2012 gu cancers symposium san francisco, ca february 2-4, 2012 jerry m. maniate md, m.ed, frcpc...

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


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



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

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


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


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


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


AXIS TrialAXIS Trial

AxitinibAxitinib5 mg po BID5 mg po BID


SorafenibSorafenib400 mg po 400 mg po

BIDBID


BIDBID

6.7 mths6.7 mths6.7 mths6.7 mths 4.7 mths4.7 mths4.7 mths4.7 mthsMedian Median PFSPFS


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


Prior Prior SunitiniSunitini

b b ≥9mths≥9mths

Prior Prior SunitiniSunitini

b b <9mths<9mths






BIDBID


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

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


Renal Cell CancerRenal Cell Cancer

QuestionsQuestions

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2012 gu cancers symposium san francisco, ca february 2-4, 2012 jerry m. maniate md, m.ed, frcpc...

Documents

mdv3100 progression

test agent slide

po bid axitinib sorafenib

po bid sorafenib

scher hi

failed docetaxel mdv3100

mths p axitinib potent

po bid rini bi