Systemic Therapies in Renal Cell Carcinoma Dr Soe Yu Aung Medical Oncology Registrar Andrew Love Cancer Centre and University Hospital Geelong 22/05/2017

Incidence Kidney cancer 5% of all adult malignancies in men and 3% in women 7th most common cancer in men and 10th most common in women Renal cell carcinoma (RCC) – 80-90% of all Kidney cancers Worldwide RCC incidence – at plateau in recent years after increasing trend for 2 decades Males > Females (2:1) Median age at Dx – 65 (2000-2004) 5-year survival – 50.9% in 1975-1977  70.6% in 2002-2008 Australia data Estimated number of new cases of Kidney cancer dx in 2017 – 3512 (2256 males + 1256 females) 2.6% of all new cancer cases dx in 2017 Estimated number of deaths from Kidney cancer in 2017 – 1049 (681 males + 368 females) 2.2% of all deaths from cancer in 2017 Age-standardized incidence rate – 12 cases per 100,000 persons (17 for males and 8.5 for females) Risk of having dx of Kidney cancer by age of 85 for an individual – 1 in 65 (1 in 49 males and 1 in 95 females). 5-year survival – 75% (2009-2013)

Risk factors Smoking Obesity Hypertension Acquired cystic kindey d/s Tuberous sclerosis syndrome ESRF, Dialysis, Renal transplant 2-3% of all RCCs – Hereditary; mostly autosomal dominant; the most common – von Hippel-Lindau (VHL) disease

Diagnostic Investigations >50% of RCCs detected incidentally Classical Triad (flank pain, gross hematuria, palpable abdo mass) - <10% of cases “Internist’s tumour” – variable clinical presentations including paraneoplastic syndromes (Hypercalcaemia, unexplained fever, erythrocytosis, Stauffer’s syndrome (cholestasis not due to liver mets or intrinsic liver d/s, and typically resolve after kidney tumour resection)) USG (KUB); CT KUB; CT CAP (staging) FDG-PET – not reliable; negative scan can’t exclude RCC Core biopsy preferable – especially for advanced d/s Final detailed histo Dx – based on nephrectomy specimen Blood tests (FBE, UEC, CMP, LDH, CRP) – for prognostic and risk assessment

WHO 2016 Classification of Renal cell tumours

Molecular classifications of Renal cell tumours Type of cancer Cytogenetics Molecular alteration Familial Syndrome Clear cell 3p- VHL gene inactivating mutation; Hypermethylation of VHL gene promoter; loss of VHL gene heterozygosity. PBRM1, SETD2, BAP1, and TORC1 pathway mutations von Hippel-Lindau (VHL) Papillary Type I Type II (poorer prognosis; hereditary leiomyomatosis) +7, +17, -Y - c-MET activating mutation (type I) - Fumarate hydratase inactivating mutation (type II) Hereditary papillary RCC; Hereditary leiomyomatosis RCC Chromophobe (indolent) -1, -Y hypodiploid FLCN mutation Birt-Hogg-Dube syndrome Oncocytoma (benign) -1, -Y

Different types of renal cell tumours (contd..) Collecting duct carcinoma – similar to transitional cell carcinoma; highly aggressive Renal medullary carcinoma – young patients with sickle traits; histologically similar to collecting duct carcinoma Acquired cystic disease-associated RCC – indolent outcome; patients with ESRF Poor histological prognostic factors Sarcomatoid and/or rhabdoid differentiation – grade IV tumour Presence of necrosis Presence of microscopic vascular invasion

Staging of RCC

Staging of RCC

Prognostic models Memorial Sloane Kettering Cancer Centre (MSKCC) model – gold std in cytokine era. Time from Dx to systemic Tx - <12 months Low Karnosfsky performance status (<80%) Anaemia Hypercalcaemia High serum LDH Good risk (0 risk factors; median survival 24months); Intermediate risk (1-2 risk factors; median survival 12 months); Poor risk (>2 risk factors; medial survival 5 months)

Prognostic models International Metastatic RCC Database Consortium (IMDC score) in TKI era Time from Dx to Tx - <1yr Low Karnosfsky performance status (<80%) Anaemia Neutrophilia Thrombocytosis Hypercalcaemia

Prognostic models

Management of Metastatic RCC ~20% of patients present with mets ~30% of patients treated for localized disease experience recurrent with distant d/s Surgery and Local therapy Cytoreductive nephrectomy – for patients with good PS (OS benefit in cytokine era) No general guidelines for local treatment of metastases yet. Favourable outcomes from local treatment of metastases can be achieved in patients with Good PS Solitary or oligo-mets Metachronous d/s with d/s free interval >2yrs Absence of progression on systemic therapy Low or intermediate Fuhrmann grade Complete resection After metastetectomy - No systemic Tx recommended

Systemic Therapies for Metastatic RCC Clear cell RCC (ccRCC) and non-ccRCC Prognostic Risk The timing to start the treatment - ???? Cytokine era (1992 – 2006) High dose IL2 IFN-alpha Targeted Therapies TKIs (Sunitinib, Pazopinib, Sorafenib, Axitinib, Carbozantinib (c-MET inhibitor), Lenvatinib) – VGEFR inhibitors Bevacizumab – Anti-VEGF-A monoclonal antibody (with IFN-alpha) Evverolimus, Temsirolimus – mTOR inhibitors Immunotherapy (check-point inhibitors) Nivolumab, Pembrolizumab – PD-1 inhibitors Atezolizumab – PDL-1 inhibitor Ipilimumab – CTLA-4 inhibitor

VHL pathway in clear cell RCC and the mechanisms of anti-VGEF agents & mTOR inhibitors

Mechanisms of immunotherapy

ESMO 2016 guidelines for metastatic ccRCC

ESMO 2016 guidelines for metastatic ccRCC

ESMO 2016 guidelines for metastatic non-ccRCC

Targeted Therapies for metastatic ccRCC (1st line)

Targeted Therapies for metastatic ccRCC (1st line)

Pazopinib vs Sunitinib (1st line)

COMPARZ study

Relative risk in AE (AE occurrence ≥10% in either arm; 95% CI for RR does not cross 1)

Toxicities of Targeted agents Sunitinib induced Hypertension (SBP>140mmHg) – assoc with improvement in clinical outcomes (a biomarker of response to sunitinib)

Targeted therapies for metastatic ccRCC (2nd line) Axitinib vs Everolimus ???

Immunotherapies for metastatic ccRCC (2nd line)

Phase III study of Nivolumab vs Everolimus for metastatic ccRCC (2nd line and beyond) FDA approved Nivolumab (240mg flat dose IV once every 2weeks) as 2nd line Tx for mets ccRCC in Nov 2015

Overall Survival (OS benefit irrespective of PDL1 expression level on tumour cells) Motzer RJ et al. N Engl J Med 2015. DOI: 10.1056/NEJMoa1510665

Subgroup analyses of Overall Survival

PFS

Objective response rate

Adverse Events

On-going Clinical Trials Nivolumab+Ipilimumab vs Sunitinib (1st line; Phase III) Pembrolizumab vs Pembrolizumab+Pazopinib (1st line; Phase II) Pembrolizumab vs Pembrolizumab+peg-IFN-alpha (1st line; Phase II) Atezolizumab vs Atezolizumab+Bevacizumab vs Sunitinib (1st line; Phase II; 3 arms) Atezolizumab+Bevacizumab vs Sunitinib (1st line; Phase III) Cancer vaccines

ESMO 2016 guidelines for metastatic ccRCC

ESMO 2016 guidelines for metastatic ccRCC

Systemic Therapy for mets ccRCC in Australia 1st line Sunitinib vs Pazopinib Clinical trial ??? 2nd line Axitinib Everolimus Sorafenib Nivolumab (compassionate programme) 3rd line Denosumab or Zolendronate for bony mets

Summary Histology subtype; Prognostic risk; Time to start systemic therapy TKIs remain the first line Immunotherapy recently approved for the second line (PBS approved on 1/8/17); New TKIs were recently approved for the second line (Carbozantinib; Lenvatinib+Everolimus) More clinical trials going on (either monotherapy or combination therapy) 5-year survival is increasing with the advent of immunotherapy (Quality-life- year compared with HD patients???) Tx for RCCs in HD patients???

Thank You….