Advanced & Metastatic Renal Cell Carcinoma

Advanced & Metastatic Renal Cell Carcinoma An Update G. Renzulli January 2013 1

Overview of Cancers of the Kidney 2

Global Epidemiology 3

Global Epidemiology of Kidney Cancer 4 Globally, kidney cancer is the 15 th most common cancer As noted in the adjoining figure, kidney cancer is most prevalent in developed countries More common in men More common in elderly, but diagnosed at all ages More than 189,000 new cases are diagnosed worldwide each year In the US in 2008, it is estimated that more than 54,000 Americans will be diagnosed and about 13,000 will die Global Burden of Kidney Cancer in Men < 1.3 < 2.1 < 3.6 < 8.3 < 22.2 Age-standardized incidence/100,000 population 4

Types of Kidney Cancers 5

Types of Kidney Cancers 6 Kidney cancers distinguished by: Cell type Growth pattern Solitary or multiple masses in one or both kidneys Genetic characteristics 6

Malignant Kidney Tumors 7 Malignant kidney tumors: Frequency of Malignant Renal Tumors Renal cell carcinoma 90% Transitional cell carcinoma 5% to 10% Wilms tumor 5% Renal Cell Carcinoma Transitional Cell Carcinoma Wilms Tumor Renal Sarcoma Renal sarcoma <1% 7

Malignant Kidney Tumors 8 Renal Cell Carcinoma Sixth leading cause of cancer death in 2000 Men generally affected more than women The most common, accounts for 90% 5 main subtypes Clear cell, papillary, chromophobic, collecting duct, other Risk factors: smoking, obesity, heredity inter alia Symptoms usually asymptomatic until advanced may include hematuria, flank pain, and palpable flank mass 8

Renal Cell Carcinoma 9

Pathogenesis 10

Pathogenesis of RCC Renal cell carcinoma comprises approximately 2% of all malignancies, with diagnosis at a median age of 65 years The various subtypes of RCC have differing clinical, pathologic, and genetic characteristics Most cases are sporadic/non-inherited, but some are inherited 11 11

Risk factors for RCC Indicators of genetic predisposition: First-degree relative increases risk of RCC ~2- to 3-fold Diagnosis <40 years of age Bilateral or multifocal RCC Non-genetic risk factors: Smoking Exposure to toxic compounds Obesity Dialysis-associated cystic kidney disease Hypertension 12

RCC Epidemiology 13

Renal Cell Carcinoma Renal Cell Carcinoma The most common type of kidney cancer in adults Approximately 90% of adult kidney cancers are RCCs Approximately 85% are clear-cell tumours; the remainder comprise less common cell types Globally, RCC accounts for approximately 2% of all malignancies Incidence rates for kidney cancer are highest in developed countries, including North America, Australia, New Zealand and Europe Within Europe, RCC accounts for 3.1% of all cancers in males and 2.3% of all cancers in females 14

Renal Cell Carcinoma Mortality to incidence ratios with RCC are higher than any other urological malignancy, reflecting the aggressive nature of this cancer type Data from GLOBOCAN 2008 showed that, in Southern Africa, the incidence of cancer of the kidney was about 500 patients of which the mortality was 426!!! The 5-year prevalence was 1019 In Europe, 2006 mortality rates for patients with kidney cancer were 2.5 and 2.0% in males and females, respectively 15

South Africa Estimated incidence, mortality and 5-year prevalence: both sexes Cancer Incidence Mortality 5-year prevalence Number (%) ASR (W) Number (%) ASR (W) Number (%) Prop. Lip, oral cavity 1157 1.5 2.8 486 0.9 1.2 2669 1.6 6.8 Nasopharynx 1239 1.6 2.8 746 1.4 1.8 3082 1.9 7.9 Other pharynx 960 1.2 2.3 784 1.4 1.9 2300 1.4 5.9 Oesophagus 6761 8.5 16.3 6409 11.7 15.6 6711 4.1 17.2 Stomach 1153 1.5 3.0 1070 2.0 2.8 1484 0.9 3.8 Colorectum 5167 6.5 13.2 3846 7.0 10.0 10756 6.6 27.6 Liver 3774 4.8 8.9 3652 6.7 8.8 2254 1.4 5.8 Gallbladder 505 0.6 1.3 489 0.9 1.3 547 0.3 1.4 Pancreas 1635 2.1 4.3 1588 2.9 4.2 1109 0.7 2.8 Larynx 1152 1.5 2.9 643 1.2 1.7 3009 1.9 7.7 Lung 6462 8.2 16.5 5992 10.9 15.5 5384 3.3 13.8 Melanoma of skin 2389 3.0 5.6 1242 2.3 3.0 6329 3.9 16.3 Kaposi sarcoma 4264 5.4 7.9 3594 6.6 6.6 7185 4.4 18.5 Breast 9012 11.4 38.1 4465 8.1 19.3 29663 18.3 148.5 Cervix uteri 6500 8.2 26.8 3467 6.3 14.8 17827 11.0 89.3 Corpus uteri 1559 2.0 6.9 466 0.9 2.1 5499 3.4 27.5 Ovary 893 1.1 3.8 645 1.2 2.8 2092 1.3 10.5 Prostate 7789 9.8 53.9 2618 4.8 19.3 20125 12.4 106.1 Testis 191 0.2 0.7 98 0.2 0.4 733 0.5 3.9 Kidney 549 0.7 1.2 426 0.8 0.9 1019 0.6 2.6 Bladder 1604 2.0 4.2 998 1.8 2.7 4081 2.5 10.5 Brain, nervous 1239 1.6 2.6 893 1.6 1.9 1589 1.0 4.1 system Thyroid 807 1.0 1.8 408 0.7 1.0 2816 1.7 7.2 Hodgkin 506 0.6 0.9 393 0.7 0.7 1539 1.0 4.0 lymphoma Non-Hodgkin 2331 2.9 4.9 1841 3.4 4.0 3831 2.4 9.8 lymphoma Multiple myeloma 531 0.7 1.3 479 0.9 1.2 816 0.5 2.1 Leukaemia 1315 1.7 2.8 1214 2.2 2.6 1306 0.8 3.3 All cancers excl. non-melanoma skin cancer 79179 100.0 189.6 54818 100.0 133.2 161785 100.0 415.4 Incidence and mortality data for all ages. 5-year prevalence for adult population only. ASR (W) and proportions per 100,000.

Renal Cell Carcinoma Due to a lack of standardised screening globally, and the fact that renal masses often remain asymptomatic and non-palpable until late in the disease course means that approximately 30% of individuals with RCC present with metastatic disease at first diagnosis Approximately 40% of individuals diagnosed with local tumours will subsequently develop metastatic disease Risk factors for RCC include smoking and obesity: other factors that have been shown to increase the risk of RCC include radiation therapy and chemical carcinogens, such as asbestos or organic solvents 17

Trends in RCC Incidence and Mortality 18 Incidence rates are rising 3 times faster than mortality rates Suggests improved overall survival over the last 25 years More cases of RCC being diagnosed in asymptomatic patients Incidence and US Death Rates (Kidney and Renal Pelvis Cancer) 1 Incidence Mortality 25 20 Incidence rates are rising faster than mortality rates, suggesting an improvement in overall survival in patients with kidney cancer, including RCC, over 30 years spanning 1975-2005. 25 20 White (1975-2005) Black (1975-2005) API* (1992-2005) AI/AN (1992-2005) Hispanic (1992-2005) 15 15 10 10 5 5 0 1975 1980 1985 1990 1995 2000 2005 0 1975 1980 1985 1990 1995 2000 2005 * API- Asian/Pacific Islander AI/AN- American Indian/Alaska Native 18

GLOBAL GLOBOCAN DATA 2008 19

Overall Survival The long-term survival of patients with advanced RCC remains low Stage 5-Year Overall Survival Stage I 90% to 95% Stage II 70% to 85% Stage III No lymph node mets: 45% to 65% Single lymph node met: 15% to 30% Stage IV Regional lymph node mets: 10% Distant met: <5% 20 20

Clinical Presentation 21

Presentation of Metastatic RCC Symptoms of metastatic disease Approximately 30% of patients have metastatic disease at presentation Sites of metastasis Most common is lung, in 75% Other common sites: lymph nodes, bone, liver, brain, adrenal gland, and the other kidney 22

Grading and Staging of RCC 23

The Fuhrman Nuclear Grading System for RCC Fuhrman Tumor Grade Nuclear Characteristics 1 Similar to normal renal cells 2 Larger than grade 1 tumors (~15 µm) with irregular morphology Nucleoli visible under high power (x400 magnification) 3 Larger nuclei than grade 2 (~20 µm) with marked variability in size/shape Large, prominent nucleoli evident even at low power magnification 4 Large, multi-lobed nuclei Similar to Grade 3 with heavy chromatin clumps 24

UICC and AJCC Consensus Report In 1997, consensus report recognized that the available evidence in the literature suggests that nuclear grade is a better prognostic indicator than other types of grading that do not use nuclear criteria. Recommended grouping grades 1 and 2 together Use of nuclear grading only for patients with clear cell and papillary RCC 25

Staging of RCC 26 Prognosis is directly related to stage, or extent to which the tumor has invaded other areas of the body Several tumor-staging systems have been developed to help predict response to treatment and survival in patients diagnosed with RCC The Robson system Developed in 1968 Stage I to stage IV RCC used to describe the extent of tumor spread beyond the renal capsule Robson system has largely been replaced by the TNM stage classification 26

Staging of RCC 27 The AJCC/TNM system Widely used Stage based on Tumour growth (T) Lymph node invasion (N) Extent of metastasis (M) Tumour stage correlates well with survival 27

5-Year Overall Survival by Stage and TNM Status Stage TNM 5-Yr Overall Survival, % I T1N0M0 90-95 II T2N0M0 70-85 III T3aN0M0 50-65 T3bN0M0 50-65 T3cN0M0 45-50 T1N1M0 25-30 T2N1M0 25-30 T3N1M0 15-20 IV T4 Any N M0 10 Any T N2 M0 10 Any T Any N M1 <5 29

RCC and its Subtypes RCC was the sixth leading cause of cancer death in 2000 RCC accounts for approximately 90% of kidney tumors There are 5 subtypes of RCC, all composed of different cell types Clear cell carcinomas Papillary/chromophilic carcinomas Chromophobic carcinomas Collecting duct carcinomas Other carcinomas Unclassified carcinomas Rare carcinomas 30

General Treatment Guidelines for Kidney Cancer Non-pharmacologic Treatments 31

2013 NCCN Guidelines: Non-pharmacologic Treatments Non-pharmacologic treatments If the tumor is resectable, surgery is the first step in treating RCC unless the patient is not a candidate for surgery because of poor health Surgery can sometimes cure RCC if the tumor is localized, however, most cases of RCC are discovered after the cancer has advanced or metastasized 32

Surgery Surgical resection is the only effective therapy for localized RCC Other treatment options may be considered if the patient is in poor physical health or elderly Choice of surgical procedure depends on the disease stage, health, and renal function of the patient Improved surgical techniques and an increase in incidentally found small tumors has allowed for the increased use of nephron-sparing surgery/partial nephrectomy in place of removal of the entire kidney/radical nephrectomy 33

General Treatment Guidelines for Kidney Cancer Pharmacologic Treatments 35

US Pharmacologic Treatments Overview Until the approval of targeted therapies, systemic treatment options for RCC consisted of immunotherapy with interleukin-2 /IL-2 and interferon-alfa/ifn-alfa or entry into clinical trials Novel molecularly targeted therapies, including several different inhibitors of tumor angiogenesis, have recently emerged as first- and second-line therapies in advanced RCC Tyrosine kinase inhibitors/tkis Mammalian target of rapamycin/mtor inhibitors Monoclonal antibodies IFN-alfa is not currently indicated for the treatment of RCC in the US 36

FDA Approval Dates for RCC Treatments Approval Dates for RCC Indications: FDA Interleukin 2/PROLEUKIN May 1992 Sorafenib/Nexavar December 2005 Sunitinib/Sutent January 2006 Temsirolimus/Torisel May 2007 Bevacizumab/Avastin in combination with IFN-alfa July 2009 Everolimus/Afinitor March 2009 1992 1993 2005 2006 2007 2008 2009 2010 37

South African registrations and commercial availability of targeted agents for RCC IFN/IL2 Sorafenib (July 2007) Sunitinib (April 2008) Temsirolimus (May 2010) Everolimus (March 2012) 2004 2006 2007 2008 2009 2010 2011 2012 Bevacizumab (May 2006) Pazopanib (Est Oct 2013) 38

Immunotherapy Works by triggering the immune system, which in turn destroys cancerous cells IL-2 and IFN-alfa, also called cytokines Used clinically to induce immune responses to RCCs IL-2 has been in use since the 1990 39

Targeted Therapy Protein kinases are enzymes that activate or inactivate cell proteins or enzymes Protein kinase inhibitors including those that specifically target receptor tyrosine kinases, or tyrosine kinase inhibitors/tkis are used as treatment for malignant diseases In one study, a TKI was shown to improve efficacy in terms of increased objective tumor response rate: 31% sunitinib vs 6% IFN-alfa, and longer median progression-free survival in the treatment of RCC 40

mtor Inhibitors The mtor pathway is a critical mediator of cell metabolism, cell growth, and angiogenesis Two drugs that inhibit the mtor protein are: Temsirolimus Everolimus 41

Differences between Everolimus and Temsirolimus Everolimus Temsirolimus rapamycin analog 15 rapamycin prodrug 15 given orally 5 administered parenterally (intravenously) 5 42

Biological Therapy options in RCC Bevacizumab Sorafenib Sunitinib Temsirolimus Everolimus Pazopanib Company Genentech / Roche Bayer / Onyx Pfizer Wyeth Novartis GSK Agent Biological NCE NCE NCE NCE NCE Dosing Intravenous Oral bid Oral q.d.4wks/q 6wks Intravenous Oral q.d. Oral q.d. Molecular Targets VEGF A VEGF-R,Flt- 3,p38, Raf,c- Kit, PDGF-R VEGF- R,Flt-3, c- Kit, PDGF- R mtor inhibitor mtor inhibitor VEGF-R, c- Kit, PDGF-R RCC indication Combination with IFN 1 st line mrcc Cytokine refractory mrcc (not in the US where prior cytokine treatment is not required) Treatment of advanced / metastatic RCC 1 st line mrcc for high risk patient TKI failure mrcc Expected: Treatment of advanced / metastatic RCC mtor: (mammalian target of rapamycin) is a protein which in humans is encoded by the FRAP1 gene. mtor is a serine/ threonine protein kinase that regulates cell growth, cell proliferation, cell motility, cell survival, protein synthesis, and transcription. mtor belongs to a related kinase protein family. 43

Explanation of Terms VEGFR: vascular endothelial growth factor receptor VEGFR are receptors for the protein vascular endothelial growth factor which is an important signaling protein involved in both vasculogenesis: the formation of the circulatory system and angiogenesis:the growth of blood vessels from pre-existing vasculature PDGFR: Platelet-derived growth factor receptors (PDGF-R) Are cell surface tyrosine kinase receptors for members of the PDGF family PDGF subunits A and B are important factors regulating cell proliferation, cellular differentiation, cell growth and development under normal circumstances and in many diseases including cancer There are two forms of the PDGF-R, alpha and beta - each encoded by a different gene C- kit : Mast/stem cell growth factor receptor (SCFR) Also known as proto-oncogene c-kit or tyrosine-protein kinase Kit or CD117, is a protein that in humans is encoded by the KIT gene CD117 is a proto-oncogene which means that overexpression or mutations of this protein can lead to cancer 44

NCCN Treatment Approach By Stage 45

Recommendations for patients with Stage I, Stage II, or Stage III RCC 44 Step 1. Surgical excision of the tumor Step 2. Observation or adjuvant therapy in a clinical trial Step 3. Follow up Every 6 months for 2 years then annually for 5 years: History and physical examination Comprehensive metabolic panel Lactate dehydrogenase/ldh level At 4 to 6 months, then as indicated: Chest and abdominal CT NCCN believes that the best management for any cancer patient is in a clinical trial. 46

Recommendations for patients with Stage IV RCC Classification Treatment Potentially surgically resectable solitary metastatic site Potentially surgically resectable primary* with multiple metastatic sites Medically or surgically unresectable* Nephrectomy + surgical metastasectomy Cytoreductive nephrectomy in select patients prior to systemic therapy First-line therapy First-line therapy *Individualized treatment based upon symptoms and extent of metastatic disease. 48

Relapse or Stage IV and Unresectable: Predominant Clear Cell Histology: First-line Therapy Clinical trial or Sunitinib (category 1) or Temsirolimus (category 1 for poor prognosis patients category 2B for selected patients of other risk groups) or Bevacizumab + IFN (category 1) or High dose IL-2 for selected patients or Sorafenib for selected patients and Best supportive care* NCCN believes that the best management for any cancer patient is in a clinical trial. *Best supportive care can include palliative RT, metastasectomy, or bisphosphonates for bony metastases. {National Comprehensive Cancer Network 2009 V2: pkid-2c} 50

Relapse or Stage IV and Unresectable: Predominant Clear Cell Histology: Subsequent Therapy Clinical trial preferred or Targeted therapy After TKI therapy Everolimus (category 1) Axitinib (category 1) Sorafinib (category 2A) Sunitinib (category 2A) Temsirolimus (category 2B) Bevacizumab (catagory 2B) Pazopanib (category 3) After Cytokine therapy Axitinib (category 1) Sorafinib (category 1) Sunitinib (category 1) Pazopanib (category 1) Temsirolimus (category 2A) Bevacizumab (category 2A) 51

Relapse or Stage IV and Unresectable: Predominant Clear Cell Histology: Subsequent Therapy Clinical trial preferred or Cytokine Therapy IL-2 (category 2B) Best Supportive Care * *Best supportive care can include palliative RT, metastasectomy, or bisphosphonates for bony metastases. {National Comprehensive Cancer Network 2009 V2: pkid-2c} 54

Relapse or Stage IV and Unresectable: Non Clear Cell Histology: First-line Therapy Clinical trial (preferred) Temsirolimus (category 1 for poor prognosis patients, category 2A for selected patients of other risk groups) or Sorafinib Sunitinib (category 1) or Pazopanib (category 3) or Erlotinib (category 3) or Axitinib (category 3) and Best supportive care* *Best supportive care can include palliative RT, metastasectomy, or bisphosphonates for bony metastases. {National Comprehensive Cancer Network 2009 V2: pkid-2c} 55

Agents represented on the SAOC Guidelines 57

Agents represented on the SAOC Guidelines 58

EAU Guidelines 59

EAU Guidelines for Localized and Metastatic RCC Localized RCC treatment consists of the following surgical procedures: Radical nephrectomy Partial nephrectomy/nephron-sparing surgery Laparoscopic nephrectomy Partial laparoscopic nephrectomy Metastatic RCC treatments: Surgery/tumour nephrectomy or metastectomy Radiation Pharmacologic therapy/immunotherapy, targeted therapy 60

Surgery for Metastatic RCC Only curative if all metastases are removed Tumor nephrectomy is recommended for metastatic RCC patients with good performance status when combined with IFN-alfa In patients with synchronous metastatic spread, metastasectomy should be performed where disease is resectable and the patient has a good performance status 61

Chemotherapy for Metastatic RCC RCCs are resistant to most chemotherapies Seems to be effective only if 5-fluorouracil/5FU is combined with immunotherapeutic agents Chemotherapy as monotherapy should not be considered effective in patients with mrcc 62

Pharmacologic Therapy for Metastatic RCC Immunotherapy Combination of cytokines, with or without additional chemotherapy, does not improve overall survival compared with monotherapy Targeted therapy approved for 1 st line or 2 nd line treatment Sorafenib: 2 nd line treatment Sunitinib: 1 st line therapy in good & intermediate-risk patients Temsirolimus: 1 st line treatment in poor-risk patients Bevacizumab: 1 st line option in combination with IFN-alfa2 Everolimus: approved for RCC/orphan status 63

Conclusions 64

Key Points If the tumor is resectable, surgery is the first step in treating RCC, unless the patient is not a candidate for surgery because of poor health IL-2 and IFN-alfa, also called cytokines, have been used clinically to induce immune responses to RCCs, but their use is often associated with toxicity Molecularly targeted therapies, including several different inhibitors of tumor angiogenesis, mtor inhibitors, and monoclonal antibodies, have emerged as 1 st line and 2 nd line therapies most commonly used in advanced RCC 65

Key Points Sorafenib and sunitinib are kinase inhibitors that target receptors involved in tumor angiogenesis Temsirolimus and everolimus inhibit mtor: a critical mediator of cell metabolism, cell growth and angiogenesis Bevacizumab is a monoclonal antibody that binds to VEGF and prevents it from activating its downstream pathway, which usually includes endothelial cell proliferation and blood vessel formation 66

Key Points NCCN Guidelines Stages I, II, and III RCC Step 1: Surgical excision Step 2: Observation or adjuvant therapy in a clinical trial Step 3: Follow up with lab tests and imaging studies Stage IV Nephrectomy and surgical metastasectomy in cases of potentially resectable solitary metastatic site Cytoreductive nephrectomy prior to targeted therapy in cases of potentially resectable primary with multiple metastatic sites If unresectable or recurrent, targeted therapy is recommended 67

Messages Ongoing evolution of treatment options Incremental improvements in outcomes Patient acceptance/preference to therapy i.e. tolerable and manageable side effects to ensure good compliance Pricing/cost will become more important as choice of available treatments increases 68

Questions 69