Renal Cancer: Front line therapyWalter 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– 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|

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

Gordan, et al; Cancer Cell, 2008Beroukhim, et al; Cancer Res, 2009CGA Network, Nature, 2013

Brannon, et al, Genes Cancer, 2010

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, 2010Varela, et al; Nature, 2011Liu, et al, Science, 2009Kapur, et al. Lancet Oncol, 2013

CGA Network, Nature, 2013

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

International prognostic modelβ SE

Square root of days from diagnosis to study entry −0.0192 0.002

ECOG performance status 0 −1.524 0.11

ECOG performance status 1 −0.838 0.11

Number of metastatic sites 0.324 0.032

Protocol immunotherapy −0.574 0.094

Natural log of hemoglobin −2.47 0.20

Natural log of LDH 0.611 0.062Square root of white blood count 0.623 0.071

1/Square root of alkaline phosphatase −6.665 1.39

Serum calcium 0.105 0.033

AG013736

XX X Sunitinib SorafenibPazopanib Axitinib

Bevacizumab/IFNA Outcome

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

IFN: Median OS 17.4 months

Stratified log-rank p=0.069

Time(months)

0 6 12 18 24 30 36 42 48 54 60

0.0

0.2

0.4

0.6

0.8

1.0

0 6 12 18 24 30 36 42 48Time(months)

0.0

0.2

0.4

0.6

0.8

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

Progression Free Survival Overall Survival

Kinase interaction map

Sorafenib Sunitinib

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

9

0 3 6 9 12 15 18 21 24 27 30 33 36Time (months)

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Ove

rall

Surv

ival

Pro

babi

lity

Sunitinib (n=375) Median: 26.4 months (95% CI: 23.0 - 32.9)IFN- (n=375)

Median: 21.8 months (95% CI: 17.9 - 26.9)

Hazard Ratio = 0.821(95% CI: 0.673 - 1.001)p =0.051 (Log-rank)

375 44 / 326 38 / 283 48 / 229 42 / 180 14 / 61 4 / 2nDeath/nRisk Sunit375 61 / 295 46 / 242 52 / 187 25 / 149 15 / 53 1 / 1nDeath/nRisk IFN-

First line: Sunitinib vs IFNA

Total DeathSunitinib 190IFN- 200

Kaplan–Meier Estimates of Progression-free Survival According to Independent Review.First line: Sunitinib vs Pazopanib

Motzer RJ et al. N Engl J Med 2013;369:722-731.

11

First line: Axitinib vs Sorafenib

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

VEGF Pathway inhibitors in renal cancer

Agent(s)Context of Definitive Trial(s)

Comparator No Prior Therapy

Prior IL2 or IFNA

Prior VEGF Pathway

Outcome

Bevacizumab/IFNA IFNA X PFS (bev)

Sunitinib IFNA X OS (sun)

Sorafenib Placebo X PFS (sor)

Pazopanib Placebo X X PFS (Paz)

Axitinib Sorafenib X PFS (Ax)

Axitinib Sorafenib X None

Pazopanib Sunitinib X None

Tivozanib Sorafenib X X OS (sor)

Dovitinib Sorafenib X (and 1 prior mTOR)

None

VEGF pathway inhibitor toxicities• Cardiac (~73%)

• Hypertension• Reversible Posterior

Leukoencephalopathy• MI• CVA

• CHF • Integument

• Hand/Foot• Mucositis• Diarrhea

• Systemic• Fatigue• Dysgeusia

• Metabolic• Liver toxicity

• Hypothyroidism

Hall, et al. J Am Coll Cardiol HF, 2013

mTOR Inhibitors

Sirolimus (Rapamycin) Temsirolimus

Everolimus (RAD001)

15Renal Cancer|

First line: Temsirolimus vs IFNA

Comparative and sequential data

Everolimus10 mg/day

Sunitinib50 mg/day***

2nd Line

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

Primary• PFS-1st line

Secondary• Combined

PFS• ORR-1st line• OS

• Safety

Study endpoints

Cross-over upon

progression

1 : 1

RANDOMIZ

E**

Everolimus10 mg/day

SCREEN

Sunitinib50 mg/day***

1st LineN = 471

Motzer, et al; ASCO 2013

17Renal Cancer|

Sunitinib versus everolimus sequential

mTOR toxicities• Metabolic

– Hyperglycemia– Hyperlipidemia– Increased creatinine

• Integument– Diarrhea– Mucositis– Pruritic rash

• Systemic– Fatigue

– Edema

– Pneumonitis

• Infectious risks• Hematologic

– Thrombocytopenia

mTOR inhibitors

AgentContext of Definitive Trial

Comparator No Prior Therapy

Prior VEGF Pathway

Outcome

Temsirolimus* IFNA X OS (tem)

Everolimus Placebo X PFS (ev)

Temsirolimus Sorafenib X OS (sor)

Everolimus Sunitinib X OS (sun)

*Poor prognosis only, included non-clear cell

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

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

22Renal Cancer|

RCC front line therapy• Current pragmatic decisions based on side effect profiles

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