ASCO Update 2004:ASCO Update 2004:Focus on Prostate and Focus on Prostate and

Renal Cell CancersRenal Cell CancersPrimo N. Lara, Jr., MDPrimo N. Lara, Jr., MD

Associate Professor Associate Professor

University of California University of California

Davis Cancer CenterDavis Cancer Center

Development of Hormonal EscapeDevelopment of Hormonal Escape

Prostate Cancer. London, England: Times Mirror International Publishers Ltd;1996:143.

Depriveandrogen

Cel

l num

bers

Time

Androgen-independentcells take over

Responsive

Dependent

Independent

Hormone Refractory Prostate CancerHormone Refractory Prostate Canceraka Androgen Independent Diseaseaka Androgen Independent Disease

Practical definition: consecutive series of increasing PSA levels after a nadir is reached with hormone therapy

Must have had a trial of anti-androgen withdrawal – 10-30% of patients will have a PSA response

Must have castrate levels of testosterone

Current Status 2004:Current Status 2004:Hormone Refractory Prostate CancerHormone Refractory Prostate Cancer

Benchmark median survival = 18 months Prognostic factors can predict response

and survival independent of therapy received

Survival and quality of life are most important outcome measures

Current Status 2004:Current Status 2004:Hormone Refractory Prostate CancerHormone Refractory Prostate Cancer

Chemotherapy results in prolongation of life, symptom control, and enhanced quality of life

Second-line hormonal therapies are generally ineffective

Novel molecular targeted therapies are now being integrated into treatment strategies

Treatment Goals in HRPCTreatment Goals in HRPC

Biochemical (PSA-only) diseaseBiochemical (PSA-only) disease

Metastatic disease: AsymptomaticMetastatic disease: Asymptomatic– Prolong life– Prevent morbidity: skeletal-related events, pain

Metastatic disease: SymptomaticMetastatic disease: Symptomatic– Palliate symptoms– Enhance quality of life– Prolong life

Prognostic factors in HRPCPrognostic factors in HRPC

PSA-related variables– Doubling time– Ratio of pre- and post-treatment slopes– PSA velocity

Prior prostatectomy Performance status Gleason score LDH Alkaline phosphatase Hemoglobin Presence of Visceral Disease

PSA-related variables as prognostic PSA-related variables as prognostic indicators in HRPCindicators in HRPC

Doubling time – PSADT < 4 months MST = 445 days– PSADT > 4 months MST = 746 days (p<0.001)

Pre-post treatment PSA ratios – Ratio –0.8 to –0.3 Hazard Ratio (survival) = 0.7 – Ratio > -0.3 Hazard Ratio = 1.0 (p=0.09)

PSA velocity – Measured within first 3 months of chemotherapy– Hazard ratio for death = 3.56 (p < 0.0001) for each unit

increase of PSA velocity

ASCO 2004: Nelson #4554, D’Amico #4506, Crawford #4505

Prognostic Variables for HRPC: Prognostic Variables for HRPC: CALGB DatabaseCALGB Database

Halabi, JCO 2003

Survival Distributions: Survival Distributions: CALGB Prognostic ModelCALGB Prognostic Model

Q1: 7.5 months Q2: 13.4 months Q3: 18.9 months

Q4: 27.2 months

Current Treatment Options: HRPCCurrent Treatment Options: HRPC

Supportive Care Radioisotopes and Palliative radiation Second line hormonal therapy Cytotoxic chemotherapy Investigational approaches

Cytotoxic Chemotherapy in HRPC: Cytotoxic Chemotherapy in HRPC: Active AgentsActive Agents

Cyclophosphamide Anthracyclines (e.g., mitoxantrone) Antimicrotubule agents

– Estramustine phosphate– Taxanes: docetaxel, paclitaxel– Vinca alkaloids: vinblastine

Randomized Trials of Mitoxantrone + Randomized Trials of Mitoxantrone + Steroid vs. Steroid Alone in HRPCSteroid vs. Steroid Alone in HRPC

Kantoff, et al Kantoff, et al

(JCO 1999) N=242(JCO 1999) N=242

Mitoxantrone + Dexamethasone

Dexa alone P-value

Median survival (months) 12.3 12.6 NS

Time to treatment failure or PD (months)

3.7 2.3 0.02

QOL/Pain control Better Worse N/A

Tannock, et al Tannock, et al

(JCO 1996) N=161(JCO 1996) N=161

Mitoxantrone + Prednisone

Prednisone alone

P-value

Median survival (months) 12 12 NS

Palliative response 29% 12% 0.01

Duration of palliation 43 weeks 18 weeks <0.0001

Docetaxel 70 mg/m2 Estramustine 280 po TID D1-5, 7-11 Q 21 d Prednisone 10 mg po QD HRPC PS 0-1 Docetaxel 35 mg/m2/wk x 3wks No prev Estramustine Q 28 d chemo N=120 Prednisone AAW Mitoxantrone 12 mg/m2 iv Prednisone

Q 21 d

RANDOMIZE

Oudard, pASCO 2003 #706

Randomized Phase II Trial of Randomized Phase II Trial of Docetaxel/Estramustine/Prednisone vs. Docetaxel/Estramustine/Prednisone vs. Mitoxantrone/PrednisoneMitoxantrone/Prednisone

N PSA50 RR

PSA NL

TTP (days)

CBR*

Bolus DEP 35 77% 20% 245 67%

Weekly DEP 33 65% 15% 188 58% MP 34 21% 3% 74 34%

* Clinical benefit response included pain control, analgesic use, pain index, PS

Oudard, pASCO 2003 #706

Randomized Phase II Trial of Randomized Phase II Trial of Docetaxel/Estramustine/Prednisone vs. Docetaxel/Estramustine/Prednisone vs. Mitoxantrone/PrednisoneMitoxantrone/Prednisone

A multicenter comparison of A multicenter comparison of docetaxel given weekly or every docetaxel given weekly or every three weeks + prednisone with three weeks + prednisone with mitoxantrone + prednisone in mitoxantrone + prednisone in

patients with hormone-refractory patients with hormone-refractory prostate cancer:prostate cancer:Study TAX-327Study TAX-327

Ronald De Wit M.D. PhDMario A.Eisenberger M.D.

Ian Tannock M.D. PhDand

TAX-327 investigators ASCO 2004 Abstract #4

TAX327Study Design

Stratification:

Pain levelPPI ≥ 2 or AS ≥ 10

vs.PPI < 2 or AS < 10

KPS≤70 vs. ≥ 80

Docetaxel 75 mg/m2 Q3 wks + Prednisone 5 mg bid

Mitoxantrone 12 mg/m2 Q3 wks +

Prednisone 5 mg bid

RANDOMIZE

Docetaxel 30 mg/m2 wkly 5 of 6 wks +

Prednisone 5 mg bid

Premedication: weekly docetaxel arm-dexamethasone 8 mg 1 hr prior to infusion; q3week docetaxel arm: dexamethasone 8 mg 12, 3, and 1 hour prior to infusion

Treatment duration in all 3 arms = 30 weeks

Grade 3-4Grade 3-4 Hematologic Toxicity (%) Hematologic Toxicity (%)

Docetaxel3 wkly

Docetaxelwkly

Mitoxantrone

Treated, n 332 330 335

Anemia 5 5 2

Neutropenia 32.0 1.5 22

Neutropenic infection

3.0 0.0 0.9

Febrile neutropenia 2.7 0.0 1.8

Septic death 0.0 0.3 0.3

Non-hematological ToxicityNon-hematological Toxicity(%)(%)

17 0.6 17 1.5 25 2.1Constipation

7 NA 37 NA30 NANail change

7 0.3 24 0.930 1.8Neuro-Sensory

10 1.2 34 4.832 2.1Diarrhea

36 1.5 36 2.441 2.7Nausea

35 5.1 49 5.553 4.5Fatigue

13 NA 50 NA65 NAAlopecia

All grades 3/4All grades 3/4All grades 3/4Toxicity

MitoxantroneDocetaxel wkly

Docetaxel 3 wkly

* NA = not applicable

Overall SurvivalOverall Survival

Mediansurvival Hazard

(mos) ratio P-value

Combined: 18.2 0.83 0.03D 3 wkly: 18.9 0.76 0.009D wkly: 17.3 0.91 0.3Mitoxantrone 16.4 – –

Months

Pro

bab

ilit

y o

f S

urv

ivin

g

0 6 12 18 24 30

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Docetaxel 3 wkly

Docetaxel wkly

Mitoxantrone

Overall SurvivalOverall Survival

Mediansurvival Hazard

(mos) ratio P-value

Combined: 18.2 0.83 0.03D 3wkly: 18.9 0.76 0.009D wkly: 17.3 0.91 0.3Mitoxantrone 16.4 – –

Months

Pro

bab

ilit

y o

f S

urv

ivin

g

0 6 12 18 24 30

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Docetaxel 3 wkly

Docetaxel wkly

Mitoxantrone

Quality of Life ResponseQuality of Life Response> 16 points FACT-P score > 16 points FACT-P score

compared to baselinecompared to baseline

Docetaxel

3-wkly

Docetaxel

wkly

Mitoxantrone

Evaluable, n 278 270 267

Response (%)

( 95% C.I )

22

(17-27)

23

(18-28)

13

(9-18)

P-value* 0.009 0.005

*Compared to mitoxantrone

Docetaxel and Estramustine versus Docetaxel and Estramustine versus Mitoxantrone and Prednisone in Men with Mitoxantrone and Prednisone in Men with Androgen Independent Prostate Cancer:Androgen Independent Prostate Cancer: Results of Southwest Oncology Group Results of Southwest Oncology Group

Intergroup Protocol 99-16Intergroup Protocol 99-16

Daniel P. Petrylak, M.D.1, Catherine M. Tangen, Dr.PH.2, Maha A. Hussain, M.D.3, Primo N. Lara Jr., M.D.4, Jeffrey A. Jones, M.D.5,

Mary Ellen Taplin, M.D.6, Patrick A. Burch, M.D.7, Graham F. Greene, M.D.8, Mitchell C. Benson, M.D.,1

Eric J. Small, M.D.9, Derek Raghavan, M.D., Ph.D,10 E. David Crawford, M.D.11

1Columbia University, New York, NY 2Southwest Oncology Group Statistical Center, Seattle, WA 3University of Michigan Comprehensive Cancer Center, Ann

Arbor, MI 4University of California, Davis, Sacramento, CA 5Baylor College of Medicine, Houston, TX 6University of Massachusetts Medical Center, Worcester, MA 7Mayo Clinic, Rochester, MN 8University of Arkansas for Medical Science,

Little Rock, AR 9University of California San Francisco Cancer Center, San Francisco, CA 10Cleveland Clinic Foundation, Cleveland, OH 11University of

Colorado Health Science Center, Denver, CO

ASCO 2004 Abstract #3

Schema: S9916Schema: S9916

D/E*Docetaxel 60 mg/m2 IV D2 every 21 days

Estramustine 280 mg po TID, D1-5Premedication: Dexamethasone 20 mg PO TID starting evening of D1

M/PMitoxantrone 12 mg/m2 IV every 21 daysPrednisone 5 mg po BID continuously

*Per protocol amendment January 15, 2001: Coumadin 2 mg PO daily + ASA 325 mg PO daily was added

Docetaxel and mitoxantrone doses could be increased to 70 mg/m2 and 14 mg/m2, respectively, if no grade 3 or 4 toxicities were seen in cycle 1

R Patient Stratification: Type of progression (progression of measurable or evaluable disease vs. increasing

PSA only; NCI CTC pain scale grade < 2 vs > 2; SWOG PS status 0-1 vs 2-3

Grade Grade >> 3 toxicity 3 toxicity

10

12

14

16

18

20

0

2

4

6

8

Pain Neurologic Metabolic Infection Hematologic GI Flu-like symptoms

Cardiovascular

D/E M/P

% o

f p

atie

nts

- there was no difference in toxic deaths between treatment arms

PSA Response RatePSA Response Rate

50%

27%

0%

10%

20%

30%

40%

50%

Docetaxel/estramustinen = 303

Mitoxantrone/prednisonen = 303

% o

f p

ati

en

ts w

ith

a >

50

% d

ec

rea

se

in

PS

A

p < 0.0001

Stratified by Treatment Arm

0%

20%

40%

60%

80%

100%

0 12 24 36 48Months

D+E

M+P

# at Risk324

324

# of Events

297

300

Medianin Months

6

3

HR: 0.73 (95% CI 0.63, 0.86), p < 0.0001

Progression Free Survival

0%

20%

40%

60%

80%

100%

0 12 24 36 48Months

D+EM+P

# at Risk

338 336

# of Deaths

217235

Medianin Months

1816

HR: 0.80 (95% CI 0.67, 0.97), p = 0.01

Overall Survival

Conclusions: Conclusions: TAX 327 & SWOG 9916TAX 327 & SWOG 9916

Docetaxel-based chemotherapy improves– Overall survival– Progression-free survival– Quality of life (Tax 327)

Contribution of estramustine is questionable

Reference standard for future studies in metastatic HRPC should be docetaxel

Bortezomib and Proteasome Bortezomib and Proteasome InhibitionInhibition

19SCap

20SSubunit

Chymo-tryptic

Site

Post-Glutamyl

Site

TrypticSite

1 2

3

4

5

6

7

26S Proteasome

Degrades ubiquitinated proteins Proteolysis is ATP-dependent

Bortezomib

19SCap

Chymotryptic site is rate-limiting in protein degradation

J Bio Chem. 1999; 274(32): 22123-22126; Science. 1995; 268(5210) 579-582; Bioorg Med Chem Lett. 1998; 8(4): 333-338.

Bortezomib in Combination with Bortezomib in Combination with DocetaxelDocetaxel

In vitro– Showed additive growth inhibition and apoptosis in

LNCaP and PC-3 prostate cancer cells

In vivo– In pancreatic xenograft models, bortezomib + docetaxel

demonstrated enhanced:• Reduction of tumor mass• p21 accumulation• Inhibition of tumor cell proliferation• Increased apoptosis• Reduced tumor microvessel density

Phase I/II Trial of Bortezomib Plus Phase I/II Trial of Bortezomib Plus Docetaxel in Patients With Advanced Docetaxel in Patients With Advanced Androgen-Independent Prostate CancerAndrogen-Independent Prostate Cancer

R. Dreicer,R. Dreicer,11 B. Roth, B. Roth,22 D. Petrylak, D. Petrylak,33 D. Agus, D. Agus,44 M. Meyers, M. Meyers,55 D. Esseltine,D. Esseltine,66 D. Rodriguez, D. Rodriguez,66 P. Oppedisano, P. Oppedisano,66 K. Wang, K. Wang,66 A. BoralA. Boral66

11Cleveland Clinic Foundation, Cleveland, OH; Cleveland Clinic Foundation, Cleveland, OH; 22Vanderbilt-Ingram Cancer Center, Vanderbilt-Ingram Cancer Center, Nashville, TN; Nashville, TN; 33Columbia University, New York, NY; Columbia University, New York, NY; 44Cedars-Sinai Prostate Cancer Cedars-Sinai Prostate Cancer Center, Los Angeles, CA; Center, Los Angeles, CA; 55Aventis Oncology, Bridgewater, NJ; Aventis Oncology, Bridgewater, NJ; 66Millennium Millennium Pharmaceuticals, Cambridge, MAPharmaceuticals, Cambridge, MA

ASCO 2004, Abstract #4654

Treatment ScheduleTreatment Schedule

Docetaxel 1x/wk (days 1 and 8), bortezomib 1x/wk (days 2 and 9) every 21 days

24 hours between docetaxel and bortezomib Dexamethasone 8 mg night before, morning of,

and evening after each docetaxel infusion

1 Cycle

Day 1 982

D D B B

D = docetaxelB = bortezomib

Rest

21

Dreicer et al, ASCO 2004 Abstract 4654

Results From Phase I: Results From Phase I: Dose-Escalation SummaryDose-Escalation Summary

No DLTs have been reported

MTD not reached

Cohort 4 (40 mg/m2 docetaxel + 1.3 mg/m2 bortezomib) expanded to further assess safety, tolerability, and efficacy

Data on phase II assessment of cohort 4 to be presented (N = 32)

Dreicer et al, ASCO 2004 Abstract 4654

Conclusions: Bortezomib + Conclusions: Bortezomib + DocetaxelDocetaxel

Combination bortezomib and docetaxel at doses below MTD demonstrated promising activity

PR rate 23%

PSA decrease by ≥ 50% confirmed in 24% of patients

All measurable tumor responses and the majority of PSA responses were observed in patients who received prior chemotherapy

Measurable tumor response was observed in 1 patient who had received prior taxane therapy

Combination of docetaxel and bortezomib was well tolerated at doses assessed; adverse events were primarily low grade and manageable

Dreicer et al, ASCO 2004 Abstract 4654

A Phase II Trial of Epothilone-B Analogue BMS-247550 (NSC #710428) Administered Every 21

Days in Patients with Hormone Refractory Prostate Cancer: Southwest Oncology Group

Study S0111

M. Hussain, J. Faulkner, U. Vaishampayan, P. Lara, D. Petrylak, D. Colevas, W. Sakr, E.D.

Crawford

ASCO 2004 Abstract # 5410

SWOG- 0111SWOG- 0111 RationaleRationale

Epothilone-B Analogue BMS-247550:– New class of non-taxane tubulin polymerizing agents

resulting in mitotic arrest at G2/M transition.– High level of anti-tumor activity against in-vitro and

in-vivo tumor models that are naturally resistant or acquired resistance to paclitaxel.

– More potent than paclitaxel in tumor models.

Taxanes have demonstrated activity in patients with hormone refractory prostate cancer.

SWOG- 0111SWOG- 0111Treatment PlanTreatment Plan

Premedication: 1hr prior to BMS-247550:

Diphenhydramine 50 mg PORanitidine 150 mg PO

BMS-247550: 40 mg/m2 IV over 3hrsQ 21 days.

Registration

• PSA was monitored prior to each course.

• Objective response was assessed after every 2 courses

SWOG- 0111SWOG- 0111 PSA ResponsePSA Response

Confirmed Response 14 34%

Unconfirmed Response

2 5%

No Response 20 49%

Not Determinable 5 12%

Total 41 100%

Confirmed PSA response = 34% (95% CI: 20% to 51%)

SWOG- 0111SWOG- 0111 ConclusionsConclusions

In a cooperative group setting single agent Epothilone-B In a cooperative group setting single agent Epothilone-B analogue (BMS-247550) is active in patients with metastatic analogue (BMS-247550) is active in patients with metastatic hormone refractory prostate cancer.hormone refractory prostate cancer.

The most frequent high grade toxicities were hematologic The most frequent high grade toxicities were hematologic and neurotoxicities.and neurotoxicities.– There were no G5 toxicitiesThere were no G5 toxicities– 31% of patient were removed from study due to toxicity.31% of patient were removed from study due to toxicity.– Measures to counteract the neuropathy effects are Measures to counteract the neuropathy effects are

needed.needed.

Further studies are warranted to define this agent’s activity:Further studies are warranted to define this agent’s activity:– in first line treatment relative to standard therapy. in first line treatment relative to standard therapy. – in the second line setting. in the second line setting.

SUMMARY: HRPCSUMMARY: HRPC HRPC is a virulent, incurable disease Aggressive palliative care must be

pursued in the absence of cure Although docetaxel-based

chemotherapy can now be considered standard treatment for metastatic HRPC, the results remain suboptimal

Whenever possible, the “standard of care” for HRPC should still be clinical trial participation

Renal Cell Carcinoma 2004Renal Cell Carcinoma 2004

~32,000 new cases; ~12,000 deaths~32,000 new cases; ~12,000 deaths Five year survival rate for Five year survival rate for

metastatic disease is 0-10%metastatic disease is 0-10% Immunotherapy with interleukin-2 Immunotherapy with interleukin-2

or interferon-alfa has generally yielded or interferon-alfa has generally yielded modest clinical benefitsmodest clinical benefits

New agents with unique mechanisms New agents with unique mechanisms of action are neededof action are needed

Image from urotext.com

ECOG 3898: Low Dose Interferon +/- ECOG 3898: Low Dose Interferon +/- Thalidomide in Advanced RCCThalidomide in Advanced RCCGordon, et al. ASCO 2004, Abstract 4516Gordon, et al. ASCO 2004, Abstract 4516

RANDOMIZE

Interferon alfa 2B 1M units SQ BID

N=353

Metastatic or locally advanced RCC

PS 0-2

(84% power to detect a 50% increase in MST from 12 to 18 months)

Interferon alfa 2B 1M units SQ BID

Thalidomide 200 mg q HS (escalated to max of 1 g)

From: Kaelin, ASCO 2004

From: Kaelin, ASCO 2004

#4502

Bevacizumab + Erlotinib in RCC

Hainsworth, et al ASCO 2004

SU11248 in Renal Cell Carcinoma: Survival Curves

Preliminary Antitumor Activity ofPreliminary Antitumor Activity ofBAY 43-9006 in Metastatic Renal Cell BAY 43-9006 in Metastatic Renal Cell

Carcinoma and Other Advanced Refractory Carcinoma and Other Advanced Refractory Solid Tumors in a Phase II Randomized Solid Tumors in a Phase II Randomized

Discontinuation Trial (RDT)Discontinuation Trial (RDT)

Mark J. Ratain MD, KT Flaherty, WM Stadler, P O'Dwyer, S Kaye,H Xiong, A Patnaik, M Gore, RJ Lee, T Eisen

ASCO 40th Annual MeetingJune 5, 2004

New Orleans, Louisiana

#4501#4501

– Designed as a CRAF-targeted agent Also inhibits wild-type and mutant BRAF

– Recently demonstrated to inhibit other targets VEGFR-2, PDGFR-b, FLT-3 and c-KIT

N

CF3

Cl

NH

NH

OO

NH

O

CH3

BAY 43-9006 (sorafenib)BAY 43-9006 (sorafenib)A Novel RAF Kinase and VEGFR InhibitorA Novel RAF Kinase and VEGFR Inhibitor

BAY 43-9006 (sorafenib) Study 100391 BAY 43-9006 (sorafenib) Study 100391 Trial SchemaTrial Schema

* May cross over to BAY 43-9006

12 Week Induction

> 25% Shrinkage Continue BAY 43-9006

Open Label

> 25% GrowthOff study

BAY 43-9006

Placebo*

Tumor Assessment

Baseline 12 weeks 24 weeks

>-25% to <25%Randomized

BAY 43-9006 (sorafenib) Study 100391 BAY 43-9006 (sorafenib) Study 100391 Enrollment by Tumor TypeEnrollment by Tumor Type

ColorectalMelanoma

Sarcoma

Pancreas

Ovarian

Thyroid

Renal Cell

Other

Total number of patients: 484

28%

42%

8%5%

BAY 43-9006 (sorafenib) Study 100391 BAY 43-9006 (sorafenib) Study 100391 RCC Bidimensional Tumor Measurements* at Week RCC Bidimensional Tumor Measurements* at Week 12:12:Change from Baseline in Target Lesions (n=89)Change from Baseline in Target Lesions (n=89)

-100

-80

-60

-40

-20

0

20

40

60

80

100

120

% C

ha

ng

e i

n T

um

or

Me

as

ure

me

nt

Number of Patients

> 25% Growth

< 25% to >-25% Change

>-25% to -49% Shrinkage

> -50% Shrinkage

7 7

45** 24 1345** 24 13

* Investigator assessed

* * 7 of 45 patients not randomized

BAY 43-9006 (sorafenib) Study 100391 BAY 43-9006 (sorafenib) Study 100391 Progression-Free Survival in RCC Patients Progression-Free Survival in RCC Patients Continuing Beyond Initial 12 WeeksContinuing Beyond Initial 12 Weeks

* Responders at 12 week assessment with >25% tumor shrinkage

12 Weeks 24 Weeks

Open Label BAY (n=37)Median = 48 weeks(88% progression free at 24 weeks)

Randomized (n=38) Median = 23 weeks(41% progression free at 24 weeks)

Epothilone B Analog (BMS 247550) in Epothilone B Analog (BMS 247550) in Metastatic RCCMetastatic RCC

Zhuang, et al. ASCO 2004, Abstract #4550Zhuang, et al. ASCO 2004, Abstract #4550

N = 54 BMS 247550 6 mg/m2/day x 5 days q 3 wks PR in 8 patients (15%) Seven additional patients had minor

responses Overall “response” rate (PR + MR) = 28% No grade 4 neuropathy observed

Epothilone B Analog (BMS 247550) in Epothilone B Analog (BMS 247550) in Metastatic RCCMetastatic RCC

Zhuang, et al. ASCO 2004, Abstract #4550Zhuang, et al. ASCO 2004, Abstract #4550

INFLIXIMAB: INFLIXIMAB: A Phase II Trial of the A Phase II Trial of the Tumour Necrosis Factor (TNFTumour Necrosis Factor (TNF) )

Monoclonal Antibody in Patients with Monoclonal Antibody in Patients with Advanced Renal Cell CancerAdvanced Renal Cell Cancer

N. R. Maisey, K. Hall, C. Lee, E. Timotheadou, R. Ahern, T. Eisen, M. Gore

Royal Marsden HospitalInstitute of Cancer Research

London, UK

#4514#4514

TNFRCC

RENAL CELL CANCER RENAL CELL CANCER TNFTNF

DNA damage / inhibition of repair

Neo-angiogenesis

Induction of MMP

Inflammatory mediators

motility and invasion

Chemoresistance

Cachexia

INFLIXIMAB INFLIXIMAB TNF TNF neutralization neutralization

Target cell

TNF receptor

Target cell

TNF

Infliximab

Baseline 84 days

RENAL CELL CANCER Infliximab, responder 2

12 weeks 21 weeks

6 weeksBaseline

RENAL CELL CANCER Infliximab, late responder

INFLIXIMAB IS ACTIVE

PR = 16% (+ ‘late responder’,

21%)

PR + SD med duration = 340 days (124-361)

All pts 1 year OS = 55%

NON-TOXIC (1 pt with allergic reaction)

CONVENIENT

RENAL CELL CANCER RENAL CELL CANCER Infliximab, conclusionsInfliximab, conclusions

TNFTNF - a new target - a new target

Summary: Renal Cell Cancer Summary: Renal Cell Cancer ASCO 2004 a “watershed year” for RCC Clinical activity in seen with:

– Angiogenesis inhibitors• SU11248• Bevacizumab + OSI-774• BAY 43-9006

– Antimicrotubule• Epothilone B analog (BMS 247550)

– Anti-TNF• Iinfliximab

Randomized trials with these new compounds are essential (and ongoing)

(And BTW, thalidomide was a bust)