Clasificación de riesgo en renal metastásico

Mauricio Lema Medina MD – Clínica de oncología Astorga, Clínica SOMA, Medellín

Clasificación del riesgo renal metastásico

51 Congreso Internacional de Urología, Medellín, Agosto 11, 2016

BHD=Birt-Hogg-Dubé; FH=fumarate hydratase; VHL=von Hippel-Lindau.Modified from Linehan WM et al. J Urol. 2003;170:2163-2172.

Histological Classificationof Human Renal Epithelial Neoplasms

RCC

Clear cell75%

Type

Incidence (%)

Associated mutations VHL

Papillary type 1

5%

c-Met

Papillary type 2

10%

FH

Chromophobe

5%

BHD

Oncocytoma

5%

BHD

CJ Creighton et al. Nature 000, 1-7 (2013) doi:10.1038/nature12222

Somatic alterations in ccRCC.


DNA methylation and ccRCC


mRNA and miRNA patterns reflect molecular subtypes of ccRCC.

RCC Therapy: Targeting VEGF at Multiple Levels

AKT

mTOR HIFɑVHL

PI3K

Cell stimuli(eg, growth factors)

Cell growthsurvival

HIFɑHIFɑ

HIFɑ

Inactivated VHL tumor suppressor gene

Hypoxia

VEGF

PDGF

VEGFR

PDGFR

TemsirolimusEverolimus

SunitinibSorafenibPazopanib

AxitinibCabozantinib

Bevacizumab

HIFɑ

Adapted from Rini BI, et al. Lancet. In press.

Tumor

EndothelialCell

Cabozantinib

For researchFor predictionFor clinical decision-making

Risk stratification

Relevant

Accepted

Practical

Relevant

Accepted

PracticalSimple

AgeMotzer score

LDHHbCa++Prior history of nephrectomyECOG status

Nuclear grade 1 through 4 tumoursStageHistology

Motzer RJ, et al J Clin Oncol 1999;17:2530–2540

mRCC: prognostic factors1.0

0.8

0.6

0.4

0.2

0

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

Years following systemic therapy

Prop

ortio

n su

rviv

ing All (670 patients, 57 alive)

Median survival: 10 monthsCI: (9, 11)

MSKCC risk factor model

22

53

25

Patients (%)

≥3

1–2

0

Number of poor prognostic features

Poor

Intermediate

Favourable

MSKCCrisk group

4

10

20

Median OS (months)

Motzer RJ et al. J Clin Oncol. 2002;20:289-296.

MSKCC Risk Factor Model in mRCC

0 risk factors (n=80 patients)1 or 2 risk factors (n=269 patients)3, 4, or 5 risk factors (n=88 patients)

Risk factors associated with worse prognosis• KPS <80• Low serum hemoglobin (13 g/dL/11.5 g/dL: M/F) • High corrected calcium (10 mg/dL)• High LDH (300 U/L)• Time from Dx to IFN- <1 yr

Time From Start of IFN- (years)

Prop

ortio

n Su

rviv

ing

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 2 1614131195436 151210876

MS:20 mo10 mo4 mo

Comparison of Risk Factor Criteria for RCC:Memorial Sloan-Kettering Cancer Center (MSKCC) and Cleveland Clinic

Foundation (CCF)

Motzer RJ, et al. J Clin Oncol. 2002; 20:289-296. Mekhail TM, et al. J Clin Oncol. 2005;23:832-841.

Risk groups are defined as follows:Favorable: 0 risk factors present Intermediate: 1 or 2 risk factorsPoor: 3,4, or 5 risk factors

MSKCC Criteria 2002Factor Poor Prognostic

FactorTime from diagnosis totreatment with IFN-alfa

< 12 months

Hemoglobin < lower limit of laboratory’s reference range

Lactate dehydrogenase > 1.5 X the upper limit of laboratory’s range

Corrected serum calcium

> 10.0 mg/dL

Karnofsky Performance Status

< 80

CCF Criteria 2005

Factor Poor Prognostic Factor

Time from diagnosis totreatment with IFN-alfa

<12 months




> 10.0 mg/dL

Prior radiotherapy Yes

Presence of hepatic, lung, or retroperitoneal node metastases

Yes (2 or 3)

Comparison of Risk Factor Criteria for RCC:Memorial Sloan-Kettering Cancer Center (MSKCC) and Cleveland Clinic

Foundation (CCF)

Motzer RJ, et al. J Clin Oncol. 2002; 20:289-296. Heng DYC, et al. The Lancet Oncology 2013 (14):141-148.

Risk groups are defined as follows:Favorable: 0 risk factors present Intermediate: 1 or 2 risk factorsPoor: 3,4, or 5 risk factors

mRCC Database Consortium 2013

Factor Poor Prognostic Factor


<80

Time from diagnosis toTreatment

< 12 months

Anemia Hb below normal

Hypercalcemia Corrected serum Ca above normal

Neutrophilia ANC above normal

Thrombocytosis Platelet count above normal

MSKCC Criteria 2002Factor Poor Prognostic

FactorTime from diagnosis totreatment with IFN-alfa

< 12 months




> 10.0 mg/dL


< 80

Figure 1

The Lancet Oncology 2013 14, 141-148DOI: (10.1016/S1470-2045(12)70559-4) Heng DYC, et al. The Lancet Oncology 2013 (14):141-148.

External validation and comparison with other models of the International Metastatic Renal-Cell Carcinoma Database Consortium prognostic model: a population-based study

Figure 2 External validation and comparison with other models of the International Metastatic Renal-Cell Carcinoma Database Consortium prognostic model: a population-based study

Heng DYC, et al. The Lancet Oncology 2013 (14):141-148.

Figure 2 The International Metastatic Renal Cell Carcinoma Database Consortium model as a prognostic tool in patients with metastatic renal cell carcinoma previously treated with

first-line targeted therapy: a population-based study

Ko JJ et al. The Lancet Oncology 2015 (16): 293-300.

MSKCC is king

Sunitinib improves PFS in 1st-line mRCC

0 3 6 9 120

0.5

1.0

15

PFS in 750 patients

Time (months)

PFS

prob

abilit

y

Hazard ratio = 0.415(95% CI: 0.32–0.54)p<0.000001

SunitinibMedian PFS = 11 monthsIFN-Median PFS = 5 months

Motzer R, et al. NEJM 2007

1.0

0.8

0.6

0.4

0.2

0Surv

ival

Dist

ributi

on F

uncti

on

0 5 10 15 20 25 30 35Time to Death (Mos)

Arm 3: IFN + Tem

Arm 2: TemArm 1: IFN

*Modified MSKCC poor risk. †Stratified by country and nephrectomy status. ‡SD 24 wks.Hudes G, et al. N Engl J Med. 2007;356:2271-2281.

RANDOMIZATION†

IFN-α 3 MU-18 MU (n = 207)CR + PR: 4.8%

CR + PR + SD‡: 15.5%

Tem 25 mg QW (n = 209)CR + PR: 8.6%

CR + PR + SD: 32.1%

3/6 Poor-Risk Features:LDH > 1.5 x ULNHb < LLNCa++ (corrected) > 10 mg/dLKPS 60-70Initial diag to random < 1 yr

Multiple sites of metastases mRCC (N = 626)

IFN-α 3 MU-6 MU + Tem 15 mg QW (n = 210) CR + PR: 8.1%

CR + PR + SD: 28.1%

Parameter IFN Arm 1

(n = 207)

TemArm 2

(n = 209)

Tem + IFN Arm 3

(n = 210)

Median survival, Mos

7.3 10.9 8.4

Comparisons Arm 2 toArm 1

Arm 3 to Arm 1

Stratified log-rank P

.008 .70

Temsirolimus Phase III Trial in Poor-Risk RCC*: Tem ± IFN-α; OS by Treatment

Phase III COMPARZ: First-line Pazopanib vs Sunitinib for Clear-Cell mRCC

• Primary endpoint: PFS • Secondary endpoints: OS, ORR, time to response, safety, QoL,

medical resource utilization

Pts with mRCC clear-cell histology and no previous

systemic therapy(N = 1110)

Motzer RJ, et al. N Engl J Med. 2013;369:722-731.

Pazopanib 800 mg/day

Sunitinib50 mg/day

(schedule 4/2)

60

COMPARZ: Efficacy Outcomes

• Mean change from baseline in 11 of 14 health-related QoL during first 6 mos of treatment favored pazopanib (P < .05 for all 11 comparisons)

– Significantly less fatigue and foot soreness with pazopanib than with sunitinib

NMedian PFS, Mos (95% CI)

Pazopanib 557 8.4 (8.3-10.9)

Sunitinib 553 9.5 (8.3-11.1)

HR: 1.05 (95% CI: 0.90-1.22)

Motzer RJ, et al. N Engl J Med. 2013;369:722-731. Motzer RJ, et al. N Engl J Med. 2014;370:1769-1770.

PazopanibSunitinib

0O

S (%

)

Mos Since Randomization

NMedian OS, Mos (95% CI)

Pazopanib 557 28.3 (26.0-35.5)

Sunitinib 553 29.1 (25.4-33.1)

HR: 0.92 (95% CI: 0.79-1.06);P = .24

20

40

60

80

100

0 8 16 24 32 40 48 56 640 4 8 12 16 20 24 28 32 36 40

PazopanibSunitinib

100

PFS

(%)

Mos

80

40

20

0

Motzer R et al. N Engl J Med. 2007; 356:115-24

MSKCC risk in relevant clinical trials in mRCCMSKCC factor No. (%) Sunitinib Interferon-alpha

0 (favorable) 143(38) 121(34)

1-2 (intermediate) 209(56) 212(59)

>=3 (poor) 23(6) 25(7)

COMPARZ: Motzer R et al. N Engl J. 2013 Aug 22;369(8):722-31 (Appendix)

Favors Pazopanib Favors Sunitinib

Global ARCC: Hudes G et al. N Engl J Med. 2007; 356:2271-2281

MSKCC factor No. (%) Temsirolimus Interferon-alpha

1-2 (intermediate) 50(24) 64(31)

>=3 (poor) 157(76) 145(64)

100

80

60

40

20

00 2 4 6 8 10 16 24

Mos

Everolimus vs Placebo: Survival Outcomes of RECORD-1

Patients at Risk, n

Everolimus 277 192 115 51 26 10 1 0

Placebo 139 47 15 6 2 0 0 0

Patients at Risk, n

Everolimus 277 267 240 204 164 155 131 101 61 30 6 0 0

Placebo 139 131 117 100 88 74 56 43 27 13 3 0 0

Prob

abili

ty (%

)

HR: 0.87 (95% CI: 0.65-1.17)

Kaplan-Meier Median, MosEverolimus : 14.78Placebo: 14.39Log-rank P = .162

HR: 0.33 (95% CI: 0.25-0.43)

Median PFS, MosEverolimus : 4.90Placebo: 1.87Log-rank P < .001

Everolimus (n = 277)Placebo (n = 139)

PFSCentral Radiology Review

OS

Everolimus (n = 277)Placebo (n = 139)

Motzer RJ, et al. Cancer. 2010;116:4256-4265.

100

80

60

40

20

00 2 4 6 8 10 12 14

Mos12 14 18 20 22

361 256 202 145 96 64 38 20 10 1 0362 224 157 100 51 28 12 6 3 1 0

Patients at Risk, nAxitinibSorafenib

1.00.9

0.80.70.60.50.40.30.20.1

00 2 4 6 8 10

Mos

Stratified HR: 0.665(95% CI: 0.544-0.812;log-rank P < .0001)

12 14 16 18 20

AxitinibSorafenib

mPFS, Mos6.74.7

95% CI6.3-8.64.6-5.6

Prob

abili

ty o

f PFS

Rini BI, et al. Lancet. 2011;378:1931-1939.

AXIS Trial: PFS (IRC Assessment)

Phase III METEOR: PFS of Cabozantinib vs Everolimus After VEGFR TKI

Choueiri T, et al. N Engl J Med. 2015.

100

80

60

40

20

00 3 6 9 12 15 18

Mos

PFS

(%)

Cabozantinib

Everolimus

CabozantinibEverolimus

187188

7.4 (5.6-9.1)3.8 (3.7-5.4)

121126

Events, n

Median PFS,Mos (95% CI)

Pts, n

HR: 0.58 (95% CI: 0.45-0.75); P < .001

MSKCC risk, No. (%)4 Everolimus + BSC, n=277 Placebo + BSC, n=139 Favorable 81 (29) 39 (28)

Intermediate 156 (56) 79 (57)

Poor 40 (14) 21 (15)

RECORD-1: Motzer RJ, et al. Cancer. 2010;116:4256-4265.

Beyond first-line mRCC

MSKCC risk, No. (%)4 Axitinib, n=192 Sorafenib, n=96 Favorable 94(49%) 53(55%)

Intermediate 84(44%) 40(42%)

Poor 7(4%) 2(2%

AXIS: Rini BI, et al. Lancet. 2011;378:1931-1939.

METEOR: Choueiri T, et al. N Engl J Med. 2015].

MSKCC risk, No. (%)4 Cabozantinib, n=187 Everolimus, n=188 Favorable 80(43%) 83(44%)

Intermediate 80(43%) 75(40%)

Poor 27(14%) 30(16%)

http://onlinelibrary.wiley.com/doi/10.1002/cncr.25219/full%23bib4



CheckMate 025: Efficacy of Nivolumab vs Everolimus in Advanced RCC

Motzer RJ, et al. N Engl J Med. 2015

1.0

0.8

0.6

0.4

0.2

00 333 6 9 12 15 18 21 24 27 30

Mos

NivolumabEverolimus

410411

25.0 (21.8-NE)19.6 (17.6-23.1)

183215

Deaths, n

Median OS,Mos (95% CI)

Pts,n

4.6 (3.7-5.4)4.4 (3.7-5.5)

318322

Progression, n

Median PFS,Mos (95% CI)

Prob

abili

ty o

f PFS

HR: 0.88 (95% CI: 0.75-1.03; P = .11)1.0

0.8

0.6

0.4

0.2

00 333 6 9 12 15 18 21 24 27 30

Mos

HR: 0.73 (98.5% CI: 0.57-0.93; P < .002)

Prob

abili

ty o

f OS

CheckMate 025: Efficacy of Nivolumab vs Everolimus in Advanced RCC

Motzer RJ, et al. N Engl J Med. 2015.

MSKCC risk, No. (%)4 Nivolumab, n=410 Everolimus, n=411 Favorable 145(35) 148(36)

Intermediate 201(49) 203(49)

Poor 64(16) 60(15)


Metastasectomy in Renal Cell Carcinoma

• Characteristics associated with improved survival in patients undergoing metastasectomy for first recurrence– Disease-free interval > 1 yr– Single site of metastasis

• Lung better than brain

• 5-yr survival of 44%– Similar 5-yr survival rates with curative resection

upon second and third recurrence

Kavolius JP, et al. J Clin Oncol. 1998;16:2261-2266.

Observation Before Systemic Therapy Safe for a Subset of Pts With mRCC

Phase II study of pts with mRCC and no previous systemic therapy– Observation with periodic CT assessment; initiation of systemic treatment per discretion of physician and

pt

– Unaffected by IMDC risk group (P = .57), location or number of metastases

Median mos of observation until start of systemic therapy: 14.1 mos

Rini B, et al. ASCO 2014. Abstract 4520.

100

80

60

40

20

00 6 12 18 24 30 36 42 48

Mos From Study Entry

Pts

Still

Und

er

Obs

erva

tion

(%)

P = .05

Meas. burden ≤ 3.0 cm (n = 19)Meas. burden > 3.0 cm or nontarget lesions only (n = 27)

1. Flanigan RC, et al. N Engl J Med. 2001;345:1655-1659. 2. Mickisch GH, et al. Lancet. 2001;358:966-970.

Cytoreductive Nephrectomy

SWOG[1]Median

Survival, MosIFN- + nephrectomy (n = 120) 11.1

IFN- (n = 121) 8.1

EORTC[2]Median

Survival, MosIFN- + nephrectomy (n = 42) 17.0

IFN- (n = 42) 7.0

Mos

P = .05 P = .03

0

20

40

60

80

100

Surv

ival

(%)

0 24 48 72 960

20

40

60

80

100

Surv

ival

(%)

0 12 24 36Mos

Debulking Nephrectomy in mRCC

Pts most likely to benefit from cytoreduction[1] include those with:

– Good performance status with adequate end-organ function

– Potentially surgically resectable primary tumor mass representing at least 75% of total tumor burden

– Good prognostic features– No central nervous system metastases

Current recommendations based on data from trials incorporating IFN alfa-2b[2]

1. NCCN. Clinical practice guidelines in oncology: kidney cancer. v.3.2015. 2. Flanigan RC, et al. J Urol. 2004;171:1071-1076.

Conclusions

• Risk classification in mRCC is vital for:– Prognostic assessment– Treatment allocation– Expected outcomes– Research

• Although the m RCC MSKCC-risk score may not be the best, it is the most widely used

• We probably should continue to use it as long is the “law of the nation” in clinical research.

Sunitnib vs IFN

COMPARZ

METEOR

CheckMate 25

MSKCC risk-score

RECORD1

Robert Motzer

@onconerd

Clasificación de riesgo en renal metastásico

Health & Medicine

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