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Renal Cancer: Front line therapy

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Renal Cancer: Front line therapy. Walter Stadler. Pathology. Clear cell (conventional) Fuhrman grading 1-4 Papillary Type 1 & 2 (by histology) OR Class 1 & 2 (by molecular profiling) Mucinous -tubular and spindle? Clear-cell papillary Chromophobe

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slide2
Pathology

Clear cell (conventional)

  • Fuhrman grading 1-4

Papillary

  • Type 1 & 2 (by histology) OR Class 1 & 2 (by molecular profiling)
  • Mucinous-tubular and spindle?
  • Clear-cell papillary

Chromophobe

  • Genetically related to benign oncocytoma

Collecting duct

  • Genetically related to urothelial
  • Medullary (only in sickle cell trait or disease)

TFE-3 translocation tumor

  • Same translocation as alveolar-soft part sarcoma
  • More than one translocation

Renal Cancer|

slide3
Clear cell subtypes

By VHL status

  • Wild type (12%)
  • HIF-1/HIF-2 express (57%)
  • HIF-2 express (30%)

2 – 4 clusters by expression profile

  • mRNA
  • miRNA

Brannon, et al, Genes Cancer, 2010

Gordan, et al; Cancer Cell, 2008

Beroukhim, et al; Cancer Res, 2009

CGA Network, Nature, 2013

slide4
Other important alterations

Histone modification gene mutatations

  • SETD2 (histone H3 methyltransferase, ~15%)
  • JARID1C (histone H3 demethylase)
  • UTX (histone H3 demethylase)

Chromatin remodeling complex mutations

  • PBRM1 (~40%)
  • BAP1 (~15%)

Ubiquitin E3 ligase complex alterations

  • SPOP overexpression in 99% ccRCC

PI3K/AKT/mTOR pathway activation (28%)

Dalgliesh, et al; Nature, 2010

Varela, et al; Nature, 2011

Liu, et al, Science, 2009

Kapur, et al. Lancet Oncol, 2013

CGA Network, Nature, 2013

slide5
International prognostic model

Manola J et al. Clin Cancer Res 2011;17:5443-5450

slide6

AG013736

X

X

Sunitinib

Sorafenib

Pazopanib

Axitinib

X

slide7

Time(months)

Bevacizumab/IFNA Outcome

Overall Survival

Progression Free Survival

1.0

--Bev/IFNA: median PFS 8.4 months

IFNA: Median PFS 4.9 months

HR= 0.71 (95% CI=0.6-0.8)

Stratified log-rank p<0.0001

----BEV/IFN:Median OS 18.3 months

IFN: Median OS 17.4 months

Stratified log-rank p=0.069

1.0

0.8

0.8

0.6

0.6

0.4

0.4

0.2

0.2

0.0

0

6

12

18

24

30

36

42

48

0.0

Time(months)

0

6

12

18

24

30

36

42

48

54

60

slide8
Kinase interaction map

Sorafenib

Sunitinib

Karaman, et al Nature Biotech. 26:127, 2008

slide9
First line: Sunitinib vs IFNA

Total Death

Sunitinib 190

IFN-a 200

9

motzer rj et al n engl j med 2013 369 722 731
Motzer RJ et al. N Engl J Med 2013;369:722-731.

Kaplan–Meier Estimates of Progression-free Survival According to Independent Review.

First line: Sunitinib vs Pazopanib

slide11
First line: Axitinib vs Sorafenib

The Lancet Oncology Volume 14, Issue 13 2013 1287 - 1294

slide13
VEGF pathway inhibitor toxicities

Hall, et al. J Am CollCardiol HF, 2013

  • Cardiac (~73%)
    • Hypertension
      • Reversible Posterior Leukoencephalopathy
      • MI
      • CVA
    • CHF
  • Integument
    • Hand/Foot
    • Mucositis
    • Diarrhea
  • Systemic
    • Fatigue
    • Dysgeusia
  • Metabolic
    • Liver toxicity
  • Hypothyroidism
slide14
mTOR Inhibitors

Sirolimus (Rapamycin)

Temsirolimus

Everolimus (RAD001)

slide16
Comparative and sequential data

R

A

N

D

O

M

I

Z

E**

Everolimus10 mg/day

Sunitinib50 mg/day***

Study endpoints

SCREEN

  • Primary
  • PFS-1st line
  • Secondary
  • Combined PFS
  • ORR-1st line
  • OS
  • Safety

Cross-over upon progression

1 : 1

Everolimus10 mg/day

Sunitinib50 mg/day***

N = 471

1st Line

2nd Line

*NCT00903175. **Stratified by MSKCC prognostic factors. ***4 weeks on and 2 weeks off.

Motzer, et al; ASCO 2013

slide18
mTOR toxicities
  • Metabolic
    • Hyperglycemia
    • Hyperlipidemia
    • Increased creatinine
  • Integument
    • Diarrhea
    • Mucositis
    • Pruritic rash
  • Systemic
    • Fatigue
    • Edema
    • Pneumonitis
  • Infectious risks
  • Hematologic
    • Thrombocytopenia
slide19
mTOR inhibitors

*Poor prognosis only, included non-clear cell

slide20
Non-clear cell: comparative trials

Sunitinib vs Temsirolimus

  • Central European Society for Anticancer Drug Research
  • Accrual complete, 22 pts total

Sunitinib vs Everolimus

  • Duke sponsored multi-institutional
  • Accrual complete

Sunitinib vs Everolimus

  • MDAnderson sponsored
  • 108 planned
slide21
RCC front line therapy

VEGF pathway directed agents are active in clear cell RCC

  • Sunitinib, Pazopanib, Sorafenib, Axitinib and Bevacizumab/IFNA improve PFS
  • There are biochemical and side-effect profile differences, but little clinical differences
  • Pazopanib is first line reference standard

mTOR inhibitors are active in RCC

  • Temsirolimus improves survival of poor prognosis RCC over IFNA
  • Role of mTOR inhibitors is decreasing

Immunotherapy is active

  • HD-IL2 leads to long term complete responses, but only in ~5% of highly selected patients
  • PD1 pathway inhibitors likely to play a role
slide22
RCC front line therapy

Current pragmatic decisions based on side effect profiles

Future decisions must be based on pathologic and molecular sub-typing

Renal Cancer|

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