Renal Cancer: Front line therapy
description
Transcript of Renal Cancer: Front line therapy
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