ASCO GU Oncology 2009 Robert Dreicer, M.D., M.S., FACP Chair Dept - - PowerPoint PPT Presentation

ASCO GU Oncology 2009

Robert Dreicer, M.D., M.S., FACP Chair Dept of Solid Tumor Oncology Taussig Cancer Institute Professor of Medicine Cleveland Clinic Lerner College of Medicine

Inclusion Criteria

• mRCC with component of

clear cell histology

• Measurable or evaluable

disease Exclusion Criteria

• Prior systemic therapy
• Evidence of CNS

metastases Stratification:

• Nephrectomy status
• MSKCC risk group
• Primary objective: OS
• Secondary objectives: PFS, ORR, and safety

IFN-/Bevacizumab (n=369) IFN- 9 MU s.c. 3x/week Bevacizumab 10 mg/kg IV q2w IFN- (n=363) IFN- 9 MU s.c. 3x/week (n = 732) R A N D O M I Z E

Phase III CALGB 90206 Trial: Study Design (abstract LBA5019)

Rini et al. J Clin Oncol 2009; 27(suppl):239s

Adverse event Bevacizumab + IFN (n=366) IFN (n=352) Any grade 3/4 adverse event 79% 61% Fatigue/asthenia/malaise 37% 30% Anorexia 17% 8% Proteinuria 15% <1% Hypertension 11% 0% Hemorrhage 2% <1% Venous thromboembolism 2% 1% Gastrointestinal perforation <1% 0% Arterial ischemia 1% 0%

Frequency of selected grade 3 or 4 AEs

LBA5019

Objective Response

Note: patients with measurable disease only

Bev + IFN (n=325) IFN (n=314) Overall Response rate 25.5%

[95% CI = 20.9-30.6]

13.1%

[95% CI = 9.5-17.3]

CR 3.7% 1.9% PR 23.4% 12.7% p < 0.0001 Duration of response 11.9 months

[95% CI = 8.3 – 14.8]

9.7 months

[95% CI = 7.6 – 19.8]

p = 0.362

LBA5019

Time(months) Overall Survival (probability) IFN BEV/IFN Stratified log-rank p=0.069

Kaplan-Meier Overall Survival Curves by Treatment Arm

6 12 18 24 30 36 42 48 54 60 0.0 0.2 0.4 0.6 0.8 1.0

363 286 221 177 148 118 98 64 37 10 1 369 314 242 190 160 139 116 94 42 17 2 IFN BEV/IFN Number of Patients at Risk

• --- BEV/IFN: Median OS 18.3 months

IFN: Median OS 17.4 months

Kaplan-Meier Overall Survival by Treatment Arm

LBA5019

Median OS (months) according to treatment arm and subsequent therapy (LBA5019)

Bevacizumab + Interferon Interferon Total

(unstratified log-rank p comparing arms)

Stratified HR Received 2nd-line therapy (n=408) 31.4 26.8 28.2

(p=0.079)

0.80

(p=0.055)

Did not receive 2nd- line therapy (n=324) 13.1 9.1 10.2

(p=0.059)

0.82

(p=0.108)

Total 18.3 17.4 18.1

(p=0.097)

0.86

(p=0.069)

Authors Conclusions LBA5019



Overall survival is greater in patients with metastatic clear cell RCC receiving bevacizumab plus interferon as initial systemic therapy compared to interferon alone, but does not meet pre-defined criteria for significance



Although the favorable effect of bevacizumab plus IFN on OS is preserved regardless of subsequent treatment, the most robust OS is achieved in patients with favorable underlying disease biology who are able to receive subsequent therapy



The combination of bevacizumab and IFN as initial therapy in metastatic RCC patients results in a significantly greater progression-free survival and objective response rate versus IFNA monotherapy



Toxicity is greater in the combination therapy arm, including more fatigue, anorexia, hypertension and proteinuria

Nephrectomized patients with advanced RCC Stratification: Country MSKCC risk group

• Primary objective: OS
• Secondary objectives: PFS, TTP, TTF, ORR, and safety
• Median follow-up: 22 months

IFN-2a/Bevacizumab (n=327) IFN- 9 MIU s.c. 3x/week* Bevacizumab 10 mg/kg IV q2w until progression IFN-/placebo (n=322) IFN- 9 MIU s.c. 3x/week* placebo 10 mg/kg IV q2w until progression (n = 649) R A N D O M I Z E

Phase III AVOREN Trial: Study design

Escudier et al. J Clin Oncol 2009; 27(suppl):239s (abstract 5020).

*Dose reduction allowed

Phase III AVOREN Trial : Final OS results

 Multiple Cox regression analysis for OS:

− HR 0.78 (0.63-0.96); P = .0219

 OS not affected by reduction of IFN dose:

− OS 26 months with reduced-dose IFN and 23.3 months

with standard IFN

Escudier et al. J Clin Oncol 2009; 27(suppl):239s (abstract 5020)).

IFN+placebo (n=322) IFN+bev (n=327) HR Log rank P Value Median OS (months) Unstratified NR NR 0.91 (0.76-1.10) .3360 Stratified 21.3 23.3 0.86 (0.72-1.04) .1291 Median OS after censoring patients at time of crossover (months) 20.8 23.3 0.84 (0.70-1.02) .0766

Phase III AVOREN trial of interferon alpha plus bevacizumab

• r placebo in nephrectomized advanced RCC: Final OS results

 Subgroup analysis demonstrated similar benefit regardless of age,

Motzer score, baseline VEGF levels, and number of metastatic sites

 However, patients without liver metastases demonstrated significant

OS benefit from the addition of bevacizumab (27.5 vs. 21.4 months, HR 0.76; P = .0155)

Escudier et al. J Clin Oncol 2009; 27(suppl):239s (abstract 5020)

Post-protocol therapy N IFN+plac vs. IFN+bev Median OS (months) HR IFN+placebo IFN+bev Subsequent TKI 120 vs. 113 33.6 38.6 0.80 (0.56-1.13) Subsequent sunitinib 92 vs. 83 39.7 43.6 0.88 (0.58-1.35) Subsequent sorafenib 50 vs. 60 30.7 38.6 0.73 (0.44-1.20)

Phase III study of pazopanib in treatment-naïve or cytokine-pretreated advanced RCC

Sternberg et al. J Clin Oncol 2009; 27(suppl):240s (abstract 5021)

Eligibility:

• Locally advanced or

metastatic RCC

• Clear cell histology
• Treatment naive or

failure of 1 prior cytokine therapy Stratification: ECOG PS Prior nephrectomy Rx naive (n=233) vs. 1 cytokine failure (n=202)

• Primary objective: PFS
• Secondary objectives: OS, ORR, duration of response, safety, health-related QOL

Pazopanib 800mg qd Placebo* (n = 435) R A N D O M I Z E 2:1 (n = 290) (n = 145) *Option to crossover via an

• pen label study at progression

Phase III study of pazopanib in treatment-naïve or cytokine-pretreated advanced RCC: Efficacy

 48% of patients on placebo arm received pazopanib at disease

progression

Sternberg et al. J Clin Oncol 2009; 27(suppl):240s (abstract 5021).

Patient population placebo (n=145)

pazopanib (n=290)

HR P Value

ORR (%)

Overall population 3 30 NR NR Treatment-naïve* 4 32 NR NR Cytokine-pretreated† 3 29 NR NR Median PFS (months) Overall population 4.2 9.2 0.46 (0.34-0.62) <.0000001 Treatment-naïve* 2.8 11.1 0.40 (0.27-0.60) <.0000001 Cytokine-pretreated† 4.2 7.4 0.54 (0.35-0.84) <.001 Median OS (months) 18.7 21.1 0.73 (0.47-1.12) .02‡

* n = 78 for placebo and 155 for pazopanib; † n = 67 for placebo and 135 for pazopanib ‡ one-sided P value

Phase III study of pazopanib in treatment-naïve or cytokine-pretreated advanced RCC: Safety

 4% of pts in the pazopanib arm and 3% in the placebo arm

experienced grade 5 adverse events

Sternberg et al. J Clin Oncol 2009; 27(suppl):240s (abstract 5021)

Grade 3/4 Adverse Events placebo (n=145) (%) pazopanib (n=290) (%) Hypertension <1 4 Diarrhea <1 4 Anorexia <1 2 Vomiting 2 3 Fatigue 2 2 Asthenia 3 Hemorrhage 2 ALT abnormalities 1 12 AST abnormalities <1 8 ALT = alanine transferase; AST = aspartate aminotransferase

RCC Treatment Algorithm: 2009

Setting Patients Therapy (level 1) Other Options (≥ level 2) Untreated Good or Intermediate risk Sunitinib Bevacizumab + IFN HD IL-2 Sorafenib Clinical trial Observation Poor risk Temsirolimus Sunitinib Clinical trial Cytokine- refractory Sorafenib Pazopanib Sunitinib Bevacizumab VEGF-R refractory Everolimus Clinical trial Sunitinib Sorafenib mTOR-refractory Clinical trial Clinical trial

*Adapted from M Atkins, ASCO 2006 & R Bukowski ASCO 2007

Randomized Trial of p53 Targeted Adjuvant Therapy for Patients with Organ- Confined Node-Negative Urothelial Bladder Cancer Abstract 5017

Walter M. Stadler, Seth P. Lerner, Susan Groshen, John

• P. Stein†, Ellenie Tuazon, David Quinn, Donald G.

Skinner, Derek Raghavan, David Esrig, Gary Steinberg, David Wood, Laurence Klotz, Craig Hall, Richard Cote

†Deceased

Years from Cystectomy Probability of Not Recurring

p53 negative( n=142) p53 positive( n=101) p< 0.001

Esrig, et al NEJM 1994; 1259-64

p53 Status May be Prognostic

STUDY DESIGN

Radical Cystectomy (P1, P2a, P2b, NO, MO) Registration - Consent to p53 Analysis and Randomized Trial IHC, p53 Altered (>10% nuclear +) IHC, p53 Wild type (≤10% nuclear +) Consent for Randomization Re- Confirmed Consent for Randomization Not Re- Confirmed MVAC x 3 Arm I Observ. Arm II Observ. Arm IV Observ. Arm III Abstract 5017

Overall Survival: MVAC vs. Observation (Arm 2)

0.00 0.10 0.20 0.30 0.40 0.50 0.60 0.70 0.80 0.90 1.00 12 24 36 48 60 72 84 96 108 120 132

Months Since Randomization Estimated Probability of Survival MVAC (n=58) Observed (n=56) p=0.75

Abstract 5017

Abstract 5017

Authors Conclusions

 Unable to confirm prognostic value of p53

 Centrally performed IHC may not be analytically valid  Stage migration led to better than expected outcomes  Preliminary data based on too small of a cohort  p53 mutation and pathway analysis pending

 Unable to confirm predictive value of p53

 See above  Randomization challenges led to underpowered trial

A Multicenter Study of Cisplatin, Gemcitabine and bevacizumab As First Line Therapy for Metastatic Urothelial Cancer: Hoosier Oncology Group Protocol GU04-75 ABSTRACT 5018

• N. M. Hahn, W. M. Stadler, R. T. Zon, D. Waterhouse, J.

Picus, S. Nattam, C. S. Johnson, S. M. Perkins, M. J. Waddell, C. J. Sweeney

Study Design

• Primary Endpoint
• Progression Free Survival (PFS)
• Secondary Endpoints
• Response Rates
• Toxicity
• Overall Survival (OS)

Abstract 5018

• Maximum of 8 cycles of Cisplatin and Gemcitabine
• Maximum 1 year of Bevacizumab therapy

*Gemcitabine reduced to 1000 mg/m2 iv d1,8 after first 17 patients due to 7 DVT/PE events Eligibility Criteria

• Metastatic UC (mUC)
• ECOG PS 0-1
• Cr < 1.5 mg/dl
• No prior CTx for mUC
• No anticoagulation
• No CNS mets

E N R O L L M E N T Cisplatin 70 mg/m2 iv d1 Gemcitabine* 1250 mg/m2 iv d1,8 Bevacizumab 15 mg/kg iv d1 Cycle length = 21 days Abstract 5018

STUDY SCHEMA

 Median chemotherapy cycles – 6 (2-8)  30% patients entered Bevacizumab maintenance

portion

 60% patients required dose modifications

• 42% discontinued therapy due to toxicity
• 21% discontinued Bevacizumab due DVT/PE

Therapy Administration

Abstract 5018

Cisplatin/Gemcitabine + Bevacizumab in Metastatic Urothelial Cancer: Results

Hahn et al. J Clin Oncol 2009; 27(suppl):239s (abstract 5018)

 Adverse events (n = 43):

− 60% of patients required dose adjustments

• 42% discontinued therapy due to toxicity
• 21% discontinued bevacizumab due to DVT/PE

− DVT/PE incidence

• Gemcitabine 1250 mg/m2 (n = 18) – 39%
• Gemcitabine 1000 mg/m2 (n = 25) – 8%

− 3 treatment-related deaths (all at 1000 mg/m2 dose)

• Cerebral hemorrhage, aortic dissection, sudden cardiac

death

 Objective response rate: 25 (58%)

Progression Free Survival

Probability of not Progressing Months

Median PFS = 8.2 m (95% CI 6.5 – 10.0) Median follow-up = 14.6 m (Range 2-37) 12-month PFS = 29% Abstract 5018

Overall Survival

Median OS = 19.1 m (95% CI 11.5 – 23.4) Median follow-up = 14.6 m (Range 2-37) 12-month OS = 65% Abstract 5018

 Bevacizumab is associated with significant

toxicity in metastatic urothelial carcinoma patients

 The PFS of 8.2 months did not meet the

designed primary endpoint

 The OS of 19.1 months is beyond that

expected from cisplatin plus gemcitabine alone

Authors Conclusions

Abstract 5018

Proposed Intergroup Phase III Trial

Antitumor Activity of MDV3100 in a Phase 1-2 Study of Castration-Resistant Prostate Cancer

Abstract No: 5011

• H. I. Scher, T. Beer, C. Higano, M. Taplin, E. Efstathiou, A. Anand,
• D. Hung, M. Hirmand, M. Fleisher, C. Sawyers

Prostate Cancer Clinical Trials Consortium

MDV3100 A Second-Generation Antiandrogen

1. Engineered for activity in prostate cancer cells that

• verexpress the androgen receptor (AR).

2. Binds the AR more potently than bicalutamide. 3. Unlike bicalutamide, MDV3100 inhibits nuclear translocation of the AR and its binding to DNA. 4. Induces apoptosis in prostate cancer cells.

Abstract 5011

Ligand

• 1. AR Binding Affinity
• DHT ~ 5nM
• Bicalutamide ~160 nM
• MDV3100 ~35 nM
• 2. Nuclear Import
• DHT: ++++
• Bicalutamide: ++++
• MDV3100: ++
• 3. DNA Binding
• DHT: ++++
• Bicalutamide: ++
• MDV3100: -
• 4. Coactivator recruitment
• DHT: ++++
• Bicalutamide: ++
• MDV3100: -

The Effects of MDV3100 on the Androgen Receptor Are Distinct from Bicalutamide

1 2

Chen, Clegg and Scher

3 4

DNA

POL II

HSP 90

LBD HD DBD NTD

Phase 1-2 Multicenter Trial in CRPC



Determine safety



Determine pharmacokinetics (PK)



Assess antitumor activity:



Exploratory:

 Circulating tumor cells

 PET: FDG - 18-fluorodeoxyglucose  PET: FDHT - 18-fluorodihydrotestosterone

Abstract 5011

Key Inclusion Criteria

• 1. Pathologic confirmation of adenocarcinoma of

prostate

• 2. Serum testosterone level <50 ng/dL
• 3. Progressive disease defined as one or more of:



3 rising PSA levels; screening PSA >2 ng/mL



RECIST



Two or more new lesions on bone scan

• 4. No more than 2 prior chemotherapy regimens,

at least one of which contained docetaxel

Abstract 5011

Trial Design

Single Dose 6 days Continuous Dosing Assess Monthly; Q3 Month Imaging Long-Term Dosing Indefinite Cohort 1 Single Dose 6 days Continuous Dosing Assess Monthly; Q3 Month Imaging Long-Term Dosing Indefinite Cohort 2 After 28 Day Safety Subsequent Dose Levels

Cohort expansion at > 60 mg/day 12 pre- and 12 post-chemotherapy Post-chemotherapy only at > 480 mg/day

Abstract 5011

Demographics/Prior Therapy (N=140)

• Med. (range)

AGE (years) 68 (44–93) PSA (ng/mL) 50 (2–2,159) N (%) PRIOR HORMONE THERAPY 140 (100%) 1 line 32 (23%) 2 lines 42 (30%) >3 lines 66 (47%) CHEMOTHERAPY 75 (54%)

Abstract 5011

MDV3100 Was Generally Well-Tolerated

Adverse Event All Doses (N = 140) 240 mg/day (N = 60) G2 G3 G2 G3 Fatigue Nausea Anorexia Seizure 29 (21%) 11 ( 8%) 4 ( 3%)  12 (9%)   3 (2%) 8 (13%) 2 ( 3%)   3 (5%)   

• 1. Only one subject discontinued treatment due to fatigue which coincided with

disease progression 2. Two witnessed seizures (one each at 600 and 360 mg/day) and a possible unwitnessed seizure (at 480 mg/day) were reported  Both patients with witnessed seizures were taking concomitant medications that can cause seizure 3. MTD determined to be 240 mg/day; patients at higher doses were lowered to 240 mg/day

Possibly Related Grade 2/3 Adverse Events in >2 Patients

Abstract 5011

Waterfall Plot of Best Percent PSA Change from Baseline

Chemotherapy-Naïve (N=65) Post-Chemotherapy (N=75)

62% (40/65) >50% Decline 51% (38/75) >50% Decline

Authors Conclusions



MDV3100 is a second-generation antiandrogen engineered for activity in cells that overexpress AR, unique from bicalutamide



The drug active in CRPC both before and following chemotherapy as demonstrated by declines in PSA, imaging, CTC conversion rates, and PET



MDV3100 is generally well-tolerated



Phase III trial will open this year

Abstract 5011

Southwest Oncology Group S9921: Prolonged Event Free Survival in High Risk Prostate Cancer (PC) Patients Receiving Adjuvant Androgen Deprivation Abstract 5009

• L. Michael Glode, Cathy M. Tangen,

Maha H.A. Hussain, David P. Wood, Jr. , Gregory P. Swanson, David I. Quinn, Nancy Dawson, Naomi Balzer-Haas,

• E. David Crawford, Benjamin Ely,

Ian M. Thompson

Background

 Study conceived 1997-98  Mitoxantrone approved 1996 by FDA for

palliative treatment of HRPC

 Canadian Palliation trial (JCO 14:1756)  CALGB 9182 (JCO 17:2506)

 Improved QOL compared to hydrocortisone alone  Improved time to treatment failure  No difference in survival

Abstract 5009

SWOG 9921

 Intergroup Participants: CALGB, ECOG  Eligibility

 Prostatectomy ≤ 120 days prior to registration and one or

more of the following:

 Path Gleason sum > 8  pT3b (seminal vesicle) or pT4 or N1  Path Gleason’s sum 7 and positive margin  Preop PSA >15ng/ml, or biopsy Gleason >7, or PSA

>10ng/ml with biopsy Gleason > 6

Abstract 5009

PSA>20,T3b, T4 or N1 or Gleason > 8,

• r T3a, + margin,

and Gleason 7 RANDOMIZE

CAB X 24 months

Mitoxantrone 12 mg/m2 d1 + Prednisone 5 mg BID d1-21 Q 3 Weeks X 6 and CAB x 24 months

983 496 487

Trial Design

Abstract 5009

Causes of Death (17 total)

 Prostate Cancer – 7  Other Cancers – 4  Cardiovascular Disease – 1  Other Causes – 5

Abstract 5009

Testosterone (T) Recovery (> 50ng/ml)

• Per protocol, T measured every 6 month intervals until > ILLN.
• Patients included in analysis: ≥1 T measurement within the first 12

months after completing CAB Median T Recovery Time* (95% CI) 6 Month* Overall T Recovery (95% CI) 12 Month* Overall T Recovery (95% CI) 18 Month* Overall T Recovery (95% CI)

9.5 Months (8.7, 10.5) 27.8% (5.6, 71.4) 75.3% (50.8, 90.0) 89.5% (69.8,96.9)

* Recovery time measured from completion of CAB Abstract 5009

Authors Conclusions

 S9921 shows better than predicted DF-survival in

high risk prostate cancer patients who received 2 years of CAB

 Potential causes: stage migration, patient selection,

lead time bias, effects of CAB itself.

 Comparable survival data are seen in selected

contemporary studies

 75% of patients have testosterone recovery to above

castrate level within one year of stopping CAB

 Much longer follow-up of S9921 will be required

to observe any differences in survival due to mitoxantrone

Abstract 5009

Phase II Trials of Abiraterone Acetate in Castration Resistant Prostate Cancer

1Ryan et al. J Clin Oncol 2009; 27(suppl):245s (abstract

5046)

2Reid et al. J Clin Oncol 2009; 27(suppl):246s (abstract 5047) 3Danila et al. J Clin Oncol 2009; 27(suppl):246s (abstract

5048)

Patient population N PSA decline ≥ 50% Tumor response (RECIST) ECOG PS Improvement (at least one level)

CRPC: Chemotherapy naïve1 33 24 (73%) PR: 9 (27%) SD: 19 (58%) 8 (61.5%) CRPC: Prior docetaxel2 47 24 (51%) PR: 6 (13%) SD: 25 (53%) 11 (35%) CRPC: Prior docetaxel3 No prior ketoconazole Prior ketoconazole 31 27 16 (52%) 8 (30%) (n = 18) PR: 3 (17%) SD: 11 (61%) 16 (48%)

Phase II Trials of Abiraterone Acetate in Castration Resistant Prostate Cancer: Grade 3/4 Adverse Events

1Ryan et al. J Clin Oncol 2009; 27(suppl):245s (abstract 5046) 2Reid et al. J Clin Oncol 2009; 27(suppl):246s (abstract 5047) 3Danila et al. J Clin Oncol 2009; 27(suppl):246s (abstract 5048)

Ryan (n = 33) Reid (n = 47)* Danila (n = 58)* Hematological Lymphopenia NR 2 (4%) 5 (9%) Anemia NR 3 (6%) NR Nonhematologic Peripheral edema 1 (3%) NR Fatigue 4 (8.5%) NR Nausea NR 3 (6%) NR Vomiting NR 3 (6%) NR

• Common toxicities (all grades) in at least two trials: peripheral

edema, fatigue, hypokalemia, arthralgia

*Experienced by ≥ 2 patients

Fleisher H, et al. abstract 5049

Circulating tumor cells (CTC) in patients with metastatic castration- resistant prostate cancer (CRPC) receiving abiraterone acetate (AA) after failure of docetaxel –based chemotherapy  Preliminary findings suggest correlation with

CTC decline and PSA decline

 Prospectively built into phase III abiraterone

program

IMPACT Overall Survival: Primary Endpoint Intent-to-Treat Population

6 12 18 24 30 36 42 48 54 60 66 25 50 75 100

Percent Survival

Survival (Months)

P = 0.032 (Cox model) HR = 0.775 [95% CI: 0.614, 0.979] Median Survival Benefit = 4.1 Mos.

Sipuleucel-T (n = 341) Median Survival: 25.8 Mos. Placebo (n = 171) Median Survival: 21.7 Mos.

PF Schellhammer, et al. LBA 9 AUA 2009

Locally Advanced Disease Rising PSA Hormone Naive

Rising PSA Castrate

Metastases Castrate Asymptomatic

Metastases Castrate Symptomatic

Organ Confined

Metastatic Disease (De novo)

Clinical States In Prostate Cancer

Metastases Castrate Symptomatic Post Docetaxel

Modified from Scher H, et al.

Conclusions: Renal Cancer

 Lots of active agents, need to sort out optimal

sequence taking into account efficacy, cost, toxicity

 New generations of TKI’s may be equally

effective but perhaps less toxic- cant emphasize how important that may be

 Combination therapy is going to be difficult,

toxicity remains significant impediment to further development

Conclusions: Urothelial Cancer

 Progress remains painfully slow  Gemcitabine/cisplatin/bevacizumab of

interest, but toxicity remains SIGNIFICANT CONCERN

 Phase III will have real time toxicity

monitoring by CALGB

Conclusions: Prostate Cancer

 Near term future for advanced prostate

cancer therapeutics, is much brighter—BUT WILL BE VERY EXPENSIVE

 Androgen receptor targeting therapy IS

HERE- STOP USING TERM HORMONE REFRACTORY/ANDROGEN INDEPENDENT

 CASTRATE RESISTANT