ASCO 2013 Best of GU Oncology - ANCO On-LineASCO 2013 Best of GU Oncology Eric J Small, MD ......

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8/26/13 1 ASCO 2013 Best of GU Oncology Eric J Small, MD UCSF Helen Diller Family Comprehensive Cancer Center University of California, San Francisco Our Challenges

Transcript of ASCO 2013 Best of GU Oncology - ANCO On-LineASCO 2013 Best of GU Oncology Eric J Small, MD ......

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ASCO 2013 Best of GU Oncology

Eric J Small, MD UCSF Helen Diller Family Comprehensive Cancer Center

University of California, San Francisco

Our Challenges

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Our Challenges

Cure Cancer

Our Challenges

Memorizing a ton of new drugs

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Our Challenges

Study To Understand Progress In Disease

Memorizing Study Names

Prostate Cancer

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Prostate Cancer: Evolving Standards in 2013

Localized!

!!

Local Rx! !

Androgen!

Deprivation!Therapy!

Recurrent/! metastatic!

Met!CRPC 1!

(asx)!

Secondary Hormones!!

Docetaxel!!

!Cabazitaxel!Abiraterone!

Enzalutamide!!

Sipuleucel T !Abiraterone!

!!

(Combined !Modality If Locally !

Advanced)! !

Non-met !CRPC!

Met! CRPC 2!(sx, visc)!

Met! CRPC 2!

(p/ docetaxel!

!Radium, Zoledronic Acid, Denosumab!

!

Prostate Cancer: Evolving Standards in 2013

Localized!

!!

Local Rx! !

Androgen!

Deprivation!Therapy!

Recurrent/! metastatic!

Met!CRPC 1!

(asx)!

Secondary Hormones!!

Docetaxel!!

!Cabazitaxel!Abiraterone!

Enzalutamide!!

Sipuleucel T !Abiraterone!

!!

(Combined !Modality If Locally !

Advanced)! !

Non-met !CRPC!

Met! CRPC 2!(sx, visc)!

Met! CRPC 2!

(p/ docetaxel!

!Radium, Zoledronic Acid, Denosumab!

!

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Targeting the Androgen Receptor (AR)

•  AR Amplification is Common in CRPC •  Ostensibly explains efficacy of AR targeted

agents such as enzalutamide and abiraterone in CRPC

•  Many unanswered questions:

How will these agents work in the NON-AR amplified pt? What’s the best way to sequence or combine? What are the mechanisms of resistance?

Enzalutamide in Hormone-Naïve Prostate Cancer Smith et al -Abstract 5001

DESIGN –  non-randomized phase 2 –  67 pts with hormone naïve Pca (39% mets) –  All receive enzalutamide 160 mg/d x 25 weeks.

RESULTS –  Safety profile: gynecomastia 38%, fatigue 34%) –  As expected, increase in circulating T and E) –  Stable bone mineral density and small changes in lipid

profiles over the short exposure

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PSA Response •  PSA response rate: 92.5% (62/67; 95% CI, 86.2%–98.8%) •  Median PSA decrease: -99.6% (95% CI, -100.0 to -86.5%)

Presented by: Matthew R. Smith, MGH Cancer Center

*4 men withdrew from the study before 25 weeks and thus were considered nonresponders for this analysis

Discussion and Caveats Enzalutamide in Hormone-Naïve Prostate Cancer

•  Enzalutmide as monotherapy has activity, and is reasonably well tolerated (but so does bicalutamide, so where’s the step forward?)

•  Bicalutamide monotherapy inferior to LHRHa, so PSA activity not necessarily the same as clinical benefit

•  Durability? •  Short term endpoints at 6 months limit metabolic conclusions •  What are next steps? We definitely need to test these drugs

earlier.

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UCSF: Potent and Selective AR Blockade in Biochemically Relapsed Prostate Cancer

ELIGIBILITY ENDPOINTS Rising PSA after prior RP and/or XRT PSA decline PSA doubling time of ≤ 12 months Amount of time off Rx No metastases on staging scans Metabolic changes

Prostate Cancer: Evolving Standards in 2013

Localized!

!!

Local Rx! !

Androgen!

Deprivation!Therapy!

Recurrent/! metastatic!

Met!CRPC 1!

(asx)!

Secondary Hormones!!

Docetaxel!!

!Cabazitaxel!Abiraterone!

Enzalutamide!!

Sipuleucel T !Abiraterone!

!!

(Combined !Modality If Locally !

Advanced)! !

Non-met !CRPC!

Met! CRPC 2!(sx, visc)!

Met! CRPC 2!

(p/ docetaxel!

!Radium, Zoledronic Acid, Denosumab!

!

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Update on COU-302 (pre-chemo abiraterone) Rathkopf et al - Abstr 5009

Ryan CJ, Smith MR, de Bono JS, et al. Abiraterone in Metastatic Prostate Cancer without Previous Chemotherapy. N Engl J Med 2012 Dec 10.

Rathkopf et al [Abstr 5009]

Median, mos HR (95% CI) p

AA + P P

Primary end points

rPFS 16.5 8.3 0.53 (0.45-0.62) < 0.0001

OS* 35.3 30.1 0.79 (0.66-0.96) 0.0151

Secondary end points Time to opiate use (cancer-related pain) NR 23.7 0.71 (0.59-0.85) 0.0002

Time to chemotherapy initiation 26.5 16.8 0.61 (0.51-0.72) < 0.0001

Time to ECOG PS deterioration 12.3 10.9 0.83 (0.72-0.94) 0.0052

Time to PSA progression 11.1 5.6 0.50 (0.43-0.58) < 0.0001

Updated Summary of COU-AA-302 Results

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Rathkopf et al [Abstr 5009] No chronic dosing safety signal

Rathkopf et al [Abstr 5009] No chronic dosing safety signal

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Discussion and Caveats Abiraterone in CRPC

•  Efficacy of Abiraterone maintained with longer follow-up

•  Prednisone alone works •  No newly emergent safety signal with chronic dosing •  Many unanswered questions:

How best to use in the non-metastatic pt? What’s the best way to sequence or combine? What are the mechanisms of resistance?

Discussion and Caveats Abiraterone in CRPC

•  Efficacy of Abiraterone maintained with longer follow-up

•  Prednisone alone works •  No newly emergent safety signal with chronic dosing •  Many unanswered questions:

How best to use in the non-metastatic pt? What’s the best way to sequence or combine? What are the mechanisms of resistance?

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METASTATIC CRPC

CALGB/Alliance A031201 Study Design

Metastatic  progressive  CRPC:•No  prior  chemo  for  mets•<1  wk  prior  keto•No  significant  pain

R  A  N  D  O  M  I  Z  E

Arm  A:Enzalutamide160mg  po daily

Arm  B:Abiraterone  1000  mg  po dailyPrednisone  5  mg  potwice  dailyEnzalutamide 160  mg  po daily

Endpoint- Overall Survival N= 1428 max

Discussion and Caveats Abiraterone in CRPC

•  Efficacy of Abiraterone maintained with longer follow-up

•  Prednisone alone works •  No newly emergent safety signal with chronic dosing •  Many unanswered questions:

How best to use in the non-metastatic pt? What’s the best way to sequence or combine? What are the mechanisms of resistance?

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The West Coast Prostate Cancer Dream Team (AACR/PCF/SU2C)

Adaptive Pathways as Mechanisms of Resistance to Abiraterone

PI: Eric Small, UCSF

Co-PI: Owen Witte UCLA

UCSF, UCLA, UCD, UCSC, UBC,OHSU

Scientific Premise: Conditional Lethality

Established Treatment

(Abiraterone)

Adaptive Response

Tumor Resistance

Current

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Scientific Premise: Conditional Lethality

Abiraterone Adaptive Response

Tumor Resistance

Abiraterone Tumor

Response Inhibition of

Alternate Pathway

Activation

Current

Future

Adaptive Response

WEST COAST PROSTATE CANCER DREAM TEAM The Genomic Characterization and Treatment of Abiraterone and Enzalutamide Resistant CRPC Patients

Patient with Abiraterone

Resistant mCRPC

Biopsy and Genomic

Characterization

Adaptive Response

Pathway Analysis

Pathway Validation and

Targeting

Novel Treatment

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Prostate Cancer: Evolving Standards in 2013

Localized!

!!

Local Rx! !

Androgen!

Deprivation!Therapy!

Recurrent/! metastatic!

Met!CRPC 1!

(asx)!

Secondary Hormones!!

Docetaxel!!

!Cabazitaxel!Abiraterone!

Enzalutamide!!

Sipuleucel T !Abiraterone!

!!

(Combined !Modality If Locally !

Advanced)! !

Non-met !CRPC!

Met! CRPC 2!(sx, visc)!

Met! CRPC 2!

(p/ docetaxel!

!Radium, Zoledronic Acid, Denosumab!

!

The TRAPEZE Study (Zoledronic Acid/Sr89 in the Taxane Era)

James et al - LBA5000

•  Trial design: Four arm Phase III in mCRPC with docetaxel/prednisolone +/- strontium or ZA or both

•  Primary endpoint: Bone PFS, OS and SREs •  What did we know before?

–  Strontium-89 + doxorubicin prolonged survival in small randomized phase II trial after “KAVE”

–  Zoledronate reduced SREs vs placebo in mCRPC in the pre-taxane era when using repetitive X-rays

Presented by: Oliver Sartor

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TRAPEZE Overall survival Zoledronic Acid Sr89

Presented by: Nick James

SRE Free Interval: ZA comparison

Presented by: Nick James

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Discussion and Caveats TRAPEZE Trial

•  No OS benefit to Zoledronic Acid or Sr 89 •  Zoledronate or Denosumab improved “SREs”

(but we already knew that)

•  It cannot necessarily be concluded that zoledronate or denosumab add benefit when used with agents that independently influence SREs such as abiraterone or enzalutamide.

Adapted from Oliver Sartor, Tulane Cancer Center

Prostate Cancer: Evolving Standards in 2013

Localized!

!!

Local Rx! !

Androgen!

Deprivation!Therapy!

Recurrent/! metastatic!

Met!CRPC 1!

(asx)!

Secondary Hormones!!

Docetaxel!!

!Cabazitaxel!Abiraterone!

Enzalutamide!!

Sipuleucel T !Abiraterone!

!!

(Combined !Modality If Locally !

Advanced)! !

Non-met !CRPC!

Met! CRPC 2!(sx, visc)!

Met! CRPC 2!

(p/ docetaxel!

!Radium, Zoledronic Acid, Denosumab!

!

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Corticosteroids in COU-301(Abiraterone post-docetaxel) Montgomery et al - Abstract 2014

•  Study Design: Retrospective analysis of impact of baseline corticosteroid use on Overall Survival

•  Background : In AFFIRM Phase 3 trial of enzalutmide vs placebo, steroid use was prognostic for OS, but study was deeply flawed

Factor Hazard Ratio P Value

Treatment 0.67 < 0.0001

LDH (> ULN [250 IU/L] vs ≤ ULN) 2.34 < 0.0001

ECOG PS (0-1 vs 2) 2.06 < 0.0001

Liver metastases (present vs absent) 1.77 < 0.0001

ALB (≤ 4 g/dL vs > 4 g/dL) 1.73 < 0.0001

Testosterone (≤ 4.99 ng/dL vs > 4.99 ng/dL) 1.51 < 0.0001

ALP (> ULN [160 IU/L] vs ≤ ULN) 1.46 < 0.0001

Results Multivariate Analysis for Overall Survival

•  Steroid use was NOT an independent predictor of Overall Survival

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Conclusions and Caveats Steroid Use in mCRPC

•  The concept that steroid use is deleterious in mCRPC is NOT substantiated

Abiraterone (COU 301)

Enzalutamide (AFFIRM)

Multivariable Analysis Informed by Univariate Analysis

Pre-specified variables not selected by univariate analysis

Steroid Use All patients – per protocol Selected patients – per physician choice

Baseline Risk Variables Balanced

Clearly imbalanced

Testicular Cancer

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ClincaI Stage 1 Seminoma

Seminoma (pT1-4 N0 M0)

Active Surveillance

Carbo AUC 7

Radiotherapy

85% of all seminomas Metastases after orchiectomy uncommon (15-19%) Excellent cure rates irrespective of treatment modality

Adapted from : Carsten Bokemeyer

•  1822 pts with a follow up 15.5 years

•  Treatment results for relapsing patients – Danish National Patient Registry – Danish Registry of Causes of Death

Surveillance for CS1 Seminoma Mortensen et al - Abstr 4502

Adapted from : Carsten Bokemeyer

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No. of relapses: 355 / 1822 (19.5 %) Stage at relapse: good prognostic group 353 (99.4 %)

Time to relapse: 0 to 24 months: 257 (72.4%) patients 25 to 60 months: 72 (20.3%) patients

Surveillance for CS1 Seminoma Results

Adapted from :Martenson

No at risk 1822

1758

1329

946

518

161

0

Cause specific survival Overall survival

Cause specific survival: 99.5% (15 years)

Overall survival:

92.1% (15 years) Death from disease: 6 Death from treatment: 4

Surveillance for CS1 Seminoma Results

Adapted from :Martenson

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Clinical Stage I NSGCT

Non-Seminoma (pT1-4 N0 M0)

Active Surveillance

BEP (1 or 2 cycles)

RPLND

Presented by: Carsten Bokemeyer

60% of all NSGCT at first presentation Excellent cure rates, disease-specific survival nearly 100%

•  Clinial stage I NS managed with “Active Surveillance”

•  1168 patients; (1999-2009) –  Lymphovascular invasion:

Positive n = 244 (21%) Negative n = 903 (77%)

•  Data was retrospectively collected from 6 institutions in Europe and North America

Surveillance for CS1 NSGCT Kollmannsberger et al - Abstr 4503

Presented by: Carsten Bokemeyer

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Results: Surveillance CS1 NSGCT

•  Relapses: n = 256 / 1168 (22%) LVI negative: n = 129 [129/903 = 14%]

LVI positive: n = 117 [117 / 244 = 48%]

•  Median time to relapse: 6 months [1-75 months]

•  IGCCCG risk category at relapse: good: n = 231 (90%) intermediate: n = 20 (8%) poor n = 5 (2%)

Presented by: Carsten Bokemeyer

Results: Surveillance Outcome

LVI + 99%

LVI - 99%

•  NED: n = 1143 (98%) •  AWD n =2 (< 1%) •  DOD n=4 (< 1%)

Testis Cancer specific survival by LVI status

0

20

40

60

80

100

5.0 0 Years

% survival

Presented by:Kolllmannsberger

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Conclusions Stage 1 Germ Cell Tumors

  Minimizing treatment-related toxicity while maintaining excellent cure rate is the primary objective

  Seminoma: Surveillance is preferred approach Single cycle of carbo AUC 7 for pts. unwilling to undergo surveillance XRT for rare pts who decide against surveillance and are unsuitable for adjuvant chemotherapy

  NSGCT: Surveillance is the emerging standard of care

If high risk (LVI) adjuvant chemotherapy (1 or 2 cycles of BEP) is an alternative option

Therapy in Metastatic GCT

Risk group 5 Yr OS Therapy “good prognosis” 90 % 3 x PEB

[*alternatively 4 x PE]

“intermediate prognosis” 80 % 4 x PEB

[*alternativly 4 x VIP]

“poor prognosis” 50 % 4 x PEB

non-seminoma [*alternativly 4 x VIP]

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Therapy in Metastatic GCT

Risk group 5 Yr OS Therapy “good prognosis” 90 % 3 x PEB

[*alternatively 4 x PE]

“intermediate prognosis” 80 % 4 x PEB

[*alternativly 4 x VIP]

“poor prognosis” 50 % 4 x PEB

non-seminoma [*alternativly 4 x VIP]

Frontline TIP for Intermediate and Poor Risk Pts

Feldman et al Abstract 4501

IGCCCG poor-risk disease or modified intermediate-risk GCT

Paclitaxel 120mg/m2 daily, days 1-2 Ifosfamide 1200mg/m2 daily, days 1-5 Cisplatin 20mg/m2 daily, days 1-5

Peg-filgrastim, 6mg subcutaneous, day 6 or 7 Cycle q 21 days x 4 1st endpoint: Complete Response (CR) rate (including surgical conversion) 2nd endpoints: PFS, OS, Toxicity Presented by: Carsten Bokemeyer

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Progression-Free Survival by Risk Group

0.00.2

0.40.6

0.81.0

Prog

ress

ion-F

ree S

urviv

al

| | | | | | ||||| | |

||| | || | | | | | | | | | || | | | | |

PFS by Stage

0 1 2 3 4 5 6

Stage 2 (n=15)Stage 3 (n=29)

Years from Treatment Start

Stage 2:

Stage 3:

15 13 10 7 1

29 22 16 12 9

Intermediate-risk Poor-risk

3-yr PFS 87% (95% CI: 56 – 96%)

3-yr PFS 76% (95% CI: 55 – 88%)

Median f/u: 3.1 years (1.1 – 5.4 years)

1100%

80%

60%

40%

20%

0%

Pro

porti

on a

live

and

prog

ress

ion-

n-fre

e

Presented by: Darren Feldman

 CR rate: 68 % estimated 3-year Overall Survival 95% (95% CI: 82 – 99%)

Select Grade 3/4* Adverse Events (n=44)

Toxicity

Grade 3 Grade 4 Total

N % N % N %

Neutropenic Fever** 11 25 1 3 12 27

Nausea 5 11 0 0 5 11

Fatigue 5 11 0 0 5 11

Orthostasis / Syncope 3 7 0 0 3 7

Vomiting 3 7 0 0 3 7

Encephalopathy 1 2 0 0 1 2

GI Bleed 0 0 1 2 1 2

DVT/PE 0 0 1 2 1 2

Renal Failure 1 2 0 0 1 2

Hemorrhagic Cystitis 1 2 0 0 1 2

** After 8 of 13 pts with neutropenic fever, the protocol was amended to use levofloxacin as prophylaxis, after which only 4 of 33 pts had neutropenic fever (despite intial PEG-GCSF!)

Presented by: Darren Feldman

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Conclusions and Caveats •  Frontline TIP is efficacious

•  Toxicity manageable, but warrants attention •  TIP compares favorably to historic BEP

•  Not yet the standard of care •  A multicenter randomized phase II study of TIP vs. BEP

underway

Slow Marker Decline Identifies Ultra-High Risk Patients

Presented by: K Fizazi

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Poor Risk GCT: Personalized Therapy GETUG 13 Phase III

Fizazi et al – LBA 4500

Poor-risk GCT (IGCCCG)

Registration 1st BEP

Day21: Tumor marker

Favorable decline 4 BEP (total)

Unfavorable decline R

Dose-dense regimen

4 BEP (total)

n=263 n=254 n=51

n=203

n=105

n=98

About 80 % poor decline

Presented by: K Fizazi

GETUG 13:dose-dense regimen (Fizazi et al.)

BEP x 1

Paclitaxel-BEP + Oxaliplatin + G-CSF

/ 3 weeks x 2 cycles

Cisplatin, Ifosfamide, Bleomycin + G-CSF

/ 3 weeks x 2 cycles

Cisplatin 20 mg/m2/d d1-5 Etoposide 100 mg/m2/d d1-5 Bleomycine 30 u/w

Paclitaxel 175 mg/m2 d1 BEP as above Oxaliplatin 130 mg/m2 d10 (omitted) G-CSF 263 µg/d (except chemo days)

Cisplatin 100 mg/m2 d1 Ifosfamide 2g/m2 d10,12,14 Bleomycine 25 U/d d10-14 (continuous IV) G-CSF as above

Presented by: K Fizazi

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Primary endpoint: PFS in randomized pts with unfavorable decline (Fizazi et al.)

Progression free survival (95%CI)

12920303137469847122234414760105

0%

20%

40%

60%

80%

100%

0 1 2 3 4 5 6 7 8Years

Unfav-BEPUnfav-DoseDense

At risk

HR: 0.66 [0.44-1.00] p=0.05

3-year PFS: 59% vs 48%

cNED: 63 vs 46 pts

OS in randomized patients with an unfavorable decline

Overall survival (95%CI)

231025353747689847132337475676105

0%

20%

40%

60%

80%

100%

0 1 2 3 4 5 6 7 8Years

Unfav-BEPUnfav-DoseDense

At risk

3-year OS: 73% vs 65% ( non-significant!)

HR: 0.78 (0.46 ; 1.31), p=0.34

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Discussion and Caveats •  First randomized trial showing benefit of dose intensification in slow

marker decline patients •  Trial met primary endpoint of 3-year PFS improvement (but not in

3-year OS (73% vs 65 %) •  Unusual dose dense regimen

•  Other /better options for dose intensified therapy ? AutoBMT?

•  Poor decline patients have a bad outcome, and some form of dose intensification is probably warranted.

Alliance 91102: 2nd-line Therapy for Progressive Disease after 1st-line Rx

PD = progression of disease; CR = complete response; PR-m = PR with normal tumor markers

IPFSG = International Prognostic Factors Study Group

Inclusion Criteria • Histologically-confirmed GCT • PD following 1st-line chemo • ≥3 but ≤6 cycles of prior cisplatin-based chemo • Adequate organ function for HDCT • Any primary site

Secondary Endpoints •  PFS •  Favorable RR (CR / PR-m) •  Toxicity & treatment-related mortality •  Validation of IPFSG model •  Biological correlates (SNP

analyses)

Stratification by IPFSG risk class and Continent

TIP (n=210)

TI-CE (n=210)

N=420 Primary Endpoint Overall Survival 1:1

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Renal Cell Carcinoma

Efficacy and Safety of Nintedanib (VEGF/FGFR) vs. Sunitinib Eisen et al Abstract #4506

Randomized Phase II Nintedanib (n=64) Sunitinib (n=32) Good/Intermediate Risk 95% 94% PFS at 9 months (1º endpt.) 43% 45% Median PFS (months) 8.4 8.4 Overall Response Rate 19% 31% Overall Survival (months) 20.4 21.2 Drug-related AE 75% 69%

AE dose reduction/disc. 25%/17% 25%/13% All grade Derm. 8% 47% All grade Dyspepsia 1.6% 22% All grade AST/ALT 17% 0

Presented by: Toni K. Choueiri, MD

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RECORD-3: Sunitinib and Everolimus Sequencing Motzer et al; Abstract 4504

RECORD-3: Sunitinib and Everolimus Sequencing

Randomized Phase II (n=471) Untreated mRCC

EVE (n=238)

SUN (n=233)

Non-inferior (HR<1.1)??

Primary Endpnt: PFS 1 (mos.) 7.85 10.71 NO : HR 1.43

Sequences

EVESUN

SUNEVE

Overall Survival (mos.) 22.4 32 NO: HR 1.24 PFS1+PFS2 (mos.) 21.1

25.8 NO: HR 1.28

First-line VEGF-targeted therapy remains standard in mRCC Consider mTOR inhibitors as first line only if recent acute vascular event or depressed EF

Presented by: Toni K. Choueiri, MD

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Targeting PD-L and PD-L1 in mRCC Cho et al: Abstract 4504 and Drake et al: Abstract 4514

Presented by: Toni K. Choueiri, MD

Presented by: Toni K. Choueiri

100

50

-50

0 21 42 63 84 105

0

126 147 168 189 210 231 252 273 294 315 336 357 378 399 420

-100

441

Nivolumab (Drake, ASCO 2013) MPDL-3280A (Cho, ASCO 2013)

Drug Nivolumab (n=34)

BMS-936559 (n=17)

MPDL-3280A (n=47)

Reference Drake (ASCO 2013)

Brahmer (NEJM 2012)

Cho (ASCO 2013)

ORR 29% 12% 13%

mPFS (m) 7.3 - -

mOS (m) >22 - -

PD1 inh. PD-L1 inh.

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RCC Conclusions •  Nintedanib: No better than Sunitinib in an

unselected mRCC population. As yet no evidence for superiority of dual VEGF/FGF targeting

•  RECORD-3: Everolimus is inferior to Sunitinib in

the front-line setting.

•  Anti-PD-1 and anti-PDL-1: preliminary safety and activity are encouraging.

•  Phase 3 study of Nivolumab (anti-PD1) in pts

previously treated with a TKI is open to accrual.

My take on GU Onc at ASCO: No homeruns. Modest increments. Not a world series year for either GU Oncology or the Giants (sigh)

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Thank you