenib in mRCC Primary endpoint: PFS Secondary endpoints: ORR, DOR, change in tumor burden, safety, PK Treatment-naïve patients with measureable clear-cell mRCC of MSKCC low/intermediate risk (N = 152) AMG 386 10 mg/kg IV QW + Sorafenib 400 mg PO BID (n = 50) AMG 386 3 mg/kg QW + Sorafenib 400 mg PO BID (n = 51) Rini BI, et al. ASCO GU 2011. Abstract 309. Progression, unacceptable toxicity, or death Placebo + Sorafenib 400 mg PO BID (n = 51)

54. AMG 386 Plus Sorafenib: Efficacy No difference in median PFS between arms AMG 386 10 mg/kg: 8.5 mos AMG 386 3 mg/kg: 8.5 mos Placebo: 9.0 mos ORR higher in patients receiving AMG 386 vs placebo (37% to 38% vs 25%) Rini BI, et al. ASCO GU 2011. Placebo + sorafenib (n = 51) AMG 386 3 mg/kg + sorafenib (n = 51) AMG 386 10 mg/kg + sorafenib (n = 50) 100 80 60 40 20 0 Progression-Free Survival (%) PFS Per Investigator assessment 120 0 10 20 30 40 50 70 80 90 100 110 60 Wks Pts at Risk, n 51 51 50 43 43 47 36 31 40 28 30 28 17 19 20 16 17 14 14 14 13 12 11 9 6 6 6 5 5 4 4 3 3 1 1 2 Best Response, % AMG 386 10 mg/kg (n = 51) AMG 386 3 mg/kg (n = 50) Placebo (n = 51) CR 0 2 2 PR 38 35 24 SD 48 45 59 PD 8 10 10 Unevaluable 6 8 4

55. OR 5% OR 9% 68% 39% Response rate PFS mPFS 5.7 mos mPFS 5.6 mos Escudier B, et al. J Clin Oncol 2009 First-line Sorafenib vs IFN: Results

56. Placebo (n=451) Sorafenib (n=452) 20% 74% Maximum % reduction in tumor measurement Baseline Week 6 RR 10% SD 74% Escudier et al., NEJM 2007 Tumor burden: ORR vs tumor shrinkage rate