1 / 42

Dr.ssa Chiara Paglino S. C. di Oncologia IRCCS Policlinico San Matteo - Pavia

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 .

taya
Download Presentation

Dr.ssa Chiara Paglino S. C. di Oncologia IRCCS Policlinico San Matteo - Pavia

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Therapyoptions in second line treatment Dr.ssa Chiara Paglino S. C. di Oncologia IRCCS Policlinico San Matteo - Pavia

  2. 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

  3. 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

  4. 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

  5. Activity of first line treatment Objective response … … and progression free survival Roma, 24 Febbraio 2012

  6. 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

  7. 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

  8. Whichis the optimalsequence of treatment? CTK Bevacizumab + INF mTORI TKIs Roma, 24 Febbraio 2012

  9. 43% 45% Starting with Bevacizumab + INFa … and this HAD an impact on the ultimate outcomeofpatients … Roma, 24 Febbraio 2012

  10. 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

  11. Whichis the optimalsequence of treatment? Bevacizumab + INF mTORI TKIs Roma, 24 Febbraio 2012

  12. 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

  13. Whichis the optimalsequence of treatment? CTK Bevacizumab + INF mTORI TKIs Roma, 24 Febbraio 2012

  14. Evidence-Basedfor TKIs→ mTORi mTORI TKIs • Phase III randomized trial • Phase II prospective trials • Retrospective studies • Safety profile Roma, 24 Febbraio 2012

  15. Everolimus Following Progression On TKI Motzer RJ, et al. Lancet 2008 Roma, 24 Febbraio 2012

  16. More then 75% of patients received Everolimusas 3rd or following Roma, 24 Febbraio 2012

  17. 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

  18. 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

  19. SequencingTKIs: no cross-resistanceand a surprise… Stenner F, et al. Oncology (submitted). Roma, 24 Febbraio 2012

  20. Why So-Su could be betterthan Su-So? Stenner F, et al. Oncology (submitted). Roma, 24 Febbraio 2012

  21. 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

  22. 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

  23. 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

  24. 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

  25. 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

  26. TKIs→ TKIs: herecomesAxitinib Roma, 24 Febbraio 2012

  27. 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

  28. Axitinib: Kaplan-meier curve for OS Rothenberg M, FDA presentetion 2011 Roma, 24 Febbraio 2012

  29. 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

  30. 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

  31. 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

  32. 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

  33. 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

  34. 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

  35. 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

  36. 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

  37. 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

  38. Side effectsobserved with VEGF-targetedtherapiesdifferbetween agents Roma, 24 Febbraio 2012

  39. Side effectsobserved with VEGF-targetedtherapiesdifferbetween agents Roma, 24 Febbraio 2012

  40. 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

  41. 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

  42. Thankyou for yourattention!

More Related