55 year male 1995 08 Renal Cell carcinoma

(55 -year male) 1995 -08: Renal Cell carcinoma

Tumor progression and metastasis Nature Reviews Cancer 13, 739– 752 (2013)

100 Meters 1500 Meters High jump 400 Meters Long jump Hurdles Javelin Discus Shot put Pole vault

Cancer Metastases • • • Local treatment invalid (operation) Disease progression Deteriorated symptoms, pain. . etc Cachexia Incurable Morbidity & mortality • Systemic therapies

Cancers can spread throughout the whole body Targeted Therapy (Metastases) Brain Lung Liver Chemotherapy L. N Bone Hormonal Therapy Chemotherapy

Ideal Systemic Therapy For Metastatic Cancer • Rational target(s) in human cancers: More Specific • Selective toxicity towards cancer cells: Less Side Effects • Surrogate marker(s) for drug treatment: Predictive Biomarker(s) • Detailed underlying mechanisms: Precision Medicine

Cancer Mortality - Metastasis Nature Reviews Cancer 2012, 12: 39 -50

Molecular and Cellular Endocrinology 2002, 198: 77 -87

Cancer Research 1941, 1(4): 293 -297

Basics of hormone control: PCa Testosterone Hypothalamus Testes Pituitary LHRH Prostate Prolactin Adrenal Cortisol ACTH, adrenocorticotropin; LH, luteinising hormone LHRH, luteinising hormone-releasing hormone Adrenal androgens

AR MEDIATES ANDROGEN EFFECTS ON PCA CELL PROLIFERATION

Mechanism of Hormonal Therapy Androgen synthesis Inhibitors Androgens Antiandrogen ACTH Adrenal gland LHRH Hypothalamus LHRH agonist or antagonist Pituitary gland Other target tissues DHT Testis X Androgen receptor Prostate cell LH Surgical Castration -ve feedback control Circulating testosterone Estrogen

Side Effects of Hormonal Therapy Hot flushes Osteoporosis Fatigue Muscle wasting/weakness • Decreased libido • Impotence • Weight gain • • • Memory problems Dry eyes Decreased appetite Increased appetite Mood swings Body hair loss Balance problems Insomnia

Castration Resistance Prostate Cancer ng/m. L Testosterone CRPC is NOT hormone refractory cancer… but is frequently hormone ultrasensitive 50 ng/m. L PSA Hormonal Therapy Castration Resistance

Castration Resistant Prostate Cancer (CRPC) Definition of EAU Guidelines, 2015 • Castrate serum testosterone level (< 50 ng/d. L, 1. 7 nmol/L) • Anti-androgen withdrawal for at least 4 weeks • PSA progression despite secondary hormonal manipulations – Three consecutive rises of PSA one week apart resulting in two 50% increase over the nadir, with a PSA > 2 ng/m. L • Progression of bone or soft tissue lesions A. Heidenreich et al. 2010, EAU Guidelines on PCa

History of Regulatory Approvals in m. CRPC • Strontium-89 1993 - Reduction in painful bone lesions • Mitoxantrone + prednisone 1996 - Reduction in pain • Samarium-153 1997 - Reduction in bone pain • Zoledronic acid 2002 - Skeletal related event reduction • Docetaxel + prednisone 2004 - Prolonged survival • Sipuleucel-T 2010 - Prolonged survival • Cabazitaxel + prednisone 2010 - Prolonged survival • Denosumab 2010 - Skeletal related event reduction • Abiraterone + prednisone 2011 - Prolonged survival • Enzalutamide 2012 - Prolonged survival • Alpharadin (Radium-223): 2012 – Prolonged survival • ……….

Current options of anti-cancer agents THE JOURNAL OF UROLOGY Vol. 194, 1537 -1547, December 2015

THE JOURNAL OF UROLOGY Vol. 194, 1537 -1547, December 2015

History of Regulatory Approvals in m. CRPC Can J urol 2014: 21(supple 1), 1 -6

Bone scan effects: representative images Baseline Week 12 • Docetaxel-pretreated Baseline Week 12 • Docetaxel-naïve Each patient had PR-CR + pain improvement PR: partial response; CR: complete response

Histologic Types of Renal Tumors Type Clear cell 75% Gene VHL Papillary type 1 Papillary type 2 5% 10% Met FH Chromophobe 5% Oncocytoma 5% BHD Jermann M et al. Cancer Chemother Pharmacol. 2006; 57: 533 -539; Linehan WM et al. J Urol. 2003; 170: 2163 -2172; Motzer RJ et al. N Engl J Med. 1996; 335: 856 -875. 20

Historical background Interferon 1 -5 Responses are delayed and almost always partial and of short duration Fever, chills, fatigue, myalgias, arthralgias, weight loss, depression, anemia, leukopenia, abnormal LFTs RR 15% Side effect PFS 3~5 mon OS 13 mon High dose IL-2 68 RR 20%, CR 8% Toxicity Hypotension, cardiac arrhythmia, metabolic acidosis, fever dyspnea, edema, neurotoxicity, oliguria, renal failure Molecular pathway Targeted agent 1990 ~. 2000 ~ 1 Interferon alfa-2 a in advanced RCC: treatment results and survival in 159 patients with long-term follow up. JCO 1993; 11: 1368 2. Interferon alfa and survival In metastatic RCC: Lancet 1999; 353: 14 3. Nephrectomy followed by interferon alfa-2 a compared with interferon alfa-2 a alone for metastatic RCC. NEJM 2001; 345: 1655 4. Interferon-alfa as a comparative treatment for clinical trials of new therapies against advanced RCC. J Clin Oncol. 2002; 20(1): 289. 5. Immunotherapy for advanced RCC. Cochrane Databases Syst Rev 2005; CD 001425 6. Results of treatment of 255 patients with metastatic RCC who received high dose recombinant interleukin-2 therapy. JCO 1995; 13: 688 -96 7. 2. High dose interleukin-2 for the treatment of metastatic RCC : a retrospective analysis of response and survival in patients treated in the surgey branch at the National Cancer Institute between 1986 and 2006 Cancer 2008; 113: 293 8. Cancer-specific survival outcomes among patients treated during the cytokine era of kidney cancer (1989 -2005): a benchmark for emerging targeted cancer therapies. Cancer. 2008; 113(9): 2457

VHL Regulates HIF- Stability

Antiangiogenesis Children’s Hospital Boston, Department of Surgery and Vascular Biology Program, Harvard Medical School, Karp Family Research Laboratories, Boston, MA, USA

Molecular Biologic Pathways in RCC m. TOR inhibitor VEGF m. Ab VEGFR & PDGFR inhibitor 24 Rini BI et al, Lancet In press 2009 Rini et al. Lancet Oncol 2009; 10: 992 -1000

VEGF Ligands D. (Lymphangiogenesis) C. (Lymphangiogenesis) A. (Endothelial Cell Proliferation/Survival) VEGF-C B. (Extra-Cellular Matrix Degredation) VEGF-A VEGF Receptors E. (Angiogenesis/ Vascular Permeability) VEGF-D VEGFR-1 S PIGF: (Endogenious VEGF-A Antagonist) VEGF-E VEGF-A – ECM PIGF VEGF-B Neuropilin-1 R 2 Substrate PY K K Substrate PY PY PY TKI: tyrosine kinase inhibitor PY K NP-1 PY K PY PY � Vascular EC � Proliferation � Migration � Differentiation � Survival � NO Production � Vascular Permeability � Tumor Angiogenesis R 3 K PY PY Substrate PY � Lymphatic EC � Proliferation � Migration � Lymphangiogenesis � Tumor Angiogenesis K

Therapeutic evolution and survival outcome of m. RCC Hsieh JJ, et al. Nat. Rev. Disease Prime 2017 Mar; 8: Article number 17009

First-line Treatment of m. RCC: Efficacy Overview Study Patients, N ORR, % Sunitinib vs IFN- 1 750 47 vs 12* Bev + IFN- vs IFN- 2, 3 649 31 vs 13 Bev + IFN- vs IFN- 4, 5 732 25. 5 vs 13. 1 Sorafenib vs IFN- 6 189 5. 2 vs 8. 7 Temsirolimus vs IFN- 7 626 8. 6 vs 4. 8 Pazopanib vs placebo 8 233 32 vs 4 1, 110 31 vs 25 Pazopanib vs sunitinib 9 Median PFS, months Median OS, months 11 vs 5 26. 4 vs 21. 8 P < 0. 001 P = 0. 051 10. 2 vs 5. 4 23. 3 vs 21. 3 P = 0. 0001 P = 0. 1291 8. 5 vs 5. 2 18. 3 vs 17. 4 P < 0. 0001 P = 0. 097 5. 7 vs 5. 6* P = 0. 50 NA 5. 5 vs 3. 1* 10. 9 vs 7. 3 P < 0. 001 P = 0. 008 11. 1 vs 2. 8 P < 0. 0001 NA 8. 4 vs 9. 5 28. 4 vs 29. 3 nss P = 0. 275 Bev, bevacizumab; NA, not available; nss, not statistically significant; ORR, objective response rate; OS, overall survival; PFS, progression-free survival. *Independent assessment. 1. Motzer RJ et al. J Clin Oncol. 2009; 27: 3584 -3590. 2. Escudier B et al. Lancet. 2007; 370: 2103 -2111. 3. Escudier B et al. J Clin Oncol. 2010; 28: 2144 -2150. 4. Rini B et al. J Clin Oncol. 2010; 28: 2137 -2143. 5. Rini B et al. J Clin Oncol. 2008; 26: 5422 -5428. 6. Escudier B et al. J Clin Oncol. 2009; 27: 1280 -1289. 7. Hudes G et al. N Engl J Med. 2007; 356: 2271 -2281. 8. Sternberg C et al. J Clin Oncol. 2010; 28: 10611068. 9. Motzer RJ et al. Presented at: European Society for Medical Oncology (ESMO) Annual Meeting; September 28–October 2, 2012; Vienna, Austria.

Sunitinib vs IFN 1 RR 47% vs 12% PFS 11 vs 5 mon OS 26. 4 vs 21. 8 mon 1 st line Interferon RR 15% Side effect Everolimus vs placebo 5 after TKI failure SD 63% vs 32% PFS 4. 9 vs 1. 9 mon OS 14. 8 vs 14. 4 mon Avastin/IFN vs IFN 2 RR 31% vs 13% PFS 10. 2 vs 5. 4 mon OS 23. 3 vs 21. 3 mon Pazopanib vs placebo 6 Temsirolimus vs IFN 3 Poor prognosis PFS 3~5 mon OS 13 mon High dose IL-2 RR 20%, CR 8% Toxicity 1990 ~ PFS 3. 8 vs 1. 9 mon OS 10. 9 vs 7. 3 mon 2 nd line OS 22. 9 vs 20. 5 mon after Cytokine Axitinib vs sorafenib 7 After 1 st line Cytokine(35%), anti-VEGF(65%) PFS 5. 5 vs 2. 8 mon OS 17. 8 vs 14. 3 mon 2007 RR 30% vs 3% PFS 9. 2 vs 4. 2 mon (1 st 11. 1 vs 2. 8 ; Cyt 7. 4 vs 4. 2) Sorafenib vs Placebo 4 Molecular pathway Targeted agent 2000 ~ 1 st line(54%) or after cytokine(46%) RR 23 VS 12% PFS 8. 3 vs 5. 7 mon (Cyt 12 vs 8 ; VEGF 6. 5 vs 4. 4) OS 20 vs 19 mon 2008 2010 2011 1. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. JCO 2009; 27(22): 3584 - 2. Bevacizumab plus interferon alfa-2 a for treatment of metastatic renal cell carcinoma Lancet 2007; 370: 2103 -11 3. Temsirolimus, interferon alfa, or both for advanced renal cell carcinoma. NEJM 2007; 356: 2271 -81 4. Sorafenib in advanced clear-cell renal cell carcinoma NEJM 2007; 356: 125 -34 5. Phase 3 trial of everolimus for metastatic renal cell carcinoma : final results and analysis of prognostic factors. Cancer. 2010; 116(18): 4256. ; 372: 449 6. Pazopanib in locally advanced or metastatic RCC. JCO 2010; 28: 1061 7. Axitinib Versus sorafenib as second-line treatment for advanced RCC: overall survival analysis and updated results from a randomised phase 3 trial. Lancet Oncol. 2013; 14(6): 552.

Pazopanib and Sunitinib Have been Reimbursed in Taiwan 1 st Line Sunitinib Pazopanib Cytokine Clear cell 2 nd Line Everolimus Axitinib* Sorafenib Axitinib Poor- risk Temsirolimus Everolimus m. RC C Cytokine Axitinib Non-clear cell *Post sunitinib Sorafenib Temsirolimus Everolimus

Toxicity profiles of available therapeutic agents against RCC Toxicity Agent HTN ATE HFS Sunitinib ++ + + Pazopanib ++ + + Sorafenib ++ + +++ Axitinib ++ + + Tivozanib ++ + + Bevacizumab ++ ++ Temsirolimus Everolimus Mucositis Diarrhea Cytopenia + + +++ Rash Dysphonia Fatigue + + ++ Hair color Metabolic Interstitial Renal changes pneumonitis toxicity ++ + + + + ++ + Hepatic toxicity ++ ++ + HTN = hypertension; ATE = arterial thrombotic events; HFS = hand-foot syndrome; 1 hypothroidism; 2 hyperlipidemia/hyperglycemia. * +, ++, or +++ based on low-, moderate-, or high-grade toxicities; cells left blank indicate no information or no known toxicity.

RCC Treatment Algorithm: 2015 Setting Patients Therapy (level 1) Other Options (≥ level 2) First line Good or Intermediate risk Sunitinib Bevacizumab + IFN Pazopanib Clinical trial HD IL-2 Sorafenib Clinical trial Observation Poor risk Temsirolimus Clinical trial Sunitinib Clinical trial Cytokine Sorafenib Pazopanib Axitinib Clinical trial Sunitinib, Bevacizumab Clinical trial VEGF Everolimus Axitinib Clinical trial TKI then TKI Trial Everolimus Trial Everything Sorafenib Other VEGF TKIs Second line Third line m. TORi then TKI or. TKI then m. TOR Temsirolimus Different TKI Rechallenge TKI *Adapted from M Atkins, ASCO 2006 & R Bukowski ASCO 2007; Rini B ASCO 2008

Check. Mate 025 Study Design Nivolumab N=410 Ph 2: ORR 3 mg/kg IV for 60 min, q 2 w Metastatic or advanced clear -cell RCC with prior 1 or 2 anti-angiogenic treatment 1: 1 randomization Everolimus N=411 Disease progression or Intolerable toxicity 10 mg PO BD Image study every 8 weeks for the first year and then every 12 weeks Survival Follow-up, every 3 mos • Subjects on both arms are allowed to continue study therapy after progression if they are assessed by investigators to be deriving clinical benefit and tolerating study drugs. • Primary Endpoint: OS • Secondary Endpoints: ORR, PFS, OS by PD-L 1 expression (IHC), AEs, Qo. L • Study sites: 146 sites in 24 countries, including US/Canada, W. Europe, and Rest of World 36

Kaplan-Meier Curve for PFS Median PFS, Mos (95% CI) Nivolumab 4. 6 (3. 7 -5. 4) Everolimus 4. 4 (3. 7 -5. 5) Probability of PFS 1. 0 Progression, n 318 322 0. 8 0. 6 HR: 0. 88 (95% CI: 0. 75 -1. 03; P =. 11) 0. 4 0. 2 0 0 3 6 9 12 15 18 21 24 27 30 33 Mos Motzer RJ, et al. NEJM 2015; 373 (19): 1803 -1813 37

OPDIVO demonstrated an unprecedented median OS of more than 2 years 1. 0 Median OS, months (95% CI) Overall Survival (Probability) 0. 9 76% 0. 8 0. 7 67% 0. 6 Nivolumab 26. 0 (22. 2– 29. 6) Everolimus 19. 7 (17. 6– 22. 3) HR (95% CI) 0. 73 (0. 61– 0. 88) P = 0. 0006 52% 0. 5 Nivolumab 0. 4 42% 0. 3 Everolimus 0. 2 0. 1 0. 0 0 3 6 9 12 15 18 Nivolumab 410 390 359 337 305 276 251 Everolimus 411 367 325 204 171 129 289 268 247 214 183 162 130 103 No. at risk 21 24 27 30 36 39 80 38 5 0 61 32 5 0 33 42 Months Adapted from poster presented by Plimack ER et al at the 15 th International Kidney Cancer Symposium; November 4– 5, 2016; Miami, FL, USA.

Father of Modern Cancer Chemotherapy Sidney Farber Cancer Center: • In June 3, 1948, Sidney Farber, MD showed that a synthetic compound, 4 aminopteroylglutamic acid (aminopterin), could induce remissions in seriously ill children with acute leukemia. 1 (The New England Journal of Medicine) • 16 children— 10 showed clinical, hematologic, and pathologic evidence of improvement. • Dr. Farber’s findings were so groundbreaking—until then, no drug had proved effective against non–solid tumor cancers—they ushered in the era of chemotherapeutics, chemical agents that could stop cancer cells from growing and replicating, in effect killing them. Dana-Farber Cancer Institute

Advanced Urothelial Cell Carcinoma of Bladder • • • Neoadjuvant Chemotherapy Adjuvant Chemotherapy Lymph Nodes Distant Meta

Stage Gross appearance Tumor grading Grade 1 Grade 2 Grade 3

Obstacles of Therapy for Advanced Bladder Cancer • Standard CXT: MVAC (methotrexate, vinblastine, doxorubicin, cisplatin) – prominent toxicity profile (toxic death rate: 3 -4%) • New CXT agents: docetaxel, paclitaxel, gemcitabine, ifosfamide – less toxicity, limited duration of response (< 6 mons), median survival rarely exceed 8 -9 mons • Is there a role of targeted therapy for advanced bladder cancer ?

Immune Checkpoint System - Priming

Immune Checkpoint System - Effector

Journal of Immunology Research Volume 2017, Article ID 6940546, 9 pa

Trial Agent Phase(No. ) Time to Response, mo ORR(%) Median OS, mo AEs, % Atezo II (119) NR 23 15. 9 Gr 3 -4: 16 Pembro II(370) 2. 0 29 NR Gr 3 -4: 18 II(310) 2. 1 15 7. 9 Gr 3 -4: 16 KEYNOTE-045 Pembro III(542) vs. chemo 2. 1 P: 21. 1 C: 11. 4 (p=0. 001) Any: P(60. 9) C(90. 2); Gr 3 -4: P(15) C(49. 4); Gr 5: : P(1. 5) Check. Mate 275 Nivo II(270) 1. 87 19. 6 P: 10. 3 C: 7. 4 (HR=0. 73; p=0. 002) 8. 74 Check. Mate 032 N 3 I 1(104) N 1 I 3(26) Nivo(78) I/II 1. 48 26. 0 38. 5 25. 6 9. 7 Gr 3 -4: 31. 7 Gr 3 -4: 30. 3 Gr 3 -4: 23. 1 NCT 01693562 Durva I/II(191) NR 17. 8 NR Gr 3 -4: 6. 8 JAVELIN Ave Ib 1. 5 17. 4 Gr 3 -4: 8. 4 First line IMvigor 210 cohort 1 KEYNOTE-052 Second line (post-cddp) IMvigor 210 Atezo cohort 2 Gr 3 -4: 18 *I: Ipilimumab; LA: Locally advanced; M: metastasis

Germ Cell Testicular Cancer • BEP: bleomycin, etoposide, and cisplatin • Survival: 1 -yr, 99. 1%; 5 -yr, 98. 3%; 10 -yr, 98. 2% • Side effects: hair loss, fatigue, mouth sore, nausea, vomiting, loss appetite, diarrhea

Penile Squamous Cell Carcinoma • Regimens: Cisplatin Fluorouracil (5 -FU) Paclitaxel (Taxol®) Ifosfamide (Ifex®) Mitomycin C Capecitabine (Xeloda®) • Survival: Cisplatin– 5 -FU, response rate of 32%, and median PFS (progression-freesurvival) and OS of 20 weeks and 8 months, respectively. • Side effect: Grade 3– 4 neutropenia: 20% Grade 3– 4 anemia: 8%