DEFINIENDO LA SECUENCIA ÓPTIMA DE TRATAMIENTO EN...
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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
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aliv
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0 1 2 3
Immunotherapy Targeted therapy Combination
+ = ?
Years 0 1 2 3
Years 0 1 2 3
Pe
rce
nt
aliv
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Pe
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nt
aliv
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Vemurafenib (N=336)
Dacarbazine (N=336)
Years 1 2 3 4
Pro
po
rtio
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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