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Therapy options in second line treatment. Dr.ssa Chiara Paglino S. C. di Oncologia IRCCS Policlinico San Matteo - Pavia. Cytokines: IL-2 and IFN- α first to report activity 1. IFN- α and high-dose IL-2: used for RCC treatment . VHL tumour suppressor gene isolated 2 .
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Therapyoptions in second line treatment Dr.ssa Chiara Paglino S. C. di Oncologia IRCCS Policlinico San Matteo - Pavia
Cytokines:IL-2 and IFN-αfirst to report activity1 IFN-α and high-dose IL-2: used for RCC treatment VHL tumour suppressor gene isolated2 High-dose IL-2: FDA-approvalbased on Phase II data Progress in the treatment of RCC … Sorafenib and sunitinib: FDA and EMEA approval Temsirolimus: FDA and EMEA-approval Bevacizumab + IFN-:FDA and EMEA-approval 2007 2009-2010 2011-2012 2005-2006 Anni ’40 Anni ’80-’90 Everolimus:FDA and EMEA-approval Pazopanib:FDA and EMEA-approval Axitinib:FDA approval Roma, 24 Febbraio 2012
Toward a treatment algorithm: patientstratifications… Advanced kidney cancer First-line treatment Clear cell histology Non-clear cell histology Poor prognosis Good/intermediate prognosis Roma, 24 Febbraio 2012
First line options Advanced kidney cancer Clear cell histology Good/intermediate prognosis (MSKCC criteria) First-line treatment standard options Sunitinib Bevacizumab + INFa Pazopanib alternative options Sorafenib High dose IL-2 Watch and see Roma, 24 Febbraio 2012
Activity of first line treatment Objective response … … and progression free survival Roma, 24 Febbraio 2012
How to use existingtherapies to improve the outcome Combinations approaches Combiningnoveltherapies with cytokines Bevacizumabplus IFN Sequential treatment Sorafenibplus IFN Combiningnovel agents • Increasedtoxicity • Limits subsequentsoptions • Increasedcost Roma, 24 Febbraio 2012
Second-line options First-line treatment Second-line treatment standard options TKIs (Sunitinib, Pazopanib, Sorafenib) CTK Everolimus after TKIs Sorafenibor Pazopanib after cytokines Axitinib after everything Bevacizumab + INF alternative options Reverse sequence of the 2 TKIs Sorafenib after Bevacizumab Sunitinib after Bevacizumab Roma, 24 Febbraio 2012
Whichis the optimalsequence of treatment? CTK Bevacizumab + INF mTORI TKIs Roma, 24 Febbraio 2012
43% 45% Starting with Bevacizumab + INFa … and this HAD an impact on the ultimate outcomeofpatients … Roma, 24 Febbraio 2012
Bevacizumab + INFa: finalresults of AVOREN OS OS Avastin + IFN-a2a (n=327) Patients with mRCC (n=649) Stratification by: Country MSKCC risk group 38.6 m 23.3 m Escudier B, et al. Cancer 2010 + TKIs 35% (n=113) 1:1 IFN-a2a + placebo (n=322) 21.3 m 33.6 m + TKIs 37% (n=120) Bracarda S, et al. BJUI 2010 Roma, 24 Febbraio 2012
Whichis the optimalsequence of treatment? Bevacizumab + INF mTORI TKIs Roma, 24 Febbraio 2012
Record 1: PFS for patients treated with everolimus after bevacizumab + IFN Central Radiology Review Investigator Assessment PFS, progression-free survival; CI, confidence internal. Hutson T. et al. ESMO 2009; abstr P-7136 Roma, 24 Febbraio 2012
Whichis the optimalsequence of treatment? CTK Bevacizumab + INF mTORI TKIs Roma, 24 Febbraio 2012
Evidence-Basedfor TKIs→ mTORi mTORI TKIs • Phase III randomized trial • Phase II prospective trials • Retrospective studies • Safety profile Roma, 24 Febbraio 2012
Everolimus Following Progression On TKI Motzer RJ, et al. Lancet 2008 Roma, 24 Febbraio 2012
More then 75% of patients received Everolimusas 3rd or following Roma, 24 Febbraio 2012
Everolimus Was as Effective After 2 TKIs as it Was After 1 TKI 1. Motzer RJ, et al. Cancer 2010;116(18):4256–4265. 2. Hutson TE, et al. Eur J Cancer Suppl. 2009;7(2):Abstract 7136. Roma, 24 Febbraio 2012
Evidence-Basedfor TKIs→ TKIs mTORI TKIs • Retrospective studies • Phase II studies • EAP • Axitinib phase III clinical trial (… not yet clinical applicable) Roma, 24 Febbraio 2012
SequencingTKIs: no cross-resistanceand a surprise… Stenner F, et al. Oncology (submitted). Roma, 24 Febbraio 2012
Why So-Su could be betterthan Su-So? Stenner F, et al. Oncology (submitted). Roma, 24 Febbraio 2012
Why So-Su could be betterthan Su-So? - Use your best agents first - Solid tumorConventionalApproach versus Solid tumorUnconventionalApproach • Tim Eisen • KCUK, London, March 2011 Roma, 24 Febbraio 2012
Why So-Su could be betterthan Su-So? Solid tumorConventionalApproach - Use your best agents first - • Tim Eisen • KCUK, London, March 2011 Roma, 24 Febbraio 2012
Why So-Su could be betterthan Su-So? Solid tumorConventionalApproach - Use your best agents first - Solid tumorUnconventionalApproach - Gradualintensification of treatment- • Tim Eisen • KCUK, London, March 2011 Roma, 24 Febbraio 2012
Evidence-Basedfor TKIs→ TKIs mTORI TKIs • Retrospective studies • Phase II studies • EAP • Axitinib phase III clinical trial (… not yet clinical applicable) Roma, 24 Febbraio 2012
TKIs→ TKIs: herecomesAxitinib Eligibility criteria: Histologically-confirmed mRCC with clear-cell component Failure of prior first-line regimen containing either: • Sunitinib • Bevacizumab +IFN-α • Temsirolimus • Cytokine(s) R ANDOMIZATION Axitinib 5 mg b.i.d. N=723 Sorafenib 400 mg b.i.d. • Stratification by: • prior regimen • ECOG PS (0 vs 1) Primary endpoint: PFS Secondary endpoints: OS, ORR, duration of response, safety, QoL Rini BI, et al. Lancet 2011;378:1931-9. Roma, 24 Febbraio 2012
TKIs→ TKIs: herecomesAxitinib Roma, 24 Febbraio 2012
Axitinib: PFS by priorregimen *One-sided log-rank test stratified by ECOG PS Rini BI, et al. Lancet 2011;378:1931-9. Roma, 24 Febbraio 2012
Axitinib: Kaplan-meier curve for OS Rothenberg M, FDA presentetion 2011 Roma, 24 Febbraio 2012
Whichis the optimalsequential treatment? Level of evidence: 1, Grade of recommendation: A2 Level of evidence: 1, Grade of recommendation: A1 mTORI TKIs Level of evidence: 2, Grade of recommendation: B Level of evidence: 1, Grade of recommendation: A1 TKIs mTORI 1. Motzer RJ, et al. Lancet 2008;372:449-56; 2. Rini BI, et al. Lancet 2011;378:1931-9; 3. Di Lorenzo G, et al. EurUrol2010;58:906-11; 2. Porta C, et al. Abs. ECCO/ESMO2011 (abs. 7131) and manuscriptsubmitted. Roma, 24 Febbraio 2012
AXIS vs. RECORD-1 1. Motzer RJ, et al. Lancet 2008;372:449-56; 2. Rini BI, et al. Lancet 2011;378:1931-9. Roma, 24 Febbraio 2012
From Evidence-Based Medicine … … what do wereallyknowaboutsequences? • The mTOR inhibitor Everolimus is active after one or two TKIs (RECORD-1 trial)1,3 • level I evidence • The AXIS study provided evidence suggesting that Axitinib is an active second line option therapy (AXIS trial) • level I evidence • Sorafenib is active after Sunitinib and vice versa (many retrospective and few prospective studies)4 • level II evidence Roma, 24 Febbraio 2012
From Evidence-Based Medicine … “Decision makers need to assess and appraise all the available evidence irrespective as to whether it has been derived from RCTs or observational studies...” Sir M. Rawlins Chairman UK NICE* Roma, 24 Febbraio 2012
Anysuggestion for clinicalpractice? TKIs No response Intolerance Short term benefit Long term benefit 2nd TKIs mTOR I mTORI TKIs TKIs mTORI mTOR I ? ? mTORi ? mTORI … butthereissomethingwrong!! Porta C, et al. EJMCO 2010 Eisen T, modified Roma, 24 Febbraio 2012
The issues of primaryrefractorypatients … • Large retrospective series (the mRCC International Data-Base Consortium, as well as the French-Italo-British cooperative study)1-3: • … in TKI-primary refractory patients shifting to a drug with a different mechanism of action (i.e., a mTOR inhibitor) is unuseful and potentially detrimental1-3 1. Vickers MM, et al. Urology 2010;76:430-4; 2. Heng DY, et al. Abs. ASCO GU 2011; Albiges L, et al. (manuscript submitted)0 Roma, 24 Febbraio 2012
Anysuggestion for clinicalpractice? TKIs No response Intolerance Short term benefit Long term benefit 2nd TKIs mTOR I mTORI TKIs TKIs mTORI mTOR I ? ? mTORi ? mTORI ? mTORI Porta C, et al. EJMCO 2010 Eisen T, modified Roma, 24 Febbraio 2012
The issues of long responders… • From a large retrospective European cooperative series1, we now know that: • … in those patients who have had a clear-cut and long-lasting benefit from a first-line TKI, no significant PFS differences were observed in second-line, irrespective of the agent used (either another TKI, or a mTOR inhibitor)1 • This is probably due by the fact that in RCC is so heavily dependant on angiogenesis, inhibiting mTOR ultimately results in a continuous, even though indirect, inhibition of angiogenesis2 1. Eladi R, et al. (manuscript in preparation); 2. Porta C, et al. BJU Int 2011 (Editorial in press) Roma, 24 Febbraio 2012
Anysuggestion for clinicalpractice? TKIs No response Intolerance Short term benefit Long term benefit mTOR I mTORI TKIs TKIs mTORI 2nd TKIs mTOR I ? ? mTORi ? mTORI ? ? mTORI mTORI Porta C, et al. EJMCO 2010 Eisen T, modified Roma, 24 Febbraio 2012
Side effectsobserved with VEGF-targetedtherapiesdifferbetween agents Roma, 24 Febbraio 2012
Side effectsobserved with VEGF-targetedtherapiesdifferbetween agents Roma, 24 Febbraio 2012
Anysuggestion for clinicalpractice? TKIs No response Intolerance Short term benefit Long term benefit mTOR I mTORI TKIs TKIs mTORI 2nd TKIs ? mTORI mTOR I ? ? mTORi ? mTORI ? mTORI Porta C, et al. EJMCO 2010 Eisen T, modified Roma, 24 Febbraio 2012
Conclusions … • Sequencing molecularly targeted agents looks the most reasonable (and feasible) way to improve the overall PFS of our advanced RCC patients • No specific sequences emerged, to date, as the ideal ones • As far as we know (expecially in the absence of specific comparative trials), after a first-line TK inhibitor, another TK inhibitor or an mTOR inhibitor are both reasonable treatment options • Since mTOR inhibitors also act as anti-angiogenic agents, and RCC is so heavily dependant on angiogenesis, a continuous inhibition of angiogenesis appears to be key in this peculiar cancer Roma, 24 Febbraio 2012