ESISTE UNA SEQUENZA OTTIMALE NEL TRATTAMENTO DEL CARCINOMA RENALE METASTATICO? Emanuele Naglieri IRCCS Oncologico Bari

QUAL’E’ LA SEQUENZA MIGLIORE? TKI I LINEA TKI mTOR inh II LINEA

PARTIAMO DALLA MIGLIORE I LINEA? O DALLA MIGLIORE II LINEA? I FARMACI DI I LINEA SONO UGUALI? CI SONO STUDI DI CONFRONTO? COSA FACCIAMO NELLA REAL LIFE? COSA VORREMMO FARE? COSA FAREMO?

Quale farmaco possiamo utilizzare in prima linea? Sutent Avastin + IFN Pazopanib Nexavar Interleukina 2

SUNITINIB OR PAZOPANIB? THIS IS THE QUESTION

Phase III non-inferiority trial of Pazopanib vs Sunitinib in first-line metastatic RCC (COMPARZ) RANDOM I S AT ION Eligibility criteria: Locally advanced or mRCC with clear-cell histology No prior systemic therapy for advanced or mRCC Measurable disease by RECIST Karnofsky PS ≥70% Pazopanib 800 mg/day N=876 Sunitinib 50 mg/day (Schedule 4/2) Primary endpoint: PFS Secondary endpoints: OS, ORR, time to response, duration of response, safety, QoL EMA CHMP has recommended conditional marketing authorisation for pazopanib Start date: August 2008 Recruitment: complete Results awaited www.clinicaltrials.gov (NCT00720941)

Primary Endpoint: Progression-free Survival (independent review) 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

SUNITINIB PIU’ EFFICACE? PAZOPANIB MENO TOSSICO?

QUALE SECONDA LINEA?

COSA POSSIAMO FARE OGGI? I LINEA PAZOPANIB II LINEA: TKI SORAFENIB SUNITINIB II LINEA: I-mTor EVEROLIMUS

COSA CI DICE LA LETTERATURA?

PRATICAMENTE NULLA…. Second Line Sorafenib After Pazopanib in Patients With RCC (SOAP) This study is not yet open for participant recruitment. (see Contacts and Locations) Verified April 2014 by Fondazione IRCCS Istituto Nazionale dei Tumori, Milano Sponsor: Fondazione IRCCS Istituto Nazionale dei Tumori, Milano Information provided by (Responsible Party):

Phase III randomized sequential open-label study to evaluate the efficacy and safety of sorafenib followed by pazopanib versus pazopanib followed by sorafenib in the treatment of advanced/metastatic renal cell carcinoma (SWITCH-2 study). SORAFENIB PAZOPANIB This study is currently recruiting participants PAZOPANIB SORAFENIB ASSOCIATED POSTER 

Meeting: 2013 ASCO Annual Meeting 
Presenter: Juergen Gschwend

Criteri per la scelta terapeutica EFFICACIA DEL FARMACO DI II LINEA? TOSSICITA’ DEL FARMACO DI II LINEA? EFFICACIA DELLA PRIMA LINEA? TOSSICITA’ DELLA PRIMA LINEA? CONFIDENZA PRESCRITTIVA? ESPERIENZA PERSONALE? ATTEGGIAMENTO FILOSOFICO?

Criteri per la scelta terapeutica EFFICACIA DEL FARMACO DI II LINEA DOPO UN TKI? PFS OS SORAFENIB 3,4 19,2 SUNITINIB SWITCH 3 (5.4) - EVEROLIMUS 5,4 14,8

TOSSICITA’ DEL FARMACO DI II LINEA? SORAFENIB ALL GRADE (%) EVEROLIMUS DIARREA 53 30 NAUSEA 22 26 VOMITO 17 20 IPERTENSIONE 29 NR FATIGUE 32 31 DISFONIA HFS 51 STOMATITE 12 44 STIPSI INFEZIONI 37 TOSSE RASH DISPNEA 24 EDEMA PERIFERICO 25

COSA POSSIAMO FARE? I LINEA SUNITINIB II LINEA: TKI AXITINIB SORAFENIB II LINEA: I-mTor EVEROLIMUS

QUAL’E’ IL FARMACO PIU’ EFFICACE? QUAL’E’ QUELLO MENO TOSSICO? COSA CI DICE LA LETTERATURA? QUAL’E’ IL FARMACO PIU’ EFFICACE? QUAL’E’ QUELLO MENO TOSSICO? QUAL’E’ QUELLO PIU’ ADATTO

EVEROLIMUS

Crossover to RAD001 upon progression Study Design and Conduct of RECORD-1 (Renal Cell Cancer Oral RAD001 Given Daily) R A N D O M I Z T RAD001 + BSC (n = 277) Stratification Prior VEGFr-TKI: 1 vs 2 MSKCC risk group: favorable, intermediate, or poor Crossover to RAD001 upon progression Study un-blinded Placebo + BSC (n = 139) December 2006 First Interim analysis at 30% events for Safety Second Interim analysis data cut-off: 15 OCT 2007 N = 410 (191 events ) End of double blind analysis data cut-off: 28 FEB 2008 (Additional follow-up based on 266 events) Survival Follow-Up: 15-Nov-08 Actual N = 416 2:1 November 2007 Primary endpoint reached at second interim analysis MSKCC = Memorial Sloan Kettering Cancer Center. 1) Motzer et al. Lancet. 2008;372:449-37; 3) Motzer et al. Presented at the 2009 ASCO Genitourinary Cancers Symposium (Abstract 278). 22

79% 21% 16% n = 108 n = 219 n = 89 n = 43 EVE 1st line 2nd line (3rd line) 3rd/4th line 2 VGFR-TKI ± 1 other prior therapy n = 108 79% EVE VGFR-TKI + 1st line 2nd line 3rd line 1 other prior therapy most commonly cks n = 219 2nd line 21% 1st line EVE VGFR-TKI n = 89 2nd line 16% 1st line EVE SUNITINIB n = 43 Motzer RJ, Cancer 2010.

RECORD-1: PFS and OS PFS* OS HR=0.33 95% CI [0.25, 0.43] 100 80 60 40 20 100 80 60 40 20 PFS Mediana Everolimus: 4.90 mesi Placebo: 1.87 mesi OS Mediana Everolimus: 14.78 mesi Placebo: 14.39 mesi Log rank P value < 0.001 Log rank P value = 0.177 Probabilità (%) Everolimus (n=277) Probabilità (%) Placebo (n=139) Everolimus (n=277) Placebo (n=139) 0 2 4 6 8 10 12 14 0 2 4 6 8 10 12 14 16 18 20 22 24 Mesi Mesi N. Pazienti / risk Everolimus 277 192 115 51 26 10 1 0 Placebo 139 47 15 6 2 0 0 0 N. Di pazienti / risk Everolimus 277 267 240 204 164 155 131 101 61 30 6 0 0 Placebo 139 131 117 100 86 74 56 43 27 13 3 0 0 Data analisi Cut-Off Febb. 2008 Data analisi Cut-Off Nov 2008 * Revisione centrale radiologica Motzer R, et al. ASCO GU 2009; Kay et al. EAU 2009 24 24

Progression-free survival in patients treated with 1 vs 2 prior VEGFr-TKIs by treatment arm Probability (%) 100 80 60 40 20 Time (months) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Number of patients at risk Everolimus 211 194 146 126 90 74 45 38 22 19 Placebo 106 99 27 66 61 46 39 25 18 6 5 4 3 2 33 29 9 7 1 Probability (%) 100 80 60 40 20 Time (months) 8 10 11 12 13 14 Number of patients at risk Everolimus Placebo Hazard ratio = 0.31 95% CI: 0.23, 0.42 Median PFS Everolimus: 5.42 months Placebo: 1.87 months Log rank P value <.001 Hazard ratio = 0.37 95% CI: 0.22, 0.63 Median PFS Everolimus: 3.78 months Placebo: 1.87 months Log rank P value <.001 Censoring times Censoring times Everolimus (n = 211) Everolimus (n = 66) Placebo (n = 106) Placebo (n = 33) Calvo E, et al. Presented at the 35th Congress of the European Society for Medical Oncology; Milan, Italy. Abstract 911.

RECORD-1 Study Overall Survival Benefit With Crossover Correction Everolimus 100 Placebo Rank preserving structural failure time (RPSFT) analysis is a statistical method that allows estimation of survival time gained by anyone receiving active treatment 90 Reconstructed placebo 80 Kaplan-Meier median OS Everolimus: 14.8 mo Placebo: 14.4 mo Reconstructed placebo: 10.0 mo 70 Probability (%) 60 50 40 30 2 4 6 8 10 12 14 16 18 20 22 Time (mo) The RPSFT estimate of relative survival time when receiving everolimus was 1.9 fold higher (90% CI: 0.5 to 8.5) than when receiving placebo only The “reconstructed” median OS for placebo was 10.0 months compared with the uncorrected value of 14.4 months Korhonen P, et al. Presented at ECCO-ESMO 2009. Abstract 7.155, Monday, 21 September, 14:00-17:00. Robins JM, et al. Comm Stat Theory Meth. 1991;20:2609-2631. 26

Cross-over upon progression RECORD-3: Phase II randomized trial comparing sequential 1st-line everolimus and 2nd-line sunitinib vs 1st-line sunitinib and 2nd-line everolimus Primary PFS-1st line Secondary Combined PFS ORR-1st line OS Safety Study endpoints 1 : 1 R A N D O M I Z E** Everolimus 10 mg/day SCREEN Sunitinib 50 mg/day*** 1st Line Everolimus 10 mg/day Sunitinib 50 mg/day*** 2nd Line Cross-over upon progression *NCT00903175. **Stratified by MSKCC prognostic factors. ***4 weeks on and 2 weeks off. Primary Endpoint: 1st-line PFS for non-inferiority of everolimus vs sunitinib Bayesian method: non-inferiority declared if observed HR ≤1.1 (1-month difference in the median first-line PFS) 318 first-line events needed (total 460 patients) Motzer RJ, JCO 2014 27

RECORD-3: Overall Survival 100 EVE→SUN (events/N = 108/238) SUN→EVE (events/N = 96/233) 90 80 70 60 Cumulative event-free probability (%) 50 40 K-M Median OS (mo) EVE→SUN SUN→EVE 22.41 32.03 Hazard Ratio = 1.24 Two-sided 95% CI [0.94, 1.64] 30 20 10 3 6 9 12 15 18 21 24 27 30 33 36 Time (months) Number of patients still at risk EVE→SUN SUN→EVE 238 208 189 165 151 137 103 66 43 15 2 233 220 198 185 164 152 115 71 38 22 6 1 Motzer RJ, JCO 2014

WHAT ABOUT AXITINIB AND SORAFENIB?

SEQUENZE TKI-TKI SWITCH III AXIS SORAFENIB SUNITINIB SUNITINIB AXITINIB AXIS SUNITINIB ET AL SORAFENIB

Overall survival SWITCH Trial Months from randomization 100 Median (one-sided n 95% CI) OS, months 90 So-Su 182 31.5 (>23.3, <36.9) 80 Su-So 183 30.2 (>23.6, <50.1) 70 HR: 1.00 (one-sided 95% CI: <1.30) p value for superiority=0.49 60 50 40 30 20 10 0 5 10 15 20 25 30 35 40 45 50 55 Months from randomization No. patients So-Su 182 148 123 105 79 58 36 25 17 9 6 Su-So 183 147 119 95 80 59 37 29 18 12 7 Intent-to-treat population OS, overall survival Michel M, et al. ASCO GU 2014. Abstract 393.

Treat until PD, unmanageable AE, or withdrawal of consent Phase III AXIS Study Axitinib vs Sorafenib as Second-line Therapy for mRCC Stratified by previous regimen, ECOG PS (0 vs 1) Axitinib* 5 mg BID (n = 361) Patients with clear-cell mRCC, refractory to 1 previous first-line therapy (N = 723) Treat until PD, unmanageable AE, or withdrawal of consent AE, adverse event; BID, twice daily; ECOG, Eastern Cooperative Oncology Group; mRCC, metastatic renal cell carcinoma; ORR, overall response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PS, performance status; QoL, quality of life; RECIST, Response Evaluation Criteria In Solid Tumors. Sorafenib 400 mg BID (n = 362) *Starting dose 5 mg BID with option for dose titration to 10 mg BID. Primary endpoint: PFS (independent review committee [IRC]) Secondary endpoints: OS, ORR (RECIST), duration of response, safety, QoL Rini BI, et al. Lancet. 2011;378:1931-1939. 32

OS AXIS

QUAL’E’ IL DATO DELLA SOPRAVVIVENZA? SUNITINIB AXITINIB

Sopravvivenza globale delle sequenze SUNITINIB SORAFENIB EVEROLIMUS OS (months) 30.2 31.5 32

Sopravvivenza globale della sequenza SUNITINIB SORAFENIB EVEROLIMUS AXITINIB OS (months) 30.2 31.5 32 ?

AXITINIB ALL GRADE (%) EVEROLIMUS DIARREA 55 30 NAUSEA 32 26 VOMITO 24 20 IPERTENSIONE 40 NR FATIGUE 39 31 DISFONIA HFS 27 STOMATITE 44 STIPSI INFEZIONI 37 TOSSE RASH 29 DISPNEA EDEMA PERIFERICO 25

SOPRAVVIVENZA GLOBALE DELLE SECONDE LINEE AXITINIB SORAFENIB EVEROLIMUS NIVOLUMAB OS 20 19.2 19.6 25

QUAL’E’ LA SEQUENZA MIGLIORE? TKI I LINEA TKI mTOR inh II LINEA

QUAL’E’ LA SEQUENZA MIGLIORE? TKI I LINEA Nivolumab II LINEA