michele milella oncologia medica a istituto nazionale tumori regina elena roma
TRANSCRIPT
Michele MilellaOncologia Medica A
Istituto Nazionale Tumori Regina ElenaRoma
Disclosures
I have very strong opinions on this talk’s topic and will try to force and bend available evidence to convince you that I’m right.
…In the beginning was Motzer!
Poor risk (20%)Median PFS: 2.5 mos
Median OS: 5 mos1-yr OS: 20%2-yr OS: 6%3-yr OS: 2%
The CCF extension
Poor risk (28%)Median OS: 7.3 mos
1-yr OS: 23%
…but they were meant for immuno/chemotherapy-treated patients!
MSKCC
CCF
What do we REALLY know?(I mean: high-quality scientific evidence…)
The Global ARCC Study: Trial Design
Stratification by:
Geographical Regions:EU + AU + CA (21%)US (29%)Other (50%)
Nephrectomy:YesNo TORISEL 15-mg IV once
weekly plus IFN-α 6 MU 3 times weekly (n=210)
RANDOMIZE
IFN-α escalating to 18 MU SC
3 times weekly (n=207)
TORISEL 25-mg IV once weekly (n=209)
Hudes et al. N Engl J Med. 2007;356:2271-2281.
Main Inclusion Criteria: Poor Prognostic Factors
• Karnofsky performance status 60 or 70• Hemoglobin less than the lower limit of normal (LLN)• Less than 1 year from time of initial RCC diagnosis to
randomization• Corrected serum calcium > 10 mg/dL• Lactate dehydrogenase > 1.5 times the upper limit of normal
(ULN)• More than 1 metastatic organ site of disease (sites defined as
different tissues with metastasis: lung, liver, bone, kidney, lymph node, etc.)
Patients had at least 3 of 6 “poor prognostic factors” for shortened survival listed below:
Hudes et al. N Engl J Med. 2007;356:2271-2281.
Baseline Characteristics /Subgroups (ITT Patient Population)
IFN TORISEL IFN + TORISEL Total
ITT Population 207 209 210 626
Subgroups by Protocol-defined Prognostic Factors:
>3 of 6 Factors, n(%) 196 (95%) 195 (93%) 198 (94%) 589 (94%)
<3 of 6 Factors 11 (5%) 14 (7%) 12 (6%) 37 (6%)
TOTAL 207 209 210 626 (100%)
Hudes et al. N Engl J Med. 2007;356:2271-2281.
Baseline CharacteristicsPoor Prognostic Factors (ITT Population)
Poor Prognostic Factors IFN TORISELIFN +
TORISEL TOTAL
ITT Population 207 209 210 626
MSKCC Risk Factors:LDH > 1.5 X upper limit of normal 48 (23%) 36 (17%) 33 (16%) 117 (19%)
Hemoglobin < lower limit of normal 168 (81%) 172 (82%) 178 (85%) 518 (83)
Corrected calcium > 10 mg/dL 72 (35%) 54 (26%) 58 (28%) 184 (29%)
Time from diagnosis to first treatment < 1 y 164 (79%) 174 (83%) 179 (85%) 517 (83%)
Karnofsky Performance Status 60-70 171 (83%) 168 (80%) 177 (84%) 516 (82%)
Additional Poor Prognostic Factors:>2 Sites of Metastasis 165 (80%) 166 (79%) 168 (80%) 499 (80%)
Hudes et al. N Engl J Med. 2007;356:2271-2281.
• Treatment arms generally well balanced for prognostic factors
Primary EndpointMedian Overall Survival
1.00
0.75
0.50
0.25
0.00
0 5 10 15 20 25 30
TORISEL (N=209) IFN-α (N=207)
Time From Registration, Months
Treatment with TORISEL was associated with a 49% increase in median OS compared with IFN-α
Prob
abili
ty o
f Sur
viva
l
Median Overall Survival
TORISEL 10.9 months
IFN-α 7.3 months
P value 0.0078
Hazard ratio (95% CI) 0.73 (0.57-0.92)
TORISEL + IFN-α (N=207)
Hudes et al. N Engl J Med. 2007;356:2271-2281.
Secondary Endpoints
Parameter TORISEL(n=209)
IFN-α(n=207)
% Difference P HR
(95% CI)†
Median PFS‡ by independent reviewMonths (95% CI)
5.5 mos (3.9, 7.0)
3.1 mos (2.2, 3.8) 77% 0.0001 0.66
(0.53, 0.81)
Median TTF§
Months (95% CI)3.8 mos (3.5, 3.9)
1.9 mos (1.7, 1.9) 100% <0.0001 0.61
(0.50, 0.74)
Overall response rate% (95% CI)
8.6% (4.8, 12.4)
4.8% (1.9, 7.8) 79% 0.1232 NA
Clinical benefit rate% (95% CI)
32.1% (25.7, 38.4)
15.5% (10.5, 20.4) 107% <0.0001 NA
Hudes et al. N Engl J Med. 2007;356:2271-2281.
Geographic areaUS 122W EU, Canada, Australia 87Asia-Pacific, E EU, Africa, S Amer 207
Corrected serum calcium level≤10 mg/mL 276>10 mg/mL 126
LDH level≤1.5 x ULN 315>1.5 x ULN 84
Hemoglobin level<1 x LLN 340≥1 x LLN 76
Diagnosis to randomization<1 y 338≥1 y 78
HistologyClear cell 339Other 73
NephrectomyYes 278No 138
Karnofsky performance status≤70 340>70 75
SexMale 287Female 129
Age<65 y 287≥65 y 129
Overall SurvivalAcross Patient Subgroups
0.0 0.5 1.0 1.5 2.0
TORISEL Better Interferon- Better
Hazard Ratio (95% CI)No. of PatientsSubgroup
Hudes et al. N Engl J Med. 2007;356:2271-2281.
VariableIFN TORISEL
N OS1 (CI)2 N OS (CI) HR P
ITT Population 207 7.3 (6.1-8.8) 209 10.9
(8.6-12.7) 0.78 0.0252
Subgroups by Protocol-defined Poor Prognostic Factors:
>3 1966.9
(5.6-8.3)196
10.9 (8.6-12.9)
0.73 0.0020
<3 11NA
(20.6-NA)13
10.2(6.9-15.4)
4.93 0.0052
Subgroups by MSKCC Risk Factors:
Poor Risk 1566.0
(4.3-7.1)145
10.2 (7.6-11.7)
0.70 0.0014
IntermediateRisk
5117.7
(11.3-24.2) 64
13.0 (9.9-15.4)
1.17 0.2441
OS by Prognostic Factors (ITT Population)
1 Median Overall Survival in months2 95% Confidence Interval
Hudes et al. N Engl J Med. 2007;356:2271-2281.
Poor prognosis patients:Who are they????
50 yr-old malemRCC (synchronous)
NefrectomizedHb 13.8
LN and pulmonary nodules
KPS 100%
80 yr-old femalemRCC (synchronous)
No nefrectomyHb 9.8
Corrected Ca++ 3.45 LN, lung, bone,
pancreasKPS 60%
Are they the same???Would you treat them the same???
So, Tem is the standard of care for poor risk mRCC pts……but, what are the alternatives?
Well, targeting the VEGF axis could be an alternative, many would say…
…but, based on which data?
Treatment (% of the overall population)
median OS(95% CI)
Registration trial
Sunitinib (6%) 5.3 mos (4.2-10.0)
IFNa (7%) 4.0 mos(2.7-7.2)
EAP
Sunitinib (n=373) 5.3 mos(4.6-6.4)
Heng 2008
Sunitinib (n=61) 6.4 mos
Sunitinib
ASCO 2008; abstr 16057
…but, based on which data?Bevacizumab/IFNa
AVO
REN
CALG
B
…but, based on which data?
Sorafenib Pazopanib
No data available
No data available
JCO 2009Cancer 2011
Ann Oncol 2011
JCO 2010
mTTP: 5.0 mos (3.5-6.5)mOS: 9.3 mos (7.3-11.5)
Temsirolimus
Sunitinib
Bevacizumab/IFN
Median OS (with 95% CI) for mRCC patients classified as poor-risk by classical MSKCC criteria
upon treatment with selected targeted agents
So, Sunitinib would be the ONLY alternative… but in which patients???
Poor risk by classical MSKCC criteria
Poor risk by modified MSKCC criteriaIntermediate risk by classical MSKCC criteria
Poor risk by both criteria
Tem SU0
2
4
6
8
10
1210.2
5.3
mO
S (m
os)
Tem SU0
0.2
0.4
0.6
0.8
1
0.7 0.66
HR v
s IFN
Tem SU0
5
10
15
20
25
13
20.7m
OS
(mos
)
Tem SU0
0.2
0.4
0.6
0.8
1
1.2 1.17
0.79
HR
vs IF
N
And it’s getting more…
…and more complicated!!!
Risk stratification in the targeted agent era
Validation of the IDC model
Poor risk (30%)Median OS: 7.8 mos
… and yet, we are missing something!
But don’t forget other things maybe important too…
Cytoreductive Surgery
Flanigan RC, NEJM 345:1655, 2001 Mickisch, Lancet 358:966, 2001
SWOG 8949 n=246 EORTC Trial n=85
OS=11 vs 8.1 months OS= 17 vs 7 months
IFNNephrectomy + IFN
Cytoreductive Surgery
Group Year N MSNephrectomy + IFN
MSIFN
p
SWOG 2001 246 11 9 <0.05
EORTC 2001 85 18 11 < 0.05
Flanigan(combined)
2004 331 13.6 7.8 < 0.05
31% decrease in risk of death with nephrectomy
Flanigan RC J Urol 171:1071, 2004
• Eligibility data: ECOG PS 0-1, clear cell histology, primary resectable lack of CNS, liver or extensive bone metastases• Absolute benefit diminishes in poor risk groups• We don’t know what mechanism underlies the improvement in survival
RCC Consortium Database N= 314 (37% Poor Risk by Heng)
Risk N OSCN -
OSCN +
HR C.I. P
Favorable 23
Intermediate 143 13.1 27.5 0.46 0.27 – 0.78 0.004
Poor 117 5.8 9.8 0.67 0.44 – 1.01 0.056
Benefit of cytoreductive nephrectomy seems to be marginal in poor risk group
Choueiri TK, J Urol 185: 60-66, 2011
• Pts treated with Sunitinib, Sorafenib, Bevacizumab• Retrospective data
Upfront Nephrectomy in Poor Risk?
Poor RiskPoor Performance status
Unresectable Primay Tumor
Upfront SystemicTherapy
Poor Risk
Resectable Primay Tumor
Upfront Therapy
Improvement in OverallPatient Status
Nephrectomy??
The same does not apply to patients treated with VEGF inhibitors…
Heng, JCO 2009
And don’t forget other things maybe important too…
VEGFR inhibitors are active in ncc-RCC
VEGFR inhibitors are active in ncc-RCC
VEGFR inhibitors are active in ncc-RCC
…but are still less active than in cc-RCC!!!
Modified from: Heng, JCO 2009
Overall Survival by Histologic Subtype (ITT Population)
Data on file, Wyeth Pharmaceuticals Inc.
VariableIFN TORISEL P
N OS1 (CI)2 N OS (CI) HR
ITT Population 207 7.3 (6.1-8.8) 209 10.9
(8.6-12.7) 0.78 0.0252
Histologic subtype
Clear cell 1708.2
(6.6-10.4)169
10.6 (8.5-13.0)
0.85 0.1304
Other 364.3
(3.2-7.3)37
11.6(8.9-15.0)
0.55 0.0095
1 Median Overall Survival in months2 95% Confidence Interval
Tem vs IFN in ncc-RCC
Dut
cher
, Med
Onc
ol 2
009
Tem vs IFN in ncc-RCC
Dutcher, Med Oncol 2009
And don’t forget other things maybe important too…
Armstrong, JCO 2012
Low LDH
High LDH
IFNa
Tem
LDH levels are predictive of Tem benefit over IFN in poor risk mRCC patients
…still a peculiarity of mTOR inhibitors?
Modified from Heng, JCO 2009
Conclusions
• Temsirolimus is the most appropriate therapeutic choice in the vast majority of pts w at least 3/6 poor risk features (and, by the way, the only one supported by evidence….)
• In selected pts w intermediate risk by strict MSKCC criteria, Sunitinib is a reasonable choice
• However, in a fraction of poor risk pts VEGF inhibitors dramatically alter disease natural history (…but how do we identify them???)
• Other factors, such as nefrectomy status, histology, LDH levels, or the necessity to obtain an objective response should be taken into account
Open questions
• How will new prognostic classifications impact on these results?
• Is there a life after first-line for poor risk patients?
• Will we ever understand the biology behind clinical classifications (if there is any…)?