Cezary Szczylik Klinika Onkologii Wojskowy Instytut...

Optymalizacja i inywidualizacja leczenia rozsianego raka nerkowokomórkowego. Czy umiemy dobrać leczenie indywidualne

Cezary SzczylikKlinika Onkologii

Wojskowy Instytut MedycznyV Pomorskie Spotkania Uroonkologiczne

Jastrzębia Góra 11-12.05.2012

Cytotoxic chemotherapy experiments performed1

IFN-α and high-dose IL-2 used for treatment of RCC in early 1980s

1980s 1995 1999 20042005/2006 2007 2009 2010

Postęp w leczeniu RCC: terapie systemowe- terapie celowane

1. Abeloff MD, et al. Clinical Oncology 3rd ed. Philadelphia, PA. 2. Cochrane Database SystRev. 2005(1):CD001425. 3. Costa LT, et al. Oncologist.2007;12:1404–1415. 4. Escudier B, et al. N Engl J Med 2007; 356:125–34 5. U.S. Food and Drug Administration (www.accessdata.fda.gov). 6. European Medicines Agency (www.emea.europa.eu)

High-dose IL-2 FDA approved2

IFN-α shows improved survival vs. hormonal therapy3

TARGET4:first evidence of PFS benefit with targeted therapy

Sorafenib: first targeted therapy licensed in the US (2005)5 Sunitinib approved in US (2006)5 Both licensed in the EU (2006)6

Temsirolimus and bevacizumab + IFN licensed5,6

Everolimus licensed in the US and EU5,6

Gemcitabine plus capecitabine or doxorubicin shows some efficacy but high toxicity3

1940s

Pazopanib EU 2010 licensed in the US5

2012 Axitinib, dovitinib

Targeted therapy licensed for the treatment of mRCC

NCCN Guidelines for the Treatment of Kidney Cancer1

Setting Category 1 Evidence2 Category 2 Evidence3

First-line therapy

Patients with relapsed or medically unresectable

Stage 4 renal cancer

Sunitinib (Clear cell histology)

Bevacizumab + IFN

(Clear cell histology) Pazopanib (Clear cell histology)

Sunitinib 2A (non-clear cell histology)

Temsirolimus 2A Sorafenib 2A (selected patients,

clear and non-clear cell histology) IFN 2B

High-dose IL-2 2A

Poor prognosis patientsonly

Temsirolimus (clear and non-clear cell

histology)

Second-line therapy

Prior cytokine Axitinib

Sorafenib Sunitinib

All 2 B: IFN, high-dose IL-2, bevacizumab2B

Temsirolimus 2A

Prior VEGFR inhibitor EverolimusSunitinib 2A, Sorafenib 2A,

Bevacizumab, Temsirolimus 2B

1. Kidney Cancer, NCCN v.2.2010 Clinical Practice Guidelines in Oncology; 2.Uniform NCCN consensus, based on high-level evidence, that the recommendation is appropriate; 3. 2A Uniform NCCN consensus, based on lower level evidence including clinical experience, that the recommendation is appropriate 2B Non-uniform NCCN consensus (but no major disagreement), based on lower level evidence including clinical experience, that the recommendation is appropriate.

Molecular pathways in RCC

ERKERK

MEKMEK

RasRas

RafRafmTORmTOR

4EBP14EBP1

EIF-4EEIF-4E

p70S6Kp70S6K

Cell growth, proliferation, angiogenesis

VEGFPDGFTGF-α

VEGFRPDGFREGFR

TSC1TSC1 TSC2TSC2

RaptorRaptor

Rheb

Activation of PI3K

AKTAKT

Proliferation, apoptosis, angiogenesis

ERKERK

4EBP14EBP1

EIF-4EEIF-4E

p70S6Kp70S6K

VEGFRPDGFREGFR

RhebActivation of PI3K

AKTAKTTSC1TSC1

TSC2TSC2

RasRas

HIF-α

HIF-β

HIF-α

HIF-β

RafRaf

MEKMEK

mTORmTORRaptorRaptor

VHLVHL

PTENPTENNF1NF1

LKB1LKB1AMPKAMPK

Tumour Suppressors: LKB1, NF1, PTEN, VHL, TSC1/TSC2 Oncogenes: Ras, AKT

Some other important actors

Adaptation de Altomare AD, Testa JR. Oncogene. 2005;24:7455-7464.

TIE2: an important player in angiogenesis in addition to the VEGF

signaling pathway

Othon Iliopoulos, MD

Assistant Professor of MedicineHarvard Medical School

Director, VHL Clinic, Massachusetts General HospitalCo-Leader, Dana-Farber/Harvard Cancer Center

Program in Kidney Cancer

Identification of Novel Therapeutic Targets in RCC

OR

How to deal with resistance to TKI

GENES regulated by HIF

VEGF Vascular Endothelial Growth Factor

Platelet Derived Growth Factor

Transforming Growth Factor-a

Fibroblast Growth Factor

Glucose transporter-1

Adenylate Kinase 3

Aldolase-A

Phosphoglyceratekinase 1

Phosphofructokinase-L

Lactose Dehydrogenase -A

EMT

Cytokine Receptor for SDF-12

Carbonic Anhydrase IXCarbonic Anhydrase XII

Matrix Metalloproteinase 2/9**

Tissue Inhibitor Metalloproteinase-1

Urokinase-type plasminogen activator

(Cell proliferation )

(Angiogenesis)

Metabolism)

(Metastasis)

(Matrix remodeling)

PDGF-B

TGF-a

FGF

C-MET

GLUT-1

AK-3

ALD-A

PGK-1

PFK-L

LDH-A

E-cadherin

CXCR4

CA IXCA XII

MMP-2/9

TIMP-1

uPA

TKI

HIF2a

Hypoxia

Vessel contraction

VEGF, VEGFRFGF, cMET ANG2, FGF, IL8 etc

60 target genes - 3 inhibited = 57

VHL

VEGFVEGFRFGF

cMETANG2FGFIL8 etc

Terapie celowane: więcej opcji w leczeniu zaawansowanego raka nerki

Phase III data

Agent/Class

Comparator Line of treatmentBenefit in PFS/OS

Main exclusion criteria

Sorafenib1Oral TKI

PlaceboCK treated

or CK unsuitableYes

Brain metastases, previous exposure to VEGF inhibitors

Sunitinib2 Oral TKI

IFN-α First line YesBrain metastases, previous systemic therapy, uncontrolled hypertension, cardiovascular events

Temsirolimus3IV mTOR inhibitor

IFN-αFirst line

poor risk onlyYes Previous systemic therapy

Bevacizumab + IFN-α4 IV anti-VEGF Ab

IFN-α First lineYes Previous systemic therapy, brain metastases,

uncontrolled hypertension, cardiovascular disease, recent major surgery, anti-coagulant medication

Everolimus5Oral mTOR inhibitor

Placebo ≥ Second lineYes Brain metastases, previous exposure to mTOR

inhibitors, uncontrolled medical conditions

Pazopanib6

Oral TKIPlacebo

First line or

CK treated Yes

Brain metastases, poorly controlled hypertension, cardiovascular or cerebrovascular events, prior exposure to targeted therapy

1. Escudier B, et al. N Engl J Med 2007;356:125–34. 2. Motzer RJ, et al. N Engl J Med 2007;356:115–24.3. Hudes G, et al. N Engl J Med 2007;356:2271–81. 4. Escudier B, et al. Lancet. 2007;370:2103–11.5. Motzer RJ, et al. Cancer 2010;116:4256–65. 6. Sternberg CN, et al. J Clin Oncol 2010;28:1061–8.CK = cytokine

mRCC w 2012: 7 leków do wyboru i kolejne w drodze!

Zakres możliwości w leczeniu RCC dramatycznie się zmienił,od chwili akceptacji 7 leków(sorafenib, sunitinib, temsirolimus, bevacizumab+IFN, everolimus, pazopanib, axitinib)

Od małego wyboru..do „bycia zepsutym” możliowściami wyboru?

Jednakże żaden z leków nie leczy wszystkich pacjentów

Jakie więc wybrać leczenie i dla którego pacjenta?

Które leczenie i w jakim etapie leczenia?

RCC treatment algorithm

Setting Therapy category 1 evidence

Therapycategory 2 evidence

Treatment naïve patients

MSKCC risk: good or intermediate

SunitinibBevacizumab + IFN-α

Pazopanib

Sorafenib*TemserolimusHigh dose IL-2

MSKCC risk: poor Temsirolimus

Treatment-refractory patients (≥second-line)

Cytokine refractory SorafenibPazopanibSunitinib

SorafenibSuinitinib

TemsirolimusBevacizumab

IFN-αIL2TKI refractory Everolimus

Prior mTor inhibitors No data

Adopted from Hudes GU ASCO 2010Systemic Therapies in Advanced Renal Cell Cancer: Current Status; Speaker: Christopher W. Ryan, MDR

MSKCC=Memorial Sloan Kettering Cancer Centre; IFN -α= interferon IL=interleukin; TKI=tyrosine kinase inhibitor*Cytokine unsuitable

Brak dowodów poziomu I nie dowodzi braku aktywności

Pytania Czy wspólne algorytmy (NCCN, EAU) są Ci przydatne w Twojej praktyce?

Czy wszystkie przypadki pacjentów których przyjmujesz są reprezentowani w tych wskazówkach

• Pacjenci z różnymi miejscami przerzutowymi np. przerzuty do mózgu

• Starsi pacjenci

• A inne typy histologiczne?

Jakie inne czynniki są dla Ciebie ważne przy wyborze terapii?

Problemy z przenoszeniem wyników badań fazy III do klinicznego procesu decyzyjnego

Mniejszość pacjentów leczonych w badaniach klinicznych z nowotworami jest w wieku ≤65 lat

Większość nowotworów obserwujemy u pacjentów ≥65 lat

Kryteria włączenianajcz esciej wykluczają schorzenia współistniejące/ dysfunkcje które są częste w wieku podeszłym

Pacjenci wymagający innego leczenia (np.warfaryny) rzadko są włączani do badań(eg. warfarin)

W badaniach klinicznych grupy pacjentów są homogenne

Aapro M, et al. Oncologist 2005;10:198–204

Study Patient

Real patientReal

patient

Real patient

Study Patient

Study Patient

vs

Populacje pacjentów nie włączonych - niespełniających kryteriów włączenia

Phase III study Krytria wyłączeniaSorafenib (TARGET)1

Ekspozycja na inne TKI

Sunitinib2Uprzednie leczenie innymi tki

Temsirolimus3 Uprzednie leczenie systemowe

Bevacizumab + IFN4 Uprzednie leczenie systemowe

Duze zabiegi chirurgiczne przed leczenieLeczenie przeciwzakrzepowe

1. Escudier B, et al. N Engl J Med 2007;356:125–34 2. Motzer RJ, et al. N Engl J Med 2007;356:115–24 3. Hudes G, et al. N Engl J Med 2007;356:2271–81

4. Escudier B, et al. Lancet 2007;370:2103–11

Przerzuty do mózgu

Przerzuty do mózgu

Perzuty do mózgu

Choroby układu krążenia CVD

CVD

Niekontrolowane nadciśnienie

Niekontrolowane nadciśnienie

Definiujemy podejście terapeutyczne skoncentrowane na pacjencie

15 March 2008

Expert roundtable meeting (Amsterdam) Cezary Szczylik (Poland) Joaquim Bellmunt (Spain) Camillo Porta (Italy) Peter Mulders (Netherlands)

Identification of patient, disease and treatment characteristics that should be considered when identifying optimal therapy for individual patients

Które parametry potencjalnie wpływają do wybory kliniczne?

Disease characteristics Sites and number of metastases

Tumor histology

MSKCC risk

Patient characteristics

Treatment aim and treatment history

– Age

– Cardiac risk– Renal impairment– General comorbidities/overall

health of patient

– Treatment-naïve patients– Failure of prior cytokines or

targeted therapy– Objective of treatment

Proponowany schemat: czynniki do rozważenia przed zaleceniem leczenia RCC

* Including controlled arrhythmiasCK = cytokine; mets = metastases PS = performance status

choroba

Good Intermediate PoorMSKCC

0–1 2–3 ≥ 4No. met sites

Lymph nodes Liver Lung Bone BrainSite of mets

Histology Clear cell Non-clear cell

leczenieRealistic aim

HistoryNaive Prior treatment

Suitable for CK Unsuitable for CK Prior CK Prior targeted therapy

pacjent

<65/70 years ≥65/70 yearsAge

0 1 2PS 3

ComorbiditiesHaematological

Controlled hypertensionRenal Cirrhosis

Wound healing

DiabetesFatigue Thyroid

Cardiac disease ≤grade 2* >grade 2*

Disease stabilization

Maintain quality of life

Prolongsurvival

Tumour shrinkage

Bellmunt J, et al. BJU Int 2010; doi: 10.1111/j.1464-410X.2010.09829.x.Porta C, et al. Cancer Treat Rev 2010;36:16–23.

Consensus on suitability of patients for sorafenib


DISEASE





TREATMENTRealistic aim



PATIENT


0 1 2PS 3



Wound healing





Prolongsurvival

Tumour shrinkage

Low Medium High

A new patient-focused approach to the treatment of metastatic renalcell carcinoma: establishing customized treatment options.

Joaquim Bellmunt, Tim Eisen, Cezary Szczylik, Peter Mulders and Camillo PortaBJU Int 2010; doi: 10.1111/j.1464-410X.2010.09829.x.

Disease characeristics: MSKCC


DISEASE








PATIENT


0 1 2PS 3



Wound healing





Prolongsurvival

Tumour shrinkage


Disease factors and treatment response: MSKCC risk score MSKCC risk factors

Low Karnofsky performance status (<80%)

High lactate dehydrogenase level (>1.5 × ULN)

Low serum haemoglobin level (<LLN)

High corrected serum calcium concentration (>10 mg/dL)

No prior nephrectomy

Interval from diagnosis to treatment (before 1990, 1990 or later)

Motzer R, et al. J Clin Oncol 2004;22:454–63MSKCC = Memorial Sloan-Kettering Cancer Center; ULN = Upper limit of normal; LLN = Lower limit of normal

1990 or later

35%

23%

42%

53%

22%

25%

Favourable (0 risk factors)Intermediate (1 risk factor)Poor (3, or more risk factors)

% of RCC patients

Before 1990

45%

26%

28%

Patient characteristics: patient’s age


DISEASE








PATIENT


0 1 2PS 3



Wound healing





Prolongsurvival

Tumour shrinkage


Wiek pacjenta jest bardzo ważnym czynnikiem w procesie decyzyjnym

Starsi pacjenci są najczęściej nielicznie reprezentowani w badaniach

klinicznych nad rakiem

Większość zachorowań na raka obserwujemy u pacjentów ≥65 rż

Kryteria wyłączenia najczęściej zawierają współistniejące choroby i

dysfunkcje typowe dla starszych chorych

Wyniki badań klinicznych na młodszych pacjentów nie zawsze

można stosować do starszych chorych

Aapro M et al. Oncologist 2005;10:198-204.

Połowa pacjentów z RCC ma w momencie diagnozy więcej niż 65 lat

Ries LAG, et al. SEER Cancer Statistics Review, 1975–2005; http://seer.cancer.gov/csr/1975_2005/index.html. Accessed Oct 2010

0

5

10

15

20

25

30

<20 20-34 35-44 45-54 55-64 65-74 75-84 85+

Age group (years)

Pe

rce

nt

of

pa

tie

nts

Diagnosis

Mortality

US kidney and renal pelvis cancer 2001–2005Age at diagnosis and mortality

Median age at diagnosis = 65 years

Czynniki wpływające na decyzje u pacjentów powyżej 65 rż?

Tolerability Potentially increased impact of toxicity even at low grades1

Comorbidities Up to 2 out of 3 cancer patients ≥70 yrs old have an average of 3 comorbidities2

Comedication Altered pharmacokinetics may increase toxicity or reduce efficacy1

Psychology Elderly patients may be less (or more) accepting of side effects (with implications for treatment compliance)1

1. Bellmunt J, et al. Crit Rev Oncol Hematol 2008;69:64–72 2. Extermann M. Cancer Control 2007;14:13–22

Need For A Patient-Focused Approach: Comorbidities Patients may present with a range of comorbidities

Hypertension, GI disorders, and diabetes are frequent in elderly patients1

Toxicities associated with some targeted agents may exacerbate comorbiditiesSuch toxicities include cardiovascular AEs or hyperglycemia2-8

Drug interactions with ongoing therapies can cause additional toxicities8

Targeted agents prescribed to patients with comorbidities should have favorable toxicity profiles

1. Bellmunt, et al. Crit Rev Oncol Hematol. 2009;69. 2. Telli, et al. Ann Oncol. 2008;19. 3. Chu, et al. Lancet. 2007;370. 4. Sutent EU [SmPC]. January 2011. 5. Hudes, et al. N Engl J Med. 2007;356.

6. Motzer, et al. Lancet. 2008;372. 7. Wu, et al. Lancet Oncol. 2008;9. 8. Bellmunt, et al. BJU Int. 2010: doi: 10.1111/j.1464-410X.2010.09829.x. [Epub].

To jak leczyć?

Pazopanib versus placebo: progression-free survival1

30

6292

7614

15938

290145

Number at risk, nPazopanib

Placebo

1.0

0.8

0.6

0.4

0.2

0.0

Pro

port

ion

pro

gre

ssio

n-f

ree

Placebo 4.2Pazopanib 9.2Hazard ratio (95% CI) 0.46 (0.34, 0.62)p value (1-sided) <0.0001

Median PFS (months)

1. Sternberg et al. J Clin Oncol 2010;DOI:10.1200/JCO.2009.23.9764.

54% reduction in

risk of progression or

death with pazopanib treatment

compared with placebo

In the overall study population, PFS was significantly greater in pazopanib- versus placebo-treated patients (p<0.0001)

Time (month)

Pazopanib

Placebo

0 5 15 2010

Progression-free survival in the treatment-naïve subpopulation1,2

31

1.0

0.8

0.6

0.4

0.2

0.0

0 5 15 2010

Pazopanib

Placebo

Placebo 2.8Pazopanib 11.1Hazard ratio (95% CI) 0.40 (0.27, 0.60)p value (1-sided)

Median PFS (months)

In the treatment-naïve subpopulation, PFS was significantly greater in pazopanib- versus placebo-treated patients (p<0.0001)

1112

397

8422

15578

Number at risk, nPazopanib

Placebo

Time (month)

60% reduction in

risk of progression or

death with pazopanib treatment

compared with placebo

<0.0001

1. Sternberg et al. J Clin Oncol 2010;DOI:10.1200/JCO.2009.23.9764.

Pro

port

ion

pro

gre

ssio

n-f

ree

Sunitinib: Phase II EFFECT Trial

Data cut-off was August 2010 1:1 randomizationstratified by risk factors

based on publishedMSKCC data [Motzer,

2002]

Sunitinib was continued in

6-week cycles until disease progression,

unacceptable toxicity, or up to 2 years

Motzer, et al. Slides presented at: ASCO GU Cancers Symposium; February 17–19, 2011; Orlando, FL.

PFS: 8.5 months

PFS: 7.0 months

When Should The “Most Potent” or Strongest

Agent Be Used?

A preclinical study showed that “potent angiogenesis inhibition ... can alter the natural history of tumours by increasing invasion and metastasis”1–3

In clinical practice, “... ‘‘more’’ of a VEGF inhibitor, in terms of dose or potency, has not consistently been ‘‘better’’ for patient outcome...”4

1. Porta C et al. Eur J Clin Med Oncol 2011;2:Epub ahead of print; 2. Pàez-Ribes M et al. Cancer Cell 2009;15:220–31;3. Ebos JML et al. Cancer Cell 2009;15:232–9; 4. Loges S et al. Cancer Cell 2009;15:167–70.

Hypotheses For Mechanisms of Increased Tumor Invasiveness Following VEGF-Targeted Therapy

Loges S, et al. Cancer Cell 2009;15:167–170.

Prolongation of PFSShortening of OS

VEGF-targeted therapy

Disease stabilization or inhibition benefit for progression-free survival

e.g. hypoxia tolerance, rescue angiogenesis

Increased metastases

Increased tumour invasiveness

Tumour cell

Host tissue

Blood vessel

Lymphatic vessel

Proportion of Patients Who Receive 2nd-LineTherapy May Depend On the 1st-Line Therapy (2)

Porta C et al. BMC Cancer 2011;11:105.

†Patients could have had more than one reason for discontinuing treatment*Sorafenib (Nexavar) is indicated for the treatment of patients with advanced renal cell carcinoma who have failed prior interferon-alpha or interleukin-2 based therapy

or are considered unsuitable for such therapy. (EU SmPC Nexavar, January 2011)

Review of medical records for 145 patients treated with sorafenib or sunitinib as 1st-line TKI between September 2005 and July 2008

First-Line Discontinued Treatment† Second-Line*

15/66 (23%)Sorafenib

0 (0%)Temsirolimus

51/66 (77%) did not receive 2nd-line

angiogenesis inhibitors

21/51 (41%)Sunitinib

28/51 (55%) did not receive 2nd-line

angiogenesis inhibitors

2/51 (4%)Temsirolimus

51 (85%) → 35 (69%) for PD→ 03 (6%) for AEs→ 14 (27%) other

66 (78%) → 53 (80%) for PD→ 10 (15%) for AEs→ 09 (14%) other

SorafenibN = 60

SunitinibN = 85

1. Porta, et al. BJU Int. 2010. [In press]. 2. Tamaskar, et al. J Urol. 2008;179. 3. Merseburger, et al. Expert Rev Anticancer Ther. 2009;9. 4. Richter, et al. Onkologie. 2008;31(suppl 4): Abstr V684. 5. Zimmermann, et al. Oncology. 2009;76. 6. Eichelberg, et al. Eur Urol. 2008;54(6):1373–78. 7. Choueiri TK et al. BJU Int 2010;105:1247–54;

8. Choueiri TK et al. ESMO 2008; abstract 593P. 9. Dudek, et al. Cancer. 2009;115. 10. Sablin, et al. J Urol. 2009;182. 11. Wang, et al. Poster P-7143 presented at ECCO 15–34th ESMO Multidisciplinary Congress; September

20–24, 2009; Berlin, Germany. 12. Buchler, et al. Ann Oncol. 2011; doi:10.1093/annonc/mdr065. 13. Herrmann E et al. World J Urol 2011;doi:10.1007/s00345-011-0673-4;

Optimizing Sequential Therapy with Sorafeniband Sunitinib: Retrospective Studies¶

36

n = 22

n = 4n = 5

n = 53n = 28

n = 30

n = 5n = 5

n = 90n = 99

n = 29n = 20

n = 31n = 7

n = 64n = 55

n = 68n = 22

4.8

11.5 4.9

4.48.6

7.85.9

6.05.1

6.43.9

8.7 4.4

8.57.9 9.8

8.9

8.47.8 4.2

7.9

5.713.2d

2.8d

8.6 12.48.1 5.3

14.5e18.0e

5.1 4.95.4 4.7

Eichelberg6c

Zimmerman5

Tamaskar2a

Sablin10

Richter3,4a

Porta1

Dudek9b

Choueiri7,8c

Buchler12

Wang11c

Nexavar

Sunitinib

a Mean PFS

b Median TTP

c Median treatment

duration

d Calculated

by subtracting

first median from overall

median

e Overall PFS

15 20Median PFS (months)

0 5 10 25

15.4e12.1e Herrmann13

n = 54n = 33

1st-line PFS was generally similar between sorafenib (4.8–11.5 months) and sunitinib (5.1–8.5 months)

Overall PFS was generally longer with the sequence sorafenib→sunitinib than the sequence sunitinib → sorafenib




Growing Body of Evidence Suggests Sustained Disease Control and No Cross Resistance withSequential TKIs

37

n = 22

n = 4n = 5

n = 53n = 28

n = 30

n = 5n = 5

n = 90n = 99

n = 29n = 20

n = 31n = 7

n = 64n = 55

n = 68n = 22

4.8

11.5 4.9

4.48.6

7.85.9

6.05.1

6.43.9

8.7 4.4

8.57.9 9.8

8.9

8.47.8 4.2

7.9

5.713.2d

2.8d

8.6 12.48.1 5.3

14.5e18.0e

5.1 4.95.4 4.7

Eichelberg6c

Zimmerman5

Tamaskar2a

Sablin10

Richter3,4a

Porta1

Dudek9b

Choueiri7,8c

Buchler12

Wang11c

Nexavar

Sunitinib

a Mean PFS

b Median TTP

c Median treatment

duration

d Calculated

by subtracting


median

e Overall PFS


0 5 10 25


n = 54n = 33


Overall PFS was generally longer with the sequence sorafenib→sunitinib than the sequence sunitinib→sorafenib




Growing Body of Evidence Suggests Sustained Disease Control and No Cross Resistance withSequential TKIs

38

n = 22

n = 4n = 5

n = 53n = 28

n = 30

n = 5n = 5

n = 90n = 99

n = 29n = 20

n = 31n = 7

n = 64n = 55

n = 68n = 22

4.8

11.5 4.9

4.48.6

7.85.9

6.05.1

6.43.9

8.7 4.4

8.57.9 9.8

8.9

8.47.8 4.2

7.9

5.713.2d

2.8d

8.6 12.48.1 5.3

14.5e18.0e

5.1 4.95.4 4.7

Eichelberg6c

Zimmerman5

Tamaskar2a

Sablin10

Richter3,4a

Porta1

Dudek9b

Choueiri7,8c

Buchler12

Wang11c

Nexavar

Sunitinib

a Mean PFS

b Median TTP

c Median treatment

duration

d Calculated

by subtracting


median

e Overall PFS


0 5 10 25


n = 54n = 33



Retrospective Studies – Conclusions Continued VEGF(R) inhibition with a 2nd TKI provided an additional

PFS benefit in patients who progressed on a 1st-line TKI

1st-line PFS was generally similar between sorafenib(4.8–11.5 months) and sunitinib (5.1–8.5 months)


Median PFS for sorafenib after previous sunitinib therapy was in the same range as that for everolimus post-sunitinib in the RECORD-1 trial (3.9 months)1

These findings suggest limited cross-resistance between TKIs

This may be related to differences between TKIs in terms of target profiles

1. Motzer RJ et al. Cancer 2010;116:4256–65.

TKI → TKI Strategy Is Supported by MultipleStudies in Almost 1,500 Patients

40

Number of Patients

Sunitinib → Nexavar Nexavar → Sunitinib

Rini et al. Phase III AXIS1 195 - -

Porta et al. (retrospective)2 99 90

Tamaskar (retrospective)3 5 4

Richter (retrospective)4,5 5 5

Zimmermann (retrospective)6 – 22

Eichelberg (retrospective)7 – 30

Choueiri (retrospective)8 7 31

Dudek (retrospective)9 20 29

Sablin (retrospective)10 22 68

Wang et al. (retrospective)11 53 23

Elfiky (retrospective)12 – 62

Buchler et al. (retrospective registry)13 64 55

Ambring et al. (retrospective registry)14 123 261

EU-ARCCS (expanded access)15 69 - -

Garcia et al. (Phase II prospective)17 27 - -

Di Lorenzo (Phase II prospective)18 52 - -

Mancuso et al. (Phase II prospective)19 13 - -

Sepulveda et al. (prospective)20 20 - -

Shepard et al. (prospective)21 18 - -

Subtotal 792 680

Total 1,472

1. Rini B et al. J Clin Oncol 2011;29 (Suppl; Abstr 4503). 2. Porta, et al. BJU Int. 2010. [In press]. 3. Tamaskar, et al. J Urol. 2008;179. 4. Merseburger, et al. Expert Rev Anticancer Ther. 2009;9. 5. Richter, et al. Onkologie. 2008;31(Suppl 4): Abstr V684. 6. Zimmermann, et al. Oncology. 2009;76. 7. Eichelberg, et al. Eur Urol. 2008;54(6):1373–78. 8. Choueiri TK et al. BJU Int 2010;105:1247–54. 9. Dudek, et al. Cancer. 2009;115. 10. Sablin, et al. J Urol.

2009;182. 11. Wang, et al. Poster P-7143 presented at ECCO 15–34th ESMO Multidisciplinary Congress; September 20–24, 2009; Berlin, Germany. 12. Elfiky, et al. Urol Oncol. 2010; doi:10.1016/j.urolonc.2010.01.008. [Epub]. 13. Buchler, et al. Ann Oncol. 2011; doi:10.1093/annonc/mdr065. 14. Ambring AE, J Clin Oncol 29: 2011 (Suppl; Abstr 4600). 15. Beck et al. Ann Oncol. 2011: doi:10.1093/annonc/mdq651. [Epub]. 16. Vickers, et al. Urol. 2010;76(2). 15.

16. Garcia J, et al. Cancer 2010;116(23): 5383–90. 17. Di Lorenzo, et al. J Clin Oncol. 2009;27(27). 18. Mancuso, et al. J Clin Oncol. 2009;27: Abstr e16027. 19. Sepulveda, et al. J Clin Oncol. 2008;26: Abstr 16100. 21. Shepard DR, et al. J Clin Oncol 2008;26(Suppl.) [Abstract 5123].

Phase III AXIS Trial Data Supports TKI-TKI Sequencing Strategy

Study Design/Methods

Key Findings

Axitinib starting dose of 5 mg BID to 7 mg BID to 10 mg BID, as tolerated

RANDOMIZE

Patients:• Metastatic RCC with clear cell

histology• One failed prior systemic

first-line regimen for mRCC• ECOG PS 0 or 1

Sorafenib 400 mg PO BID Continuous

Dosing

Ind

epe

nd

ent

Rev

iew

Co

mm

itte

e

Independent Central Review Axitinib (n=361) Sorafenib (n=362)

Median PFS, months [95% CI] 6.7 months [6.3-8.6] 4.7 months [4.6-5.6]

HR (p-value) 0.665; p<0.0001

Median PFS Subgroup Analysis

Prior-Cytokine 12.1 months 6.5 months

HR (p-value) 0.464; p<0.0001

Prior-Sunitinib 4.8 months 3.4 months

HR (p-value) 0.741; p=0.011

Treatment-refractory

mRCC*

*Prior therapies (first-line) included: 54% sunitinib, 35% cytokine, 8% bevacizumab, and 3% temsirolimus

Rini B et al. J Clin Oncol 2011;29 (Suppl; Abstr 4503)

http://onlinelibrary.wiley.com/doi/10.1002/cncr.v116:23/issuetoc

Retrospective Analysis: Similar 1st-Line PFSfor So and Su – SoSu Favored Over SuSo

Key Findings

104 (55%) pts had received prior systemic therapy, mostly with cytokines

Median PFS 1st TKI: 8.4 mos (So ) vs. 7.8 mos (Su); HR: 1.05 [95% CI: 0.78-1.40], P=0.7583

Median PFS after 2nd TKI: 7.9 mos (So-Su) vs. 4.2 mos (Su-So); HR: 0.54 [95% CI: 0.39-0.74], P=0.0002

Only ECOG PS significantly associated with duration of PFS

Porta C, Paglino C. BJU Intl 2011;5: 747-48

Median PFS:7.9 Months

*PD during the 1st and 2nd TKI was determined by radiologic assessment (RECIST) ~ every 12 weeks.

Median PFS:4.2 Months

n=99

n=90Sunitinib

Sorafenib

• Retrospective chart analysis of pts treated with So-Su or Su-So between 03/04 and 04/09 at 12 centers across Italy

• Pts treated under EU EAPs or, following market approval of the TKIs, in general clinical practice

• Pts treated with any other agent between So and Su were excluded

• Primary objective: PFS 1st and 2nd TKI*

1st Line Therapy 2nd Line Therapy

Sorafenib8.4 Months

Sunitinib7.8 Months

Czech Registry Data: Similar Duration of 1st-LineSo and Su Treatment

Key Findings

Buchler T, et al. Ann Oncol 2011: doi: 10.1093/annonc/mdr065 [Epub].

*No predefined number of cycles, treatment continued until PD severe toxicity. **Dose modifications were at the discretion of attending

medical oncologist.

n=122

n=138

Sunitinib4.3 mos

Sorafenib3.2 mos

• Retrospective analysis• RENIS database on all mRCC pts treated with

targeted agents in 13 designated hospitals or hospital networks where biological anti-neoplastic treatments funded by public health insurance according to Czech healthcare regulations

• Pts treated between 05/06 and 10/10, whose data entered in database until 10/09

• Until 10/09, neither So or Su were reimbursed, so all mRCC pts required to undergo a clinical trial of other treatment, mostly conventional dose IFN


Sorafenib*5.7 mos

Sunitinib*6.3 mos

Median Time:13 mosGrp A

Grp BMedian Time:

12 mos

So -Su Su - So

Overall PFS 17.7 mos 18.8 mos

OS at 1 year 83% 84%

TIME ON THERAPY

Swedish Registry Data: Similar Duration of 1st-LineSo and Su Treatment - SoSu Favored Over SuSo (1/2)

Key Findings

Median time on 1st-line therapy was 148 days (So) vs. 138 days (Su)

Median treatment duration was 252 days (So-Sun ) vs. 234 days (Su-So)

Median time to death was 398 days (So-Su) vs. 347 days for Su-So

The corresponding difference for the risk of death was significantly different (p=0.0278) in favor of So (vs. Su) as the 1st-line treatment

Ambring AE, J Clin Oncol 29: 2011 (Suppl; Abstr 4600)

Sorafenib148 Days

Sunitinib138 Days

n=123

n=261

Sunitinib

Sorafenib

• Retrospective analysis• Register data from 3 Swedish national registers

‒The Cancer Register ‒The Prescribed Drug Register‒The Cause of Death Register

• Pts diagnosed with RCC between 01/1980 and 12/2008 and treated with one or both of the studied drugs between 07/2005 and 12/2009 were eligible for the study

• 1st line treatment and monotherapy were defined as one treatment group (1st line treatment/monotherapy) and sequential therapy as another. The two treatment groups were analyzed separately


n=43

n=54

Total Time: 252 Days

Total Time: 234 Days

mTOR inhibitor mTORinhibitor

2nd TKI

mTORinhibitor

2nd TKI

But Still Open Question: When to Switch, andWhat To Switch To?

2nd TKI

Long-term benefit before

failure No response

Short-term benefit before

failure Intolerance

Adapted from Porta C et al. Eur J Clin Med Oncol 2011;2(4);Epub ahead of print

NEW

DAT

A A

T A

SCO

-GU

!1st TKI

No Cross-resistance Between TKIs: Tom Baker CancerCenter Retrospective Study — TTF in Second-Line Therapya

Class Drug n

VEGF-targeted NexavarSunitinibBevacizumabAxitinib

8093118

mTOR inhibitors

TemsirolimusEverolimus

213

a After adjustment for MSKCC prognostic factors (favorable, intermediate, poor), the hazard ratio for TTF favored VEGF-targeted treatment in the second-line setting.

46 Vickers, et al. Urol. 2010;76(2).

International mRCC Database Consortium Data Questions Benefit Between Second TKI or mTOR

Second-Line PFS VEGF vs. mTOR

aHeng, et al. J Clin Oncol. 2009.47 Heng, et al. Slides presented at the 2011 ASCO GU Cancers Symposium; February 17–19, 2011;

Orlando, FL.

International mRCC Database Consortium Data Questions Benefit Between Second TKI or mTOR

Second-Line Overall Survival VEGF vs. mTOR

48 Heng, et al. Slides presented at the 2011 ASCO GU Cancers Symposium; February 17–19, 2011; Orlando, FL.

aHeng, et al. J Clin Oncol. 2009.

1. Motzer RJ et al. Cancer 2010;116:4256–65; 2. Hutson et al. ECCO/ESMO 2009;abstract P7136.

0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0

Hazard ratio

HR

Overall population1 0.33 < 0.001416

n p

Median PFS (months)

Eve Pbo

4.9 1.9

NR, not reported

Everolimus Was As Effective After Two TKIsAs It Was After One TKI

Median PFS was longest when everolimus was received after treatment with sorafenib

Prior sunitinib1 0.34 184 NR

Prior sorafenib1 0.25 124 NR

Prior sorafenib and sunitinib1

0.32 108 NR

Prior bevacizumab and sorafenib +/or sunitinib2

0.30 38 0.001

5.9

3.9

4.0

5.8

2.8

1.8

1.8

1.8

79%

Everolimus: Phase III RECORD-1 Trial — Prior Therapy Detail

50

21%

Patients received a median of two prior anti-neoplastic medications; 79% of patients enrolled in the Phase III RECORD-1 trial received everolimus third-line or later.

First-LineAgent

First-LineAgent

First-LineAgent

First-LineAgent

Second-LineAgent

Second-LineAgent

Second-LineAgent

Third-LineAgent

Third-LineAgent

Fourth-LineAgent n = 82

n = 104

n = 141

n = 89mTOR as

Second-LineAgent

mTOR asThird-Line

Agent

mTOR asFourth-Line

Agent

mTOR asFifth-Line

Agent

Motzer, et al. Cancer. 2010;116.

Everolimus Is As Effective After Two TKIs AsAfter One: PFS by Prior Nexavar and Sunitinib Treatment

Kliknij, aby edytować style wzorca tekstuDrugi poziomTrzeci poziom

○ Czwarty poziomPiąty poziom

51 Escudier, et al. Slides presented at: 2008 ESMO Congress; September 12–16, 2008; Stockholm, Sweden.

Prospective Studies Will Help To Identify theOptimum Treatment Sequence For Each Patient (1)

SorafenibSunitinib

• mRCC patients• Treatment-naïve• Stratification by

MSKCC risk score

Sorafenib SunitinibSWITCH1(Phase III)

n = 3461o endpoint PFS

mTORSunitinib

• mRCC patients• Treatment-naïve• Karnofsky PS >70

mTOR SunitinibRECORD 32(Phase II)


1. www.clinicaltrials.gov NCT00732914. 2. www.clinicaltrials.gov NCT00903175. 3. www.clinicaltrials.gov NCT00474786. 4. www.clinicaltrials.gov NCT00502307

Study 4043(Phase III)

• mRCC patients• Previous treatment with sunitinib• No other previous therapy• Stratification

• Duration of response to sunitinib therapy; MSKCC risk score; histology; nephrectomy

Temsirolimus

Sorafenib


• 0 or 1 previous therapy (CT, HT or CK)• No prior VEGF-directed therapy• Stratification:

• Geographic region• No. of prior therapies (0 or 1)• No. of metastatic sites/organs involved

(1 or ≥2)

Tivozanib

Sorafenib

TIVO-14(Phase III)


Przyszłość w leczeniu raka nerkowokomórkowego

Lepsze zrozumienie biologii molekularnej dla losów przyszłych terapii

Aktywne kontynuowanie badań nad

– Nowymi lekami i ich kombinacjami

– Leczeniem sekwencyjnym

– Eskalacją dawki

– Rolą chirurgii

– Leczeniem neo-adjuwantowym i adjuwantowym

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