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Oltre la prima linea di terapia

Oltre la prima linea di terapia. Dr. Camillo Porta S.C. di Oncologia Medica I.R.C.C.S. Policlinico San Matteo , Pavia. Let’s start with ESMO guidelines …. Escudier B, et al. Ann Oncol 2012;23(suppl. 7):vii65-vii71. Why thinking to sequences ?.

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Oltre la prima linea di terapia

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  1. Oltre la prima linea di terapia Dr. Camillo Porta S.C. di OncologiaMedica I.R.C.C.S. Policlinico San Matteo, Pavia

  2. Let’s start with ESMO guidelines … Escudier B, et al. Ann Oncol 2012;23(suppl. 7):vii65-vii71.

  3. Whythinking to sequences? • Irrespective of the agents used in 1st line, 75-80% of advanced RCC patients will obtain a clinicall significant benefit (i.e., a DCR): • 84% with Sunitinib1 • 77% with Bevacizumab + IFN2 • 68% with Pazopanib (including 1st and 2nd line patients)3 • Besides those, unfortunate 20-25% who will not respond to anything, succumbing to the disease quite soon, the vast majority of patients will receive more than one line of treatment • Furthermore, with few exceptions, combinations of molecularly targeted agents proved to be too toxic 1. Motzer RJ, et al. NEJM 2007; 2. Escudier B, et al. Lancet 2007; Sternberg CN, et al. J Clin Oncol 2010

  4. What the guidelinessuggest … Escudier B, et al. Ann Oncol 2012;23(suppl. 7):vii65-vii71.

  5. PFS AvailabeRCTs in 2nd line RECORD-11 4.9 N= 277 Everolimus p = <0.001 1.9 Placebo N= 139 AXIS2 6.7 Axitinib N= 361 p = <0.0001 4.7 Sorafenib N= 362 INTORSECT3 4.3 Temsirolimus N= 259 p = not significant 3.9 Sorafenib N= 253 0 5 10 15 20 25 (Months) 1. Motzer RJ, et al. Cancer 2010;116:4256–65; 2. Rini BI, et al. Lancet 2011;378:1931–9; 3. Hutson TE, et al. ESMO 2012;abstract LBA22

  6. PFS AvailabeRCTs in 2nd line RECORD-11 OS 14.8 4.9 Everolimus N= 277 OS: p = not significant 1.9 14.4 Placebo N= 139 AXIS2,3 20.1 6.7 Axitinib N= 361 OS: p= not significant 4.7 19.2 Sorafenib N= 362 INTORSECT4 12.3 4.3 Temsirolimus N= 259 OS: p=0.014 statistically significant 16.6 3.9 Sorafenib N= 253 0 5 10 15 20 25 (Months) 1. Motzer RJ, et al. Cancer 2010;116:4256–65; 2. Rini BI, et al. Lancet 2011;378:1931–9; 3. Hutson TE, et al. ESMO 2012;abstract LBA22

  7. Otherevidencesupporting the sequence of TKIs Stenner F, et al. Oncology 2012;82:333-40.

  8. Third-line treatment • Motzer RJ, et al. Lancet 2008;372:449-56; 2. Motzer RJ, et al. Cancer 2010;116:4256-65.

  9. RECORD-1: which line of Tx? 1st Line 2nd Line 3rd Line 4th Line mTOR 5th Line n = 82 mTOR 4th Line 3rd Line 2nd Line 1st Line n = 104 79% mTOR 3rd Line 2nd Line 1st Line n = 141 mTOR 2nd Line 1st Line n = 89 21% • Motzer RJ, et al. Lancet 2008;372:449-56; 2. Motzer RJ, et al. Cancer 2010;116:4256-65; • 3. Calvo E, et al. Eur J Cancer2012;48:333-9.

  10. Everolimus: after 1 or 2 TKIs? Beware of time-lead bias HR = 0.32 in both cases Calvo E, et al. Eur J Cancer 2012;48:333-9.

  11. TKI/VEGF inhibitor TKI/VEGF inhibitor mTOR inhibitor TKI/VEGF inhibitor Whichsequenceafter a 1st line? Probably, Sorafenib and Sunitinib are both effective in this setting3,4 Level of evidence: 1, Grade of recommendation: A1 Level of evidence: 2, Grade of recommendation: B ? mTOR inhibitor Level of evidence: 1, Grade of recommendation: A2 Level of evidence: 1, Grade of recommendation: A1 We do now know that Everolimus is as effective after 1 TKI, as it is after both1 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. Eur Urol 2010;58:906-11; 4. Porta C, et al. Abs. ECCO/ESMO 2011 (abs. 7131) and manuscript submitted.

  12. Special situations … no longer smart Looked smart … Porta C, et al. EJMCO 2010;2:1-6.

  13. Primaryrefractory and long-responders • From large retrospective series1-3 we now know that: • … in TKI-primary refractory patients (irrespective of the definition used), shifting to a drug with a different mechanism of action (i.e., a mTOR inhibitor) is not only unuseful, but also potentially detrimental1-3 • … continuing the same TKI on which tumor has progressed could be even better than shifting to a different drug3 • From another large retrospective European cooperative series4, 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 • VickersMM, et al. Urology 2010;76:430-4; 2. Heng DY, et al. Ann Oncol2012;23:1549-55; • 3. AlbigesL, et al. (manuscript submitted); 4. Elaidi RT, et al. (manuscript submitted).

  14. ThankYou for Your kindattention!!! c.porta@smatteo.pv.it

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