Escudier B, et al. Ann Oncol 2012;23(suppl. 7):vii65-vii71.

• 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

Escudier B, et al. Ann Oncol 2012;23(suppl. 7):vii65-vii71.

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

(Months)15 200 5 10 25

4.9

PFS

6.7

4.7

4.3

3.9

RECORD-11

AXIS2

1.9

INTORSECT3

Everolimus

Placebo

Axitinib

Sorafenib

Temsirolimus

Sorafenib

p = <0.001

p = <0.0001

p = not significant

N= 277

N= 139

N= 361

N= 362

N= 259

N= 253

14.8

20.1

19.2

12.3

16.6

14.4

OS

OS: p = not significant

OS: p= not significant

OS: p=0.014statistically significant

(Months)15 200 5 10 25

4.9

PFS

6.7

4.7

4.3

3.9

RECORD-11

AXIS2,3

1.9

INTORSECT4

Everolimus

Placebo

Axitinib

Sorafenib

Temsirolimus

Sorafenib

N= 277

N= 139

N= 361

N= 362

N= 259

N= 253

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

Stenner F, et al. Oncology 2012;82:333-40.

1. Motzer RJ, et al. Lancet 2008;372:449-56; 2. Motzer RJ, et al. Cancer 2010;116:4256-65.

1. 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 Cancer 2012;48:333-9.

1st Line

mTOR2nd Line

1st Line

1st Line

1st Line

2nd Line

2nd Line

2nd LinemTOR3rd Line

3rd Line

3rd LinemTOR4th Line

mTOR5th Line

4th Line n = 82

n = 104

n = 141

n = 89 21%

79%

Calvo E, et al. Eur J Cancer 2012;48:333-9.

Beware of time-lead bias

HR = 0.32 in both cases

mTORinhibitor

TKI/VEGF inhibitor

Level of evidence: 1,Grade of recommendation: A1

TKI/VEGF inhibitor

TKI/VEGF inhibitor

Level of evidence: 1,Grade of recommendation: A2

mTORinhibitor

Level of evidence: 1,Grade of recommendation: A1

We do now know that Everolimus is as effectiveafter 1 TKI, as it is after both1

?

Probably, Sorafenib and Sunitinib are both effective in this setting3,4

Level of evidence: 2,Grade of recommendation: B

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.

Porta C, et al. EJMCO 2010;2:1-6.

Looked smart …… no longer smart

• 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

1. Vickers MM, et al. Urology 2010;76:430-4; 2. Heng DY, et al. Ann Oncol 2012;23:1549-55;3. Albiges L, et al. (manuscript submitted); 4. Elaidi RT, et al. (manuscript submitted).

• 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

c.porta@smatteo.pv.it