Oltre la prima linea

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Oltre la prima linea di terapia
Dr. Camillo Porta S.C. di Oncologia
Medica I.R.C.C.S. Policlinico San Matteo, Pavia
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Lets start with ESMO guidelines
Escudier B, et al. Ann Oncol 201223(suppl.
7)vii65-vii71.
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Why thinking 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
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What the guidelines suggest
Escudier B, et al. Ann Oncol 201223(suppl.
7)vii65-vii71.
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Availabe RCTs in 2nd line
RECORD-11
4.9
Everolimus
p lt0.001
1.9
Placebo
AXIS2
6.7
Axitinib
p lt0.0001
4.7
Sorafenib
INTORSECT3
4.3
Temsirolimus
p not significant
3.9
Sorafenib
15
20
0
5
10
25
(Months)
1. Motzer RJ, et al. Cancer 2010116425665 2.
Rini BI, et al. Lancet 201137819319 3. Hutson
TE, et al. ESMO 2012abstract LBA22
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Availabe RCTs in 2nd line
RECORD-11
OS
14.8
4.9
Everolimus
OS p not significant
14.4
1.9
Placebo
AXIS2,3
20.1
6.7
Axitinib
OS p not significant
19.2
4.7
Sorafenib
INTORSECT4
12.3
4.3
Temsirolimus
OS p0.014 statistically significant
16.6
3.9
Sorafenib
15
20
0
5
10
25
(Months)
1. Motzer RJ, et al. Cancer 2010116425665 2.
Rini BI, et al. Lancet 201137819319 3. Hutson
TE, et al. ESMO 2012abstract LBA22
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Other evidence supporting the sequence of TKIs
Stenner F, et al. Oncology 201282333-40.
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Third-line treatment

1. Motzer RJ, et al. Lancet 2008372449-56 2.
   Motzer RJ, et al. Cancer 20101164256-65.

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RECORD-1 which line of Tx?

• Motzer RJ, et al. Lancet 2008372449-56 2.
  Motzer RJ, et al. Cancer 20101164256-65
• 3. Calvo E, et al. Eur J Cancer 201248333-9.

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Everolimus after 1 or 2 TKIs?
Beware of time-lead bias
HR 0.32 in both cases
Calvo E, et al. Eur J Cancer 201248333-9.
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Which sequence after 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
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 2008372449-56 2.
Rini BI, et al. Lancet 20113781931-9 3. Di
Lorenzo G, et al. Eur Urol 201058906-11 4.
Porta C, et al. Abs. ECCO/ESMO 2011 (abs. 7131)
and manuscript submitted.
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Special situations
no longer smart
Looked smart
Porta C, et al. EJMCO 201021-6.
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Primary refractory 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

• Vickers MM, et al. Urology 201076430-4 2. Heng
  DY, et al. Ann Oncol 2012231549-55
• 3. Albiges L, et al. (manuscript submitted) 4.
  Elaidi RT, et al. (manuscript submitted).

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Thank You for Your kind attention!!!
c.porta_at_smatteo.pv.it