1. LE TERAPIE A BERSAGLIO MOLECOLARE NEOPLASIE UROLOGICHE G. Cartenì Direttore U.O.S.C. di Oncologia Medica Ospedale A. Cardarelli - Napoli I PROGRESSI DELL’ONCOLOGIA MEDICA:

2. 1. Cho D, et al. Clin Cancer Res 2007; 13(2 Pt 2): 758s-763s; 2. Sternberg CN, et al. Eur Urol 2009; supplements 8: 758- 761; 3. Bracarda S, et al. Eur Urol 2009; supplements 8: 815-819; 4. Gan HK, et al. Curr Oncol 2009; 16: S45-S51; 5. Oudard S, et al. Cancer Treat Rev 2012; 38(8): 981-987. Targeted therapies Few response rates and high toxicity (1-5) RCC is generally resistant (2) Largely ineffective ( 1-4 ) standard chemotherapy Radio and Hormone therapy Immunotherapy with cytokines Check point inhibitors

3. Cabozantinib Between 2005 and 2015 the clinical guidelines evolved to keep up with clinical developments… 1992-2005 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 Sunitinib High-dose IL-2 Sorafenib Temsirolimus Bevacizumab + IFN-α Everolimus IFN-α Year of EMA approval 1992-2005 2005 2006 2007 2008 2009 2010 2011 2012 20132015 2016 Sunitinib High-dose IL-2 Sorafenib Temsirolimus Bevacizumab + IFN-α Everolimus IFN-α Level and grade of recommendation for first-line pazopanib and sunitinib are the same in 2015 RCC guidelines from EAU, 1 ESMO 2 and NCCN 3 Pazopanib Axitinib 1.Ljungberg B, et al. EAU RCC Guidelines, 2015. 2.Escudier B, et al. Ann Oncol 2014;25 Suppl 3:iii49–56. 3.NCCN. RCC guidelines. 201.5 EAU Guidelines 2015 1 Nivolumab

8. AIOM 2015 Linee guida AIOM 2015 TUMORI DEL RENE

9. Overall survival improvement with TKIs introduction Heng et al. Lancet Oncol. 2013 February ; 14(2): 141–148 Motzer et al. J Clin Oncol. 2000 may;18(9):1928-35. 2000 mOS 10 months 2000 mOS 10 months 2009 mOS 22 months 2009 mOS 22 months

10. COMPARZ: OS (updated analysis) 1 1.Motzer RJ, et al. N Engl J Med 2014;370:1769–70. Number at risk Pazopanib Sunitinib 557 521 462 409 360 320 284 243 221 197 169 99 51 21 4 1 0 553 501 435 377 339 304 281 237 211 180 153 100 45 20 4 1 0 Median OS Pazopanib (n=557): 28.3 months (95% CI: 26.0–35.5) Sunitinib (n=553): 29.1 months (95% CI: 25.4–33.1) HR: 0.915 (95% CI: 0.786–1.065) Months since randomisation Probability of OS 4 816122420 0 4028 484460 36325652 64 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0

11. Overall Survival in the ITT Population MSKCC Favorable Risk Group Median OS Pazopanib (n=151): 42.5 months (95% CI: 37.9–) Sunitinib (n=152): 43.6 months (95% CI: 37.1–47.4) HR: 0.876 (95% CI: 0.634–1.210) Stratified log-rank P=0.419 1.Motzer RJ, et al. N Engl J Med 2014;370:1769–70.

12. Overall Survival in the ITT Population MSKCC Intermediate Risk Group Median OS Pazopanib (n=322): 26.9 months (95% CI: 23.1–35.6) Sunitinib (n=328): 26.1 months (95% CI: 20.7–31.6) HR: 0.898 (95% CI: 0.739–1.091) Stratified log-rank P=0.273 12 1.Motzer RJ, et al. N Engl J Med 2014;370:1769–70.

13. Overall Survival in the ITT Population MSKCC Poor Risk Group Median OS Pazopanib (n=67): 9.9 months (95% CI: 7.3–12.3) Sunitinib (n=52): 7.7 months (95% CI: 5.4–11.9) HR: 0.849 (95% CI: 0.563–1.281) Stratified log-rank P=0.419 1.Motzer RJ, et al. N Engl J Med 2014;370:1769–70.

14. COMPARZ: AEs affecting ≥30% of patients in either group 1 Pazopanib (n=554), %Sunitinib (n=548), % All gradesGrade 3/4All gradesGrade 3/4 Any event * >9959/15>9957/17 Diarrhoea639/0577/<1 Fatigue5510/<16317/<1 Hypertension4615/<14115/<1 Nausea452/0462/0 Decreased appetite371/0 3/0 ALT increased3110/2182/<1 Hair colour changes300/010<1/0 Hand−foot syndrome296/05011/<1 Taste alteration26<1/0360/0 Thrombocytopenia102/<13412/4 * 2% of patients on pazopanib and 3% of patients on sunitinib had grade 5 AEs Risk greater for sunitinib and 95% CI for relative risk does not cross 1 Risk greater for pazopanib and 95% CI for relative risk does not cross 1 1.Motzer et al. New Engl J Med 2013;369:722–31 (supplementary material).

15. COMPARZ: relative risk of AEs favouring pazopanib 1 0.1 Relative risk (95% CI) Favours pazopanib 1 10 Thrombocytopenia Anaemia Neutropenia Mucositis Serum TSH increased Epistaxis Hypothyroidism Leucopenia Pyrexia Dyspepsia Hand–foot syndrome Peripheral oedema Serum creatinine increased LDH increased Taste alteration Constipation Pain in extremity Rash Fatigue 1.Motzer et al. ESMO 2012;Abstract LBA8_PR (oral presentation). Favours sunitinib Serum AST increased Upper abdominal pain Alopecia Serum ALT increased Weight decreased Hair colour change

16. DrugControlStudy DesignPFS, MosOS, Mos VEGF Inhibitors Sorafenib [1,2] Placebo Pts previously treated with IL-2 or IFN-α 5.5 vs 2.8 (HR: 0.44; P <.000001) 17.8 vs 15.2 (HR: 0.88; P =.146) 17.8 vs 14.3 ‡ (HR: 0.78; P =.029) Axitinib [3,4] Sorafenib Pts previously treated with sunitinib, bevacizumab with IFN- α, temsirolimus, or cytokines 8.3 vs 5.7 † (HR: 0.66; P <.0001) 20.1 vs 19.2 (HR: 0.97; P =.374) mTORi Everolimus [5] Placebo Pts previously treated with VEGFR TKI 4.9 vs 1.9* (HR: 0.33; P <.001)* 5.5 vs 1.9 † (HR: 0.32; P <.001) † 14.8 vs 14.4 (HR: 0.87; P =.162) Temsirolimus [6] Sorafenib Pts previously treated with sunitinib 4.3 vs 3.9* (HR: 0.87; P =.19) 12.3 vs 16.6 † (HR: 1.31; P =.01) 1. Escudier B, et al. N Engl J Med. 2007;356:125-134. 2. Escudier B, et al. J Clin Oncol. 2009;27:3312-3318. 3. Rini BI, et al. Lancet. 2011;378:1931-1939. 4. Motzer RJ, et al. Lancet Oncol. 2013;14:552-562. 5. Motzer R, et al. Cancer. 2010;116:4256-4265. 6. Hutson TE, et al. J Clin Oncol. 2014;32:760-767. Pivotal Phase III Data in Second Line *Independent review. † Investigator. ‡ Post-crossover placebo-censored OS data.

17. Options for Dose Adjustments and Schedule Changes for VEGF Inhibitors  Dose adjustment: 37.5 mg/day  Alternative schedule: 2 wks on/1 wk off  Phase II studies on alternate schedule, dose escalation ongoing  Dose adjustment: 400 mg/day  Additional dose decrease or increase in 200 mg steps  Dose adjustment: 3 mg BID  Additional dose decrease to 2 mg BID, if necessary  Conversely, dose can be increased to 7 mg in pts without AEs or HTN SunitinibPazopanib Axitinib

18. Emerging Options in mRCC

19. Phase III METEOR Trial: Cabozantinib vs Everolimus in RCC After PD on VEGFR TKI  Primary endpoint: PFS  Secondary endpoints: OS, ORR Choueiri T, et al. N Engl J Med. 2015;[Epub ahead of print]. Patients with clear-cell RCC with measurable disease and progression within 6 mos of treatment with a VEGFR TKI, Karnofsky PS > 70% (N = 658) *Dose reductions as needed for AEs: cabozantinib 40 mg then 20 mg, everolimus 5 mg then 2.5 mg Treat until clinical benefit no longer evident or unacceptab le toxicity Cabozantinib 60 mg/day* (n = 324) Everolimus 10 mg/day* (n = 324) Tki anti cMET

20. Phase III METEOR: PFS of Cabozantinib vs Everolimus After VEGFR TKI Choueiri T, et al. N Engl J Med. 2015;[Epub ahead of print]. 100 80 60 40 20 0 0369121518 Mos PFS (%) Cabozantinib Everolimus Cabozantinib Everolimus 187 188 7.4 (5.6-9.1) 3.8 (3.7-5.4) 121 126 Events, n Median PFS, Mos (95% CI) Pts, n HR: 0.58 (95% CI: 0.45-0.75); P <.001

21. Phase III METEOR: Safety of Cabozantinib vs Everolimus After PD on VEGFR TKI Cabozantinib  Most common grade 3/4 AEs –Hypertension (15%) –Diarrhea (11%) –Fatigue (9%)  Most common leading to d/c –Diarrhea (16%) –Hand–foot syndrome (11%) –Fatigue (10%) Everolimus  Most common grade 3/4 AEs –Anemia (16%) –Fatigue (7%) –Hyperglycemia (5%)  Most common leading to d/c –Pneumonitis (4%) –Fatigue (3%) –Stomatitis (3%) Choueiri T, et al. N Engl J Med. 2015;[Epub ahead of print].  AEs as expected and managed with dose reductions: occurred in 60% with cabozantinib, 25% with everolimus

29. Novel Immunotherapeutic Approaches in RCC CTLA-4, cytotoxic T-lymphocyte antigen-4; HCV, hepatitis C virus; IgG, immunoglobulin G; mAb, monoclonal antibody; MOA, mechanism of action; PD-1, programmed death-1; PD-L1, PD ligand-1; PD-L2, PD ligand-2; RCC, renal cell carcinoma. 1.YERVOY [package insert]. Priceton, NJ: Bristol-Myers Squibb; 2013. 2.Hodi SF et al. N Engl J Med. 2010;363(8):711-723. 3.ESMO 2014: Immune checkpoint inhibitors provide antitumor activity across malignant diseases. September 27, 2014. 4.Yao S et al. Nat Rev Drug Discov. 2013;12(2):130-146. 5.BMS. Positive phase 3 data for opdivo (nivolumab) in advanced melanoma patients previously treated with yervoy (ipilimumab) presented at the ESMO 2014 congress; first phase 3 results presented for a PD-1 immune checkpoint inhibitor. September 29, 2014. 6.Brahmer JR et al. J Clin Oncol. 2010;28(19):3167-3175. 7.KEYTRUDA [package insert]. Whitehouse Station, NJ: Merck & Co, Inc; 2014. 8.Hamid O et al. N Engl J Med. 2013;369(2):134-144. 9.Amplimmune. Product development. www.amplimmune.com/proddev.html. Accessed December 17, 2014. 10.Cho D et al. Oral presentation at ASCO 2013. 4505. Immunotherapeutic Agents MOA: Checkpoint inhibitors Ipilimumab (Yervoy ®, BMS) [1] Fully human IgG1 MAb that inhibits CTLA-4 to promote antitumor immunity [2] Tremelimumab (Pfizer) [3] Fully human IgG2 MAb targeting CTLA-4 for potential treatment of cancer [4] Nivolumab (Opdivo TM, BMS) [5] Fully human IgG4 PD-1 receptor blocking antibody that selectively prevents interaction with PD- L1 and PD-L2, inhibiting downregulation of antitumor T cell function [6] Pembrolizumab (Keytruda ®, Merck) [7] Humanized IgG4κ monoclonal antibody that inhibits the PD-1 receptor [8] Pidilizumab (CureTech) [3] PD-1-specific humanized IgG1 antibody targeting the PD-1 pathway for potential treatment in advanced solid tumors and HCV [4] AMP-514 (Amplimmune) [9] An anti-PD-1 antibody with unique properties for the treatment of Cancer [9] MPDL3280A (Genentech) [3] An IgG1 engineered anti-PD-L1 monoclonal antibody that targets the PD-L1 ligand to disrupt the PD-1 pathway [10] Durvalumab (MEDI4736) (AstraZeneca) [3] Engineered human IgG1 PD-L1 antibody that specifically blocks the interaction between PD-L1 and PD-1 for potential treatment of solid tumors [4] AMP-224 (Amplimmune) [9] Human IgG1 Fc-fusion protein that blocks the interaction between PD-1 and PD-L2 for potential treatment of multiple cancers [4]

30. CheckMate 025 Phase III Study: Nivolumab vs Everolimus in Advanced RCC  Primary endpoint: OS  Secondary endpoints: ORR, PFS, OS by PD-L1 status, safety Pts with advanced clear-cell RCC and 1-2 prior regimens with antiangiogenic treatment (N = 658) Motzer RJ, et al. N Engl J Med. 2015;[Epub ahead of print]. Treat until clinical benefit no longer evident or unacceptabl e toxicity Nivolumab 3 mg/kg q2w (n = 329) Everolimus 10 mg PO QD (n = 329)

31. CheckMate 025: Efficacy of Nivolumab vs Everolimus in Advanced RCC Motzer RJ, et al. N Engl J Med. 2015;[Epub ahead of print]. 1.0 0.8 0.6 0.4 0.2 0 03336912151821242730 Mos Nivolumab Everolimus 410 411 25.0 (21.8-NE) 19.6 (17.6-23.1) 183 215 Deaths, n Median OS, Mos (95% CI) Pts, n 4.6 (3.7-5.4) 4.4 (3.7-5.5) 318 322 Progression, n Median PFS, Mos (95% CI) Probability of PFS HR: 0.88 (95% CI: 0.75-1.03; P =.11) 1.0 0.8 0.6 0.4 0.2 0 03336912151821242730 Mos HR: 0.73 (98.5% CI: 0.57-0.93; P <.002) Probability of OS

32. Ongoing Trials of PD-1 + VEGF Pathway Blockade as First-line Therapy in Advanced RCC Study Phase (Number of Pts) TreatmentStatus Nivolumab NCT01472081I (175) Nivo + Sun; Nivo + Paz; Nivo + Ipi at 3 different dose combinations* Closed to accrual Pembrolizumab NCT02014636I/II (228)Pem±PazRecruiting NCT02133742Ib (60)Pem + AxiRecruiting NCT02348008Ib/II (61)Pem + BevRecruiting Atezolizumab NCT01984242 (IMmotion150) II (305)Atezo± Bev vs SunClosed to accrual NCT02420821 (IMmotion151) III (830)Atezo + Bev vs SunRecruiting Avelumab NCT02493751Ib (55)Avel + AxiRecruiting *Previous systemic therapy for metastatic disease allowed for SUN and PAZ combination arms. Clinicaltrials.gov.

33. Strategies to Optimize Immunotherapy Benefit in the Clinic Inflamed tumors (TIL+, PD-L1+) Tolerant tumors (TIL+, PD-L1-) PD-1/PD-L1 monotherapy PD-1/PD-L1 combination therapy  Anti-VEGF  Cytokines  IDO inhibitors  Other checkpoint inhibitors Noninflamed tumors (TIL-, PD-L1-) PD-1/PD-L1 combination therapy  Vaccines  Engineered T cells