VHL tumour
suppressor gene
isolated 2
Cytokines:
IL-2 and IFN-α
first to report activity1
Sorafenib and sunitinib:
FDA and EMEA approval
Temsirolimus:
FDA and EMEA-approval
IFN-α and high-dose IL-2:
used for RCC treatment
Bevacizumab + IFN-:
FDA and EMEA-approval
Anni ’40
Anni ’80-’90
High-dose IL-2:
FDA-approval
based on Phase II data
2005-2006
2007
2009-2010
2011-2012
Everolimus:
FDA and EMEA-approval
Pazopanib:
FDA and EMEA-approval
Axitinib:
FDA approval
Advanced kidney cancer
Clear cell histology
Good/intermediate prognosis
Non-clear cell histology
Poor prognosis
Advanced kidney cancer
Clear cell histology
Good/intermediate prognosis
(MSKCC criteria)
IFN + Bevacizumab (AVOREN)
IFN + placebo (AVOREN)
(n=327)
(n=322)
180 (55)
202 (63)
Sunitinib
83 (25)
92 (29)
Sorafenib
60 (18)
Bevacizumab
10 (3)
12 (4)
7 (2)
6 (2)
mTOR inhibitors
14 (4)
6 (2)
Cytokines
32 (10)
52 (16)
Chemotherapy
28 (9)
47 (15)
Total patients with ≥1 treatment
VEGF inhibitors
Other
43%
50 (16)
45%
Escudier B, et al. Cancer 2010
Avastin +
IFN-a2a (n=327)
Patients with mRCC
(n=649)
Stratification by:
Country
MSKCC risk group
OS
23.3 m
38.6 m
+ TKIs 35%
(n=113)
1:1
IFN-a2a + placebo
(n=322)
Bracarda S, et al. BJUI 2010
OS
21.3 m
33.6 m
+ TKIs 37%
(n=120)
Central Radiology Review
PFS, progression-free survival; CI, confidence internal.
Hutson T. et al. ESMO 2009; abstr P-7136
Investigator Assessment
Motzer RJ, et al. Lancet 2008
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.
Stenner F, et al. Oncology (submitted).
Stenner F, et al. Oncology (submitted).
CONVENTIONAL APPROACH
UNCONVENTIONAL APPROACH
CONVENTIONAL APPROACH
CONVENTIONAL APPROACH
UNCONVENTIONAL APPROACH
Eligibility criteria:
Histologically-confirmed
mRCC with clear-cell
component
Failure of prior first-line
regimen containing either:
• Sunitinib
• Bevacizumab +IFN-α
• Temsirolimus
• Cytokine(s)
N=723
R
A
N
D
O
M
I
Z
A
T
I
O
N
Axitinib
5 mg b.i.d.
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.
*One-sided log-rank test stratified by ECOG PS
Rini BI, et al. Lancet 2011;378:1931-9.
Rothenberg M, FDA presentetion 2011
Level of evidence: 1,
Grade of recommendation: A2
Level of evidence: 1,
Grade of recommendation: A1
Level of evidence: 1,
Grade of recommendation: A1
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; 2. Porta C, et al. Abs.
ECCO/ESMO 2011 (abs. 7131) and manuscript submitted.
1. Motzer RJ, et al. Lancet 2008;372:449-56; 2. Rini BI, et al. Lancet 2011;378:1931-9.
Sir M. Rawlins
Chairman UK NICE*
No response
Porta C, et al. EJMCO 2010
Eisen T, modified
Intolerance
Short term
benefit
Long term
benefit
• Large retrospective series (the mRCC International Data-Base Consortium, as
Phase
III study study)1-3
PD: as best response
well as the French-Italo-British
cooperative
Bevacizumab
20%
Pazopanib
18%
2° PFS
TKI
Sunitinib
Heng
Albiges
2,8 mo
Sorafenib
6,6 mo
2° PFS mTOR
2,0 mo
5,0 mo
OS
12%from 2° line
7,4 mo
20%
5,9 mo
– … in TKI-primary refractory patients
(i.e., a mTOR inhibitor)
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
No response
Porta C, et al. EJMCO 2010
Eisen T, modified
Intolerance
Short term
benefit
Long term
benefit
• 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,
(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)
No response
Porta C, et al. EJMCO 2010
Eisen T, modified
Intolerance
Short term
benefit
Long term
benefit
Axitinib (%)
Sorafenib (%)
All
grade
Grade
3/4
All
grade
Grade
3/4
Neutropenia
6
1
8
1
11
Anemia
35
<1
52
4
32
5
Elevation of Hgb
9
NA
1
NA
3
22
1
Thrombocytopenia
15
<1
14
0
3
17
1
Lymphopenia
33
3
36
4
Hypophosphatemia
13
2
50
16
Hypercalcemia
30
<1
7
0
All
grade
Grade
3/4
All
grade
Grade
3/4
Diarrhea
55
11
53
7
Hypertension
40
16
29
Fatigue
39
11
Nausea
32
Vomiting
24
Event
Axitinib (%)
Sorafenib (%)
Event
19
<1
8
0
Stomatitis
15
1
12
<1
HFSR
27
5
51
16
Rash
13
<1
32
4
Hypocalcemia
10
1
28
1
Alopecia
4
0
32
0
Hyperlipasemia
27
5
46
15
Hypothyroidism
No response
Porta C, et al. EJMCO 2010
Eisen T, modified
Intolerance
Short term
benefit
Long term
benefit
• 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