Ahmed Zeeneldin

Associate professor of Medical Oncology , NCI2013

¡ AdenoCA: § Clear§ Papillary§ Chromophobe§ Unclassified§ Sarcomatoid

¡ TCC of renal pelvis¡ Rare tumors

¡ Metastatic: lung, ovary, colon, breast

TNM staging

T1 T2 T3 T4 M1

N0 I (95%) II (80%) III (65%) IV (25%) IV

N1 III III III IV IV

T1: limited to kidney <= 7cmT1a: <=4cmT1b: >4-7 cm

T2: limited to kidney > 7cmT2a: 7-10 cmT2b: >10 cm

T3: outside capsule but limited to Gerota’s fasciaT3a perinephric fat and limited to Gerota’s fascia, OR RV T3b: infradiaph IVCT3c: supradiaph IVC or IVC wall

T4: beyond Gerota’s fascia or into adrenal

N1: one + LN

M1: mets

¡ H&P: § PS >1§ Time from Dx to start of systemic therapy <1y

¡ Lab: § CBC: HB <1N, ANC >1N& Plts>1N§ KFT & urine§ LFT§ Others: calcium>10, LDH>1.5N, coagulation profile

¡ Imaging:§ CT with contrast: CAP§ MRI if we cannot use CT e contrast : CAP or to detect IVC invasion§ Others if indicated: MRI/CT brain, Bone scan§ PET alone : is not standard due to high false positive and negative

¡ Needle biopsy: diagnostic and guide surveillance

§ Local Tx▪ Surgery▪ Thermal ablation, RFA▪ RT: limited role

§ Systemic Tx: ▪ Chemotherapy not in clear cell type▪ Cytokines▪ Targeted therapy:

▪ VGEF pathway: TKIs, anti-VEGF mcAb▪ mTORi

§ Surveillance ▪ Limited life expectancy▪ Severe Comorbidities

Stage TNM Surgery RTx CTx Cytokine and Targeted therapy

I T1: <4 cm<7om

PN*/RN No No No adjuvant

II T2<10 cm>10 cm

RN No No No adjuvant

III T3N1

RN No No No adjuvant

IV T4M1

RN/CRS/Metastatectomy Bone/brain met

No** Yes

* in T1 tumors (up to 7cm) Surveillance may be used in selected cases and thermal ablation if surgically unfit **May be given in non-clear cell histology

PN: Partial nephrectomy, RN: radical nephrectomy, CRS: cytoreductive surgery

¡ Surgery§ Thermal ablation§ Surveillance

¡ No role for adjuvant RTx or systemic Tx

Tan et al. JAMA. 2012;307(15):1629-35.

Simmons et al., Urology. 2009;73(5):1077-82

T1a (<4cm) RN PNNo >5000 <2000Death due to RCC 2% 4%RR of death 1 0.54 (0.34-0.85)

T1b-T3 (>4cm) RN PNNo 75 35Overall mortality 11% 11%RCC specific mortality 3% 3%Recurrence 3% 6% (NS)

OS: HR 1.07 (0.89, 1.28)Scherr et al. BMC CANCER; MAR 31, 2011; 11

DFS: HR 1.03 (0.87, 1.21)

¡ Stage IV categories:§ Locally advanced: T4§ Distant: M1

¡ Options:§ Surgery: § RTx: Bone or Brain mets§ Systemic therapy:

¡ Types of surgery:§ 1ry : RN or CRS§ 2ry: Metastatectomy

▪ Solitary mets: lungs, bone and brain¡ Beneficial for patients treated with:§ Cytokines: INF, IL§ Targeted therapy

¡ More benefit in:§ Lung only mets§ Good prognostic features (0 score)§ Good PS

T1-3 T4

M0 PN/RN CRS

M1 multiple RN CRS

M1 single* RN +metastatectmoy

CRS+ metastatectmoy

¡ Resectable Stage IV RCC¡ RR of death decreased by

30%¡ Independent of § patient performance status, § the site of metastases and § the presence of measurable

disease.

Flanigan et al, N Engl J Med. 2001;345(23):1655-9.

INF alone

INF + Surgery

MOS (P<0.002) 7.8 m 13.6 m

OS BENEFIT WAS MORE WITH PS>80%

VEGFTx alone CSR+VEGFTx

MOS p<0.01 9m 20m

¡ Indications§ Metastatic (M1)§ Irresectable (T4)§ Recurrent

¡ Risk stratification

¡ Memorial Sloan Kettering cancer center (MSKCC): § for Advanced stages treated with immunotherapy

▪ INF treated¡ International mRCC Database Consortium (IMRDC)

prognostic model or Heng’s model:§ For patients treated with anti-VEGF therapy

▪ sunitinib, sorafenib, or bevacizumab plus interferon

INF ERAMSKCC MODEL

1. Clinical1. Interval from original

diagnosis to the start of cytokine therapy < 1 year

2. KPS < 80 (ECOG >1)2. Lab:

1. Calcium (corrected S) > 10mg/dl (2.5 mmol/liter)

2. HB <1 LLN---------3. LDH >1.5 ULN

ANTI-VEGF ERAIMRDC (HENG) MODEL

1. Clinical1. Interval from original

diagnosis to the start of anti-VEGF therapy < 1year

2. KPS < 80 (ECOG >1)2. Lab:

1. Calcium (corrected S) > 10mg/dl (2.5 mmol/liter)

2. HB <1 LLN3. ANC >1x ULN4. Plts > 1x ULN--------------------------

¡ Chemotherapy not in clear cell type¡ Cytokines¡ Targeted therapy:

¡ Agents:§ IL-2 (not other ILs same results as combinations with LAK)§ INF a (not INFγ)

¡ Mechanism of action§ Poorly understood§ Induction of antitumor immunity through direct killing of tumor

cells by activated T cells (LAK) and natural killer (NK) cells§ INFa also may have antiangiogenic effects

¡ May be used in§ Goof PS 0-1§ Good organ function§ Clear RCC + alveolar features§ Better after nephrectomy

Drug Route Dose DurationIL-2 (Proleukin)

IV 15min 600,000 -720,000 IU/kg q 8h, D1-5

q2w X2à q3m X3*

IV or SC 0.1 dose ? X2 q2w àX3 q3m*

INFa(roferon a)

SC 9 MU 3times q w Continuous

IL2 + INFa SC Both: 5MU/sqm ?Continuous

Drug Toxicity RR% CR% RD m PFS m OS mIL-2 +++++ 20 10 19m ~17m

++ 13 Lower ~15mINFa ++ 15 3 <12m 5m ~13m

(+4m)IL2 + INFa ++ 10 15m 13m

IL2

¡ Hypotension ¡ Cardiac arrhythmia ¡ Metabolic acidosis ¡ Fevers/chills ¡ Nausea/vomiting ¡ Dyspnea¡ Peripheral edema ¡ Oliguria, rising creatinine ¡ Transminase elevations ¡ Neurotoxicity ¡ Skin rash, pruritus

INFA

¡ Less than IL-2¡ Fatigue¡ Fever, chills¡ myalgia¡ Flu-like¡ Nausea¡ rash

INFa is recommended to be the control arm in future studies

¡ VEGF pathway§ VEGF Receptor-TKI§ Anti-VEGF mcAb

¡ mTOR inhibitors

TKI Route Dose Duration ToxicitySunitinb (sutent) PO 50mg qd x 4w

and 2w offContinuous

Pazopanib (Votrient) PO 800 mg qd Continuous LiverAxitinb (Inlyta) PO 5mg BID ContinuousTivozanib (AV 951 ) PO 1.5 mg qd 3w

and 1w offContinuous

Sorafinib (Nexavar) PO 400mg BID Continuous

mcAb Route Dose Duration ToxicityBevacizumab (avastin) +INF

IV 10 mg/kg q2w Continuous

PFS: 11 VS 5 M (P <0.001)

¡ 90% had nephrectomy¡ 90% were low or intermediate risk

Motzer et al, N Engl J Med 2007;356:115-124.

OS : 26 M VS 22 M (P0.051)

No improvement in PFS in poor risk patinets

¡ Mainly retrospective data¡ Effectiveness following cytokine therapy¡ effective after soreafenib and vice versa

- Most patients were low or intermediate risk- OS still immature- PFS all p <0.001

all patinets: 9m vs 4mTx naieve: 11m vs 3mprior cytokine: 7m vs 4m

Cora et al, JCO 2010;28:1061-1068.

Pazopanib Sunitinb

No 557 553

PFS 8.4m 9.5m NS

OS 28.4m 29.3m ns

RR 31% 25% 0.03

No improvement in PFS Cross over of INF patients and dose escalation of sorafenib

improvement in PFS (6m vs 3m) Cross over of placebo patientsàOS (19 vs 16 m, NS)

Can also be used after sunitinb or avastin

improvement in PFS (7m vs 5m)Cytokine pretreated: PFS 12m vs 7m

Sunitinb pretreated: PFS 5vs 3m

¡ PFS: ++ (5à8.5 m) OS not matureCALGB trial Brian et al, Clin Oncol 2008; 26:5422-5428

¡ PFS: ++ (5à10 m, S) OS (21 vs 23m , NS)AVERON trial Brian et al, Clin Oncol 2008; 26:5422-5428

¡ Subgroup analysis: not poor MSKCC riskAVERON trial Brian et al, Clin Oncol 2008; 26:5422-5428

¡ TKIs may be used after Avastin¡ Sorafenib after sunitinb: 10%RR¡ Axitinib after sorafenib: 23% RR

TKI Vs. RR% CR% SD% PFS m OS m

Sunitinb (sutent) INF 31 vs.6 0 48 vs49 11 vs. 5m 26 vs. 22*

Pazopanib (Votrient) Placebo 30 vs 3 9 vs 4 m 23 vs 22 m

Axitinb (Inlyta) sorafenib 18 vs 9 27 vs 20 7 vs. 5m ??

Tivozanib (AV 951 ) sorafenib 33 vs 23 12 vs 10 m ??

Sorafinib (Nexavar) Placebo 5.5 vs. 2.5 m 18 vs 15m

mcAb Vs. RR% CR% SD% PFS m OS m

Bevacizumab (avastin) +INF

INF 31 vs. 13 10 vs 5.5 23 vs 21 m

¡ Hypertension: 25%¡ Renal impairment RR1.36¡ Arterial thromboembolism: 1.4%¡ Thyroid dysfunction¡ Cutaneous toxicity : hand foot syndrome¡ Glucose metabolism: hypoglyemia¡ Hepatotoxicity¡ Muscle wasting

¡ In 25% of patients receiving Sunitinib or sorafenib¡ Severe in 25% of the 25% i.e. 6%¡ May predict good response to TKI

HT NO HT

RR 55% (x5) 10%

PFS 13m (X5) 3m

OS 31m (x5) 7m

Drug Route Dose Duration ToxicityTemsorilimus (Torisel) IV 15mg q w Continuous

Everolimus (Afinitor) PO 10 mg qd Continuous

Drug Vs. RR% CR% SD% PFS m OS m

Temsorilimus (Torrisel) INF 6m vs 3m 11 vs 7ms

Everolimus (Affinitor) placebo 1vs 0 63 vs 32 5m vs 2 m 15 vs 14.s m

OS

PFS

PFS: 5VS 2 M (P <0.001)

Independent prognostic factors for shorter OS low performance status, high corrected calcium, low hemoglobin, and prior sunitinib (P < .01).

Cross over

OS: 14.8 VS 14.4 M (P = 0.18)

¡ Common: asthenia, rash, anemia, nausea, and anorexia¡ Hypersensitivity ¡ pneumonitis

Regimen Setting Therapy Options

1st line

MSKCC risk: Good (0) or intermediate (1-2)

Sunitinibpazopanibbevacizumab + IFN-α

High-dose IL-2

MSKCC risk:Poor (>2)

Temsirolimus Sunitinib

2nd line

Cytokine-refractory

SorafenibSunitinibpazopanib

Temsirolimusbevacizumab

TKI Refractory Everolimus

Sequential TKIs (Sorafenib, Sunitinibpazopanib) or BevacizumabTemsirolimus

mTOR inhibitors TKI Bevacizumab

¡ Bevacizumab (+erlotinib) x 8 w§ PFS = 11m§ OS = 25 m§ Most was SD

¡ Sunitinb 2-3 cycles § PR: 6%§ Tumor necrosis was common§ PFS: 8m

¡ Sorafenib 33 days§ Shrinkage by 10%

¡ Temsorilimus: No 1¡ TKIs: sorafenib and sunitinb¡ Erlotinib¡ Chemotherapy: Dox-Gem with sarcomatoid

varaints¡ Collecting duct: Gem-cis/carbo

Stage TNM Surgery RTx CTx Cytokine and Targeted therapy

I T1 PN*/RN No No No adjuvant

II T2 RN No No No adjuvant

III T3N1

RN No No No adjuvant

IV T4M1

RN/CRS/Metastatectomy Bone/brain met

No** Yes-àrisk stratification

Workup

Stage I-III

(T1-3 & N-0r N+, M0)

Surgery (PN, RN)

Stage IV

(T4 or M1)

Surgery

(RN, CRN, met’mySystemic therapy

(Cytokines, VGEF targeted, mTORi)

Good risk IL-2

Sunitinib

Pazopanib

INF-bevaciz

Intermediate riskSunitinib

Pazopanib

INF-bevaciz

Poor risktemsorilimus

?everolimus