DEFINIENDO LA SECUENCIA ÓPTIMA DE TRATAMIENTO EN …basesbiologicascancer.com/wp-content/uploads/2015/05/Presentaci… · SECUENCIA ÓPTIMA DE TRATAMIENTO EN MELANOMA AVANZADO BRAF+

MESA REDONDA 4

DEFINIENDO LA SECUENCIA ÓPTIMA DE TRATAMIENTO EN CÁNCER AVANZADO

MELANOMA

Salvador Martín Algarra

Clínica Universidad de Navarra

Pamplona

En los últimos años ha habido considerables avances en el conocimiento de la biología molecular del melanomay de los mecanismo de la respuesta inmune, que han permitido identificar nuevos

agentes que están cambiado los algoritmos terapéuticos en esta enfermedad.

•Actitud más proactiva a referir pacientes con melanoma avanzado a Oncología Médica.

•Estácambiado el perfil de pacientes.

Avances en terapias dirigidas e inmunoterapia de melanoma

• Aumento en el número de Ensayos Clínicos para Melanoma.

• Informacion y experiencia extrapolable a otras neoplasias.

Avances en terapias dirigidas e inmunoterapia de melanoma

Agentes Activos en Melanoma avanzado

• Ipilimumab

• Vemurafenib

• Trametinib

• Dabrafenib

• Pembrolizumab

• Nivolumab

+ Cobimetinib

+ Trametinib

• DTIC, Fotemustina, Temozolamida, Paclitaxel, Carboplatin, Bevacizumab… • IL-2, IF … • ILP…

• Radiocirugía

• RT Modulada

• Cirugía

Nab-Paclitaxel

Nuevos

• Imatinib …

Agentes Activos en Melanoma avanzado

• Ipilimumab en 1ª y 2ªlínea

• Vemurafenib

• Trametinib

• Dabrafenib

• Pembrolizumab UC tras Pr a Ipilimumab

• Nivolumab UC tras Pr a Ipilimumab

+ Cobimetinib (UC)

+ Trametinib (UC)

• DTIC, Fotemustina, Temozolamida, Paclitaxel, Carboplatin, Bevacizumab… • IL-2, IF … • ILP…

Nab-Paclitaxel

• Imatinib …

SECUENCIA ÓPTIMA DE TRATAMIENTO EN MELANOMA AVANZADO

Documentos de Consenso

Marquez I. et al

ESMO&EDF/EADO/EORTCSeptember 2012

• EDF, EADO y EORTC

• Eur J Cancer (C Garbe et al)

ESMO

Ann Oncol (R Dummer et al)

Both publications agree that....

• Current data are not mature and an definite algorithms for MM cannot be established.

• Therapeutic decisions in stage IV melanoma must be taken with a multidisciplinary perspective.

• This area is changing quickly.

• More data is needed to define the optimal sequence.

Garbe et al

La dosis aprobada de Ipilimumab es de 3 mg/kg en pacientes con melanoma avanzado previamente tratados

Searching for the Algorithm

•Mutation testingof tumour tissue (at least BRAF; CKIT in subtypes) is a

prerequisite for treatment decisions.

•BRAF mutated patients should be offered treatment with BRAF

inhibitors or experimental drugs blocking the MAP kinase and PI3K

pathways, preferably still in the context of clinical trials designed to

reduce the emergence of drug resistance.

Searching for the Algorithm

•Patients whose disease progresses on first-line treatment and with

health status of presumably six or more months should be offered

ipilimumabor other immunotherapies in the context of clinical trials as

they are made available.

•BRAFwtpatients and those progressive under BRAFi and

immunotherapies should be considered for Chemotherapy.

•c-KIT inhibitors may have a role in the small proportion of ckit mutant

melanomas

Aspects to consider:

• “It may be necessaryor even desirabletodeviatefromtheseguidelines in theinterestofspecificpatientsorunderspecialcircumstances.”

Aspects to consider in Immunotherapy

• PatientswithstablediseaseorinitialdiseaseprogressionafterIpilimumab may benefitwithprolongedsurvival. Unfortunately, no predictivebiomarkers are so far available.

• PD-1 antibodiesshowed in a largephase II trialhighefficacywithan ORR of 28% and a PFS rateof 41% after24weeks.

• Preliminaryevidencesuggeststhattheexpressionof PD-L1onthetumourtissue may selectforpatientswithanimproved response to PD-1 axisinhibitors.

Dummer et al

Dummer et al

Dummer et al. Determine mutational status in stage IV patients

Instrucciones no específicas

Recomendado

Trat

amie

nto

en

1ª

línea

Trat

amie

nto

en

2

ª/3

ª lín

ea

NRAS mutated BRAF mutated BRAF WT

Symptomatic, large tumor burden

Asymptomatic, small tumor burden

Vemurafenib

Ipilimumab ¿Vemurafenib?

1st line?

Ipilimumab ¿2nd line?

Inhibitor

Clínical Trial or Chx/Biochx?

Clínical Trial or Chx/Biochx?

Actualmente fuera de indicación

¿Ipilimumab? Ipilimumab

Ipilimumab is approved by EMA only on 2ªline

Conclusions

• Current recommendations are not definite and must be applied with judicious clinical criteria.

• Ipilimumab is active regardless mutational status (BRAF) and currently is approved by EMA in second line, although FDA and some guides also consider its use in first line.

• Future advances with immunotherapy (anti-PD1, anti PD-1L) as well as with targeted therapies (BRAF, MEK, c-KIT, RAS, PI3Ki, inhibitors ) will have a great impact in future consensus documents (2015?).

Srivastava N, McDermott D.Update on benefit of immunotherapy and targeted therapy in melanoma: the changing landscape. Cancer Manag Res. 2014 Jun 20;6:279-89.

.

Treatment algorithms in stage IV melanoma

Espinosa E, GrobJJ, Dummer R, Rutkowski P, Robert C, Gogas H, Kefford R, Eggermont AM, Martin Algarra S, Hauschild A, SchadendorfD.

Am J Ther. 2015 Jan-Feb;22(1):61-7

•A review of the recent key studies … performed, followed by a discussion in an expert forum…. to generate a therapeutic algorithm for stage IV melanoma.

• Genotyping for BRAF/ KIT should be performed before selection of therapy.

• Most BRAF-mutated melanoma patients and particularly those with a high tumor load,VemurafeniborDabrafenibare the treatment of choice.

• KIT inhibitors can be effective in KIT-mutant tumors, especially in those patients with mutations at exons 11 and 13.

• Ipilimumab is a good option for patients with nontargetable or nondetected mutations and those who progress under therapy with vemurafenib or a KIT inhibitor.

• There is still a role forchemotherapy either as first-line treatment in BRAF wild-type patients or as salvage therapy in second or third line…

• Participation inClinical Trialsis strongly encouraged, either in first or in subsequent lines.

.

Treatment algorithms in stage IV melanoma Espinosa E, GrobJJ, Dummer R, Rutkowski P, Robert C, Gogas H, Kefford R, Eggermont AM, Martin

Algarra S, Hauschild A, SchadendorfD. Am J Ther. 2015 Jan-Feb;22(1):61-7

• Más realista

• Más adecuada

• Más prometedora

SECUENCIA ÓPTIMA DE TRATAMIENTO EN MELANOMA

SECUENCIA ÓPTIMA DE TRATAMIENTO EN MELANOMA AVANZADO

• Más realista

SECUENCIA ÓPTIMA DE TRATAMIENTO EN MELANOMA AVANZADO

• BRAF

• Metástasis cerebrales

• LDH

• Karnosky/ECOG

• Volumen tumoral

• Cinética deprogresión

• Características del Paciente/Centro

• Aprobacion por organismos reguladores

• Resultados de ensayos clinicos

KIT

• Metastasis única resecable (PET/TC y RM SNC). • Paliación en situaciones singulares. • Enfermedad residual en respuesta mantenida. • ILP…

SECUENCIA ÓPTIMA DE TRATAMIENTO EN MELANOMA AVANZADO aa

Cirugía

• Metastasis SNC (Radiocirugía). • Paliación (dolor/compresion/sangrado). • Tras cirugía de metástasis (?). • …

SECUENCIA ÓPTIMA DE TRATAMIENTO EN MELANOMA AVANZADO

Radioterapia

• Vemurafenib

• Dabrafenib

• Ipilimumab

• Ensayo Clínico que incluya Nivolumab+/- Ipilimumab o Pembrolizumab.

+ Cobimetinib

+ Trametinib

SECUENCIA ÓPTIMA DE TRATAMIENTO EN MELANOMA AVANZADO BRAF+ con baja carga tumoral, ECOG/LDH normal, sin mts cerebrales

• Vemurafenib

• Dabrafenib

+ Cobimetinib

+ Trametinib

SECUENCIA ÓPTIMA DE TRATAMIENTO EN MELANOMA AVANZADO BRAF+ con alta carga tumoral, ECOG/LDH elevado, con mts cerebrales

GEM 12-02 Ipilimumab+Rtholocraneal

• Radioterapia SNC

• Quimioterapia (Fotemustina, Temozolamida, … )

• Ensayo Clínico que incluya Nivolumab+/- Ipilimumab o Pembrolizumab.

• Ipilimumab

• Quimioterapia

• Ensayo Clínico que incluya Nivolumab+/- Ipilimumab o Pembrolizumab.

SECUENCIA ÓPTIMA DE TRATAMIENTO EN MELANOMA AVANZADO BRAF wt

SECUENCIA ÓPTIMA DE TRATAMIENTO EN MELANOMA AVANZADO

• Más adecuada

SECUENCIA ÓPTIMA DE TRATAMIENTO EN MELANOMA AVANZADO

• Más prometedora

Maximizing clinical benefit by combining the 2 compounds or by smart sequencing strategies

35

Years

Pe

rce

nt

aliv

e

0 1 2 3

Immunotherapy Targeted therapy Combination

+ = ?

Years 0 1 2 3

Years 0 1 2 3

Pe

rce

nt

aliv

e

Pe

rce

nt

aliv

e

Vemurafenib (N=336)

Dacarbazine (N=336)

Years 1 2 3 4

Pro

po

rtio

n a

live

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0

Ipilimumab + gp100 (A) Ipilimumab alone (B) gp100 alone (C)

Clear increase in disease survival at 1 and 2y.

Long term survivors rate doubled

Ipilimumab improve Long Term Survival

Hodi, FS, et al. N Engl J Med 2010;363:711–723

Comparison HR P-value Arms A vs C 0.68 <0.001 Arms B vs C 0.66 0.003

Survival Rate

Ipilimumab + gp100

N=403 (95% CI)

Ipilimumab + placebo

N=137 (95% CI)

gp100 + placebo

N=136 (95% CI)

1 year 44% (0.39,0.49) 46% (0.37,0.54) 25% (0.18,0.33)

2 year 22% (0.17,0.26) 24% (0.16,0.32) 14% (0.08,0.2)

Curti BD. N Engl J Med 2014;371:1929-1930.

Comparison of Major Clinical End Points for BRAF Monotherapy with Combined BRAF and MEK Inhibition.

Survival End Points.

Robert C et al. N Engl J Med 2015;372:320-330

Robert C et al. N Engl J Med 2015. DOI: 10.1056/NEJMoa1503093

Kaplan–Meier Estimates of Progression-free and Overall Survival.

Combination&Sequential Studies with Ipilimumab

• Ipilimumab + RT (France)

• Ipilimumab + Fotemustine in brain metastasis patients (Italy)

• Ipilimumab + IL-2 (Germany)

• Ipilimumab + RT in brain metastasis patients (Spain)

• Ipilimumab + Low dose IFN as adyuvant thx (EADO)

• Ipilimumab + High dose IFN en neoadyuvant (HECOG)

• Ipilimumab + Vemurafenib (CA184-161)

Postow MA et al. N Engl J Med 2015;372:2006-2017.

• Inmunoterapia de combinación (Anti-PD1+ Otros: Anti CTLA4 Anti CD137….)

• En portadores de mutacion BRAF V600: BRAFi+MEKi

• Ensayo Clínico

SECUENCIA ÓPTIMA DE TRATAMIENTO EN MELANOMA AVANZADO

Adequate clinical and laboratory profiling

& New therapeutic options

= Optimize treatment strategies to achieve long-term

survival