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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Renal Cancer: Front line therapy

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Renal cancer front line therapy

Renal Cancer: Front line therapy

Walter Stadler


Renal cancer front line therapy

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|


Renal cancer front line therapy

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


Renal cancer front line therapy

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


Renal cancer front line therapy

International prognostic model

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


Renal cancer front line therapy

AG013736

X

X

Sunitinib

Sorafenib

Pazopanib

Axitinib

X


Renal cancer front line therapy

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


Renal cancer front line therapy

Kinase interaction map

Sorafenib

Sunitinib

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


Renal cancer front line therapy

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


Renal cancer front line therapy

First line: Axitinib vs Sorafenib

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


Renal cancer front line therapy

VEGF Pathway inhibitors in renal cancer


Renal cancer front line therapy

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


Renal cancer front line therapy

mTOR Inhibitors

Sirolimus (Rapamycin)

Temsirolimus

Everolimus (RAD001)


Renal cancer front line therapy

First line: Temsirolimus vs IFNA

Renal Cancer|


Renal cancer front line therapy

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


Renal cancer front line therapy

Sunitinib versus everolimus sequential

Renal Cancer|


Renal cancer front line therapy

mTOR toxicities

  • Metabolic

    • Hyperglycemia

    • Hyperlipidemia

    • Increased creatinine

  • Integument

    • Diarrhea

    • Mucositis

    • Pruritic rash

  • Systemic

    • Fatigue

    • Edema

    • Pneumonitis

  • Infectious risks

  • Hematologic

    • Thrombocytopenia


Renal cancer front line therapy

mTOR inhibitors

*Poor prognosis only, included non-clear cell


Renal cancer front line therapy

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


Renal cancer front line therapy

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


Renal cancer front line therapy

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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