2012 GU Cancers Symposium
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Transcript of 2012 GU Cancers Symposium
2012 GU Cancers 2012 GU Cancers SymposiumSymposium
San Francisco, CASan Francisco, CAFebruary 2-4, 2012February 2-4, 2012
Jerry M. Maniate Jerry M. Maniate MD, M.Ed, MD, M.Ed, FRCPCFRCPC
Assistant Professor, Department of MedicineAssistant Professor, Department of MedicineUniversity of TorontoUniversity of Toronto
Dr. H. James Watt Hematology/Oncology Dr. H. James Watt Hematology/Oncology ClinicClinic
Service of Hematology/OncologyService of Hematology/Oncology
Director of Medical EducationDirector of Medical EducationSt. Joseph’s Health CentreSt. Joseph’s Health Centre
ObjectivesObjectivesIn the next 30 minutes...In the next 30 minutes...
OutlineOutlineProstate CancerProstate Cancer
Bone Targeted TherapyBone Targeted Therapy
Renal Cell CancerRenal Cell Cancer
Highlights of GUCA Highlights of GUCA SymposiumSymposium2500 attendees2500 attendees
284 Prostate cancer abstracts284 Prostate cancer abstracts
136 Renal cell carcinoma abstracts136 Renal cell carcinoma abstracts
Novel Targets & Novel Novel Targets & Novel AgentsAgents
MDV3100MDV3100Specific inhibitor of androgen receptorSpecific inhibitor of androgen receptor
No known effect on androgen productionNo known effect on androgen production
Preclinical: anti-proliferative activity on prostate Preclinical: anti-proliferative activity on prostate cancer cells that harbour amplification of ARcancer cells that harbour amplification of AR
Scher, Lancet 2010; 375: 1437Scher, Lancet 2010; 375: 1437Scher, JCO, March 1, 2006Scher, JCO, March 1, 2006
MDV3100MDV3100
Progression measured as rising PSAProgression measured as rising PSA
Improved OS post-docetaxelImproved OS post-docetaxel
Median OS: 18.4 mths vs.Median OS: 18.4 mths vs.
Not hormone resistant but rather castrate Not hormone resistant but rather castrate resistant due to drive of AR signalingresistant due to drive of AR signaling
Scher, Lancet 2010; 375: 1437Scher, Lancet 2010; 375: 1437Scher, JCO, March 1, 2006Scher, JCO, March 1, 2006
Post-chemotherapy: failed Post-chemotherapy: failed docetaxeldocetaxel
Post-chemotherapy: failed Post-chemotherapy: failed docetaxeldocetaxel
MDV3100MDV3100160 mg po OD160 mg po ODMDV3100MDV3100
160 mg po OD160 mg po ODPlaceboPlaceboPlaceboPlacebo
Primary EP:Primary EP:Overall SurvivalOverall Survival
Primary EP:Primary EP:Overall SurvivalOverall Survival
AFFIRM Study. Scher HI et al. JCO 30, 2012 (suppl 5; abstract LBA1)
Secondary EP:Secondary EP:Radiographic PFSRadiographic PFSTime to first SRETime to first SRE
Time to PSA progressionTime to PSA progressionCirculating tumour cell count conversion Circulating tumour cell count conversion
raterate
Secondary EP:Secondary EP:Radiographic PFSRadiographic PFSTime to first SRETime to first SRE
Time to PSA progressionTime to PSA progressionCirculating tumour cell count conversion Circulating tumour cell count conversion
raterate
AFFIRM StudyAFFIRM Study
N = 1199 pts (800 vs. 399)N = 1199 pts (800 vs. 399)
Balanced demographics / disease Balanced demographics / disease characteristicscharacteristics
520 death events reached520 death events reached
Independent Drug Monitoring Committee Independent Drug Monitoring Committee (IDMC) concluded that the trial be stopped, (IDMC) concluded that the trial be stopped, unblinded and that the patients on placebo be unblinded and that the patients on placebo be offered the test agentoffered the test agent
Post-chemotherapy: failed Post-chemotherapy: failed docetaxeldocetaxel
Post-chemotherapy: failed Post-chemotherapy: failed docetaxeldocetaxel
MDV3100MDV3100160 mg po OD160 mg po ODMDV3100MDV3100
160 mg po OD160 mg po ODPlaceboPlaceboPlaceboPlacebo
AFFIRM Study. Scher HI et al. JCO 30, 2012 (suppl 5; abstract LBA1)
18.4 mths18.4 mths18.4 mths18.4 mths 13.6 mths13.6 mths13.6 mths13.6 mths p<0.001p<0.001Median OSMedian OS
PFSPFSTime to PSA progressionTime to PSA progressionSafetySafety
TO FOLLOWTO FOLLOW
AFFIRM StudyAFFIRM Study
Survival benefit observed across subgroups vs. Survival benefit observed across subgroups vs. placeboplacebo
Median duration of Tx: 8.3 vs. 3.0 mthsMedian duration of Tx: 8.3 vs. 3.0 mths
Tumour response on imagingTumour response on imaging
No difference in adverse eventsNo difference in adverse events
No myelosuppressionNo myelosuppression
0.6% had seizures (5 pts: 2 with brain mets, 2 0.6% had seizures (5 pts: 2 with brain mets, 2 had lidocaine for biopsies)had lidocaine for biopsies)
PREVAIL StudyPREVAIL Study
Asymptomatic or minimally symptomatic men Asymptomatic or minimally symptomatic men with metastatic PrCa who are chemotherapy with metastatic PrCa who are chemotherapy naivenaive
Bone Targeted TherapyBone Targeted Therapy
Radium-223 ChlorideRadium-223 ChlorideALSYMPCA StudyALSYMPCA Study
ALSYMPCA StudyALSYMPCA Study
Radium-223 acts as a calcium mimicRadium-223 acts as a calcium mimic
Integrated into boneIntegrated into bone
Alpha emitter that provides localized effectAlpha emitter that provides localized effect
Induces dsDNA breaks in adjacent tumour cellsInduces dsDNA breaks in adjacent tumour cells
Short penetrationShort penetration
Phase 2: Nilsson, Lancet OncoPhase 2: Nilsson, Lancet Onco
GUCA 2012, Abstract 8GUCA 2012, Abstract 8
ALSYMPCA StudyALSYMPCA Study
Phase 3: post-docetaxel and docetaxel Phase 3: post-docetaxel and docetaxel ineligibleineligible
BSC ± Radium-223BSC ± Radium-223
6 injections at 4-wk intervals6 injections at 4-wk intervals
N = 541 (radium) vs. 268 (placebo)N = 541 (radium) vs. 268 (placebo)
No cytotoxic chemotherapyNo cytotoxic chemotherapy
Primary EP: OSPrimary EP: OS
Secondary EP: QoL, safetySecondary EP: QoL, safety
ALSYMPCA StudyALSYMPCA Study
Planned interim analysis at 320 deathsPlanned interim analysis at 320 deaths
Balanced baseline characteristicsBalanced baseline characteristics
Results:Results:
OS: 14.0 mths vs. 11 mths (stat sig)OS: 14.0 mths vs. 11 mths (stat sig)
No routine imaging unlike DEN & Zometa No routine imaging unlike DEN & Zometa studiesstudies
ALSYMPCA StudyALSYMPCA Study
SRE: include spinal cord compression, SRE: include spinal cord compression, pathologic fracturespathologic fractures
Reduced risk for SCC with Radium-223 vs. Reduced risk for SCC with Radium-223 vs. placeboplacebo
A/E:A/E:
Modest increase in neutropenia but only 2%Modest increase in neutropenia but only 2%
Very well toleratedVery well tolerated
Bone Protection in Bone Protection in MetCRPCMetCRPCCan we prolong bone metastases free survival?Can we prolong bone metastases free survival?
Fracture prevention?Fracture prevention?
Should we place patients on bone protective Should we place patients on bone protective agent?agent?
Zoledronate vs. Denosumab?Zoledronate vs. Denosumab?
What is the optimal scheduling?What is the optimal scheduling?
Individualization of options?Individualization of options?
Bone Protection in Bone Protection in MetCRPCMetCRPC
Considerations for individualization:Considerations for individualization:Poor dentitionPoor dentitionConvenience: IV vs. SCConvenience: IV vs. SCRenal dysfunctionRenal dysfunctionSide effectsSide effectsCost and co-paymentsCost and co-paymentsAre these agents necessary when other Are these agents necessary when other agents are being used?agents are being used?
Renal Cell CarcinomaRenal Cell Carcinoma
RCC in the Vulnerable RCC in the Vulnerable PatientPatientComorbidity ScoresComorbidity Scores
RCC & Comorbidity RCC & Comorbidity ScoresScores
Accounting for comorbidities is important for Accounting for comorbidities is important for clinical prognosisclinical prognosis
SEER Registry (1995- 2007 data)SEER Registry (1995- 2007 data)
1155 people with T1a N0 M0, well-1155 people with T1a N0 M0, well-differentiateddifferentiated
At 10 years:At 10 years:
4% mortality for RCC causes4% mortality for RCC causes
51% from non-RCC causes51% from non-RCC causes
Competing RisksCompeting RisksWhat diseases did the patient have What diseases did the patient have before the cancer diagnosis?before the cancer diagnosis?
Which ones are relevant?Which ones are relevant?
Charlson Comorbidity Charlson Comorbidity IndexIndexDeveloped by fitting a statistical model to Developed by fitting a statistical model to evaluate predictors of mortalityevaluate predictors of mortality
Developed by fitting a Developed by fitting a statistical model to statistical model to evaluate predictors of evaluate predictors of mortalitymortality
As CCI score As CCI score increases, the increases, the mortality rate mortality rate increasesincreases
Charlson Comorbidity Charlson Comorbidity IndexIndex
203 older pts with cancer203 older pts with cancer
Little or no correlation between comorbidty Little or no correlation between comorbidty (CCI or Cumulative Illness Rating Scale - (CCI or Cumulative Illness Rating Scale - Geriatrics) and functional status (ECOG or Geriatrics) and functional status (ECOG or ADLs)ADLs)
An assessment of comorbid medical conditions An assessment of comorbid medical conditions can provide information that is independent of can provide information that is independent of patient’s functional status. Thus need to patient’s functional status. Thus need to assess both.assess both.
J Clin Oncol. 1998;16(4):1582
Charlson Comorbidity Charlson Comorbidity IndexIndex
CAUTIONS:CAUTIONS:
**Other measures may be more appropriate**Other measures may be more appropriate
Nomograms are statistical models that can Nomograms are statistical models that can be used to predict outcomes, and are visual be used to predict outcomes, and are visual representations of the modelrepresentations of the model
Be careful of extrapolation to unusual valuesBe careful of extrapolation to unusual values
Metastatic RCCMetastatic RCCWhen to treat?When to treat?
What are the deciding factors for when to What are the deciding factors for when to start systemic therapy?start systemic therapy?
Metastatic RCC: GoalMetastatic RCC: GoalDelay as long as possible a patient from Delay as long as possible a patient from reaching a lethal tumour burden while reaching a lethal tumour burden while maintaining QoLmaintaining QoL
RCC is an inherently diverse disease with RCC is an inherently diverse disease with a diverse biologya diverse biology
Who can we observe?Who can we observe?Good performance statusGood performance status
Low volumeLow volume
Slow growingSlow growing
AsymptomaticAsymptomatic
When should we start?When should we start?Increased pace of diseaseIncreased pace of disease
New organ sitesNew organ sites
Symptoms from diseaseSymptoms from disease
MD / patient anxietyMD / patient anxiety
Therapy in mRCCTherapy in mRCC
Advantages:Advantages:
Reduction in Reduction in tumour burdentumour burden
Delay worsening Delay worsening of diseaseof disease
Relatively Relatively convenient, oral convenient, oral therapytherapy
Disadvantages:Disadvantages:
Chronic therapyChronic therapy
Chronic toxicityChronic toxicity
Sunitinib in Elderly Pts with Sunitinib in Elderly Pts with mRCCmRCC
Pooled data analysis of 1059 ptsPooled data analysis of 1059 pts
65% (689 pts): Sunitinib 50 mg/d (4wks on, 65% (689 pts): Sunitinib 50 mg/d (4wks on, 2wks off)2wks off)
35% (370 pts): continuous OD dosing35% (370 pts): continuous OD dosing
1st line setting: 74% (783 pts)1st line setting: 74% (783 pts)
2nd line setting: 26% (276 pts)2nd line setting: 26% (276 pts)
Hutson TE et al. J Clin Oncol. 29: 2011 (suppl; abstract 4604)
Sunitinib in Elderly Pts with Sunitinib in Elderly Pts with mRCCmRCC
Median PFS: 9.0 vs. 10.9 mths (p=0.0830)Median PFS: 9.0 vs. 10.9 mths (p=0.0830)
Median OS: 23.3 vs. 23.7 mths (p=0.5441)Median OS: 23.3 vs. 23.7 mths (p=0.5441)
No difference when age takenNo difference when age taken
Overall tolerability is similarOverall tolerability is similar
In younger pts: increased HFS, chest painIn younger pts: increased HFS, chest pain
Hutson TE et al. J Clin Oncol. 29: 2011 (suppl; abstract 4604)
Ph.3 AXIS Trial for Ph.3 AXIS Trial for mRCCmRCCWhat is the effect of prior first-line What is the effect of prior first-line treatment duration and axitinib dose treatment duration and axitinib dose titration on axitinib efficacy?titration on axitinib efficacy?
Axitinib:Axitinib: potent and selective 2nd-gen potent and selective 2nd-gen VEGFR-I (VEGFR-1, -2, and -3)VEGFR-I (VEGFR-1, -2, and -3)
Rini BI et al. GUCA Symp 2012; abstract 354
AxitinibAxitinib
Potent and selective second-generation Potent and selective second-generation inhibitor of VEGFR-1, -2, and -3inhibitor of VEGFR-1, -2, and -3
If no toxicity > grade 2 and BP <150/90 mmHg If no toxicity > grade 2 and BP <150/90 mmHg without anti-HTN meds for >2 wks ➜ increase without anti-HTN meds for >2 wks ➜ increase axitinib to 7mg po BID and then to 10 mg po axitinib to 7mg po BID and then to 10 mg po BIDBID
Rini BI et al. GUCA Symp 2012; abstract 354
AXIS TrialAXIS Trial
AxitinibAxitinib5 mg po BID5 mg po BID
AxitinibAxitinib5 mg po BID5 mg po BID
SorafenibSorafenib400 mg po 400 mg po
BIDBID
SorafenibSorafenib400 mg po 400 mg po
BIDBID
6.7 mths6.7 mths6.7 mths6.7 mths 4.7 mths4.7 mths4.7 mths4.7 mthsMedian Median PFSPFS
Rini BI et al. GUCA Symp 2012; abstract 354
At least one At least one total daily total daily
dose > dose > 10mg10mg
6.6 mths6.6 mths6.6 mths6.6 mths
8.3 mths8.3 mths8.3 mths8.3 mthsAt least one At least one total daily total daily
dose ≤ dose ≤ 10mg10mg
N =132 ptsN =132 pts
N = 227 ptsN = 227 pts
Second Line mRCC (clear cell)Second Line mRCC (clear cell)Second Line mRCC (clear cell)Second Line mRCC (clear cell)
p<0.000p<0.00011
AXIS TrialAXIS Trial
Second Line mRCC (clear cell)Second Line mRCC (clear cell)Second Line mRCC (clear cell)Second Line mRCC (clear cell)
p<0.000p<0.00011
Rini BI et al. GUCA Symp 2012; abstract 354
Prior Prior SunitiniSunitini
b b ≥9mths≥9mths
Prior Prior SunitiniSunitini
b b <9mths<9mths
6.3 mths6.3 mths6.3 mths6.3 mths
4.5 mths4.5 mths4.5 mths4.5 mths
AxitinibAxitinib5 mg po BID5 mg po BID
AxitinibAxitinib5 mg po BID5 mg po BID
SorafenibSorafenib400 mg po 400 mg po
BIDBID
SorafenibSorafenib400 mg po 400 mg po
BIDBID
6.7 mths6.7 mths6.7 mths6.7 mths 4.7 mths4.7 mths4.7 mths4.7 mthsMedian Median PFSPFS
N =195 pts N =195 pts (53.9%)(53.9%)
N =194 pts N =194 pts (53.7%)(53.7%)
ForetinibForetinibOral multi-kinase inhibitor targeting MET, Oral multi-kinase inhibitor targeting MET, VEGF, RON, AXL and TIE-2 receptorsVEGF, RON, AXL and TIE-2 receptors
Activating mutations and/or Activating mutations and/or amplifications in MET in papillary RCCamplifications in MET in papillary RCC
Choueiri TK et al. GUCA Symp 2012; abstract 355
Locally adv. or met papillary RCCLocally adv. or met papillary RCCLocally adv. or met papillary RCCLocally adv. or met papillary RCC
Intermittent Intermittent armarm
ForetinibForetinib240 mg/d on day 240 mg/d on day 1-5 of every 14 1-5 of every 14
daysdays37 pts37 pts
Intermittent Intermittent armarm
ForetinibForetinib240 mg/d on day 240 mg/d on day 1-5 of every 14 1-5 of every 14
daysdays37 pts37 pts
Daily dose Daily dose armarm
ForetinibForetinib80 mg/d80 mg/d37 pts37 pts
Daily dose Daily dose armarm
ForetinibForetinib80 mg/d80 mg/d37 pts37 pts
ORR 13.5%ORR 13.5%PFS 9.3 mthsPFS 9.3 mths1-yr OS 70%1-yr OS 70%
Median OS not reachedMedian OS not reached
ORR 13.5%ORR 13.5%PFS 9.3 mthsPFS 9.3 mths1-yr OS 70%1-yr OS 70%
Median OS not reachedMedian OS not reached
Choueiri TK et al. GUCA Symp 2012; abstract 355
Locally adv. or met papillary RCCLocally adv. or met papillary RCCLocally adv. or met papillary RCCLocally adv. or met papillary RCC
Intermittent Intermittent armarm
ForetinibForetinib240 mg/d on day 240 mg/d on day 1-5 of every 14 1-5 of every 14
daysdays37 pts37 pts
Intermittent Intermittent armarm
ForetinibForetinib240 mg/d on day 240 mg/d on day 1-5 of every 14 1-5 of every 14
daysdays37 pts37 pts
Daily dose Daily dose armarm
ForetinibForetinib80 mg/d80 mg/d37 pts37 pts
Daily dose Daily dose armarm
ForetinibForetinib80 mg/d80 mg/d37 pts37 pts
ORR 13.5%ORR 13.5%PFS 9.3 mthsPFS 9.3 mths1-yr OS 70%1-yr OS 70%
Median OS not reachedMedian OS not reached
ORR 13.5%ORR 13.5%PFS 9.3 mthsPFS 9.3 mths1-yr OS 70%1-yr OS 70%
Median OS not reachedMedian OS not reached
Choueiri TK et al. GUCA Symp 2012; abstract 355
Foretinib: ToxicityForetinib: Toxicity
Grade 3/4:Grade 3/4:
Fatigue 6.8%Fatigue 6.8%
HTN 50%HTN 50%
Diarrhea 6.8%Diarrhea 6.8%
Non-fatal pulmonary embolism: 11%Non-fatal pulmonary embolism: 11%
No sig diff between the 2 cohorts in efficacy or No sig diff between the 2 cohorts in efficacy or safetysafety
SummarySummaryProstate CancerProstate Cancer
Bone Targeted TherapyBone Targeted Therapy
Renal Cell CancerRenal Cell Cancer