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

2. 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 ( )
5-year survival – 50.9% in  70.6% in
Australia data
Estimated number of new cases of Kidney cancer dx in 2017 – 3512 (2256 males females)
2.6% of all new cancer cases dx in 2017
Estimated number of deaths from Kidney cancer in 2017 – 1049 (681 males 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% ( )

3. 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

4. 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

5. WHO 2016 Classification of Renal cell tumours

7. 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

8. 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

9. Staging of RCC

10. Staging of RCC

11. 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)

12. 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

13. Prognostic models

14. 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

15. 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

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

19. Mechanisms of immunotherapy

21. ESMO 2016 guidelines for metastatic ccRCC

22. ESMO 2016 guidelines for metastatic ccRCC

23. ESMO 2016 guidelines for metastatic non-ccRCC

24. Targeted Therapies for metastatic ccRCC (1st line)

25. Targeted Therapies for metastatic ccRCC (1st line)

26. Pazopinib vs Sunitinib (1st line)

27. COMPARZ study

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

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

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

32. Immunotherapies for metastatic ccRCC (2nd line)

33. 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

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

35. Subgroup analyses of Overall Survival

36. PFS

37. Objective response rate

38. Adverse Events

39. 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

40. ESMO 2016 guidelines for metastatic ccRCC

41. ESMO 2016 guidelines for metastatic ccRCC

42. 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

43. 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???

44. Thank You….