Adjuvant and Neoadjuvant Approaches to

Renal Cell Carcinoma

Fabio Calabrò

Department of Medical OncologySan Camillo-Forlanini Hospital

Highlights in the management of Kidney CancerRome, November 7-8, 2008

New Approaches to Renal Cell Carcinoma

• Adjuvant therapy• Cytoreductive surgery (upfront

nephrectomy)• Neoadjuvant therapy

New Approaches to Renal Cell Carcinoma

• Adjuvant therapy• Citoreductive suregry (upfront

nephrectomy)• Neoadjuvant therapy

Adjuvant treatment for RCC

Treatment N Author OutcomeRT vs Obs 72 Kjaer Os 50 v 62%

NS

MPA vs Obs 136 Pizzocaro Relapse 33 v 33% NS

Tumor + BCG v Obs 43120

AdlerGalligioni

DFS NSDFS 63 vs 72%

IFN vs Obs 283 Messing OS 5.1 vs 7.4 yrs NS

HD-IL-2 vs Obs 69 Clark Relapse 76 v 65% NS

Aut Tum Vacc vs Obs 553 Jocham PFS 77 v 68% (p=0.02)

IL-2 + IFN v Obs 303 Passalacqua RFS OS NS

HSPPC-96 vs Obs 818 Wood RFS NS

IL-2 + IFN + 5FU vs Obs

309 Aitchison DFS OS (preliminary) NS

Adjuvant Trials in RCC in the TKI’s Era

Rationale

• Poor prognosis for selected groups after nephrectomy

• No proven adjuvant treatment• Efficacy of TKI’s in advanced disease• TKI’s are suitable for prolonged use

Adjuvant Therapy in the TKI’s EraEssentials

• Effective therapy• Feasible therapy• Selection of patients

UCLA Prognostic Groups

Tstage

1 2 3 4

Grade 1-2 3-4 1 >1

PS 0 ≥1 Any Any 0 ≥1

Risk Low Intermediate High

Zisman A. J Clin Oncol 23:4559 2002

Prognostic Models

Center Histology

Surgery

ClinicalVariables

PathVariables

Recurr Accuracy Ext Validation

MSKCC PapillaryChromo

PartialRadical

Disease related

Histo, Size, pT

Localdistant

0.74 No

MSKCC ccRCC PartialRadical

Disease related

Size, pT, G,V.I.,necrosis

LocalDistant

0.82 Yes

MayoClinic

CcRCC Radical pT, N, size G,necrosis, histo

Distant

0.82 No

UCLA All RCC PartialRadical

ECOG PS TNM Grade

LocalDistant

NA No

Crispen PL, Cancer 113:450, 2008

Adjuvant Therapy in RCCPrognostic Molecular Markers

• Cell proliferation / cell cycle regulation• Ki67, p53, p27

• Cell adhesion• EpCAM, VACM

• Apoptosis• Survivin, Smac/DIABLO

• Degradation of the extracellular matrix• MMP-2, MMP-9, uPA

• Hypoxia inducible factors• CA IX, HIF-1

Molecular MarkersPrognostic Model

Kim HL Clin Cancer Res 10:5464, 2004

Adjuvant Trials for RCC

Treatment N Sponsor Outcome

G250Ab v Placebo 856 Wilex Recruiting

Sunitinib vs PlaceboSorefenib vs Placebo

1332 ECOG Recruiting

Sorafenib vs PlaceboSorafenib 1yr vs 3 yr

1656 MRC/EORTC Recruiting

Sunitinib vs Placebo 228 EAU/Pfizer Recruiting

ECOG 2805 (ASSURE)Adjuvant Sorafenib Sunitinib

Unfavorable REnal Cell Carcinoma

Group ASunitinib 50mg (4 capsules) orally q.d. 4 weeks followed by rest 2 weeks for nine cycles†

Group BSorafenib 400mg (2 tablets) orally b.i.d. 6 weeks for nine cycles†

*Accrual goal = 1,332; †one cycle = 6 weeks

Stratification

Tumour–node–metastases

Intermediate or high risk

Very high risk

Histological sub-type Clear cell Non-clear cell

(except collecting ductor medullary)

ECOG PS 0 1

Surgery Laparoscopic Open

Group C

Placebo

Primary objective: disease-free survival

randomization

S-TRAC

High risk ptsT3 N0-x M0

Fuhrman’s grade >2PS >1

ORT4 N0-X

Fuhrman’s grade anyPS any

ORAny T, N1-2

Fuhrman’s grade anyPS any

RANDOMIZATION

Sunitinib 50 mg/die(4w/2w) for 1 year

Placebo for 1 year

SORCEA phase III, randomised, double-blind controlled study comparing SOrafenib with placebo in patients with Resected primary renal

CEll carcinoma at high or intermediate risk of relapse

Patients with resected RCC

athigh or

intermediate risk of relapse

RANDOMISATION

Sorafenib (400mg b.i.d.)

3 years

Sorafenib (400mg b.i.d.)

1yearPlacebo 2 years

Placebo3 years

Adjuvant Therapy in RCCThe Ideal Trial

• Innovative trial design• Translational component• Health economic component• Validation of prognostic models

Adjuvant therapy in RCCConclusions

• Currently, there is NO evidence that targeted therapy will be active as adjuvant treatment

• Immunotherapy and vaccine have limited activity

• TKI’s are under evaluation

New Approaches to Renal Cell Carcinoma

• Adjuvant therapy• Cytoreductive surgery (upfront

nephrectomy)• Neoadjuvant therapy

Cytoreductive surgeryAdvantages

• Decrease of tumor burden and metastatic cells

• Removal of a potential source of angiogenic growth factors

• Enhance response to therapy• Elimination of a source of symptoms• Spontaneous regression of metastases (?)

Cytoreductive surgeryDisdvantages

• Growth of metastatic disease in the recovery period

• Morbidity and mortality associated with any major operation

• Potential for rapid progression despite surgery

Cytoreductive surgeryPhase III Trials Inclusion Criteria

• ECOG PS 0-1• Clear cell histology• No prior treatment• Primary tumor amenable for surgery• Lack of CNS, liver or extensive bone

metastases

Cytoreductive SurgerySWOG 8949 n=246

Median survivalNephrectomy + IFN 11.1 monthsIFN alone 8.1 months P=0.05

Flanigan RC, NEJM 345:1655, 2001

SWOG TrialMedian Survival

Stratified Subgroup IFN alone Nephr + IFN P

All Patients 8.1 11.7 0.012

Performance status

0 11.7 17.4 0.08

1 4.8 6.9

Type of metastases

Lung only 10.3 14.3 0.008

Other 6.3 10.2

Flanigan RC, NEJM 345:1655, 2001

Cytoreductive SurgeryEORTC Trial n=85

Time to progression Overall survival

Mickisch, Lancet 358:966, 2001

Cytoreductive SurgeryCombined Analysis

Group Year N Median SurvivalNephrectomy +

IFN

MSIFN

p

SWOG 2001 246 11 9 <0.05

EORTC 2001 85 18 11 < 0.05

Flanigan(combined)

2004 331 13.6 7.8 < 0.05

31% decrease in risk of death with nephrectomy

Flanigan RC J Urol 171:1071, 2004

Cytoreductive SurgeryCombined Analysis

Group RR %Nephrectomy

+ IFN

RR %IFN

Unable to receive post-surgery IFN

Operative mortality

SWOG 3.6 3.3 NR 1 (0.8%)

EORTC 19 12 NR 1 (2.4 %)

Flanigan(combined)

6.9 5.7 5.6% 2 (1.4%)

Flanigan RC J Urol 171:1071, 2004

Cytoreductive surgerySummary

• Robust data• 2 phase III randomized trials• 40-50% survival advantage

• Safe• Did not delay systemic therapy• No increase in perioperative mortality

• Prognostic Factors (retrospective data)• No hepatic or brain metastases• No collecting duct or sarcomatoid• Good PS (0-1)• Resectability

RCC in 2008

• Sunitinib improves PFS in first-line RCC: 11 vs 5 months; p< 0.001; HR: 0.42)

• Sorafenib improves PFS in second-line RCC: 5.5 vs 2.8 months; p< 0.01; HR: 0.44)

• Temsirolimus improves OS in poor risk metastatic kidney cancer (10.9 vs 7.3 months; p< 0.008; HR:0.73)

• Everolimus (RAD 001) improves PFS in second line (4 vs 1.9 months; p< 0.0001; HR:0.30)

• Bevacizumb + IFN improves PFS in first line (10.2 vs 5.4 months; p< 0.0001; HR:0.63)

Motzer, NEJM 2007, 356: 115-24 Escudier, NEJM 2007, 356: 125-34Hudes , NEJM 2007, 356: 2271-81, Motzer, Lancet 2008, Jul 22 epub

Nephrectomy and targeted therapy Bevacizumab

Author Line Phase Drugs N Nephr%

ORR PFS OS

Bukowski 1 II BevBev/Erlotinib

5351

100100

1314

8.59.9

NR

Yang 2 II Bev HDBev LDPlacebo

393740

908995

1000

4.83.02.5

NS

Avoren 1 III Bev + IFNIFN

327322

100100

30.612.4

10.2

5.4

+

Nephrectomy and targeted therapy Sorafenib

Author Line Phase Drugs N Nephr%

ORR PFS OS

Szczylik 1 II SorafenibIFN

9792

9895

59

5.75.6

NA

TARGET 2 III SorafenibPlacebo

451452

9493

102

5.52.8

17.814.3

Nephrectomy and targeted therapy Sunitinib

Author Line Phase Drugs N Nephr%

ORR PFS OS

Motzer 1 III SunitinibIFN

375375

9189

316

115

NR

Motzer 2 II Sunitinib 106

100 34 8.3 NR

Nephrectomy and targeted therapy Sunitinib

RR PFSmonths

MedianOS

Prior nephrectomy

18% 12 19

No priornephrectomy

9% 6.5 11.1

Szczylik C. Proc ASCO 2008 abstr. # 5124

Nephrectomy and targeted therapy Sunitinib

Szczylik C. Proc ASCO 2008 abstr. # 5124

Nephrectomy and targeted therapy Temsirolimus

Author Line Phase Drugs N Nephr%

ORR PFS OS

ARCC 1 III TemsirolimusTem + IFNIFN

209210207

666767

8.68.14.8

3.83.71.9

10.98.47.3

RAND Appropriateness Panel

• Good surgical risk, – symptoms related to the primary, – limited metastatic tumor burden to the lung or bone

• Good surgical risk and planned immunotherapy– If limited metastatic burden or asymptomatic primary– Extensive metastatic burden if primary symptomatic

Nephrectomy inappropriate

Nephrectomy appropriate

• Poor surgical risk• No primary tumor related symptoms• Extensive metastatic burden

• Poor surgical risk and planned targeted therapy• No symptoms• Limited metastatic burden

Halbert J Cancer 107: 2375, 2006

RAND Appropriateness Panel

Surgical

risk

Symptoms

NephrectomyImmunotherapy

NephrectomyTargeted Therapy

Metastatic burden Metastatic burden

Limited Extensive

Limited Extensive

GoodYes Approp Approp Appropr Uncertai

n

No Appropr Uncertain

Uncertain

Uncertain

PoorYes Uncertai

nUncertain

Uncertain

Uncertain

No Uncertain

Inappropr

Inappropr

InapproprHalbert J Cancer 107: 2375, 2006

RAND Appropriateness Panel

Surgical

risk

Symptoms

NephrectomyImmunotherapy

NephrectomyTargeted Therapy

Metastatic burden Metastatic burden

Limited Extensive

Limited Extensive

GoodYes Approp Approp Appropr Uncertai

n

No Appropr Uncertain

Uncertain

Uncertain

PoorYes Uncertai

nUncertain

Uncertain

Uncertain

No Uncertain

Inappropr

Inappropr

InapproprHalbert J Cancer 107: 2375, 2006

Cytoreductive surgeryConclusions

• Survival advantage• Safe and effective in selected patients• Newer therapies may alter the

appropriateness of any given option• Well designed trials are clearly needed

New Approaches to Renal Cell Carcinoma

• Adjuvant therapy• Cytoreductive surgery (upfront

nephrectomy)• Neoadjuvant therapy

Neoadjuvant ApproachRationale

• Success of neoadjuvant therapies in other cancers

• Assurance that patients will receive systemic treatment

• Potential for more rapid determination of response

• Response as a selection tool• Ability to analyze post-treatment tissue

Neoadjuvant ApproachAdvantages

• Select for surgery responding patients• Downstaging• Eliminates morbidity and mortality in

those that would’n benefit anyway• Screen for patients with borderline PS• Harvest of treated tissue for mechanistic

studies

Neoadjuvant ApproachDisdvantages

• May add morbidity/mortality to surgery• May decondition good surgial

candidates• No proven benefit• Unclear timing of surgery

Neoadjuvant Approach

Agent ORR Tumor shrinkage rate

Sunitinib 40-45% ~70-75%

Bevacizumab+ IFN

10-15%25-30%

~70-75%

Sorafenib 2-10% ~70-75%

Temsirolimus 9% ~35%

Neoadjuvant ApproachBevacizumab

Four cycles of Bevacizumab in previously untreated patient

Neoadjuvant ApproachSorafenib

4 weeks of Sorafenib in previously untreated patient

Baseline: 9.5 cm Week 4: 7.9 cm

Neoadjuvant ApproachSurgical issues

• Therapy may impact on wound healing, recovery• Higher incidence of wound complications

• Local tumor progression increase complexity of surgery

• Timing• When to operate responders• Risk of progression and death in non responders

Surgical morbidity associated with Targeted Therapies before Cytoreductive Nephrectomy

Odds ratio P value

All complications 0.560 0.145

Re-exploration 1.100 0.993

Readmission 1.000 0.997

Thromboembolic 1.200 0.990

Cardiovascular 1.115 0.607

Pulmonary 0.765 0.447

Gastrointestinal 1.154 1.000

Infectious 1.009 0.995

Incision related 0.995 0.880

Margulis V. J Urol 180:94, 2008

Neoadjuvant Bevacizumab

N=50MetastaticClear Cell

No prior therapyBevacizumab

10 mg/KgQ 14 days

(+Erlotinib 150 mg

daily for 8 weeks)

ResponseOr stable

ProgressiveGood PS

Progressive Poor PS

NephrectomyContinue Bevacizumab

NephrectomyNew therapy

New therapyBSC

Nephrectomy performed during week 2 or 3 of cycle 2Erlotinib discontinued after 25 patients

Neoadjuvant ApproachPresurgical Bevacizumab (phase II)

• N= 46• RR= 10%• Clinical benefit= 69.6%• Median PFS= 6 months• No major perioperative complications

Jonash E. PROC ASCO 2008 abstr # 5104

Pre and Post Surgical SunitinibMD Anderson n=50

N=50MetastaticClear Cell

No prior therapySunitinib

50 mg/die4wk/2wk

ProgressivePoor PS

Stable Response

ProgressiveGood PS

NephrectomyContinue Sunitinib

NephrectomyNew treatment

New treatmentBSC

Neoadjuvant Approach2 key questions

• Do patients who receive targeted therapy need a nephrectomy?

• Can we use targeted therapy to select patients who will benefit from surgery?

French Study

Untreated PatientsMetastatic RCCPrimary in place

Nephrectomy Followed bySuntininb

Suntinib

Powered for equivalence

EORTC Study

440 Untreated Patients

Metastatic RCCPrimary in place

Nephrectomy Followed bySuntininb

SuntinibFollowed by

NephrectomyIn non progressors

Powered for superiority

Neoadjuvant ApproachConclusions

• Initial observations suggest that targeted agents are active in the primary tumor

• Nephrectomy after targeted therapy is safe and permits proper patient selection

• Future trials are needed to assess the use of neoadjuvant therapy in localized and metastatic RCC