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Dr. Camillo Porta Medical Oncology, I.R.C.C.S. San Matteo University Hospital Foundation,

Beyond the first line: the role of Sorafenib. Dr. Camillo Porta Medical Oncology, I.R.C.C.S. San Matteo University Hospital Foundation, Pavia, Italy & Italian Nephro-Oncology Group (GION). The ‘embarassment of the riches’ …. *AVOREN study. Why thinking to sequences?.

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Dr. Camillo Porta Medical Oncology, I.R.C.C.S. San Matteo University Hospital Foundation,

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  1. Beyond the first line: the role of Sorafenib Dr. Camillo Porta Medical Oncology, I.R.C.C.S. San Matteo University Hospital Foundation, Pavia, Italy & Italian Nephro-Oncology Group (GION)

  2. The ‘embarassment of the riches’ … *AVOREN study

  3. Why thinking to sequences? • Irrespective of the agents used in 1st line, 75-80% of advanced RCC patients will obtain a clinically 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. Optimizing the sequence of Tx is crucial *Model based on assumption that PFS benefits in separate studies may be observed with sequential therapy 1. Motzer, et al. JCO 2009; 2. Escudier, et al. ESMO 2008; 3. Porta, et al. EAU 2009 4. Escudier, et al. Lancet 2007; 5. Escudier, et al. NEJM 2007; 6. Choueiri, et al. JCO 2008 7. Rini, et al. JCO 2008; adapted from Escudier, Cancer 2009

  5. Does really success depends on a good start? • In 1st line, patients are usually treated: • 80% of patients with a TKI (mainly Sunitinib) • 18% of patients with the combination of Bevacizumab + IFN-a • 2% still with some form of immunotherapy (e.g., IFN-a, IL-2, IFN-a + IL-2 …)

  6. Does really success depends on a good start? • In 1st line, patients are usually treated: • 80% of patients with a TKI (mainly Sunitinib) • 18% of patients with the combination of Bevacizumab + IFN-a • 2% still with some form of immunotherapy (e.g., IFN-a, IL-2, IFN-a + IL-2 …)

  7. Does really success depends on a good start? • In 1st line, patients are usually treated: • 80% of patients with a TKI (mainly Sunitinib) • 18% of patients with the combination of Bevacizumab + IFN-a • 2% still with some form of immunotherapy (e.g., IFN-a, IL-2, IFN-a + IL-2 …)

  8. 43% 45% Starting with Bevacizumab + IFN-a Escudier B, et al., J Clin Oncol 2010 … and this HAD an impact on the ultimate outcome of patients …

  9. Bevacizumab + IFN-a: final results of AVOREN OS (primary end-point) PFS (secondary end-point) Escudier B, et al., Lancet 2007

  10. Does really success depends on a good start? • In 1st line, patients are usually treated: • 80% of patients with a TKI (mainly Sunitinib) • 18% of patients with the combination of Bevacizumab + IFN-a • 2% still with some form of immunotherapy (e.g., IFN-a, IL-2, IFN-a + IL-2 …)

  11. TKI/VEGF inhibitor 1 TKI/VEGF inhibitor 2 mTOR inhibitor TKI/VEGF inhibitor mTOR inhibitor ? TKI – TKI – mTORI or TKI – mTORI – TKI? Probably, Sorafenib if the 1st TKI is Sunitinib1 We do now know that Everolimus is as effective after 1 TKI as it is after both …2 1. Di Lorenzo G, et al. Eur Urol 2010; 2. Motzer RJ, et al., Lancet 2009

  12. Sequencing TKIs … the rule? Number of patients

  13. Limited cross-resistance … and a surprise n=99 7.8 4.2 Porta Sorafenib 8.4 7.9 n=90 Sunitinib n=5 8.6 5.9 Tamaskar n=4 7.7 4.4 n=5 8.9 8.5 Richter* n=5 7.9 9.8 Zimmerman n=22 11.6 5.0 Eichelberg 9.2 n=30 5.7 n=7 8.1 5.3 Choueiri‡ n=31 8.6 12.4 n=20 5.7 2.9 Dudek† n=23 4.8 13.4§ n=22 5.1 3.9 Sablin‡ n=68 6.0 5.8 0 5 10 15 20 25 PFS (months) *Mean PFS; †Median duration of stable disease‡Treatment duration§Calculated by subtracting first median from overall median Paglino C, Porta C. Oncol Rev 2010;4:1–3

  14. Why So-Su seems to be better than Su-So?

  15. Does really success depends on a good start? • In 1st line, patients are usually treated: • 80% of patients with a TKI (mainly Sunitinib) • 18% of patients with the combination of Bevacizumab + IFN-a • 2% still with some form of immunotherapy (e.g., IFN-a, IL-2, IFN-a + IL-2 …)

  16. 100 100 75 75 % of patients 50 50 25 25 0 0 0 2 4 6 8 10 12 14 0 2 4 6 8 10 12 14 16 18 20 Sorafenib is the standard of care after IT ... PFS (Independently Assessed) OS (Prior to Crossover) Sorafenib (n=384) = 5.5 mo. Placebo (n=385) = 2.8 mo. HR = 0.44 (95% CI, 0.35-0.55) p<0.000001 Sorafenib (n=451) = not reached Placebo (n=452) = 14.7 mo. HR = 0.71 (95% CI, 0.54-0.94) p=0.015* % of patients Time from randomization (months) Escudier B, et al. N Engl J Med 2007;356:125-34; J Clin Oncol 2009;27:3312-8.

  17. 100 100 75 75 % of patients % of patients 50 50 25 25 0 0 0 0 4 4 8 8 12 12 16 16 20 20 24 24 28 28 32 32 36 36 40 40 ... As demonstrated by the TARGET study Intent-to-Treat Placebo Patients Censored Sorafenib (n=451) = 17.8 mo. Placebo (n=452) = 15.2 mo. HR = 0.88 (95% CI, 0.74-1.04) p=0.146† Sorafenib (n=451) = 17.8 mo. Placebo (n=452) = 14.3 mo. HR = 0.78 (95% CI, 0.62-0.97) p=0.0287‡ 48% of the placebo patients crossed over!! Time from randomization (months) Escudier B, et al. N Engl J Med 2007;356:125-34; J Clin Oncol 2009;27:3312-8.

  18. Any suggestion for clinical practice? Porta C, et al. EJMCO 2010 (E-pub) … and then, one should also consider the type of progression …

  19. How to deal with with issue at our best? Perform clinical trials!!!

  20. e.g., the SWITCH trial … PFS 1 PFS 2 • Number of countries: >4 (Germany, Netherlands, Austria, Nordic countries) • Number of sites: 80 • Planned number of patients: 540 • Study started: Feb 2009 • Estimated completion date: 2012 mRCC patients treatment-naïve Stratification by MSKCC risk score Primary endpoint:total PFS PDor toxicity Sorafenib Sunitinib Sunitinib Sorafenib www.clinicaltrials.gov NCT00732914

  21. ThankYouforYourkindattention!!! T c.porta@smatteo.pv.it

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