Cáncer Renal avanzado. Nuevas estrategias para el...

Daniel Castellano

Oncología Médica.Unidad de Tumores GenitoUrinarios

Hospital Universitario 12 de Octubre.

I + 12 Research Institute

Cáncer Renal avanzado. Nuevas estrategias para el tratamiento individualizado.

1. US FDA. Sorafenib, 2005. 2. US FDA. Sunitinib malate, 2006. 3. US FDA. Temsirolimus, 2007. 4. US FDA. Everolimus, 2009. 5. US FDA. Bevacizumab, 2009. 6. US FDA. Pazopanib, 2009. 7. US FDA. Axitinib, 2012.

1992-2005 2005 2006 2007 2008 2009 2010 2011 2012

IFN-α

High dose interleukin-2

Sunitinib (Jan 2006)2

Sorafenib (Dec 2005)1

Temsirolimus (May 2007)3

Pazopanib (Oct 2009)6

Bevacizumab + IFN-α (Jul 2009)5

Everolimus (Mar

2009)4

Axitinib (Jan 2012)7

Treatment options for metastatic RCC have been revolutionised in a short period of time…

Tivozanib (2012 ??)

http://en.wikipedia.org/wiki/File:Food_and_Drug_Administration_logo.svg

RCC: efficacy proven across histological subtypes

1. Linehan WM, et al. J Urol 2003; 2. Motzer RJ, et al. N Engl J Med 1996

3. Escudier B, et al. N Engl J Med 2007; 4. Beck J, et al. ECCO 2007

5. Knox JJ, et al. EMUC 2007; 6. Chouieri TK, et al. J Clin Oncol 2008

7. Golshayan AR, et al. ASCO-GU 2008; 8. Motzer RJ, et al. J Clin Oncol 2002

Clear cell

Papillary (type I + II) Tumour type

Incidence (%

of all RCCs)2

Histology1

75–85 12–14

Chromophobic

4–6

Note: patients may have more

than one histological subtype

5

VEGFR-2

VEGFR-1

PDGFR-α

VEGFR-3 PDGFR-ß c-Kit Flt-3

Overview of targeted agents in mRCC1–5 Anti-angiogenesis Bevacizumab VEGF-A VEGF-B

VEGF-C

VEGF-D VEGF-E

Pazopanib Sorafenib Raf

Sunitinib

Preclinical in vitro data need to be validated in a clinical setting References are in slide notes

Patient-focused treatment strategy

Need to define

– the optimal setting for each treatment

– the best treatment for each given patient

For any given patient, treatment decisions require

consideration of multiple factors

– disease characteristics

– patient characteristics

– treatment aim and previous treatment history

Which parameters potentially influence

treatment choices?

Disease characteristics

– sites and number of metastases

– tumour histology

– MSKCC risk

Patient characteristics

– age

– cardiac risk

– renal impairment

– general comorbidities/overall health of patient

Treatment aim and previous treatment history

– objective of treatment

– suitability for cytokine therapy

– failure of prior therapy

Proposed schema: factors to consider prior to

prescribing treatment for RCC

TREATMENT History

Aim

Naive

Tumour

shrinkage

Suitable

for CK

Prior targeted

therapy

Disease

stabilisation

Maintain

QoL

Prolong

survival

Unsuitable

for CK Prior CK

No. met sites

Site of mets

Histology

DISEASE

MSKCC Good Intermediate

2–3 0–1

Lymph nodes Liver Brain

Clear cell Non-clear cell

>4

Lung Bone

Poor

* Including controlled arrhythmias

PATIENT

Age

P.S.

Comorbidity

≥65 years

0 1 2 3

Haematological

Diabetes Fatigue Thyroid Cirrhosis Renal

Cardiac disease ≤ grade 2* > grade 2* Controlled HT

Wound

healing

<65 years

CK = cytokine; HT = hypertension; mets = metastases; PS = performance status; QoL = quality of life

TREATMENT History

Aim

Naive

Tumour

shrinkage

Suitable

for CK

Disease

stabilisation Prolong

survival

Unsuitable

for CK Prior CK

Prior targeted

therapy

Maintain

QoL

Aim of treatment for RCC

Robust

evidence

and guidelines

Selecting first-line treatment: A clinician’s perspective

Patient

characteristics

Experience

Patient

preference

Efficacy is key when selecting

first-line treatment, but there are also other considerations…

Algoritmo CCRm - 2012 Setting Patients Therapy Options

First-line Favourable- or

intermediate-risk

Sunitinib

Pazopanib

Tivozanib ?

Beva - IFN-α

HD IL-2

Cytokines

Sorafenib

Poor-risk Temsirolimus Sunitinib

Second-line Prior cytokine Axitinib

Pazopanib

Sorafenib

Sunitinib

Prior VEGF–TKI Axitinib Sorafenib ?

Prior VEGF–TKI Everolimus Clinical trial

Adapted from EAU guidelines 2010, ESMO Clinical Recommendations 2009,

NCCN guidelines 2010 SOGUG 2010

Agent n

Median PFS

(months)

Median OS

(months) ORR (%)

Sunitinib vs IFN-α1 750 11 vs 5 p<0.001

26.4 vs 21.8 p=0.051

47 vs 12 p<0.001

Bevacizumab + IFN-α vs IFN-α2,3 649 10.2 vs 5.4 p<0.0001

23.3 vs 21.3 p=0.1291

31 vs 13 p=0.0001

Bevacizumab + IFN-α vs IFN-α4,5 732 8.5 vs 5.2 p<0.0001

18.3 vs 17.4 p=0.069

26 vs 13 p<0.0001

Pazopanib vs placebo6,7 435 11.1 vs 2.8 p<0.0001

22.9 vs 20.5* p=0.224

30 vs 3* p<0.001

Poor-risk patients

Temsirolimus vs IFN-α8† 626 5.5 vs 3.1 p<0.001

10.9 vs 7.3 p=0.008

8.6 vs 4.8 NS

*Includes cytokine refractory and treatment-naïve patients; †Poor-risk patients (modified MSKCC criteria)

NS, not studied

Recommended targeted agents for first-line treatment:

Results from pivotal trials

1. Motzer RJ, et al. J Clin Oncol 2009;27:3584–90; 2. Escudier B, et al. Lancet 2007;370:2103–11; 3. Escudier B, et al. J Clin Oncol 2010;28:2144–50;

4. Rini BI, et al. J Clin Oncol 2008;26:5422–8; 5. Rini BI, et al. J Clin Oncol 2010;28:2137–43; 6. Sternberg C, et al. J Clin Oncol 2010;28:1061–8;

7. Sternberg C, et al. Eur J Cancer 2013;49:1287–96; 8. Hudes G, et al. New Engl J Med 2007;356:2271–81

No. en riesgo

Sunitinib: 375 240 156 54 10 1

IFN-α: 375 124 46 15 4 0

Sunitinib : Estudio fase III como tratamiento de primera línea en el CCR avanzado

Sunitinib

50 mg diario (Esquema 4/2)

N=375

IFN-α

3 MU SC, TIW primera semana,

6 MU SC, TIW segunda semana,

9 MU SC, TIW a partir de entonces

N=375

Criterios de elegibilidad

≥18 años de edad

CCRm

Histología de células claras

Sin tratamiento sistémico previo

Enfermedad medible por RECIST

ECOG PS 0 o 1

Función orgánica adecuada

N=750

ALEATOR I ZAC I ÓN

Motzer RJ, et al. N Engl J Med 2007

Motzer RJ, et al. ASCO 2007; Motzer RJ, et al. J Clin Oncol 2009

0 5 10 15 20 25 30

Tiempo (meses)

HR=0.538

(95% IC 0.439–0.658)

P<0.000001

Sunitinib Mediana: 11.0 meses (95% IC: 10.7–13.4)

IFN-α Mediana: 5.1 meses (95% IC: 3.9–5.6)

1.0

0.8

0.6

0.4

0.2

0

Pro

babili

dad d

e S

LP

Mediana de SG Mediana de la SLP (revisión central

independiente)

Pro

babili

ty o

f surv

ival

HR=0.821

(95% IC: 0.673–1.001)

P=0.051 (log-rank)

Sunitinib (n=375)

Mediana: 26.4 meses

(95% IC: 23.0–32.9)

IFN-α (n=375)

Mediana: 21.8 meses

(95% IC: 17.9–26.9)

Total deaths

Sunitinib 190

IFN-α 200

0 3 6 9 12 15 18 21 24 27 30 33 36

1.0

0.8

0.6

0.4

0.2

0

nMuertes/nRiesgo

Sunitinib 375 44/326 38/283 48/229 42/180 14/61 4/2

IFN-α 375 61/295 46/242 52/187 25/149 15/53 1/1

Tiempo (meses)

RECIST = Response Evaluation Criteria in Solid Tumors; ECOG = Eastern Cooperative Oncology Group; SLP = supervivencia libre de

progresión; SG = supervivencia global

Programa de acceso expandido de Sunitinib: Escenario “Real”

• Programa internacional que incluyó 4,564 pacientes con CCRm

(vírgenes al tratamiento o refractarios a citokinas)

4,349 1,316 136 0

Gore ME, et al. Lancet Oncol 2009

1.0

0.8

0.6

0.4

0.2

0

Pro

babili

dad

0 10 20 30

No. en riesgo

0 10 20 30

Tiempo (meses)

1.0

0.8

0.6

0.4

0.2

0

Pro

babili

dad

Mediana: 10.9 meses

(95% lC: 10.3–11.2)

Mediana: 18.4 meses

(95% lC: 17.4–19.2)

SLP SG

4,349 2,429 525 0

Tiempo (meses)

Pro

port

ion

pro

gre

ssio

n-f

ree

19

Progression-free survival in the treatment-naïve subpopulation

1.0

0.8 0.6 0.4 0.2

0.0

0 5 15 20 10

Pazopanib

Placebo

Placebo Pazopanib Hazard ratio (95% CI) p value (1-sided)

Median PFS (months)

1 11 2

39 7

84

22

155 78

Number at risk, n

Pazopanib Placebo

Time (month)

2.8 11.1 0.40 (0.27, 0.60) <0.0001

In the treatment-naïve subpopulation, PFS was significantly greater in pazopanib- versus placebo- treated patients (p<0.0001) 1. Sternberg et al. J Clin Oncol 2010;28:1061-1068

Pazopanib 11.1 mo

COMPARZ study design:

Phase III, open-label, non-inferiority trial

Pazopanib 800 mg QD

Continuous daily dosing Enrolment criteria:

•Locally advanced or mRCC

•Clear-cell histology

•No prior systemic therapy

•Measurable disease (RECIST 1.0)

•KPS ≥70

•Adequate organ function

N=927

Sunitinib 50 mg QD

Schedule 4/2

Randomised

1:1

KPS, Karnofsky Performance Scale; RECIST, Response Evaluation Criteria in Solid Tumors; Schedule 4/2, 4 weeks on treatment, 2 weeks off

www.clinicaltrials.gov (NCT00720941; NCT01147822)

Study start: August 2008

VEG108844

Phase III

n=927

VEG113078

Phase II (Asia)

n=183

COMPARZ:

1,110 patients

N=1,110

COMPARZ primary endpoint: PFS (IRC-assessed)

N Median PFS (95% CI)

Pazopanib 557 8.4 mo (8.3, 10.9)

Sunitinib 553 9.5 mo (8.3, 11.1)

HR (95% CI ) = 1.047 (0.898,1.220)

Pro

po

rtio

n p

rog

ressio

n-f

ree

1.0

0.8

0.6

0.4

0.2

0

Months Number at risk

Pazopinib 557 361 245 136 105 61 46 19 13 1

Sunitinib 553 351 249 147 111 69 48 18 10 3

0 4 8 12 16 20 24 28 32 36 40

Motzer RJ, et al. Presented at ESMO 2012; Abstract LBA8

PFS (ITT population) Pazopanib (n=557) Sunitinib (n=553)

Median PFS, months (95% CI) 8.4 (8.3, 10.9) 9.5 (8.3, 11.1)

HR (95% CI) 1.0466 (0.8982, 1.2195)

PFS (PP population) Pazopanib (n=501) Sunitinib (n=494)

Median PFS, months (95% CI) 8.4 (8.3, 10.9) 10.2 (8.3, 11.1)

HR (95% CI) 1.069 (0.910, 1.255)

PP, per-protocol

1. GSK. Clinical Study Register. Study 108844. Available at: http://download.gsk-clinicalstudyregister.com/files/ae28e535-6855-4956-8022-084cdeda4d38

(last accessed February 2013); 2. Motzer RJ, et al. Presented at ESMO 2012; Abstract LBA8; 3. Available at

http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/001141/WC500094275.pdf (last accessed April 2013)

COMPARZ: PFS (IRC-assessed)1,2

Non-inferiority met if upper bound of 95% CI for HR <1.25 (EMA requested ≤1.223)

Laboratory Abnormalities

Chemistry labs (≥35%)

ALT AST Hypoalbuminemia Bilirubin Creatinine Hyperglycemia Hyponatremia Hypophosphatemia Hematology labs Leukopenia Neutropenia Thrombocytopenia Lymphopenia Anemia

Pazopanib

(n = 554), % All Grades 60 61 33 36 32 54 35 36 43 37 41 38 31

Sunitinib

(n = 548),% All Grades 43 60 42 27 46 57 32 52 78 68 78 55 60

Yellow highlight: Risk greater for pazopanib and 95% CI for relative risk does not cross 1

Laboratory Abnormalities

Chemistry labs (≥35%)

ALT AST Hypoalbuminemia Bilirubin Creatinine Hyperglycemia Hyponatremia Hypophosphatemia Hematology labs Leukopenia Neutropenia Thrombocytopenia Lymphopenia Anemia

Pazopanib

(n = 554), % All Grades 60 61 33 36 32 54 35 36 43 37 41 38 31

Sunitinib

(n = 548),% All Grades 43 60 42 27 46 57 32 52 78 68 78 55 60

Blue highlight: Risk greater for sunitinib and 95% CI for relative risk does not cross 1

COMPARZ: Common AEs (treatment-emergent)

AE*

Pazopanib (n=554), % Sunitinib (n=548), % Risk ratio 95% CI

All

grades Grade 3/4

All

grades Grade 3/4 All grades

Any event† >99 59/15 >99 57/17 NA NA

Diarrhoea 63 9/0 57 7/<1 1.09 0.99, 1.20

Fatigue 55 10/<1 63 17/<1 0.87 0.79, 0.96

Hypertension 46 15/<1 41 15/<1 1.14 1.00, 1.31

Nausea 45 2/0 46 2/0 0.98 0.86, 1.11

Decreased appetite 37 1/0 37 3/0 NA NA

ALT increased 31 10/2 18 2/<1 1.74 1.40, 2.17

Hair colour changes 30 0/0 10 <1/0 NA NA

HFS 29 6/0 50 11/<1 0.59 0.50, 0.68

Taste alteration 26 <1/0 36 0/0 NA NA

Thrombocytopenia 10 2/<1 34 12/4 0.30 0.23, 0.40

*AE ≥30% in either arm; †2% of patients in pazopanib arm and 3% of patients in sunitinib arm had grade 5 AEs

ALT, alanine transaminase; AST, aspartate transaminase; HFS, hand–foot syndrome; NA, not applicable

TIVO-1 Trial: Phase III Head-to-Head Trial of Tivozanib Vs. Sorafenib

First head-to-head RCC registration trial vs. an active comparator – Primary end point: PFS – Secondary end points: OS, ORR, QOL

Treatment schedule (1 cycle = 4 wks) – Tivozanib: 1.5 mg/day for 3 wks, followed by 1-wk break – Sorafenib: 800 mg/day for 4 wks

Eligibility Requirements

Advanced clear cell RCC

Prior nephrectomy

No prior VEGF treatment

ECOG PS: 0–1

Tivozanib Extension Protocol

Tivozanib (n = 250)

Sorafenib (n = 250)

R A N D O M I Z E

1:1

Continue tivozanib

until PD

Continue sorafenib until PD

PD

QOL = quality of life. US NIH, 2011a, 2011b.

[TITLE]

Study design*

Previously untreated

metastatic RCC

R

A

N

D

O

M

I

Z

E

Axitinib 5 mg BID†

(n=192)

2:1

Sorafenib 400 mg BID

(n=96)

Randomization stratified by ECOG PS (0 vs 1).

* ClinicalTrials.gov: NCT00920816.

† Titrated stepwise to 7 mg BID and then 10 mg BID in patients without grade 3 or 4

(CTCAE v3.0) axitinib-related AEs for a consecutive 2-week period, unless BP >150/90 mmHg.

Hutson TE et al. Abstract No. 348, ASCO-GU 2013 26

Progression-free survival (IRC Assessment)

*Stratified by ECOG PS; assuming proportional hazards, HR <1 indicates a reduction in favor of axitinib

and HR >1 indicates a reduction in favor of sorafenib.

IRC = independent radiology committee; mPFS = median progression-free survival.

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0 0 2 4 6 8 10

Time (months)

12 14 16 18 20

PF

S (

pro

ba

bilit

y)

22 24

1-sided P=0.038

Stratified HR, 0.77*

(95% CI 0.56–1.05)

Axitinib

Sorafenib

No. events (%)

111 (58)

60 (63)

192 154 132 114 91 78 63 54 19 6 0

96 73 60 43 34 24 20 19 10 0 0

Patients at risk, n

Axitinib

Sorafenib

34

13

1

0

= censored for axitinib

= censored for sorafenib

27

mPFS, mo (95%CI)

10.1 (7.2–12.1)

6.5 (4.7–8.3)

Conclusions

Study did not achieve its primary endpoint statistically – Statistical design: HR=0.56 (high bar)

– Actual: HR=0.77 (95% CI 0.56–1.05);1-sided P=0.038 – PFS difference observed in subgroups vs sorafenib

Patients with nephrectomy: 10.3 vs 6.4 mo* (P=0.009) PS 0: 13.7 vs 6.6 mo† (P=0.022)

– ~90% patients from outside the US (variability in PS 0 vs 1)

First-line therapy with axitinib demonstrated – Numerically longer PFS (3.6-mo improvement) – Significantly higher ORR – Acceptable safety profile

OS data not yet mature * Unstratified HR, 0.67 (95% CI 0.47–0.93) † Unstratified HR, 0.64 (95% CI 0.42–0.99)

28 Hutson TE et al. Abstract No. 348, ASCO-GU 2013

Robust

evidence

and guidelines


Patient

characteristics

Experience

Patient

preference



Modelos Integrados de Predicción Pronóstica en CCR avanzado

Comorbidities Are Common

In Patients With RCC

• 54% of patients with kidney cancer have at

least one comorbidity.1

• 72% of patients ≥75 years of age with kidney

cancer have at least one comorbidity.1

• The most common comorbidities are heart

disease, hypertension, and diabetes.1

1. Coebergh JWW, et al. J Clin Epidemiol. 1999;52:1131–1136.

Extent of Comorbidities Correlates with OS in

RCC Patients Undergoing Nephrectomy

• Retrospective study of patients with RCC who underwent radical or partial nephrectomy (N = 697)

• Cormorbidities were scored based on the Adult Comorbidity Evaluation-27 (ACE-27) validated tool

• 75% of patients had at least 1 comorbidity

• Median follow-up was 36.5 months

• Overall survival for all patients at 1, 3, and 5 years was 92.0%, 75.3%, and 52.7%, respectively

Berger DA, et al. Urology. 2008;72(2):359–363.

1 0 0

8 0

6 0

4 0

2 0

0

0 1 2 3 4 5

P e

r c e n

t S

u r v

i v i n

g

D u r a t i o n ( Y e a r s )

N o n e

M i l d

M o d e r a t e

S e v e r e

Severe vs. None

Adjusted HR: 2.9

95% CI: 1.7-4.9

P < 0.0001

Multivariate models of associations between AEs and

survival in patients with mRCC on sunitinib Schedule 4/2

AE Endpoint

AE at any time point AE by the 12-week landmark

HR 95% CI p value* HR 95% CI p value*

Hypertension PFS

OS

0.29

0.30

0.22,

0.40

0.24,

0.43

<0.0001

<0.0001

–

0.65

–

0.51,

0.84

NS

0.0008

Hand–foot

syndrome

PFS

OS

0.75

0.58

0.60,

0.94

0.44,

0.77

0.0148

0.0001

–

0.67

–

0.46,

0.98

NS

0.0415

Asthenia/fatigue PFS

OS

0.49

0.72

0.38,

0.64

0.54,

0.96

<0.0001

0.0245

–

–

–

–

NS

NS *Wald chi-square test

Donskov F, et al. Presented at ESMO 2012; Abstract 785O

Results of a retrospective analysis of pooled data from 770 patients

Patient

preference

Experience

Patient

characteristics

Robust

evidence

and guidelines




PISCES Study

Pazopanib versus sunitinib patient preference study in treatment naïve advanced or metastatic renal cell carcinoma

(A randomised, double-blind, cross-over patient preference study of pazopanib versus sunitinib

in treatment-naïve locally advanced or metastatic renal cell carcinoma)

ONCE/PAZ/0049/12 Date of preparation:May 2012

2-week washout Period 2 Period 1 Off study

Patient choice of treatment to progression

Randomisation n=169

Sunitinib 50 mg 4/2, 10 weeks

Pazopanib 800 mg once daily, 10 weeks

Sunitinib 50 mg 4/2, 10 weeks

Study design1

Pazopanib

800 mg once daily, 10 weeks

• 1:1 randomisation Time (weeks)

0 12 22 10

Double-blind

• Both drugs were over-encapsulated

• Patients on sunitinib received placebo during 2-week ‘off-period’ 1. ClinicalTrials.gov. NCT01064310.

Pati

ents

(%

)

90 80 70 60 50 40 30 20 10 0

Primary endpoint: Patient preference for study treatments (Primary analysis population) 1 100

Preferred pazopanib Preferred sunitinib No preference

90% CI (for difference): 37.0-61.5; p<0.001 70% (n=80) 22% (n=25)

8% (n=9)

1. Escudier B, et al. ASCO 2012 oral presentation;abstract 4502.

*Modified MSKCC poor risk; †Stratification by country and nephrectomy status ‡SD 16 weeks; §p=0.0069

IFN 3 MU-18 MU (n=207)

CR + PR – 7%

CR + PR + SD‡ – 29%

Med. OS 7.3 months§

IFN 6 MU + TEM 15 mg QW

(n=210) CR + PR – 11%

CR + PR + SD – 41%

Med. OS 8.4 months

TEM 25 mg QW (n=209)

CR + PR – 9%

CR + PR + SD – 46%

Med. OS 10.9 months§

Randomize†

3/6 Poor Risk Features

• LDH >1.5 x ULN

• Hgb < LLN

• Ca++ (cor) >10

• KPS <70%

• DFI <1 year

• Multiple sites of metastases

Metastatic RCC (N=626)

Temsirolimus: Estudio Fase III de 1º línea en MSKCC-mal pronóstico

Parameter

IFN

Arm 1

(n=207)

TEMSR

Arm 2

(n=209)

TEMSR + IFN

Arm 3

(n=210)

Median survival (mos) 7.3 10.9 8.4

Comparisons Arm 2:Arm 1 Arm 3:Arm 1

Stratified log-rank p 0.0069 0.6912

Parameter

IFN

Arm 1

(n=207)

TEMSR

Arm 2

(n=209)

TEMSR + IFN

Arm 3

(n=210)

Median survival (mos) 7.3 10.9 8.4

Comparisons Arm 2:Arm 1 Arm 3:Arm 1

Stratified log-rank p 0.0069 0.6912

1.0

0.8

0.6

0.4

0.2

0

Su

rviv

al d

istr

ibu

tio

n f

un

cti

on

0 5 10 15 20 25 30 35Time to death

Arm 3: IFN + Temsirolimus

Arm 2: TemsirolimusArm 1: IFN

Hudes G et al. N Engl J Med. 2007;356:2271–2281.

2005-P

resent

Kane 2006

Median PFS: 1st Line Treatement in mRCC from

Pivotal Studies Progression Free Survival

BCS 2–3

Multiple studies Gore ASCO 2008 Torisel PI Nexavar PI

0 1 2 3 4 5 6 7 8 9 10 11 12 13141516

Time (months) Kane et al. Clin Cancer Res. 2006;12:7271, Gore et al. ASCO 2008, Nexavar PI, Figlin

et al. ASCO 2008, Escudier ASCO 2008

Tivozanib

INF-α alone

INF-α+ IL-2+5-FU Temsirolimus Sorafenib

3-5 5.3 5.5 5.7

EscudierASCO 2008 Figlin ASCO 2008 StembergASCO 2009

Bevacizumab + INF-α Sunitinib Pazopanib

Motzer 2012

10.2

11.0

11.1

12.7

Beyond the first Line:

Understanding resistance mechanisms can allow identification of optimal treatment strategies

Potential approaches to overcoming resistance include

Adjust dose or scheduling of TKI1,2

Switch from one TKI to another3

Switch from a TKI to an mTOR inhibitor4

Use of novel agents

Combination of traditional agents with new agents?

1Escudier B, et al. J Clin Oncol 2009; 2Escudier B, et al. J Clin Oncol 2009 3Rini BI, et al. J Clin Oncol 2009; 4Motzer RJ, et al. Lancet 2008

5Hainsworth JD, et al. J Clin Oncol 2010; 6Rini BI, et al ASCO GU 2010

AXIS1032: Axitinib pivotal trial in second-line setting

Primary endpoint: PFS

Rini BI, et al. Lancet 2011;378:1931–9

ECOG PS, Eastern Cooperative Oncology Group performance status; *Starting dose 5 mg BID with option for dose titration to 10 mg BID

Axitinib

5 mg BID*

Sorafenib 400 mg BID

n=723

R

A

N

D

O

M

I

S

E

1:1

Eligibility:

mRCC clear-cell histology

Failure of one first-line

regimen containing:

‒ Sunitinib

‒ Bevacizumab + IFN-α

‒ Temsirolimus, or

‒ Cytokines

Stratification by prior

regimen and ECOG PS

First Phase III, head-to-head study vs a targeted agent in second-line mRCC

Axitinib European SmPC

Axitinib* showed greater efficacy in extending mPFS vs

sorafenib

0 2 4 6 8 10 12 14 16 18 20

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

Time (months)

p< 0.0001 (log-rank)

Stratified HR 0.67

(95% CI, 0.56, 0.81)

Axitinib

Sorafenib

mPFS, mo 95% CI

6.8

4.7

6.4, 8.3

4.6, 6.3

PFS

(p

rob

abili

ty)

PFS in overall ITT population

90% power to show improvement in PFS using a one-sided log-rank test at a significance of 0.025 *Axitinib is indicated for advanced RCC after failure of prior treatment with sunitinib or a cytokine; ITT, intention-to-treat;

mPFS, median progression-free survival

OS: Overall population

43

Motzer R, et al. Cancer 2010

*Central radiology review

Switch from a tyrosine kinase inhibitor

to an mTOR inhibitor: RECORD-1

0 2 4 6 8 10 12 14

Pro

ba

bili

ty (

%) Log-rank P value <0.001

Everolimus (n=277)

Placebo (n=139)

HR=0.33

(95% CI: 0.25–0.43)

Median PFS

Everolimus: 4.90 months

Placebo: 1.87 months

PFS*

100

80

60

40

20

0

Months

OS

Pro

ba

bili

ty (

%)

100

80

60

40

20

0

0 2 4 6 8 10 12 14 16 18 20 22 24

Log-rank P value = 0.177

Everolimus (n=277)

Placebo (n=139)

HR=0.87

(95% CI: 0.65–1.17)

Median OS



Months

OS = overall survival; PFS = progression-free survival

RECORD-1: Phase III evidence for the sequence of

sunitinib or sorafenib followed by everolimus

HR = 0.34

(95% CI: 0.23–0.51)

Median PFS



PFS in patients with prior sunitinib treatment PFS in patients with prior sorafenib treatment

HR = 0.25

(95% CI: 0.16–0.42)

Median PFS



Log-rank P value = <0.001

Everolimus (n=81)

Placebo (n=43)

100

80

60

40

20

0

Pro

ba

bili

ty (

%)

Months

0 2 4 6 8 10 12 14

100

80

60

40

20

0

Pro

ba

bili

ty (

%)

Months

0 2 4 6 8 10 12 14

Patients at risk

Everolimus124 80 44 20 7 1 0 0

Placebo 60 15 8 2 0 0 0 0

81 63 43 23 15 7 1 0

43 23 6 3 2 0 0 0

Motzer R, et al. Cancer 2010; Escudier B, et al. ESMO 2008

Log-rank P value = <0.001

Everolimus (n=124)

Placebo (n=60)

RECORD-1: representative of second line?

In RECORD-1 almost 80% of patients were treated with everolimus third-line

or later1,2

First- line

Second- line

Third- line

Fourth-line

mTOR fifth- line

n=82

n=104

n=141

n=89

First- line

Second- line

Third- line

mTOR fourth-

line

First- line

Second- line

mTOR third- line

First- line

mTOR second-

line

79%

21%

1Zustovich F, et al. Crit Rev Oncol Hematol 2011;83:112-122; 2Motzer RJ, et al. Cancer 2010;18:4256–65

Beyond the second Line:

Understanding resistance mechanisms can allow identification of optimal treatment strategies

Potential approaches to overcoming resistance include

New pathways

Switch from one TKI to another3

Switch from a TKI to an mTOR inhibitor4

Combination of traditional agents with new agents?

Enhancing Immune Responsiveness

Ipilimumab is a human monoclonal antibody that blocks CTLA-4

CTLA-4 is an immune check point molecule that downregulates

pathways of T-cell activation

Ipilimumab

Fong L and Small E, J Clin Oncol 2008

APC APC APC

T cell T cell T cell

T-cell

activation

TCR

MHC

CD28

B7

TCR

MHC

CD28 B7

CTLA4

T-cell

inactivation

T-cell

activation A B C

CTLA4

Anti-CTLA4

mAb

CTLA4

Ipilimumab in mRCC

Phase II study of ipilimumab in patients with

mRCC

Patients received either 3 mg/kg

followed by 1 mg/kg or all doses

at 3 mg/kg every 3 weeks

Lower dose schedule

1/21 patients had a partial response

Higher dose schedule

5/40 patients had a partial response

Responses observed in patients

who had not responded to

IL-2 therapy previously

Toxicity

Grade 3/4 immune-mediated toxicity observed in 33%

of patients

Significant association between auto-immune events

and tumour regression was observed

Yang J et al. J Immunother 2007

Enhancing Immune Responsiveness

Programmed Death (PD)-1 pathway

PD-1 downregulates T-cell function upon binding to its ligand (PD-L1)

PD-L1 has been shown to be overexpressed in RCC

In patients with mRCC, overexpression of PD-L1 has been shown to

be associated with

Adverse pathology

Aggressive tumour behaviour

Poor survival

APC/

tumour

cell

T-cell T-cell

inactivation PD-1

PD-L1

Thompson RH, et al. Clin Cancer Res 2007

Increased B7H1 Expression in RCC Diminishes Survival

Thompson et al, 2006.

Resolving RCC Lytic Bone Metastasis in

Patient Treated With Anti-PD-1 (10 mg/kg)

3/25/08 4/14/09

B7H1 Control Ig

Responses may be

correlated with PD-

L1 expression

3/4 PRs in PDL-1+

tumors,

0/5 PDL-1 negative

Brahmer et al, 2010.

Phase III TKI258 (dovitinib)

Patients with advanced RCC, PD to prior VEGF and m-TOR targeted therapy

Dovitinib

n=275

-Primary end point: PFS -Prior Cytokines allowed

Study Design: International, Prospective, Randomized, Open-label, Multicenter

Sorafenib

n=275

RANDOMI Z A T I ON

1:1

3º Line Treatment

Phase III Anti-PD-1 study

Patients with advanced RCC, PD to prior 2 VEGF targeted therapy

Anti-PD-1

N=350

-Primary end point: PFS/OS -Prior Cytokines allowed

Study Design: International, Prospective, Randomized, Open-label, Multicenter

Everolimus

n=350

RANDOMI Z A T I ON

1:1

3º Line Treatment

Algoritmo CCRm – 2014? Setting Patients Therapy Options

First-line Favourable- or

intermediate-risk

Sunitinib

Pazopanib

Tivozanib ?

Beva - IFN-α

HD IL-2

Cytokines

Sorafenib

Poor-risk Temsirolimus Sunitinib

Second-line Prior cytokine Axitinib

Pazopanib

Sorafenib

Sunitinib

Prior VEGF–TKI Axitinib Sorafenib ?

Prior VEGF–TKI Everolimus Clinical trial

Adapted from EAU guidelines 2010, ESMO Clinical Recommendations 2012,

NCCN guidelines 2013 SOGUG 2010

Third-line Prior TKI – TKI Everolimus

Anti-PD1??

Clinical Trial

Prior TKI – mTOR Sorafenib/Dovitinib Clinical trial

2013 2014 2015

Dovitinib

Anti-PD1

Sunitinib (Adjuvant

Treatment)

Future Treatment options for metastatic RCC …

18

Possible areas of unmet medical need

Currently approved treatments are not curative, and Patients develop progressive disease – Evolving need for effective therapeutics with unique

mechanisms of action for patients who progress

Non–clear cell histologies – Few studies are available to determine efficacy

Biomarkers, new pathways, gene profile,

mechanisms of resistance !!!

Tipo Tratamiento: - Secuencial

- Individualización

Control Complicaciones

Tumorales

Tratamiento Integral

Manejo Efectos Adversos

Medicina Basada Evidencia

(Est.Clínicos) Uso Racional de

Recursos

Beneficio Clínico

Manejo Integral Multidisciplinar del Carcinoma Renal Avanzado

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