ASCO 2006 Update: Genitourinary Cancer Selected Abstracts

1
ASCO 2006 UpdateGenitourinary CancerSelected
Abstracts

• Primo N. Lara, Jr., MD
• Professor of Medicine
• University of California
• Davis Cancer Center

2
The Star of the ShowKidney Cancer

• Targeted therapies hit their mark
• Angiogenesis inhibitors
• Sunitinib, Sorafenib
• mTOR inhibitors
• Temsirolimus, Everolimus
• EGFR/ERB2 inhibitor
• Lapatinib

3
Iressa
Here Lies Interferon
Killed by Sunitinib Temsirolimus
4
The Von-Hippel Lindau Gene

• Located in the short arm of chromosome 3
• Tumor suppressor function
• Found in up to 80 of sporadic (non-hereditary)
  renal cell cancers

5
Inactivation of VHL An Early Step in Kidney
Carcinogenesis
Loss of remaining VHL allele
Mutation/s at non-VHL loci

• VHL (/-)

VHL (-/-) Cysts
VHL (-/-) Tumor
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Sporadic Renal Cell Cancer VHL Two-Hit
Hypothesis

• At birth

• First Hit

Second Hit Cancer
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Consequences of VHL Gene Mutation
Ubiquitin Ligase Complex Disrupted
HIF Accumulation
VEGF, PDGF?
Glut-1, Erythropoietin
TGF-?, CXCR4
Autocrine Growth Metastasis
Angiogenesis
Increased Metabolism
8
Horizontal vs. Vertical Targeted Strategies
9
Phase 3 Randomized Trial of Sunitinib malate
(SU11248) versus Interferon-alfa as First-line
Systemic Therapy for Patients with Metastatic
Renal Cell Carcinoma
Abstract LBA3

• RJ Motzer, TE Hutson, P Tomczak, MD
  Michaelson, RM Bukowski, O Rixe, S Oudard,
  ST Kim, CM Baum, RA Figlin and the SU11248 Study
  Group
• Supported by Pfizer Inc

10
Sunitinib Mechanism of Action in RCC
Loss of VHL Protein Function
? VEGF
? PDGF
VEGF
PDGF
VEGFR
PDGFR
Pericyte/Fibroblast/ Vascular Smooth Muscle
Vascular Endothelial Cell
Sunitinib
Vascular permeability
Cell survival, proliferation, migration
Vascular formation, maturation
Inhibition of RCC pathogenesis and progression
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Randomization Scheme
R A N D O M I Z A T I O N
Sunitinib (N375)

• N750
• Stratification Factors
• LDH ?1.5 vs gt1.5xULN
• ECOG PS 0 vs 1
• Presence vs Absence of Nephrectomy

IFN-? (N375)
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Study Treatment
Arm A Sunitinib 50 mg po daily on Schedule 4/2
(4 weeks on/2 weeks off)
Arm B IFN-? 3 MU TIW 1st week ? 6 MU TIW 2nd
week ? 9 MU TIW 3rd week ? thereafter SC
Injection
vs

• Repeated 6-week cycles
• Response and safety assessments
• Dose reduction for toxicity
• Treatment continued unless progression or
  intolerance

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Progression-Free Survival
(Independent Central Review)
No. at Risk Sunitinib 235 90 32 2 No. at Risk
IFN-? 152 42 18 0
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Hazard Ratios Showing Treatment Effect for
Progression-free Survival Adjusted By MSKCC Risk
Features (Independent Central Review)
IFN-? benefit
Sunitinib benefit
Sunitinib vs. IFN-? treatment effect without
adjusting for risk factors
Prior nephrectomy (yes vs no)
ECOG score (0 vs 1)
LDH (1.5 vs gt1.5 x ULN)
Time since diagnosis (1 yr vs lt1 yr)
Hemoglobin (LLN vs ltLLN)
Corrected calcium (10 vs gt10 mg/dL)
LLN lower limit of normalULN upper limit of
normal Cox proportional hazards analysis
Motzer et al. JCO 1999172530-40 Motzer et al.
JCO 200220289-296
15
Overall Survival
No. at Risk Sunitinib 341 190 84 15 1 No. at
Risk IFN-? 296 162 66 10 0
The observed p-value did not meet the
pre-specified level of significance for this
interim analysis
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Outcome Summary

Sunitinib vs IFN-? P lt0.000001
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Abstract 4524
Randomized Phase III Trial of Sorafenib in
Advanced Renal Cell Carcinoma (RCC)Impact of
Crossover on Survival

• Eisen T, Bukowski RM, Staehler M, Szczylik C,
  Oudard S, Stadler WM, Schwartz B, Simantov R,
  Shan M, Escudier B
• For the Sorafenib TARGETs Clinical Trial Group

Eisen T et al. Oral presentation, ASCO 2006
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Sorafenib (Nexavar)A Novel, Orally-Active
Multi-Kinase Inhibitor

• Approved in the US in Dec 2005 for advanced RCC
• In vitro inhibitor of C-Raf, wild-type B-Raf,
  b-raf V600E, VEGFR-2/-3, PDGFR-b, c-Kit, and
  Flt-31
• Broad-spectrum anti-tumor activity and inhibition
  of angiogenesis in several tumor xenografts1
• Sorafenib prevented tumor growth in RCC VHL/
  xenografts, via inhibition of angiogenesis2

1. Wilhelm S, Chien DS. Curr Pharm Des
2002822552257
2. Chang YS, et al. Clin Cancer Res 2005119011S
19
Phase III TARGETsTreatment Approaches in Renal
Cancer Global Evaluation Trial
Study Design

• Eligibility criteria
• Confirmed, advanced disease
• Clear-cell histology
• Measurable disease
• Failed one prior systemic therapy in last 8
  months
• Low/intermediate risk MSKCC groups included
• ECOG PS 0 or 1
• Good organ function
• No brain metastasis

Sorafenib400 mg bidn451

• Primary endpoints
• Survival (alpha0.04)
• PFS (alpha0.01)

Placebon452
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TARGETsSingle, Planned Progression-Free
Survival Analysis
Independently assessed PFS analysis
performed March, 2005 (data cut-off Jan 28, 2005)
Escudier B et al. Oral presentation, ASCO, 2005
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TARGETsOverall Survival at Time of Crossover
Median OS Sorafenib Not reached Placebo 14.7
months Hazard ratio 0.72 p-value 0.018
At 220 events, May 31, 2005 OBrien-Fleming
stopping boundary for significance was plt0.0005
Escudier B et al. Oral presentation, ECCO 13, 2005
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TARGETsOverall Survival Analysis 6 months
post-crossover
216 out of 452 placebo patients had crossed over
to sorafenib
Sorafenib
Placebo
Median OS Placebo 15.9 months Sorafenib 19.3
months Hazard ratio 0.77 p-value 0.015
Of 367 events, a total of 122 deaths were
reported in the low-risk and 245 in the
intermediate-risk groups
At 367 events, Nov. 30, 2005OBrien-Fleming
stopping boundary for significance was plt0.0094
23
TARGETsSecondary Overall Survival Analysis with
Censored Placebo Patients
Sorafenib
Placebo (censored at Jun 30, 2005)
Median OS Placebo 14.3 months Sorafenib
19.3 months Hazard ratio 0.74 p-value 0.01
Results from a planned OS analysis in which
placebo data were censored at June 30, 2005
Results on sorafenib arm are not censored
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Sorafenib Interferon
Interferon toxicity predominates
25
(No Transcript)
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A Phase 3, Randomized, 3-Arm Study of
Temsirolimus (TEMSR) or Interferon-Alpha (IFN) or
the Combination of TEMSR IFN in the Treatment
of First-Line, Poor-Risk Patients With Advanced
Renal Cell Carcinoma
Abstract LBA4

• G Hudes, M Carducci, P Tomczak, J Dutcher, R
  Figlin,
• A Kapoor, E Staroslawska, T OToole,
• S Kong, and L Moore

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Phase 3 Study of TEMSR and IFN in Advanced RCC

• 626 patients with advanced metastatic RCC with
  poor-risk features
• 209 sites (26 countries)

R A N D O M I Z E
n 207

• Geographic Regions
• WEU AU CA (22)
• US (30)
• EEU Other (48)
• Nephrectomy
• Yes (67)
• No (33)

n 209
n 210
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Poor-Risk Features for Eligibility

• Minimum of 3 poor-risk features required
• 1. LDH gt 1.5 X upper limit of normal
• 2. Hemoglobin lt lower limit of normal
• 3. Corrected calcium gt 10 mg/dL
• 4. Time from diagnosis to first treatment lt 1
  yr
• 5. Karnofsky Performance Status 60-70
• 6. Multiple organ sites of metastasis

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Percent () of Patients with Any Grade 3-4
Adverse Event
p lt 0.001 vs. IFN and vs. TEMSR IFN
Dose Reductions and Delays
30
Overall Survival by Treatment Arm
Arm 2 Temsirolimus
Probability of Survival
Arm 1 IFN
Arm 3 IFN Temsirolimus
Time from Randomization, Months
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Overall Survival by Treatment Arm
OBrien-Fleming boundary for significance
0.0155
32
Conclusions

• Temsirolimus significantly improved OS and PFS of
  poor-risk RCC patients as compared with IFN
• 3.6 month (49) improvement in median OS
• 1.8 month (95) improvement in median PFS
• Temsirolimus was better tolerated than IFN
• mTOR is an important therapeutic target in RCC

33
Everolimus (RAD001) an orally bioavailable mTOR
inhibitor
34
RAD001 for Renal Cell CarcinomaPhase 2
StudyAmato,et al. Abstract 4530

• Design
• Single-arm, IRB-approved trial
• Primary endpoint of time to progression
• Secondary endpoint of overall response rate
• 2-stage design, target accrual of 40 patients
• Eligibility
• Metastatic RCC
• No more than 1 prior therapy
• Adequate PS, hematology, and chemistry studies
• Normal cardiac function

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RAD001 for Renal Cell CarcinomaPhase 2 Study

• Treatment regimen 10 mg of daily oral therapy
• Dose reduced to 5 mg for grade 3 /4 toxicity
• Monitoring of CBC, chemistry, lipid profile, and
  pulmonary function
• Response assessed by RECIST
• Treatment continued unless progression or
  intolerability

36
RAD001 for Renal Cell CarcinomaIndependent
radiology review of serial CT scans
RECIST PR rate 36 Median TTP 6 months
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Proposed Phase III Trial of RAD001 plus Sunitinib
or Sorafenib

R

R
At progression
A
Sunitinib

Sorafenib

A
Advanced
N
N
or
D
metastatic
D
O
renal cell
O
cancer (no
M
M
prior
I

systemic
I
Sorafenib
therapy)

Z
Sunitinib
RAD001

Z
RAD001

E

E

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Phase III Trial of the Dual EGFR/HER-2 inhibitor
Lapatinib in RCC (Ravaud, et al. 4502)
Median time to progression (TTP) and overall
survival (OS) in weeks Tamoxifen or Megestrol
acetate
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Intergroup Adjuvant Phase III Trial (ASSURE)
Sorafenib 1 Cycle 400mg po BID X 42 days Total
9 cycles
Non-Metastatic Kidney Cancer Disease Stage
II III IV  
NEPHRECTOMY
Stratify UISS II III IV V Histologic
Subtype Clear cell Non-clear cell  
RANDOMIZE
Sunitinib 1 Cycle 50 mg po q am and placebo q
pm X 28 days, then placebo BID x 2 weeks Total
9 cycles
Placebo 1 cycle 2 pills BID X 42 days for 9
cycles
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Advanced Renal Cell Cancer Post-ASCO 2006 Menu

• Previously untreated, frontline
• High dose interleukin-2 (select patients)
• Sunitinib
• Temsirolimus (poor risk patients)
• Second line and beyond
• Sorafenib (also approved for frontline)
• Bevacizumab
• Interferon (select patients)
• Emerging contenders
• Everolimus (RAD001)
• Lapatinib? (subset of EGFR over-expressors?)

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Prostate Cancer ASCO 2006

• Intermittent vs. continuous androgen blockade (
  4513)
• Absolute PSA nadir as predictor of survival (
  4517)
• Nomogram for salvage radiation after
  prostatectomy ( 4514)
• Intermittent chemotherapy for HRPC (4518)

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Intermittent vs. Continuous Maximal Androgen
Blockade (MAB)
Da Silva, Abstract 4513
N766
N626
RANDOMIZE
Continuous MAB (n312)
MAB Cyproterone acetate LHRH agonist X 14 weeks

• Prostate
• Cancer
• T3/T4 M0
• or
• M1

PSA ?80 or lt 4
Intermittent MAB (n314)
Treatment resumed on the intermittent arm if PSA
gt 20 or PSA gt 10 with symptoms
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Intermittent vs. Continuous Maximal Androgen
Blockade (MAB)

• Most were M0 (68)
• Mean age 73 years
• At randomization
• Median PSA 1.2
• PSA gt 4 in 22
• Progression defined as
• Rising PSA x 2
• Increasing pain
• Performance status decline by 2 levels

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Relevant Outcomes

• Patients on the intermittent arm enjoyed
  substantial drug-free holiday periods
• 50 gt 1 year
• 29 gt 3 years
• Patients with PSA declines lt 2 ng/mL enjoyed even
  longer holidays
• Median time off therapy 1.5 years
• The majority of patients who resumed MAB
  responded

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Survival OutcomesMedian Follow-up 51 months
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Intermittent vs. Continuous MAB Issues and
Insights

• MAB vs. single agent LHRH agonist still
  controversial
• Patient-based meta-analyses (8000 patients in 27
  trials) showed no significant benefit to MAB
• Cyproterone acetate is not the ideal
  anti-androgen trend to worse survival in
  meta-analyses
• Intermittent therapy better tolerated and not
  associated with worse outcome
• Intermittent therapy is a reasonable option for
  patients requiring androgen deprivation
• We need to complete SWOG 9346!!!

Prostate Cancer Trialists Collaborative Group
Lancet, 2000
47
S9346 Study Schema
S9346 Induction Registrations Men with newly
diagnosed stage D2 prostate cancer and PSA gt 5
ng/ml
Late Induction Registration Started AD lt 6 months
prior to registration
Early Induction Registration (to start AD after
registration)
AD Goserelin Bicalutamide x 7 months
Men treated with AD for 7 months who achieve a
PSA lt 4 ng/ml
If PSA gt 4 ng/ml, off protocol
Randomization
Continuous AD
Intermittent AD
Androgen Deprivation
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S9346 Study StatusHussain,et al. Abstract 4517

• Accrual goal 1,512 eligible randomized.
• As of 5/23/06
• Induction Registrations n2423
• Randomized n1316
• PSA assessments were pre-specified by the study
  at scheduled intervals months 1, 4, 6 and 7 of
  the induction period

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At Risk PSA 0.2 ng/ml 453
210 63 0.2 lt
PSA 4.0 219 77
20 PSA gt 4.0
92 17 7
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Multivariate Proportional Hazards Model Testing
Effect of PSA lt 4 ng/ml or lt 0.2 at Months 6,7 on
Subsequent Risk of Death (Estimates and p-values
adjusted for other variables in the model)
comparison of these two estimates with a Wald
chi-square, p lt0.0001. Significant (plt0.05)
univariate predictors with lt 15 missing included
in model
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Conclusions

• In hormone naive D2 prostate cancer patients
  treated with AD
• Absolute PSA value after 7 months of ADT is the
  most powerful prognostic predictor of Risk of
  Death.
• The observed variability in survival is striking
  overall survivals ranging from 13 to 75 months.
  This variability is a clear reflection of the
  biologic heterogeneity of this disease.
• These findings should be considered in the design
  of future trials.

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Predicting the outcome of salvage radiotherapy
(RT) for recurrent prostate cancer after
prostatectomyStephenson et al, Abstract 4514

• Objective Develop a nomogram for salvage RT
  outcomes from a database of 1,540 patients with
  post-prostatectomy biochemical (PSA) recurrence
• Method Cox proportional hazards regression
  analysis
• Primary endpoint Disease progression after
  salvage RT
• PSA gt 0.2 followed by another increase
• Initiation of systemic therapy
• Clinical recurrence

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Progression-Free Probability after Salvage
Radiotherapy

• Disease Progression 866 patients (56)
• 6-Yr PFP 32 (CI, 28-35)
• 10-Yr PFP 19 (CI, 15-23)

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Outcome Stratified by Pre-Radiotherapy PSA
PSA lt 0.5
PSA 0.5-1.0
PSA 1.0-1.5
PSA gt 1.5
328 178
96 32
11 414 231
134 51
24 243 122
65 26
12 513 279
97 37
11
Early intervention when the PSA is lowest is
associated with improved outcome
55
Nomogram Predicting 6-Year Progression-Free
Probability after Salvage Radiotherapy
Concordance Index 0.69
56
Salvage RT NomogramTake Home Points

• Earlier intervention (when PSA is lt 0.5)
  associated with best outcomes (cure rate of
  50)
• Results still need to be prospectively validated
  in a randomized trial
• Salvage RT can be offered to highly selected
  patients but likelihood of cure is low

57
Intermittent chemotherapy in HRPC Beer et al,
Abstract 4518

• ASCENT Trial
• Docetaxel/DN101 vs. Docetaxel/Placebo
• Eligibility for Intermittent Chemotherapy
• PSA response (50 reduction confirmed 4 weeks
  apart) AND
• Serum PSA lt 4 ng/ml
• No other evidence of disease progression
• Intermittent Chemotherapy Protocol
• Serum PSA and clinical examination every 4 weeks
• Measurable disease assessment every 8 weeks in
  patient with measurable disease
• Chemotherapy resumed after a confirmed PSA
  increase of 50 when the PSA was gt 2 ng/ml or
  for any other evidence of disease progression.

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Intermittent chemotherapy in HRPC Results from
ASCENT

• 18 of patients entered intermittent chemotherapy
• The median duration of the first chemotherapy
  holiday was 17 weeks (range 4 74 weeks)
• Response to re-treatment after the first
  treatment holiday (n34)
• 56 of patients responded with a 50 reduction
  in serum PSA from their post-holiday baseline
• 21 met criteria for stable PSA for at least 12
  weeks
• 24 progressed on therapy

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(No Transcript)
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Testis Cancer ASCO 2006

• Stage I NSGCT
• Surveillance 5 vs. 2 CT scans (Mead, 4519)
• PET scanning (Huddart, 4520)
• Metastatic GCT
• Conventional vs. high dose chemo (Bajorin,
  4510)
• Salvage high dose chemo (Einhorn, 4549)
• Survivorship issues (Fossa, 4508 Raghavan,
  4509)

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BEP vs BEP High-dose ChemotherapyBajorin, et
al. Abstract 4510
Randomi ze
Stratify Risk Poor vs Intermediate Center
MSKCC, ECOG, SWOG, CALGB
BEP x 4 cycles
BEP x 2 cycles HD-CEC x 2 cycles
Trial Considerations Use International Risk
Criteria for eligibility BEP as standard arm
Randomize all patients insufficient patients to
randomize by marker decline status. Target
accrual was 218 pts to detect an improvement of
20 in CR at 1 year (alpha0.05 and 80 power).
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Patient Eligibility

• Poor-risk GCT
• All mediastinal NSGCT
• Gonadal NSGCT with AFP gt 10,000, HCG gt 50,000,
  LDH gt 10 x ULN or nonpulmonary visceral
  metastases
• Intermediate GCT
• Seminoma with nonpulmonary visceral metastases
• NSGCT with AFP 1,000-10,000, HCG 10,000-100,000,
  or LDH 3-10 x ULN

Modified IGCCCG criteria from J Clin Oncol
15594, 1997
63
Event-Free Survival
BEP vs BEP High-dose Chemotherapy
Survival
P.94
P.40
64
Salvage therapy with high dose carboplatin
etoposide (HDCE) in GCT patients Einhorn, et al.
Abstract 4549

• Retrospective review of 184 patients treated with
  tandem transplant (HDCE stem cell transplant)
• Cytoreduction with 0-2 courses of standard dose
• vinblastine ifosfamide cisplatin (VeIP)
  preceded
• tandem transplant
• - VeIP not given if progression within 4 weeks
  of last platinum course (N 30
  platinum refractory)
• Carboplatin 700 mg/M2 Etoposide 750 mg/M2 x 3
  days
• Maintenance daily oral etoposide for 3 months
  given to most patients achieving serologic CR

65
HDCE as salvage therapy Results

• Median time to second HDCE 28 days (range
  20-42)
• Three early drug-related deaths ARDS (1) and
  liver failure (2)
• Three patients developed AML (2 fatal), 1 GBM
• 11 of 184 (6) received only 1 course HDCE due to
  progressive disease (6) or toxicity (5)
• 117 of 184 (64) are continuously NED with median
  follow-up 42 months
• 97 of 117 (83 ) greater than 2 year NED
• 6 additional patients currently NED with
  further therapy

66
HDCE as salvage therapy Results

• of
  Pts. Continuously NED ()
• Entire series 184 117 (64)
• Second-line therapy 133 92 (69)
• Third-line or later 51 25 (49)
• Platinum refractory 30 15 (50)
• hCG gt 1,000 20 12 (60)
• AFP gt 1,000 7 2 (29)
• progression within 4 weeks last platinum
• at start of high dose chemotherapy

67
Survivorship Issues in Testis CancerFossa et al,
Abstract 4508Raghavan, et al. Abstract 4509

• Abstract 4508
• N 39,657 survivors
• Excess non-cancer deaths due to infections and
  digestive disease
• Abstract 4509
• Case (survivors) and control subjects (male
  friend)
• 951 surveys sent, 300 returned, 298 valid
• Only 67 control subjects replied
• Cases (vs. controls) had an excess of late
  toxicity cardiovascular, neurological,
  hematologic, musculoskeletal, and neoplastic

68
Survivorship Issues in Testis CancerFossa et al,
Abstract 4508Raghavan, et al. Abstract 4509

• Issues
• 1) What causes late toxicity? Treatment vs.
  Disease
• Variability in treatments
• - Type chemo, RT
• - Dose-schedule
• - RT fields, etc. etc.
• 2) Duration of follow-up
• In GCT survivors LIFELONG!!!
• 3) Management of late complications