Scuola di uro Oncologia CONTROVERSIE ONCOLOGICHE L’oncologo risponde all’urologo: PRIMA LINEA DI TRATTAMENTO G. Cartenì Direttore 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 ossee Associazione di farmaci ? terapie sequenziali ? How to choose first line treatment • Prognostic profile (Motzer/Heng) • Toxicity profile and comorbidities • Disease characteristics (site/sympthoms) • Sequential strategies • Oral/iv administration • Physician experience • Patient preference • Biomarkers in development…! Linee Guida EAU 2010 First-line treatment guidelines for clear cell mRCC: ESMO 2012 Risk status Favourable or intermediate Poor risk Recommendation Level of evidence Sunitinib I, A Bevacizumab + IFN-α II, A Pazopanib II, A Temsirolimus II, A Escudier B, et al. Ann Oncol 2012;23(Suppl 7):vii65–71 How to choose first line treatment • Prognostic profile (Motzer/Heng) • Toxicity profile and comorbidities • Disease characteristics (site/sympthoms) • Sequential strategies • Oral/iv administration • Physician experience • Patient preference • Biomarkers in development…! 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 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, 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; 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% CI for HR <1.25 (EMA requested ≤1.223) PFS (ITT population) Median PFS, months (95% CI) HR (95% CI) PFS (PP population) Median PFS, months (95% CI) HR (95% CI) Pazopanib (n=557) Sunitinib (n=553) 8.4 (8.3, 10.9) 9.5 (8.3, 11.1) 1.0466 (0.8982, 1.2195) Pazopanib (n=501) Sunitinib (n=494) 8.4 (8.3, 10.9) 10.2 (8.3, 11.1) 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: PFS (IRC-assessed) Non-inferiority met if upper bound of 95% CI for HR <1.25 (EMA requested ≤1.223) PFS (ITT population) Median PFS, months (95% CI) HR (95% CI) PFS (PP population) Median PFS, months (95% CI) HR (95% CI) Pazopanib (n=557) Sunitinib (n=553) 8.4 (8.3, 10.9) 9.5 (8.3, 11.1) 1.0466 (0.8982, 1.2195) Pazopanib (n=501) Sunitinib (n=494) 8.4 (8.3, 10.9) 10.2 (8.3, 11.1) 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: PFS (IRC-assessed) Non-inferiority met if upper bound of 95% CI for HR <1.25 (EMA requested ≤1.223) PFS (ITT population) Median PFS, months (95% CI) HR (95% CI) PFS (PP population) Median PFS, months (95% CI) HR (95% CI) Pazopanib (n=557) Sunitinib (n=553) 8.4 (8.3, 10.9) 9.5 (8.3, 11.1) 1.0466 (0.8982, 1.2195) Pazopanib (n=501) Sunitinib (n=494) 8.4 (8.3, 10.9) 10.2 (8.3, 11.1) 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, noninferiority trial Enrolment criteria: •Locally advanced or mRCC •Clear-cell histology •No prior systemic therapy •Measurable disease (RECIST 1.0) •KPS ≥70 •Adequate organ function Pazopanib 800 mg QD Continuous daily dosing Randomised N=927 1:1 N=1,110 Sunitinib 50 mg QD Schedule 4/2 Study start: August 2008 VEG108844 Phase III n=927 VEG113078 Phase 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 off www.clinicaltrials.gov (NCT00720941; NCT01147822) Primary Endpoint: Progression-free Survival (independent review) N Median PFS (95% CI) 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) Pazopanib Sunitinib 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 Pazopanib Sunitinib COMPARZ: Timing of assessments Sunitinib Mean change from baseline Pazopanib Week 6 Week 6 Week 6 Disease assessments QoL assessments Week 4 Week 4 Week 4 Time QoL, quality of life Motzer RJ, et al. Presented at ESMO 2012; Abstract LBA8 Cella D, et al. Presented at ASCO-GU 2012; Abstract 346 Most Common Adverse Events (treatment-emergent) Pazopanib (n = 554) % Sunitinib (n = 548) % Adverse Event a Any event b Diarrhea Fatigue Hypertension Nausea Decreased appetite ALT increased Hair color changes Hand-foot syndrome Taste Alteration Thrombocytopenia a AE All Grs Gr 3/4 All Grs Gr 3/4 >99 59/15 >99 57/17 63 9/0 57 7/<1 55 10/<1 63 17/<1 46 15/<1 41 15/<1 45 2/0 46 2/0 37 1/0 37 3/0 31 10/2 18 2/<1 30 0/0 10 <1/0 29 6/0 50 11/<1 26 <1/0 36 0/0 10 2/<1 34 12/4 ≥30% in either arm b 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 All grades Grade 3/4 All grades Grade 3/4 Any event† >99 59/15 >99 57/17 NA NA Diarrhoea 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 NA ALT 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 NA Thrombocytopenia 10 2/<1 34 12/4 0.30 0.23, 0.40 AE* *AE ≥30% in either arm; †2% of patients in pazopanib arm and 3% of patients in sunitinib arm had grade 5 AEs ALT, alanine transaminase; AST, aspartate transaminase; HFS, hand–foot syndrome; NA, not applicable All grades Treatment Duration and Dose Adjustments Pazopanib (n = 554) Sunitinib (n = 548) 8.0 (0−40) 7.6 (0−38) Dose reductions, % 44 51 Discontinuations due to AEs1, % 24 19 Median duration of treatment (months, range) 1. Most common reason: pazopanib arm (liver event, 6%); sunitinib arm (cytopenia, 3%) Quality of Life Results (first 6 months1) Treatment difference : mean change from baseline 2 P -value Fatigue/Total score 2.32 <0.001 Kidney Symptom Index/Total score 1.41 0.018 Physical 0.78 0.027 Emotional 0.05 0.409 Treatment Side Effects 0.31 0.033 Functional Well Being 0.31 0.098 Expectations of Therapy 1.41 0.284 Feelings about Side Effects 8.50 <0.001 Satisfaction with Therapy 3.21 <0.001 Worst mouth/throat soreness 0.505 <0.0001 Worst foot soreness 0.204 0.0016 Worst hand soreness 0.267 0.0008 Limitations due to mouth/throat soreness 0.94 <0.001 Limitations due to foot soreness 0.65 0.014 Instrument FACIT-F FKSI-19 Cancer Treatment Satisfaction Questionnaire (CTSQ) Supplementary Quality of Life Questionnaire (SQLQ) 1Pre-specified Domain Description 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 (first 6 months1) Treatment difference : mean change from baseline 2 P -value Fatigue/Total score 2.32 <0.001 Kidney Symptom Index/Total score 1.41 0.018 Physical 0.78 0.027 Emotional 0.05 0.409 Treatment Side Effects 0.31 0.033 Functional Well Being 0.31 0.098 Expectations of Therapy 1.41 0.284 Feelings about Side Effects 8.50 <0.001 Satisfaction with Therapy 3.21 <0.001 Worst mouth/throat soreness 0.505 <0.0001 Worst foot soreness 0.204 0.0016 Worst hand soreness 0.267 0.0008 Limitations due to mouth/throat soreness 0.94 <0.001 Limitations due to foot soreness 0.65 0.014 Instrument FACIT-F FKSI-19 Cancer Treatment Satisfaction Questionnaire (CTSQ) Supplementary Quality of Life Questionnaire (SQLQ) 1Pre-specified Domain Description 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 FACIT- F Supplementary Quality of Life Questionnaire Timing Every 2 weeks Every 2 weeks Treatment difference2,3 P value Fatigue/Total score 2.5 0.002 Worst mouth/throat soreness 0.38 <0.001 Worst foot soreness 0.08 0.026 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 Domain Description 1. Escudier BJ, et al.. J Clin Oncol 30, 2012 (suppl; abstr CRA4502) 2. Cella D, et al. ESMO Congress 2012 poster 792PD 3. Yellow Font: favors pazopanib P-value <0.05 is statistically significant How to choose first line treatment • Prognostic profile (Motzer/Heng) • Toxicity profile and comorbidities • Disease characteristics (site/sympthoms) • Sequential strategies • Oral/iv administration • Physician experience • Patient preference • Biomarkers in development…! How to choose first line treatment • Prognostic profile (Motzer/Heng) • Toxicity profile and comorbidities • Disease characteristics (site/sympthoms) • Sequential strategies • Oral/iv administration • Physician experience • Patient preference • Biomarkers in development…! How to choose first line treatment • Prognostic profile (Motzer/Heng) • Toxicity profile and comorbidities • Disease characteristics (site/sympthoms) • Sequential strategies • Oral/iv administration • Physician experience • Patient preference • Biomarkers in development…! How to choose first line treatment • Prognostic profile (Motzer/Heng) • Toxicity profile and comorbidities • Disease characteristics (site/sympthoms) • Sequential strategies • Oral/iv administration • Physician experience • Patient preference • Biomarkers in development…! How to choose first line treatment • Prognostic profile (Motzer/Heng) • Toxicity profile and comorbidities • Disease characteristics (site/sympthoms) • Sequential strategies • Oral/iv administration • Physician experience • Patient preference • Biomarkers in development…! Significantly more patients preferred pazopanib over sunitinib (primary endpoint)1 100 p<0.001 90 80 Patients (%) 70 60 50 70% (n=80) 40 30 20 22% (n=25) 10 8% (n=9) 0 Preferred pazopanib Preferred sunitinib 1. Escudier B, et al. J Clin Oncol 2012;30 suppl: abstr CRA4502. No preference 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 ossee Associazione di farmaci ? terapie sequenziali ? 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) Criticità I criteri RECIST rappresentano lo standard di valutazione di risposta al trattamento in studi clinici su farmaci antitumorali1 • La risposta parziale è definita come tumor shrinkage pari al 30% Un tumor shrinkage del < 30% è un risultato positivo per il paziente. Il controllo del tumore potrebbe essere un endpoint clinicamente più rilevante2 • Si basa sulle risposte agli Potrebbe non essere appropriato per valutare la risposta alle targeted agenti antitumorali therapies (differente meccanismo citotossici d’azione) • Non si misurano le necrosi tumorali Le targeted therapies possono determinare necrosi tumorale piuttosto che tumor shrinkage3 1. Therasse P, et al. J Natl Cancer Inst 2000; 92:205–16 2. 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: - Numero delle lesioni valutabili; - 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 tengono conto di: • Tecniche di imaging funzionale come la PET o la RMN • Valutazione anatomica volumetrica del tumore • Necessità di nuove metodiche di immagine atte a studiare la vascolarizzazione e la necrosi tumorale FDG-PET DCE-US DCE-MRI Imaging funzionale con DCE-US Valutazione della risposta a sorafenib • Abdominal lymph node from an RCC in a 37 year-old woman (good responder) treated with sorafenib DCE-US before treatment shows contrast uptake throughout the tumour estimated at 81% DCE-US after 3 weeks of treatment shows contrast uptake throughout the tumour estimated at 48% Lamuraglia et al.EJC 2006 DCE-US after 6 weeks of treatment shows contrast uptake throughout the tumour estimated at 31% identifying patients with progression-free survival of >250 days sensitivity specificity 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 therapy Smith 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 Valutazione dello stato di malattia in corso di trattamento con targeted therapies Necessario fare riferimento a criteri: – Diagnostica strumentale – Clinici – Laboratorio Criteri clinici Esame obiettivo Performance status Sintomi tumore-correlati Perdita di peso Consumo di analgesici Qualità di vita del paziente Criteri di laboratorio Emocromo completo Funzionalità epatica Funzionalità renale LDH Calcemia Tossicità o progressione di malattia? Quando finisce una prima linea di trattamento ? In assenza di una sicura progressione obiettiva, i criteri clinici che depongono per un beneficio per il paziente, devono sempre orientare verso la prosecuzione del trattamento con l’agente target in corso E viceversa…. • Sintomi all’esordio – Ematuria – Anemia – Dolori addominali – Calo ponderale – Astenia – 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 cliniche – Molto ridotto il dolore addominale – Astenia quasi assente – Hgb 11 g/dl – Calcemia 8.6 mg/dl – LDH 650 – Karnofsky 80% 18.05.2010 27.07.2010 11.11.2010 04.02.2011 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 ossee Associazione di farmaci ? terapie sequenziali ? ccRCC Predictive markers of target therapy • Bio-Clinical – Hypertension (>90 mm/hg DBP) – LDH – 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 in solid tumors OS with landmark at 8 weeks. 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 tumors Objective Remission According to Response Evaluation Criteria in Solid Tumors Based on Increased Thyroid-Stimulating Hormone Levels Schmidinger M, Cancer 2011 Implicazioni cliniche • Trattiamo FINO alla tossicità ? • Trattiamo LA tossicità ? • Ruolo dei farmaci per la tossicità ? Take home messages • Metodi di valutazione e misure profilattiche verso gli effetti collaterali possono confondere questi risultati • Gran parte dei risultati derivano da studi retrospettivi (validazione in studi prospettici) • I ‘potenziali benefici’ derivanti dalla somministrazione contemporanea di medicinali devono essere considerati • Nessuno di questi marcatori •ideale: il marcatore ideale predittivo •valutabile prima del trattamento, piuttosto che durante il trattamento 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 ossee Associazione di farmaci ? terapie sequenziali ? Key Factors for Successful Therapy Management in mRCC Dosing Side-effect Management Optimum Efficacy Schedule Treatment Duration 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 ossee Associazione di farmaci ? terapie sequenziali ? Zoledronic acid significantly extended (A) the time to first skeletal complication compared with placebo and (B) the time to first pathologic fracture compared with placebo Rosen et al. Cancer 2004; 100: 2613-21 mRCC patients: 74 total reduction of skeletal complications: 74% (ZA) vs 37% (placebo) (p=0.015) absolute reduction: 37% 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 Trials Key Inclusion Criteria • Adults with breast, prostate, other solid tumors, or multiple myeloma and ≥1 bone metastasis Key Exclusion Criteria • current or prior IV bisphosphonate administration • creatinine clearance <30 mL/min R A N D O M I Z A T I O N Denosumab 120 mg SC and Placebo IV* every 4 weeks (n=2862) E N D O F Zoledronic acid 4 mg IV* and Placebo SC every 4 weeks (n=2861) S T U D Y Recommended: Daily supplementation with calcium (≥500 mg) and vitamin D (≥400 U) 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 Characteristics Characteristics, n (%) or Median (Q1, Q3) Denosumab (n=2862) Zoledronic Acid (n=2861) 1026 (36) 1020 (36) Prostate 950 (33) 951 (33) 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) Colon 30 (1) 29 (1) Other§ 449 (16) 445 (16) Tumor type† Breast Lipton A, Fizazi K, Stopeck A, et al. Eur J Cancer 2012 Primary Endpoint: Time to First On-Study SRE Proportion without SRE 1.0 HR 0.83 (95% CI: 0.76, 0.90) P<0.001 (Superiority) 17% Risk Reduction 0.8 0.6 KM Estimate of Median Months 0.4 0.2 Denosumab 27.66 Zoledronic Acid 19.45 0 0 6 12 18 24 30 570 522 197 178 22 26 Month Patients at Risk: Denosumab 2862 Zoledronic Acid 2861 1666 1596 1077 991 Lipton A, Fizazi K, Stopeck A, et al. Eur J Cancer 2012 Time to First and Subsequent On-Study SRE Cumulative Mean Number of SRE 2.0 HR 0.82 (95% CI: 0.75, 0.89) P<0.001 (Superiority) 18% Risk Reduction Total Number of Events 1.5 Denosumab 1360 Zoledronic Acid 1628 1.0 0.5 0 0 3 6 9 12 15 18 21 Month 24 27 30 33 36 Lipton A, Fizazi K, Stopeck A, et al. Eur J Cancer 2012 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 ossee Associazione di farmaci ? terapie sequenziali ? Combination or Sequential Therapy Why Combine? Why Sequence? Mechanistically Mechanistically • “Vertically” block a pathway • “Horizontally” block multiple pathways Goals • increase response rates and prolong PFS • target resistant pathways upregulated by prior therapy Goals • maintain prolonged disease stability • decrease toxicity by diminishing drug interactions What are we looking for ? 1 Maior increases in response rate over monotherapy 2 Ability to achieve a CR from therapy or in conjunction with metastasectomy 3 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: Sunitinib Combinations Combinations of Targeted Agents in mRCC: Sorafenib Combinations Combinations of Targeted Agents in mRCC: Bevacizumab Combinations Sequenzial therapy: goals 1 Maximize efficacy and duration of first-line agent 2 Minimize toxicity 3 Choose both initial and subsequent therapy on the basis of robust predictive biomarkers RECORD-1 vs AXIS: trial design discrepancies RECORD-1 (everolimus) AXIS (axitinib) 12/2006-10/2007 9/2008-7/2010 Placebo Sorafenib 2 or more prior therapies (TKI) 26% 0% MSKCC poor-risk 14% 33% Allowed TKI-intolerant patients Yes No Allowed crossover Yes No Allowed dose esclation No Yes N=43, 13% of pts N=194, 26% of pts Accrual disease Comparator Only prior sunitinib Attenzione ai confronti indiretti! [TITLE] Presented By Thomas Powles, MD at 2013 ASCO Annual Meeting [TITLE] [TITLE] [TITLE] [TITLE] TKI TKI mTOR TKI TKI TKI mTOR mTOR TKI mTOR Ongoing clinical trials will solve all our doubts …