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Scuola di uro Oncologia

CONTROVERSIE ONCOLOGICHEL’oncologo risponde all’urologo:

PRIMA LINEA DI TRATTAMENTO

G. CartenìDirettore U.O.S.C. di Oncologia

Medica A.O.R.N.A. Cardarelli Napoli

Roma, 12/13 Luglio 2013

Quali criteri vengono utilizzati per scegliere il farmaco da utilizzare in prima linea ?

Come monitorizzare la terapia ? Criteri di successo/insuccesso

La gestione delle complicanze/effetti collaterali

Trattamento delle metastasi osseeTrattamento delle metastasi ossee

Associazione di farmaci ? terapie sequenziali ?

How to choose first line treatment

• Prognostic profile (Motzer/Heng)Prognostic profile (Motzer/Heng)• Toxicity profile and comorbidities• Disease characteristics (site/sympthoms)• Sequential strategies• Oral/iv administration

Ph i i i• Physician experience• Patient preference• Biomarkers in development !Biomarkers in development…!

Linee Guida EAU 2010Linee Guida EAU 2010

First-line treatment guidelines for clear cell mRCC:clear cell mRCC:

ESMO 2012

Risk status Recommendation Level of evidenceRisk status Recommendation Level of evidence

Favourable orSunitinib I, A

Favourable or intermediate Bevacizumab + IFN-α

PazopanibII, AII, A

Poor risk Temsirolimus II, A

Escudier B, et al. Ann Oncol 2012;23(Suppl 7):vii65–71

Randomized, Open Label, Phase III Trial of Pazopanib versus Sunitinib in First-line Treatment of Patients with Metastatic Renal Cell Carcinoma (mRCC): Results of the

COMPARZ TrialCOMPARZ Trial

Robert Motzer1, T. E. Hutson2, James Reeves3, Robert Hawkins4, Jun Guo5, Paul Nathan6, Michael Staehler7, Paul de Souza8, Jaime R. Merchan9, Kate Fife10, Jie Jin11, Robert Jones12, Hirotsugu Uemura13, Ugo De Giorgi14, Ulrika Harmenberg15, Jinwan Wang16, David Cella17, Lauren McCann18, g , g , , ,Keith Deen18, and Toni K. Choueiri19

1Memorial Sloan Kettering Cancer Center, NY, NY, USA; 2Baylor Sammons Cancer Center/Texas Oncology, Dallas, TX, USA; 3Florida Cancer Specialists, Fort Myers, FL, USA; 4University of Manchester and The Christie Hospital NHS Foundation Trust Manchester United Kingdom; 5 Renal Cancer and Melanoma Unit Peking University Cancer Hospital Beijing China;of Manchester and The Christie Hospital, NHS Foundation Trust, Manchester, United Kingdom; Renal Cancer and Melanoma Unit, Peking University Cancer Hospital, Beijing, China; 6Mount Vernon Hospital, Middlesex, United Kingdom;7 Department of Urology, Interdisciplinary Centre on Renal Tumors, University of Munich, Munich, Germany; 8University of Western Sydney School of Medicine, MMRG, CRG, Sydney, Australia; 9 University of Miami, Sylvester Cancer Center, Miami, FL, USA:10 Oncology Centre, Addenbrooke's Hospital, Cambridge, United Kingdom; 11 Peking University First Hospital, Beijing, China; 12Institute of Cancer Sciences University of Glasgow, Glasgow, United Kingdom;13 Department of Urology, Kinki University Faculty of Medicine, Osaka, Japan; 14IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (I.R.S.T.), Meldola, Italy; 15Department of Oncology, Radiumhemmet Karolinska University Hospital, Stockholm, Sweden; 16 Cancer Hospital, CAMS & PUMC, Beijing, China; 17Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL , USA; 18GlaxoSmithKline, Inc., Collegeville, PA, USA; 10Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

COMPARZ: PFS (IRC-assessed)Non inferiority met if upper bound of 95%

PFS (ITT population) Pazopanib (n=557) Sunitinib (n=553)

Non-inferiority met if upper bound of 95% CI for HR <1.25 (EMA requested ≤1.223)

PFS (ITT population) Pazopanib (n 557) Sunitinib (n 553)

Median PFS, months (95% CI) 8.4 (8.3, 10.9) 9.5 (8.3, 11.1)

HR (95% CI) 1.0466 (0.8982, 1.2195)

PFS (PP l ti ) P ib ( 501) S iti ib ( 494)PFS (PP population) Pazopanib (n=501) Sunitinib (n=494)

Median PFS, months (95% CI) 8.4 (8.3, 10.9) 10.2 (8.3, 11.1)( ) ( ) ( )

HR (95% CI) 1.069 (0.910, 1.255)

PP, per-protocol

1. GSK. Clinical Study Register. Study 108844. Available at: http://download.gsk-clinicalstudyregister.com/files/ae28e535-6855-4956-8022-084cdeda4d38 (last accessed February 2013); 2. Motzer RJ, et al. Presented at ESMO 2012; Abstract LBA8; 3. Available at http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/001141/WC500094275.pdf (last accessed April 2013)

COMPARZ study design:Phase III, open-label, non-, p ,

inferiority trial

Pazopanib 800 mg QDContinuous daily dosingEnrolment criteria:

•Locally advanced or mRCC•Clear-cell histology RandomisedClear cell histology•No prior systemic therapy •Measurable disease (RECIST 1.0)•KPS ≥70•Adequate organ function

N=927

Sunitinib 50 mg QD

Randomised1:1

N=1,110Adequate organ function Sunitinib 50 mg QDSchedule 4/2

Study start: August 2008

VEG108844 VEG113078VEG108844Phase III

n=927

VEG113078Phase II (Asia)

n=183

COMPARZ:1,110 patients

KPS, Karnofsky Performance Scale; RECIST, Response Evaluation Criteria in Solid Tumors; Schedule 4/2, 4 weeks on treatment, 2 weeks offwww.clinicaltrials.gov (NCT00720941; NCT01147822)

Primary Endpoint: Progression-free Survival

(independent review)(independent review)

N Median PFS (95% CI)

P ib 557 8 4 (8 3 10 9)Pazopanib 557 8.4 mo (8.3, 10.9)Sunitinib 553 9.5 mo (8.3, 11.1)

HR (95% CI ) = 1.047 (0.898,1.220)

PazopanibpSunitinib

Interim Analysis of Overall Survival

N Median OS (95% CI)

Pazopanib 557 28.4 mos (26.2, 35.6)Sunitinib 553 29.3 mos (25.3, 32.5)

HR (95% CI ) = 0.908 (0.762,1.082)P-value = 0.275

PazopanibpSunitinib

COMPARZ: Timing of assessments

Sunitinib

elin

e

SunitinibPazopanib

Week 6 Week 6 Week 6

e fro

m b

ase

Disease assessments

ean

chan

geM

e

QoL assessmentsWeek 4 Week 4 Week 4

Time

QoL, quality of lifeMotzer RJ, et al. Presented at ESMO 2012; Abstract LBA8Cella D, et al. Presented at ASCO-GU 2012; Abstract 346

Most Common Adverse Events (treatment-emergent) ( g )

Adverse Event aPazopanib (n = 554) % Sunitinib (n = 548) %

All Grs Gr 3/4 All Grs Gr 3/4d e se e t G s G 3/ G s G 3/Any event b >99 59/15 >99 57/17Diarrhea 63 9/0 57 7/<1Fatigue 55 10/<1 63 17/<1Hypertension 46 15/<1 41 15/<1N 45 2/0 46 2/0Nausea 45 2/0 46 2/0Decreased appetite 37 1/0 37 3/0ALT increased 31 10/2 18 2/<1ALT increased 31 10/2 18 2/ 1Hair color changes 30 0/0 10 <1/0Hand-foot syndrome 29 6/0 50 11/<1Taste Alteration 26 <1/0 36 0/0Thrombocytopenia 10 2/<1 34 12/4a AE ≥30% in either arma AE ≥30% in either armb 2% of patients in pazopanib arm and 3% of patients in sunitinib arm had grade 5 adverse events.

COMPARZ: Common AEs (treatment-emergent)

Pazopanib (n=554), % Sunitinib (n=548), % Risk ratio 95% CI

AE*

p ( ), ( ),All

grades Grade 3/4 All grades Grade 3/4 All grades

Any event† >99 59/15 >99 57/17 NA NAAny event† >99 59/15 >99 57/17 NA NADiarrhoea 63 9/0 57 7/<1 1.09 0.99, 1.20 Fatigue 55 10/<1 63 17/<1 0.87 0.79, 0.96 Hypertension 46 15/<1 41 15/<1 1.14 1.00, 1.31 Nausea 45 2/0 46 2/0 0.98 0.86, 1.11 Decreased appetite 37 1/0 37 3/0 NA NADecreased appetite 37 1/0 37 3/0 NA NAALT increased 31 10/2 18 2/<1 1.74 1.40, 2.17 Hair colour changes 30 0/0 10 <1/0 NA NA

HFS 29 6/0 50 11/<1 0.59 0.50, 0.68

Taste alteration 26 <1/0 36 0/0 NA NAThrombocytopenia 10 2/<1 34 12/4 0 30 0 23 0 40Thrombocytopenia 10 2/<1 34 12/4 0.30 0.23, 0.40

*AE ≥30% in either arm; †2% of patients in pazopanib arm and 3% of patients in sunitinib arm had grade 5 AEsALT, alanine transaminase; AST, aspartate transaminase; HFS, hand–foot syndrome; NA, not applicable

Treatment Duration and Dose Adjustments

Pazopanib SunitinibPazopanib (n = 554)

Sunitinib(n = 548)

M di d ti f t t tMedian duration of treatment (months, range)

8.0 (0−40) 7.6 (0−38)

Dose reductions, % 44 51

Discontinuations due to AEs1, % 24 19

1. Most common reason: pazopanib arm (liver event, 6%); sunitinib arm (cytopenia, 3%)

Quality of Life Results (first 6 months1)

Instrument Domain DescriptionTreatment difference : mean change from

baseline 2P ‐value

FACIT-F Fatigue/Total score 2.32 <0.001

FKSI 19

Kidney Symptom Index/Total score 1.41 0.018

Physical 0.78 0.027

Emotional 0 05 0 409FKSI-19 Emotional 0.05 0.409

Treatment Side Effects 0.31 0.033

Functional Well Being 0.31 0.098

Cancer Treatment SatisfactionQuestionnaire (CTSQ)

Expectations of Therapy 1.41 0.284

Feelings about Side Effects 8.50 <0.001

Satisfaction with Therapy 3 21 <0 001(CTSQ) Satisfaction with Therapy 3.21 <0.001

SupplementaryQ lit f Lif

Worst mouth/throat soreness 0.505 <0.0001

Worst foot soreness 0.204 0.0016Quality of Life Questionnaire (SQLQ)

Worst hand soreness 0.267 0.0008

Limitations due to mouth/throat soreness 0.94 <0.001

Limitations due to foot soreness 0.65 0.0141Pre-specified analysis. HRQoL changes in mean scores over time were analyzed with a repeated measures analysis of covariance (ANCOVA). 2Yellow Font: favors pazopanib. Blue Font: favors sunitinib. P-value <0.05 is statistically significant

Quality of Life Results: PISCES1

Randomized double-blind, placebo-controlled, cross-over study in patients with metastatic renal cell carcinoma

Instrument Timing Domain Description Treatment difference2,3

P value

FACIT- F Every 2 weeks Fatigue/Total score 2.5 0.002

Supplementary E 2

Worst mouth/throat soreness 0.38 <0.001

Worst foot soreness 0.08 0.026Supplementary Quality of Life Questionnaire

Every 2 weeks

Worst hand soreness 0.16 0.005

Limitations due to mouth/throat soreness 0.60 <0.001

Limitations due to foot soreness 0.58 0.003

1. Escudier BJ, et al.. J Clin Oncol 30, 2012 (suppl; abstr CRA4502)2 Cella D et al ESMO Congress 2012 poster 792PD2. Cella D, et al. ESMO Congress 2012 poster 792PD3. Yellow Font: favors pazopanibP-value <0.05 is statistically significant

Significantly more patients preferred pazopanib over

iti ib ( i d i t)1sunitinib (primary endpoint)1

100

80

90

100p<0.001

60

70

s (%

)

70%

40

50

Pat

ient

s 70%(n=80)

10

20

30

22%8%

(n=9)

0

10

Preferred pazopanib Preferred sunitinib No preference

(n=25)

1. Escudier B, et al. J Clin Oncol 2012;30 suppl: abstr CRA4502.

Valutazione dello stato di malattia in corso di trattamento con targeted

therapies

Necessario fare riferimento a criteri:– Diagnostica strumentale

– Clinici

– Laboratorio

Criteri di risposta (RECIST) -CriticitàCriticità

I criteri RECIST rappresentano lo standard di valutazione di

• La risposta parziale è ⇒ Un tumor shrinkage del < 30% è

pprisposta al trattamento in studi clinici su farmaci antitumorali1

p pdefinita come tumor shrinkage pari al 30%

un risultato positivo per il paziente.Il controllo del tumore potrebbe essere un endpoint clinicamente più rilevante2rilevante2

⇒ Potrebbe non essere appropriato per valutare la risposta alle targeted

• Si basa sulle risposte agli agenti antitumorali per valutare la risposta alle targeted

therapies (differente meccanismo d’azione)

agenti antitumorali citotossici

⇒ Le targeted therapies possono determinare necrosi tumorale piuttosto che tumor shrinkage3

• Non si misurano le necrosi tumorali

1. Therasse P, et al. J Natl Cancer Inst 2000; 92:205–162. Nygren P, et al Acta Oncologia 2008; 47:316–29

3. Abou-Alfa G, et al. J Clin Oncol 2006;24:4293–300

Revisione criteri di risposta (RECIST v. 1.1)

Principali modifiche proposte:Principali modifiche proposte:- Numero delle lesioni valutabili;

f- Dimensioni dei linfonodi patologici;- Conferma della risposta;- Supporto FDG-PET per valutare le progressioni.

Come valutare la risposta al trattamento nell’era delle

targeted therapies?

• I criteri RECIST e la loro più recente revisione non• I criteri RECIST e la loro più recente revisione non tengono conto di:• Tecniche di imaging funzionale come la PET o la RMNg g• Valutazione anatomica volumetrica del tumore

Necessità di nuove metodiche di immagine atte a• Necessità di nuove metodiche di immagine atte a studiare la vascolarizzazione e la necrosi tumorale

FDG-PETDCE-USDCE-MRI

Imaging funzionale con DCE-USValutazione della risposta a

f ibsorafenib

• Abdominal lymph node from an RCC in a 37 year-old ( d d ) t t d ith f ibwoman (good responder) treated with sorafenib

DCE-USbefore treatment shows contrast uptake

DCE-US after 3 weeks of treatmentshows contrast uptake

DCE-US after 6 weeks of treatment shows contrast uptakecontrast uptake

throughout the tumour estimated at 81%

shows contrast uptake throughout the tumour estimated at 48%

contrast uptakethroughout the tumour estimated at 31%

Lamuraglia et al.EJC 2006

identifying patients with progression-free survival of >250 days

sensitivity specificity

identifying patients with progression free survival of 250 days

MASS criteria

86% 100%

SACT criteria

75% 100%

CONCLUSION: Assessment of metastatic RCC target lesions on CECT for changes in morphology, attenuation, size, and structure by MASS Criteria is more accurate than response assessment by

SACT Criteria, RECIST, or modified Choi Criteria. Furthermore, the use of MASS Criteria for imaging response assessment showed high interobserver agreement and may predict disease outcome in

patients with metastatic RCC on targeted therapySmith AD, Shah SN, Rini BI, Lieber ML, Remer EM. Morphology, Attenuation, Size, and Structure (MASS) criteria: assessing response and predicting clinical outcome in metastatic renal cell carcinoma on antiangiogenic targeted therapy. AJR Am J Roentgenol. 2010 Jun;194(6):1470-8

patients with metastatic RCC on targeted therapy

Valutazione dello stato di malattia in corso di trattamento con targeted

therapies

Necessario fare riferimento a criteri:Necessario fare riferimento a criteri:– Diagnostica strumentale

– Clinici– LaboratorioLaboratorio

Criteri cliniciCriteri clinici

Esame obiettivo

Performance statusPerformance status

Sintomi tumore-correlati

Perdita di peso

Consumo di analgesiciConsumo di analgesici

Qualità di vita del paziente

Criteri di laboratorioCriteri di laboratorio

Emocromo completo

Funzionalità epatica

Funzionalità renaleFunzionalità renale

LDH

Calcemia

Tossicità o progressione di malattia?Tossicità o progressione di malattia?

Q d fi iQuando finisce una prima plinea di

trattamento ?trattamento ?

In assenza di una sicura progressioneIn assenza di una sicura progressione obiettiva, i criteri clinici che depongono per un beneficio per il paziente, devono sempre orientare verso la prosecuzione p pdel trattamento con l’agente target in corsocorso

E viceversa….

• Sintomi all’esordio

– Ematuria

– Anemia

– Dolori addominali

– Calo ponderale

– Astenia

Dispnea– Dispnea

– Il paziente viene trasportato a braccia alla visita

• Emoglobina: 9.0 gr/dl

• LDH 920

• PS: sec Karnofsky 70%

• Pluri‐metastatico

22.01.2010

• Maggio 2010

– Praticati due cicli di Sutent

– Netto miglioramento delle condizioni clinicheNetto miglioramento delle condizioni cliniche

– Molto ridotto il dolore addominale

– Astenia quasi assente

– Hgb 11 g/dl

– Calcemia 8.6 mg/dl

LDH 650– LDH 650

– Karnofsky 80%

18.05.2010

27.07.2010

11.11.2010

04.02.2011

ccRCCPredictive markers ofPredictive markers of

target therapy• Bio‐Clinical

– Hypertension (>90 mm/hg DBP)yp ( / g )

– LDH

Hypothiroidism (increased TSH)– Hypothiroidism (increased TSH)

Hypertension Biomarker of Efficacy with Sunitinib

B Rini, J Natl Cancer Inst 2011; 103:763-773.

Diastolic blood pressure Biomarker of efficacy with axitinib

OS with landmark at 8 weeks.in solid tumors

B Rini, Clin Cancer Res; 17(11); 3841–9.2011

Serum LDH Biomarker with Temsirolimus

Andrew J Armstrong et al, J Clin Oncol 30:3402-3407. 2012

Hypothyroidism (increased TSH)Biomarker of activity with TKI in solid y

tumors

Obj ti R i i A di t R E l ti C it i i S lid T B dObjective Remission According to Response Evaluation Criteria in Solid Tumors Based on Increased Thyroid-Stimulating Hormone Levels

Schmidinger M, Cancer 2011

Implicazioni clinicheImplicazioni cliniche

• Trattiamo FINO alla tossicità ?

• Trattiamo LA tossicità ?Trattiamo LA tossicità ?

• Ruolo dei farmaci per la tossicità ?

Take home messagesTake home messages

• Metodi di valutazione e misure profilattiche verso gli effetti collaterali possono confondere questi risultati

G t d i i lt ti d i d t di t tti i• Gran parte dei risultati derivano da studi retrospettivi (validazione in studi prospettici)

• I ‘potenziali benefici’ derivanti dalla somministrazione• I potenziali benefici derivanti dalla somministrazione contemporanea di medicinali devono essere considerati

• Nessuno di questi marcatori ideale: il marcatore idealeNessuno di questi marcatori ideale: il marcatore ideale predittivo valutabile prima del trattamento, piuttosto che durante il trattamento

Key Factors for Successful Therapy Management in mRCCTherapy Management in mRCC

D iDosing

Treatment Duration

Optimum Efficacy

Side-effect Management

Duration y

Schedule

Zoledronic acid significantly extended (A) the time to first skeletalcomplication compared with placebo and (B) the time to first

pathologic fracture compared with placeboRosen et al. Cancer 2004; 100: 2613‐21

pathologic fracture compared with placebo

mRCC patients: 74 total

reduction of skeletal complications: 74% (ZA) vs 37% (placebo) (p=0.015)absolute reduction: 37%

ti t Fi t O St d SRE 424 d 72 d ( 0 007)time to First On‐Study SRE: 424 days vs 72 days (p=0.007)

Rosen et al. Cancer 2004; 100: 2613‐21

Three Identical International, Randomized, Double‐Blind Active‐Controlled TrialsDouble‐Blind, Active‐Controlled Trials

Key Inclusion Criteria RA E

NDenosumab 120 mg SC and • Adults with breast, prostate,

other solid tumors, or multiple myeloma and ≥1 bone metastasis

ANDOMI

ND

OF

Placebo IV* every 4 weeks(n=2862)

Key Exclusion Criteria• current or prior IV bisphosphonate

administration

IZATIO

STUD

Zoledronic acid 4 mg IV* andPlacebo SC every 4 weeks

( 2861)administration• creatinine clearance <30 mL/min

Recommended: Daily supplementation with calcium (≥500 mg) and vitamin D (≥400 U)

ON Y(n=2861)

Primary Endpoint: Time to first on-study skeletal-related event (SRE) (Non-inferiority)

Lipton A, Fizazi K, Stopeck A, et al. Eur J Cancer 2012

Baseline CharacteristicsBaseline Characteristics

Ch i i (%) M di (Q1 Q3)Characteristics, n (%) or Median (Q1, Q3) Denosumab(n=2862)

Zoledronic Acid(n=2861)

Tumor type†

Breast 1026 (36) 1020 (36)

Prostate 950 (33) 951 (33)

Non small cell lung 350 (12) 352 (12)Non‐small cell lung 350 (12) 352 (12)

Multiple myeloma 87 (3) 93 (3)

Renal 70 (2) 85 (3)

Small cell lung 61 (2) 48 (2)

Bladder 28 (1) 35 (1)

Rectal 25 (1) 35 (1)Rectal 25 (1) 35 (1)

Colon 30 (1) 29 (1)

Other§ 449 (16) 445 (16)


Primary Endpoint: Time to Fi t O St d SREFirst On‐Study SRE

RE

1.0

0.8

HR 0.83 (95% CI: 0.76, 0.90)P<0.001 (Superiority)

Risk Reduction17%

with

out S

R 0.8

0.6

Pro

porti

on

0.4

0.2

KM Estimate of Median Months

Denosumab 27.66

Z l d i A id 19 45

Month0 6 12 18 24 30

0

Zoledronic Acid 19.45

Patients at Risk:Denosumab 2862 1666 1077 570 197 22Zoledronic Acid 2861 1596 991 522 178 26

Month


Time to First and S b t O St d SRESubsequent On‐Study SRE

2.0 HR 0.82 (95% CI: 0.75, 0.89)P<0.001 (Superiority)

Risk Reduction18%

SRE

1.5

umbe

r of S Total Number of

Events

Denosumab 1360

Z l d i A id 16281.0

ve M

ean

N Zoledronic Acid 1628

0.5

Cum

ulat

i

Month0 3 6 9 12 15 18 21 24 27 30 33 36

0


Combination or Sequential Therapy

Why Combine? Why Sequence?Why Combine?

Mechanistically

y Seque ce?

Mechanistically• “Vertically” block a pathway• “Horizontally” block multiple pathways

y• target resistant pathways upregulated by prior therapy

Goals• increase response rates and prolong PFS

Goals• maintain prolonged disease stabilityd t i it b di i i hi d• decrease toxicity by diminishing drug interactions

What are we looking for ?

1 Maior increases in response rate over monotherapymonotherapy

2 Ability to achieve a CR from therapy or in conjunction with metastasectomy

3 Relative tolerability3 Relative tolerability

Combination Therapy

Antiangiogenic therapy combinations

‐ Sorafenib plus bevacizumab (Sosman et al. JCO 2006)

‐ Sorafenib and AMG 386 (Rini et al. JCO 2011)

‐ Sunitinib plus Bevacizumab (Feldman et al. JCO 2009)

Antiangiogenic therapy‐mTOR inhibitor combinations

‐ Sunitinib plus Temsirolimus (Patel et al. Clin Genitourinary Cancer 2009)

‐ Bevacizumab plus Temsirolimus (Merchan et al JCO 2007 abstract 5034; )Escudier et al. JCO 2011 abstract 4516 )

Immunotherapy‐Antiangiogenic therapy combinations

‐ Sunitinib+IFN (Motzer et al. Clin Genitourinary Cancer 2009)

‐ Sorafenib+ IFN (Jonasch et al. Cancer 2010)

‐ Bevacizumab+ IFN (Rini et al, JCO 2008)

Combinations of Targeted Agents in mRCC:Agents in mRCC:

Sunitinib Combinations


Sorafenib Combinations


Bevacizumab Combinations

Sequenzial therapy: goals

1 Maximize efficacy and duration of first-line agentagent

2 Minimize toxicity3 Choose both initial and subsequent

therapy on the basis of robust predictivetherapy on the basis of robust predictive biomarkers

RECORD‐1 vs AXIS: trial

RECORD 1 AXIS

design discrepancies

RECORD‐1 (everolimus)

AXIS

(axitinib)

Accrual disease 12/2006‐10/2007 9/2008‐7/2010Accrual disease 12/2006 10/2007 9/2008 7/2010

Comparator Placebo Sorafenib

2 or more prior therapies (TKI) 26% 0%2 or more prior therapies (TKI) 26% 0%

MSKCC poor‐risk 14% 33%

Allowed TKI intolerant patients Yes NoAllowed TKI‐intolerant patients Yes No

Allowed crossover Yes No

ll d d l iAllowed dose esclation No Yes

Only prior sunitinib N=43, 13% of pts N=194, 26% of pts

Attenzione ai confronti indiretti!

[TITLE]

Presented By Thomas Powles, MD at 2013 ASCO Annual Meeting

[TITLE]

TKI TKImTOR

TKITKI mTORTKI

TKI TKI mTORmTOR

Ongoing clinical trials will solve all our doubts …

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