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