MANAGEMENT OF METASTATIC RENAL CELL CARCINOMA. please read and if you have anything to share/feedback, please mail me at farazrizvi.amu@gmail.com. Since now this is paid membership on slideshare, if you want original slides, feel free to ask me on my email

1. METASATIC RENAL CELL
CARCINOMA- WHAT’S
NEW?
10TH March 2022
(WORLD KIDNEY DAY)
DR. FARAZ BADAR
SENIOR RESIDENT
D/O RADIOTHERAPY (JNMCH, AMU, ALIGARH)

2. LET’S FIRST REVISE THE
BASICS

3. BASIC FACTS ON EPIDEMIOLOGY AND
RISKS
• 2 % of malignancies worldwide, incidence increasing
• Median age 65 years, M:F = 2:1
• Risk Factors
• Smoking (strongest… 38% ↑↑ risk in a meta-analysis)
• Obesity
• Hypertension
• ?Hemodialysis
• Familial (VHL disease, Birt-Hogg-Dube…)

4. PATHOLOGIC CLASSIFICATION
• 16 subtypes in WHO classification
• Major are
• Clear cell (70- 80%)
• Papillary type I and II (5-10%)
• Chromophobe (<5%)
• Collecting duct

5. MOLECULAR BIOLOGY
• Familial, inherited vs sporadic, non familial
• 4% of RCCs are familial
• >90% Clear cell RCC  somatic mutation in VHL gene @3p
• VHL: Tumor suppressor gene
• Downregulates HIF-ɑ…..mutation l/t overexpression - VEGF/PDGF/TGF ↑

6. CLINICAL FEATURES
• Localized disease: Asymptomatic in 2/3rd to 3/4th
• Metastatic disease: variable presentation depending on site
• Sites: Lungs , liver, bone and brain
• Metastasis to unusual sites: fingertips, eyelids, face, nose

7. Approximately one third of patients treated with curative intent will develop metastatic
disease recurrence1.
30% of patients have metastatic disease at their initial presentation1

8. RISK STRATIFICATION
75% -80% of mRCC fall in poor or intermediate risk categories
MSKCC  IFN ERA
IMDC  TKI ERA

9. MANAGEMENT
RECENT UPDATES

10. MANAGEMENT OPTIONS IN 2022
• Cytoreductive nephrectomy
• Systemic therapies
• Targeted agents
• VEGF directed therapies
• Inhibitors of mTOR
• Immunotherapy
• IL-2
• IFN- α
• IMMUNE CHECKPOINT INHIBITORS

11. CYTOREDUCTIVE
NEPHRECTOMY
STILL IN THE RACE

12. Flanigan RC et al. New EnglJ Med 2001; 345:1655-9.
Red: SUNITINIB ALONE
BLUE: NEPHRECTOMY PLUS SUNITINIB
MéjeanA et al. New EnglJ Med 2018; 379:417-27.
CARMENA TRIAL
CONLUSION: CN beneficial in pre TKI era,
no level I evidence to use in 2022,
NCCN recommends it (in ECOG PS<2, NO BRAIN METS)

13. CLASSICAL IMMUNOTHERAPY – ROLE OF IL-2 AND IFN
• Standard of care before targeted therapy
• High dose IL-2 still has a category 2B recommendation by NCCN
• Single agent IFN no longer used
• IFN + Bevacizumab was approved and recommended till recently
• NCCN/ ESMO removed the combo from recent guidelines

14. UPDATE HIGHLIGHTS : NCCN
THE ERA OF COMBINATION IMMUNE +
TARGETED THERAPY HAS ARRIVED

15. UPDATE HIGHLIGHTS : ESMO
SAME COMBOS AS CAT 1 NCCN

16. IN SHORT…
• New TKI added  CABOZANTINIB (CARBOSUN TRIAL)
• Spurt of Phase III data accumulation
• Till 2018-19, TKIs alone was SOC.
• Immune checkpoint inhibitors driving force with established TKIs
• ICI-based therapy particularly active in sarcomatoid
• ESMO/NCCN  Sunitinib still 1st line, if ICI not available.

17. PRACTICE CHANGING TRIALS

18. SOME IMPORTANT AGENTS

19. SUNITINIB
• VEGF TKI
• Taken orally
• Acts against VEGF receptors 1,2,3 and PDGF receptor Beta
• A/E: Fatigue, diarrhea, mucositis, Hypertension, hand-foot syndrome
• SOC as monotherapy from 2006- 2015/16
• Dose: 50 mg OD for 4 weeks f/b 2 weeks off
• Alternate: 50 mg OD 2 weeks on/1 week off

20. CARBOZANTINIB
• Multitargeted TKI
• VEGF….MET….AXL….are the targets
• Dose: 60 mg OD
• METEOR - Improves PFS and ORR vs Everolimus
• A/E: HTN, fatigue, diarrhea
• FDA approved in 2nd line in 2016
• CARBOSUN  improves median PFS and ORR vs SUNITINIB
• INDICATION: 2nd line setting in clear cell, cat 1 in non clear cell
(multiple targets)

21. NIVOLUMAB
• Human monoclonal antibody
• Blocks PD-1 (programmed death receptor-1)
• PD-1 expressed on T sells
• Its interaction with PD ligands blocks immune response
• Dose: 3mg/kg IV every 2 weeks until progression
• A/E: colitis, DM, hypophysitis, pneumonitis

22. TAKE HOME MESSAGE
• Clear cell RCC m/c type
• LN, lungs and bone mets….look for uncommon sites too
• No role of conventional chemo
• RT mets, palliation (SABR)
• ccRCC’s Achilles heel: Angiogenesis & Immunogenicity
• TKI + PD-1 inhibitors have invaded mRCC space
• Stick to TKIs till logistics become favourable

23. THE EVOLUTION….

24. CHECKMATE 214 ADVERSE EVENTS

25. KEYNOTE- 426 ADVERSE EVENTS

26. KEYNOTE- 426 ADVERSE EVENTS