michele milella oncologia medica a istituto nazionale tumori regina elena roma

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…)?