Daniel Castellano Oncología Médica. Unidad de Tumores Genito-Urinarios

Hospital Universitario 12 de Octubre I + 12 Research Institute

Actualización en el tratamiento de Cáncer Renal

Avanzado

epidemiología

2-3% del total de tumores malignos Edad media de aparición: 65 años

epidemiología

-Tabaquismo - Obesidad - Hipertensión arterial - Otros (menos claros):

- - - -

Exposición a tóxicos (asbestos) Enfermedad renal crónica – diálisis Poliquistosis renal Infección crónica por hepatitis C

Factores Pronósticos

• Síndrome Von Hippel-Lindau se caracteriza por mutación del gen VHL y desarrollo de tumores vasculares incluido CCR.

• La función normal del gen VHL (pVHL) es ayudar a destruir HIFa dentro de la célula.

• Mutación del genVHL (90% somática) conduce a una pVHL modificada no funcionante que permite incremento de niveles intracel. de HIFa y b.

• Sobre-expresión de HIFa induce expresión de genes hipoxia tisular.

• Sobre-expresión consecuente de VEGF, PDGF,TGF promueve angiogenesis tumoral y proliferación.

Rini, et al. Lancet Oncol. 2009;10:992-1000.

Pazopanib

MSKCC criteria

Karnofsky PS <80

Low serum hemoglobin

High corrected calcium

High LDH

Time from diagnosis to treatment <1 year

Motzer RJ, et al. J Clin Oncol 2002; Hudes G, et al. N Engl J Med 2007

MSKCC Risk prognostic model for RCC

MSKCC Risk prognostic model for RCC

= Grupo Buen Pronóstico = Grupo Intermedio Pronóstico

= Grupo Mal Pronóstico

Motzer RJ, et al. J Clin Oncol 2002; Hudes G, et al. N Engl J Med 2007

aRCC, advanced renal cell carcinoma; FDA, US Food and Drug Administration; IFN-α, interferon α; IL-2, interleukin-2; mTOR, mammalian target of rapamycin; VEGF, vascular endothelial growth factor. *Approved by the FDA in RCC. 1. Escudier B et al. N Engl J Med. 2007;356:125-134. 2. Motzer RJ et al. N Engl J Med. 2007;356:115-124. 3. Hudes G et al. N Engl J Med. 2007;356:2271-2281. 4. Motzer RJ et al. Lancet. 2008;372:449-456. 5. Escudier B et al. Lancet. 2007;370:2103-2111. 6. Rini BI et al. J Clin Oncol. 2008;26:5422-5428. 7. Sternberg CN et al. J Clin Oncol. 2010;28:1061-1068. 8. Rini BI et al. Lancet. 2011;378:1931-1939. 9. Motzer RJ et al. N Engl J Med. 2015;373(19):1803-1813.

IFN-α

1992–

2005

High-dose IL-2

Cytokines

Pazopanib7

Temsirolimus3

Sorafenib1

Everolimus4

Axitinib8

Bevacizumab + IFN-α5,6

Sunitinib2

2009 2010 2007 2011 2008 2012

VEGF- and mTOR-Targeted therapies (based on FDA approval dates)

2006 2016

Nivolumab9*

Investigational therapies

Nivolumab + Ipilimumab?

2018

Cabozantinib*

2018+

Lenvatinib*

Atezolizumab + Bevacizumab?

Avelumab + Axitinib

Pembro + Axitinib

The Evolving Treatment Landscape of RCC

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

Modelos Integrados de Predicción Pronóstica en CCR avanzado

Grupo Buen Pronóstico Grupo Intermedio Pronóstico Grupo Mal Pronóstico

MSKCC criteria

Karnofsky PS <80

Low serum hemoglobin

High corrected calcium

High LDH

Time from diagnosis to treatment <1 year

5

VEGFR-2 VEGFR-1

PDGFR-α VEGFR-3 PDGFR-ß c-Kit Flt-3

Overview of TKI´s agents in mRCC 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

ESMO Guidelines 2015

Patterns of tumor progression on VEGF or VEGFR inhibitors

Chan

ge in

Tum

or

Mea

sure

men

ts (

%)

Chan

ge in

Tum

or

Mea

sure

men

ts (

%)

Chan

ge in

Tum

or

Mea

sure

men

ts (

%)

Primary refractory Early progressors Late progressors

Group A Group B Group C

Trial TARGET[1]

Experimental Arm Sorafenib

Control Arm Placebo

Study Eligibility 2L, after systemic tx

N 903

ORR, % PR: 10% vs 2%*

mPFS, mo 5.5 vs 2.8*

mOS, mo 19.3 vs 15.9

INTORSECT[2] Temsirolimus Sorafenib 2L, after sunitinib 512 8% vs 8% 4.3 vs 3.9 12.3 vs 16.6*†

RECORD-1[3] VEG105192[4,5] AXIS[6,7]

Everolimus Pazopanib Axitinib

Placebo Placebo Sorafenib

2L, after systemic tx 1L/2L 2L, after systemic tx

416 435 723

PR: 1.8% vs 0% 30% vs 3%* PR: 19% vs 9%*

4.9 vs 1.9* 9.2 vs 4.2* 6.8 vs 4.7*

14.8 vs 14.4 22.9 vs 20.5 20.1 vs 19.2

1. 2. 3. 4. 5. 6. 7.

• Despite significant mPFS improvements, mOS changes were generally not significant[1-6] Escudier B et al. N Engl J Med. 2007;356(2):125-134. Hutson TE et al. J Clin Oncol. 2014;32(8):760-767. Motzer RJ et al. Cancer. 2010;116(18):4256-4265. Sternberg CN et al. Eur J Cancer. 2013;49(6):1287-1296. Sternberg CN et al. J Clin Oncol. 2010;28(6):1061-1068. Motzer RJ et al. Lancet Oncol. 2013;14(6):552-562. INLYTA. Summary of product characteristics.

Recommended targeted agents for second-line treatment: Results from pivotal trials

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

> RR of axitinib in comparison with sorafenib

Mejor tasa de respuesta % Axitinib Sorafenib

Respuesta Parcial* Estabilización de la enfermedad Progresión de la enfermedad Indeterminado

19.4 49.9 21.6 6.1

9.4 54.4 21.0 11.6

Risk ratio (95% CI) 2.1 (1.4–3.0)

*Axitinib vs. sorafenib: P = 0.0001

Rini B, et al. ASCO 2011

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

(pro

babi

lity)

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

For Internal Use Only

AXIS Study: PFS by Prior Regimen

Prior Treatment Regimen

Axitinib (n = 361)

Sorafenib (n = 362) HR* P

Cytokines (n = 251)

IRC 12.1 6.5 0.464 < 0.0001

Investigator 12.0 8.3 0.636 0.005 Sunitinib (n = 389)

IRC 4.8 3.4 0.741 0.011 Investigator 6.5 4.5 0.636 0.0002

Temsirolimus (n = 24) IRC 10.1 5.3 0.511 0.143 Investigator 2.6 5.7 1.210 0.634

Bevacizumab (n = 59) IRC 4.2 4.7 1.147 0.637 Investigator 6.5 4.5 0.753 0.213

22

*One-sided log-rank test stratified by ECOG PS. Rini BI et al. Lancet. 2011;378(9807):1931-1939.

23

Everolimus + BSC (n=272)

Placebo + BSC (n=138)

Si hay progresión

A L E A T O R I Z A C I Ó

NN

2:1

• CCR metastático de células claras

• 1 o 2 regímenes previos de VEGFR-TKI

1er Análisis interino 2º Análisis interino Análisis final =

N=416

Motzer RJ, et al. Lancet. 2008; Escudier B, et al. ESMO 2008; Motzer RJ, et al. ASCO GU 2009

RECORD-1: Resultados (I)

SLP (todos los pacientes)

1.0

0.8

0.6

0.4

0.2

0

Pro

porc

ión

sin

prog

resi

ón

Tiempo meses 0 2 4 6 8 10 12 14

Pacientes en riesgo Everolimus 277 192 115 51 26 10 1 0 Placebo 139 47 15 6 2 0 0 0

Mediana de SLP (meses) Everolimus: 4.90 Placebo: 1.87 HR=0.33 (95% IC: 0.25–0.43) Log-rank P=<0.001 Everolimus Placebo

SG (todos los pacientes)

1.0

0.8

0.6

0.4

0.2

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

Pacientes en riesgo Everolimus 227 267 240 204 164 155 131 101 61 30 6 0 0 Placebo 139 131 117 100 88 74 56 43 27 13 3 0 0

Mediana SG (meses) Everolimus: 14.78 Placebo: 14.39 HR=0.87 (95% IC: 0.65–1.17) Log-rank P=<0.001 Everolimus Placebo

Pro

porc

ión

sin

prog

resi

ón

Tiempo meses

BSC = mejor tratamiento de soporte

For Internal Use Only

RECORD-1 Subgroup Analysis: 1 or 2 Previous VEGFr-TKIs

Calvo E et al. Eur J Cancer. 2012;48:333-339.

100

80

60

40

20

0

1 2 3 4 0 5 6 7 8 9 10 1 1 12 13 14

188 143 121 87 205 71 43 36 22 19 8 6 1 0 0

Number of patients at risk Everolimus

Time, months

Prob

abili

ty, %

Everolimus (n = 205), 1 previous VEGFr-TKI Everolimus (n = 72), 2 previous VEGFr-TKIs

67 49 44 28 72 21 8 7 4 3 2 2 0 0 0 Everolimus

One previous VEGFr-TKI: 5.4 months everolimus vs 1.9 months placebo (HR, 0.32; 95% CI, 0.24–0.43; P < 0.001). Two previous VEGFr-TKIs: 4.0 months everolimus vs 1.8 months placebo (HR, 0.32; 95% CI, 0.19–0.54; P < 0.001).

Median PFS:

24

E07080- VEGFR2/FGFR inhibitor

Stratification factors:

•

•

Hemoglobin (normal vs low) Corrected serum calcium (≥ vs < 10 mg/dL)

Key eligibility criteria: •Advanced or metastatic RCC

•Measurable disease

•Progression on/after 1 prior VEGF-targeted therapy •Progression within 9 mos of stopping prior treatment •ECOG PS ≤1

10 mg PO qd

Study Design

Lenvatinib 18 mg PO qd

+

Everolimus

5 mg PO qd

Lenvatinib

24 mg PO qd

Everolimus

Patients were treated until: • Disease progression

• Unacceptable toxicity

R A N D O M I Z E

Patient Characteristics and Prior Therapy

Lenvatinib/Everolimus (n = 51)

Lenvatinib (n = 52)

Everolimus (n = 50)

MSKCC risk group, %

Favorable Intermediate Poor

24 37 39

21 35 44

24 38 38

Prior VEGF-targeted therapy*, %

Sunitinib Pazopanib Sorafenib Other

71 18 2 10

67 25 0 8

56 26 4 14

*Lenvatinib/Everolimus total sum exceeds 100% due to rounding In total, 5 patients had prior checkpoint inhibitor therapy and 14 patients had prior cytokine therapy

Prog

ress

ion-

free

Sur

viva

l

Number at risk Lenvatinib/Everolimus Lenvatinib Everolimus

51 52 50

41 41 29

27 29 15

23 20 11

16 11 7

10 6 3

5 4 1

1 1 0

0 0 0

Primary Endpoint: Prog.-free Survival Median, mos (95% CI)

Lenvatinib/Everolimus 14.6 (5.9–20.1)

Lenvatinib Everolimus

7.4 (5.6–10.2)

5.5 (3.5–7.1)

1.0

0.8 0.6 0.4

0.2 0.0

Time (mos) 0 3 6 9 12 15 18 21 24

Lenvatinib/Everolimus vs Everolimus HR 0.40 (95% CI 0.24–0.68); P < 0.001 Lenvatinib vs Everolimus HR 0.61 (95% CI 0.38–0.98); P = 0.048

Summary of Efficacy

Lenvatinib/Everolimus (n = 51)

Lenvatinib (n = 52)

Everolimus (n = 50)

Progression-free survival

Median (mo) 95% CI Benefit vs everolimus Objective response rate, % 95% CI Benefit vs everolimus

14.6 5.9–20.1 P < 0.001 43 29–58 P < 0.001

7.4 5.6–10.2 P = 0.048 27 16–41 P = 0.007

5.5 3.5–7.1 NA 6 1–17 NA

Overall survival (updated)

Median (mo) 95% CI Benefit vs everolimus

25.5 16.4–NE P = 0.024

19.1 13.6–26.2 P = 0.118

15.4 11.8–19.6 NA

NA, not applicable; NE, not estimable.

METEOR: Phase III study of second-line treatment with cabozantinib vs everolimus in mRCC

• • • •

Primary endpoints: PFS Secondary endpoints: OS, ORR Exploratory endpoints: patient-reported outcomes, biomarkers, safety, PK Stratification: MSKCC risk group, number prior VEGFR TKI

RA ND O M I SA T I ON

1. www.clinicaltrials.gov (NCT01865747); 2. http://www.meteorclinicaltrial.com

Eligibility1,2

mRCC with clear cell component Mensurable disease

Progression on prior VEGFR TKI within 6 mon of enrollment No limit to the number of prior therapies PD-1/PD-L1 allowed

Brain metastases allowed if treated

N=650

Cabozantinib 60 mg po daily

(n~325) Everolimus 10 mg po daily (n~325) No cross-over allowed

Escudier B, et al. ASCO GU 2016

Escudier B, et al. ASCO GU 2016

METEOR: PFS in Subgroups (independent radiology review committee)

Escudier B, et al. ASCO GU 2016

METEOR: All cause adverse events

METEOR: Phase III study of second-line treatment with cabozantinib vs everolimus in mRCC

Escudier B, et al. ASCO GU 2016

New agents in clinical development for RCC

Novel agent Target /MoA Combined with Status Presenting author

Abstract Nº

Aflibercept (AVE0005)

VEGF-A SINGLE AGENT Phase 2 completed

Pili 4549

Buparlisip (BKM120)

PI3K Plus bevacizumab Phase 1 completed

Mc Kay 4559

CRLX101 HIF, topo-I Plus bevacizumab Phase 2 ongoing

Keefe, Voss 4543, TPS4579

Dalantercept ALK1 Plus axitinib Phase 2 ongoing

Voss 4567, TPS4583

Lenvatinib (E7080)

VEGFR2, FGFR, PDGFR

Plus everolimus Phase 2 completed

Motzer 4506

LY2510924 CXCR4 Plus sunitinib Phase 2 completed

Hainsworth 4547

RX-0201 AKT1 Plus everolimus Phase 1 completed

Peterson TPS4580

Tivantinib MET Plus erlotinib Phase 2 complete

Twardowski 4523

TRC 105 Endoglin Plus bevacizumab Phase 2 negative

Dorff 4542

Targeted Immunotherapy

Tumor antigens released by tumor cells

Tumor antigens presented to T cells T cells are

activated and proliferate

T cells recognize tumor antigens

T cells kill tumor cells

The T-cell antitumor response

APC = antigen-presenting cell. Andersen MH, et al. J Invest Dermatol. 2006;126:32–41; Pardoll DM. Nat Rev Cancer. 2012;11:252–264; Mellman I, et al. Nature. 2011;480:480–489; Heemskerk B, et al. EMBO J. 2013;32:194–203; Boudreau JE, et al. Mol Ther. 2011;19:841–853; Janeway CA, et al. Immunobiology: The Immune System in Health and Disease. 6th ed. New York, NY: Garland Science; 2004.

1

4

2 3

5

Tumor cell

APC

Inactive T cell

Activated T cell

Activated T cell

Tumor cell

Tumor cell

Tumors use complex, overlapping mechanisms to evade and suppress the immune system

APC = antigen-presenting cell; MHC = major histocompatibility complex; TGF-ß = tumor growth factor-ß. Drake CG, et al. Adv Immunol. 2006;90:51–81; Vesely MD, et al. Annu Rev Immunol. 2011;29:235–271.

Inhibition of tumor antigen presentation

e.g. down regulation of MHC I

1 APC

Recruitment of immunosuppressive cell

types e.g. T-reg

4

Regulatory T cell

Secretion of immunosuppressive factors

e.g. TGF-ß

2

Tumor cell

Inhibition of attack by immune cells

e.g. disruption of T-cell checkpoint pathways

3

Inactive T cell

Regulating the T-cell immune response

T-cell responses are regulated through a complex balance of inhibitory (‘checkpoint’) and activating signals

Tumors can dysregulate checkpoint and activating pathways, and consequently the immune response

Targeting checkpoint and activating pathways is an evolving approach to cancer therapy, designed to promote an immune response

The image shows only a selection of the receptors/pathways involved. CD = cluster of differentiation; CTLA-4 = cytotoxic T-lymphocyte antigen-4; LAG-3 = lymphocyte-activation gene-3;

PD-1 = programmed cell death-1; TIM-3 = T-cell immunoglobulin domain and mucin domain-3. Adapted from Mellman I, et al. Nature. 2011;480:481–489; Pardoll DM. Nat Rev Cancer. 2012;12:252–264.

PD-1

CTLA-4

Inhibitory receptors

Activating receptors

TIM-3

LAG-3

Antagonistic (blocking) antibodies

Agonistic antibodies

T-cell stimulation

CD28

OX40

CD137

PD-1/PD-L1 Inhibitors Currently in Clinical Development Target Agent

Nivolumab

(MDX1106, BMS936558)

Class IgG4 fully human Ab

KD

3 nM

PD-1 PD-L1

Pembrolizumab (MK-3475) Pidilizumab (CT-011) AMP-224 BMS935559 (MDX-1105) MPDL3280A MEDI4736 MSB0010718C

IgG4 engineered humanized Ab IgG1 humanized Ab Fc-PD-L2 fusion protein IgG4 fully human Ab IgG1 engineered fully human Ab IgG1 engineered fully human Ab NA

29 pM - - - - - -

43

Study design

Previously treated mRCC

Stratification factors

Region MSKCC risk group

Number of prior anti-angiogenic therapies

Nivolumab 3 mg/kg intravenously

every two weeks

Everolimus 10 mg orally once daily

Ran

dom

ize

1:1

• Patients were treated until progression or intolerable toxicity occurred • Treatment beyond progression was permitted if drug was tolerated and

clinical benefit was noted MSKCC, Memorial Sloan-Kettering Cancer Center.

OS: Prior therapy

Nivolumab Everolimus

Favors

Subgroup

Nivolumab Events/patients

Everolimus Events/patients

Hazard ratio (95% CI)

Prior therapy Sunitinib Pazopanib

123/257 53/126

138/261 79/136

Months on first-line therapy <6 ≥6

61/110 122/300

81/130 134/281

Prior anti-angiogenic therapies 1 2

144/317 37/90

162/312 53/99

0 1 2

Targeted therapy sequencing in RCC

Novel treatment options with different mechanisms of action are needed

Sunitinib

Pazopanib

Everolimus

Axitinib

First-line Second-line Nivolumab

Cabozantinib

Lenvatinib?

Escudier B et al. Ann Oncol. 2014;25(suppl 3):iii49-iii56.

* Sunitinib is first option for non-clear cell RCC

*Temsirolimus is approved for poor risk pts

*

*

Current treatment landscape: anti-VEGF agents and mTOR inhibitors

2nd-

line

1s

t-lin

e

Months

Median OS

Sunitinib vs. IFN-α Motzer et al. JCO 2009

Pazopanib vs. sunitinib Motzer et al. NEJM 2013

Bev + IFN-α vs. IFN-α + placebo Escudier et al. JCO 2010

Pazopanib vs. placebo Sternberg et al. EJC 2013

Temsirolimus vs. IFN-α Hudes et al. NEJM 2007

Temsirolimus vs. sorafenib Hutson et al. JCO 2014

Sorafenib vs. placebo Escudier et al. JCO 2009

Everolimus vs. placebo Motzer et al. Cancer 2010

Axitinib vs. sorafenib Motzer et al. Lancet Oncol 2013

HR 0.82; P = 0.051

HR 0.91; P = 0.221

HR 0.91

HR 0.73; P = 0.008

HR 0.86; P = 0.129

HR 0.88; P = 0.146 HR 0.87; P = 0.162

HR 0.97; P = 0.374

HR 1.31; P = 0.010

Agent under investigation Comparator

¿ Que hemos aprendido en la última década de CCR?

• 1.- A clasificar histopatológicamente los pacientes.

• 2.- A agruparlos/clasificarlos por grupos de riesgo y OS.

• 3.- Son tumores proangiogénicos donde funcionan todos los fármacos antiangiogénicos

• 4.- La secuenciación de fármacos es el gold-estándar en la enfermedad avanzada.

• 5.- Un buen manejo de la toxicidad y comorbilidades de los pacientes es clave para su mejor OS

• 6.- La nueva Inmunoterapia abre nuevas líneas de investigación prometedoras en CCR

• 7.- Quedan muchas preguntas por resolver como la ausencia de biomarcadores, terapias mas eficaces en tumores no células claras y mejoras en calidad de vida.