Kinase inhibitors in localized and metastatic kidney cancers inmetastatic kidney cancers in

senior adult patientssenior adult patients.Jean-Pierre Droz, MD, PhD, ,

Professor of Medical Oncology, Claude-Bernard Lyon 1 University Geriatric Oncology Program

PROLOG program of the French National Cancer Institute Centre Léon-Bérard, Lyon, France

Three major pathological subgroupsThree major pathological subgroups.

Clear cell Papillary Chromophobe cell

VEGF receptor blockade.

VEGFBevacizumab

VEGF

VEGFR-2

Vascular endothelial cellplasma membrane

PI3K RafP PSorafenib

AxitinibSorafenib

Akt/PKB MEKP PVascular permeability

SorafenibSunitinib

p38MAPKErkEndothelial cell

survival

Endothelial cell

Temsirolimus

Rini B, et al. J Clin Oncl. 2005;23:1028-1043.

Endothelial cell migration

Endothelial cell proliferation

0.80.91.0

0 50.60.70.8

0 20.30.40.5

Sunitinib (n=375)M di t h d

00.10.2 Median not reached

IFN-α (N=375)Median not reached

Hazard Ratio = 0.65(95% CI: 0.449–0.942)P = 0.0219*

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16Durée (Mois)

Overall survival= S(ASCO 2008)

Progression-freeSurvival= SSurvival= S

Hypertension 24%/8%

Hand /foot syndrom 20%/5% Trials’inclusion criteriaNausea /vomiting 44%/3%Diarrhea 53%/5%

Rash 19%/1%

Trials inclusion criteriaand toxicities.

Anemia 71%/3%

Leucopenia /neutro 78%/5%

Thrombocytopenia 65%/8%Median age 62 years (27-87)

y p

Asthenia 51%/7%

Pain 11%/1%

Anorexia NR

Age > 70 years ?

Perform. status ≥ 80 (100= 62%)Anorexia NR

Hyperglycemia NR

Lipids /lipase 30-40%/1%

Edema NR

Creatinine clear. + ???

Cardiac comorb. significant < 1y?Edema NR

Creatinine increase 66%/1%

Weight loss NR

Hypertension controlled

Haematological +Stomatitis 25%/1%

Liver toxicity # 50%/2%

Cardiac toxicity 10%/2% (EVF)

Liver +

Lipids Proteinuria NR

Thrombosis NR

Perforation NR

Coagulation +

NEJM 2007;356:125-134

O ll i l NSOverall survival= NS

Progression-free Survival= S

Hypertension 17%/4%

Hand /foot syndrom 30%/1%

Trials’inclusion criteriaNausea /vomiting 20%/0%Diarrhea 43%/2%

Rash 40%/1%

Trials’inclusion criteriaand toxicities.

Anemia 34%/3%

Leucopenia /neutro NR

Thrombocytopenia NR

Median age 58 years (19-86)

Age > 70 years ?y p

Asthenia 35%/5%

Pain 10%/0%

Anorexia NR

Perform. status ≥ 60 (100= 49%)

Creatinine clear. ?

Anorexia NR

Hyperglycemia NR

Lipids /lipase 12%/7%

Edema NR

Cardiac comorb. ?

Hypertension ?Edema NRCreatinine increase NR

Weight loss 10%/0%

yp

Haematological +Liver +Stomatitis NR

Liver toxicity NR

Cardiac toxicity 1 pt

Liver +Lipids ?

Proteinuria NR

Thrombosis 1 pt

Perforation NR

Coagulation +

Overall and Progression-free survivalsare significantly improved.

Temsirolimus > combination > IFN.

Overall survival= S

Hypertension NR

Hand /foot syndrom NR

Nausea /vomiting 37%/2% Trials’inclusion criteriagDiarrhea 27% /1%

Rash 47%/4%

Anemia 45%/20%

Trials inclusion criteriaand toxicities.

Median age 59 years (23-86)

A > 70 30% (> 65 )

Anemia 45%/20%

Leucopenia /neutro 6%/1%

Thrombocytopenia 14%/1%

A th i 51%/11 % Age > 70 years 30% (> 65 y)

Perform. status ≥ 60

Asthenia 51%/11 %

Pain 28%/5%

Anorexia 32%/3%

Creatinine clear. # ≥ 60 (< 80= 82%)

Cardiac comorb. ?

Hyperglycemia 26%/11%

Lipids /lipase 24%/1%

Edema 27%/2%

Hypertension ?

Haematological +

Creatinine increase 14%/3%

Weight loss 19%/1%

Stomatitis NR

Liver +

Lipids +

Liver toxicity NR

Cardiac toxicity NR

Proteinuria NR

Coagulation Proteinuria NR

Thrombosis NR

Perforation NR

Overall survival= NSOverall survival= NS

Progression-freeSurvival= SSurvival S

Hypertension 26%/3%

Hand /foot syndrom NR Trials’inclusion criteriaNausea /vomiting NRDiarrhea 20%/2%

Rash NR

and toxicities.

Anemia NRLeucopenia /neutro 7%/4%

Thrombocytopenia 6%/2% bleeding 33% Median age 61 years (18-81)y p g

Asthenia 33%/12%

Pain NRAnorexia NR

Age > 70 years +

Perform. status ≥ 70(70-80= 23%)

Creatinine clear. +??Anorexia NRHyperglycemia NRLipids /lipase NREdema NR

Cardiac comorb. ?

Edema NRCreatinine increase NRWeight loss NR

Hypertension Not controlled

Haematological +Stomatitis NR

Liver toxicity NR

Cardiac toxicity 1 pt

Liver +Lipids

Proteinuria 18%/7%

Thrombosis 3%/2%

Perforation 5 (1%)

Coagulation +

Summary: standard management.y g

MSKCC Treatment optionsgroups

First- line Second- line

Standard Option Standard Option

favorable Sunitinib Beva+IFNIL2 ?IL2 ?

Sorafenib SunitinibT i

Intermediate-i k

Sunitinib Beva+IFN Temsiro-limus ?

riskPoor- risk Temsiro- Sunitinib

limus

Major treatment limits in elderlyMajor treatment limits in elderly.Sunitinib Sorafenib Temsirolimus Bevacizumab

Median age 62 years (27-87) 58 years (19-86) 59 years (23-86) 61 years (18-81)Age > 70 years ? ? 30% (> 65 y) +Perform. status ≥ 80 (100= 62%) ≥ 60 (100= 49%) ≥ 60 ≥ 70(70-80= 23%)Creatinine clear. + ??? # ≥ 60 (< 80= 82%) +??

Cardiac comorb. significant < 1y? ? ?

Hypertension t ll d ? t ll dHypertension controlled ? controlled

Haematological + + + +Liver + + + +Lipids +Coagulation + + +

Comparative side effects (1)Comparative side effects (1).Sunitinib Sorafenib Temsirolimus Bevacizumab

Hypertension 24%/8% 17%/4% NR 26%/3%

Hand /foot syndrom 20%/5% 30%/1% NR NRNausea /vomiting 44%/3% 20%/0% 37%/2% NRDiarrhea 53%/5% 43%/2% 27% /1% 20%/2%Diarrhea 53%/5% 43%/2% 27% /1% 20%/2%

Rash 19%/1% 40%/1% 47%/4% NRAnemia 71%/3% 34%/3% 45%/20% NRLeucopenia /neutro 78%/5% NR 6%/1% 7%/4%

Thrombocytopenia 65%/8% NR 14%/1% 6%/2% bleeding33%

Asthenia 51%/7% 35%/5% 51%/11 % 33%/12%

Pain 11%/1% 10%/0% 28%/5% NR

= very frequent = frequent

Comparative side effects (2).Sunitinib Sorafenib Temsirolimus Bevacizumab

p ( )

Anorexia NR NR 32%/3% NR

H l i NR NR 26%/11% NRHyperglycemia NR NR 26%/11% NR

Lipids /lipase 30-40%/1% 12%/7% 24%/1% NR

Edema NR NR 27%/2% NR

Creatinine increase 66%/1% NR 14%/3% NR

Weight loss NR 10%/0% 19%/1% NRStomatitis 25%/1% NR NR NRLiver toxicity # 50%/2% NR NR NRCardiac toxicity 10%/2% (EVF) 1 pt NR 1 ptProteinuria NR NR NR 18%/7%Proteinuria NR NR NR 18%/7%Thrombosis NR 1 pt NR 3%/2%Perforation NR NR NR 5 (1%)

Conclusions: difficult to treat elderly!!Conclusions: difficult to treat elderly!!• Few patients included in trials; no specificFew patients included in trials; no specific

reports in elderly.• Inclusion criteria do not allow to include elderly• Inclusion criteria do not allow to include elderly

patients: what behind?M i i i hi h i i ld l• Many toxicities which are important in elderly: HTA, CxVx, anorexia, fatigue /asthenia, hand /foot syndrom, anemia, neutropenia, renal toxicity.

• The need for retrospective /prospective cohort studies.studies.