Post on 29-Apr-2018
SIMPOSIO EDUCACIONAL MELANOMA ¿CUÁL ES EL PAPEL ACTUAL DE LA
QUIMIOTERAPIA?
Luis de la Cruz Merino
Sº Oncología Médica
HUVMacarena (Sevilla)
Melanoma: Enfermedad Avanzada
INTRODUCCIÓN
TRATAMIENTO SISTÉMICO CLÁSICO √ MONOTERAPIA √ POLIQUIMIOTERAPIA √ INMUNOQUIMIOTERAPIA
ABRAXANE
CONSIDERACIONES FINALES
INTRODUCCIÓN
-Incidencia y mortalidad anuales en Europa: 62.000 / 13.800
Ferlay J, Autier P, Boniol M, Heanue M, Colombet M, Boyle P. Estimates of the
cancer incidence and mortality in Europe in 2006. Ann Oncol 2007; 18: 581-92
-Incidencia esperada en población 1/68
-Supervivencia media melanoma avanzado 6-9 meses
-Sólo 5% de largos supervivientes
Tradicionalmente considerado poco quimiosensible
Potencial antigénico/inmunogénico: regresiones espontáneas, asociación
fenómenos autoinmunes-mejor pronóstico, TIL, neoantígenos
(melanA/MART-1, tirosinasa, gp-100,etc)
MMM según última edición TNM…
TRATAMIENTO SISTÉMICO CLÁSICO
Tratamiento sistémico
Tasas de respuesta < 20%
DTIC, Temozolamida, Nitrosoureas (Fotemustina)
Cisplatino y otras
Subgrupos con mejor pronóstico: metástasis cutáneas, PB,etc
DTIC sigue siendo el estándar a comparar:
√ TRO 15-25% TRC < 5% MDR 5-6 meses
Inmunomoduladores: IL-2 e IFN α-2b, TRO 10-20%
Mejores resultados IL-2 a altas dosis en bolo: 7% largos supervivientes
(Atkins Cancer J Sci Am 2000)
VARIOS AGENTES, ACTIVIDAD MODESTA…
Tratamiento sistémico
Middleton et al JCO 2000
305 pax TMZ vs DTIC
*SV mediana 7.7 vs 6.4 meses (P 0.054)
SLP 1.9 vs 1.5 meses(p .012)
TMZ mejor tolerado y beneficio QoL
(QLQ C-30 EORTC)
ENSAYO NEGATIVO
Avril et al JCO 2004
229 pax FTM vs DTIC
*TRO 15,2% vs 6.8% (p .043)
SV mediana 7.3 vs 5.6 meses (P 0,067)
Mayor toxicidad hematológica grupo
Fotemustina (G 3-4)
No diferencias QoL
ENSAYO POSITIVO
Tratamiento sistémico
Metanálisis Cancer 2003. TMX no aporta beneficio en TRO y SG
Los esquemas de combinación TRO sin impacto en SG
- ´80 combinaciones. Legha-CVD, Dartmouth-CBDT - Estudios fase II resultados favorables
Tratamiento sistémico
Metaanálisis Melanoma Research 2001 Huncharek 3273 pax de 20 estudios
Combinaciones presentan un 23% TRO sin impacto SG
2010: NINGÚN TRATAMIENTO INCREMENTO SG RESPECTO A DTIC
a partir de 2010…….
RESPUESTA INMUNE
RUTA MAP-KINASAS
Hodi 2010
Hodi 2010
NUEVOS QT ABRAXANE
ABRAXANE
Phase 3 Study of
nab®-Paclitaxel vs Dacarbazine in
Chemotherapy-naïve Patients with
Metastatic Malignant Melanoma
Evan M. Hersh,1 Michele Del Vecchio,2 Michael P. Brown,3 Richard
Kefford,4 Carmen Loquai,5 Alessandro Testori,6 Shailender Bhatia,7
Ralf Gutzmer,8 Andrew Haydon,9 Caroline Robert,10 Alicia Clawson,11
Ileana Elias,11 Markus F Renschler,11 Axel Hauschild12
1 Arizona Cancer Center, Tucson, AZ, USA ; 2 Istituto Nazionale Tumori, Milano, Italy; 3 Royal Adelaide Hospital, Australia; 4
Westmead Hospital and Melanoma Institude, Australia; 5 Universitätsmedizin Mainz, Germany; 6 Istituto Europeo di Oncologia,
Milano, Italy; 7 Seattle Cancer Care Alliance, USA; 8 Medizinische Hochschule Hannover, Germany; 9 Alfred Hospital,
Melbourne, Australia; 10 IGR Centre de Lutte Contre le Canc, Villejuif, France; 11 Celgene, Summit, NJ, USA; 12
Universitätsklinkum Schleswig-Holstein, Kiel, Germany
Hersh, et al. Phase 3 Study of nab® -Paclitaxel vs Dacarbazine in Chemotherapy-naïve Patients with Metastatic Malignant Melanoma. Presented at: The Society of Melanoma Reserach; November 8-11, 2012; Los Angeles, CA.
nab-Paclitaxel: Phase I and II Studies
nab-Paclitaxel, 30-min IV infusion, weekly 3 of 4 weeks
Phase 1, Advanced Solid Tumors [4]
(14 Melanoma pts)
80-200 mg/m2 weekly
N = 39
DCR, % 38
The 150 mg/m2 dose level was well tolerated in lightly pretreated patients
Phase 2, Metastatic Melanoma [5] 150 mg/m2Chemo-naïve N = 37
PR, %
DCR, %
PFS, median month
OS, median month
22
49
4.5
9.6
• No premedication; No special tubing; No acute toxicities typical of taxanes
• While cremophor-paclitaxel [1,2] or docosahexaenoic acid-paclitaxel [3] produced limited clinical benefit, nab-paclitaxel produced promising efficacy:
1. Walker, Melanoma Res, 2005
2. Pfugfelder, Plos Once, 2011
3. Bedikian, Ann Oncol, 2011
4. Nyman, JCO, 2005
5. Hersh, Cancer. 2010
DCR, disease control rate; OS, overall survival; PFS, progression-free survival; PR, partial response
Hersh, et al. Phase 3 Study of nab® -Paclitaxel vs Dacarbazine in Chemotherapy-naïve Patients with Metastatic Malignant Melanoma. Presented at: The Society of Melanoma Reserach; November 8-11, 2012; Los Angeles, CA.
BRIM 3
Median OS for vemurafenib confirmed to be better than for DTIC
Preferred Termnab-Paclitaxel
(n = 257)
Dacarbazine
(n = 258)
Patients with at least 1 TRAE, %Patients with at least 1 serious TRAE, %
509
287
Hematologic Adverse events, %* Neutropenia
Leukopenia Lymphocytopenia
Thrombocytopenia Anemia
20
128
02
10
711
65
Nonhematologic Adverse Events, %* Peripheral Neuropathy**
Fatigue Alopecia
25
85
0
20
Neuropathy, median days Time to Onset
Time to Improvement by 1 grade
101
2867
-
--
* Except for lymphocytopenia, all events P < 0.05** All but 2 neuropathy cases were grade 3
Hersh, et al. Phase 3 Study of nab® -Paclitaxel vs Dacarbazine in Chemotherapy-naïve Patients with Metastatic Malignant Melanoma. Presented at: The Society of Melanoma Reserach; November 8-11, 2012; Los Angeles, CA.
CA033
A Phase III Trial of nab-Paclitaxel vs
Dacarbazine in Chemotherapy-Naive
Patients With Metastatic Melanoma: A
Subanalysis Based on BRAF Status
EM Hersh, M Del Vecchio, MP Brown, R Kefford, C
Loquai, A Testori, C Robert, M Li, I Elias, MF Renschler, A
Hauschild
Hersh EM, Del Vecchio M, Brown MP, et al. A phase III trial of nab-paclitaxel vs dacarbazine in chemotherapy-naive patients with metastatic
melanoma: a subanalysis based on BRAF status [abstract 9030]. Poster presentation at: Annual Meeting of the American Society of Clinical Oncology
2013; May 31-June 4; Chicago, IL.
31
CA033 (Hersh): Phase III Trial of nab-P vs DTIC in
Chemotherapy-Naive Metastatic Melanoma Study Design (Cont)
• Endpoints
Primary efficacy endpoint: PFS per blinded radiology assessment,
RECIST v1.0
Other endpoints: OS, ORR, DCR, and safety/tolerability using NCI
CTCAE v3
• Methods
Protocol modified in 2011 to collect BRAF mutational status and analysis plan
amended prior to data lock to include PFS and OS by BRAF status
DCR, disease control rate; HR, hazard ratio; NCI CTCAE, National Cancer Institute Common Terminology Criteria for Adverse
Events; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; RECIST, Response Criteria In Solid
Tumors.
Hersh EM, Del Vecchio M, Brown MP, et al. A phase III trial of nab-paclitaxel vs dacarbazine in chemotherapy-naive patients with metastatic
melanoma: a subanalysis based on BRAF status [abstract 9030]. Poster presentation at: Annual Meeting of the American Society or Clinical Oncology
2013; May 31-June 4; Chicago, IL.
CA033 (Hersh): Phase III Trial of nab-P vs DTIC in
Chemotherapy-Naive Metastatic Melanoma Objective of the Subanalysis
• To evaluate the efficacy and safety of nab-paclitaxel vs
dacarbazine by BRAF mutation status
Hersh EM, Del Vecchio M, Brown MP, et al. A phase III trial of nab-paclitaxel vs dacarbazine in chemotherapy-naive patients with metastatic
melanoma: a subanalysis based on BRAF status [abstract 9030]. Poster presentation at: Annual Meeting of the American Society of Clinical Oncology
2013; May 31-June 4; Chicago, IL.
33
BRAF Status Wild Type Mutant Unknown
Patient Characteristics nab-P
n = 116 DTIC
n = 108 nab-P n = 65
DTIC n = 67
nab-P n = 83
DTIC n = 90
Age Median years (range)
64 (21 - 85)
65 (38 - 86)
56 (25 - 82)
55 (30 - 87)
63 (32 - 85)
68 (28 - 83)
Sex, % Male 71 69 68 66 57 61
Region, % North America Western Europe Australia
45 36 19
44 32 23
38 48 14
43 48 9
46 49 5
43 52 4
ECOG PS, % 0 1
74 25
70 29
74 26
67 31
73 27
67 33
DTIC, dacarbazine; ECOG PS, Eastern Cooperative Oncology Group performance status; LDH, lactate dehydrogenase; nab-P,
nab-paclitaxel; ULN, upper limit of normal.
Hersh EM, Del Vecchio M, Brown MP, et al. A phase III trial of nab-paclitaxel vs dacarbazine in chemotherapy-naive patients with metastatic
melanoma: a subanalysis based on BRAF status [abstract 9030]. Poster presentation at: Annual Meeting of the American Society of Clinical Oncology
2013; May 31-June 4; Chicago, IL.
34
CA033 (Hersh): Phase III Trial of nab-P vs DTIC in
Chemotherapy-Naive Metastatic Melanoma Baseline Patient Characteristics
BRAF Status Wild Type Mutant Unknown
Patient Characteristics nab-P
n = 116 DTIC
n = 108 nab-P n = 65
DTIC n = 67
nab-P n = 83
DTIC n = 90
Metastatic stage, %
M1a M1b M1c
12 25 63
5 34 61
12 29 58
7 22 70
6 22 72
12 19 69
LDH category, %
< 0.8 × ULN 0.8 - 1.1 × ULN > 1.1 - 2 × ULN
55 29 16
65 19 17
54 26 20
34 36 30
47 25 24
51 28 20
Prior therapy for metastatic disease, %
Yes 5 10 12 9 5 8
DTIC, dacarbazine; ECOG PS, Eastern Cooperative Oncology Group performance status; LDH, lactate dehydrogenase; nab-P,
nab-paclitaxel; ULN, upper limit of normal.
Hersh EM, Del Vecchio M, Brown MP, et al. A phase III trial of nab-paclitaxel vs dacarbazine in chemotherapy-naive patients with metastatic
melanoma: a subanalysis based on BRAF status [abstract 9030]. Poster presentation at: Annual Meeting of the American Society of Clinical Oncology
2013; May 31-June 4; Chicago, IL.
35
CA033 (Hersh): Phase III Trial of nab-P vs DTIC in
Chemotherapy-Naive Metastatic Melanoma Baseline Patient Characteristics (Cont)
DTIC, dacarbazine; mo, months; nab-P, nab-paclitaxel; PFS, progression-free survival.
Hersh EM, Del Vecchio M, Brown MP, et al. A phase III trial of nab-paclitaxel vs dacarbazine in chemotherapy-naive patients with metastatic
melanoma: a subanalysis based on BRAF status [abstract 9030]. Poster presentation at: Annual Meeting of the American Society of Clinical Oncology
2013; May 31-June 4; Chicago, IL.
36
CA033 (Hersh): Phase III Trial of nab-P vs DTIC in
Chemotherapy-Naive Metastatic Melanoma Results: Independent Assessment of PFS by BRAF Status
DTIC, dacarbazine; mo, months; nab-P, nab-paclitaxel; OS, overall survival.
Hersh EM, Del Vecchio M, Brown MP, et al. A phase III trial of nab-paclitaxel vs dacarbazine in chemotherapy-naive patients with metastatic
melanoma: a subanalysis based on BRAF status [abstract 9030]. Poster presentation at: Annual Meeting of the American Society of Clinical Oncology
2013; May 31-June 4; Chicago, IL.
37
CA033 (Hersh): Phase III Trial of nab-P vs DTIC in
Chemotherapy-Naive Metastatic Melanoma Results: Interim OS by BRAF Status
CA033 (Hersh): Phase III Trial of nab-P vs DTIC in
Chemotherapy-Naive Metastatic Melanoma Results: Poststudy Anticancer Therapy by BRAF status
• Among patients with a BRAF mutation, the treatment effect in favor of
nab-P vs DTIC on interim OS remained after adjustment for subsequent
ipilimumab and/or BRAF inhibitor therapy
– Adjusted median OS (ipilimumab and BRAF inhibitor): 12.2 vs 8.8 months (HR
0.633; P = 0.067)
– Adjusted median OS (BRAF inhibitor): 12.0 vs 8.4 months (HR 0.838; P = 0.463)
DTIC, dacarbazine; HR, hazard ratio; nab-P, nab-paclitaxel; OS, overall survival.
Hersh EM, Del Vecchio M, Brown MP, et al. A phase III trial of nab-paclitaxel vs dacarbazine in chemotherapy-naive patients with metastatic
melanoma: a subanalysis based on BRAF status [abstract 9030]. Poster presentation at: Annual Meeting of the American Society of Clinical Oncology
2013; May 31-June 4; Chicago, IL.
BRAF Status Wild Type Mutant Unknown
Anticancer Therapy nab-P
n = 116 DTIC
n = 108 nab-P n = 65
DTIC n = 67
nab-P n = 83
DTIC n = 90
Poststudy therapy, % 81 75 83 72 61 62
BRAF inhibitor Ipilimumab
< 1 41
2 44
40 18
30 16
5 20
3 28
38
CA033 (Hersh): Phase III Trial of nab-P vs DTIC in
Chemotherapy-Naive Metastatic Melanoma Authors’ Conclusions
• The treatment effect (PFS and interim OS) was independent of
BRAF mutation status, benefiting all patients who received nab-
paclitaxel vs dacarbazine
– Interim OS of 16.9 months in patients with a BRAF mutation is
promising
• AEs were manageable; grade ≥ 3 peripheral neuropathy
occurred with nab-paclitaxel treatment, but symptoms
improved within 2 to 3 months and ≈ 40% of patients were able
to resume treatment
• nab-Paclitaxel should be considered as a new standard
chemotherapy option in chemotherapy-naive patients with
metastatic melanoma irrespective of BRAF mutation status
AE, adverse event; OS, overall survival; PFS, progression-free survival.
Hersh EM, Del Vecchio M, Brown MP, et al. A phase III trial of nab-paclitaxel vs dacarbazine in chemotherapy-naive patients with metastatic
melanoma: a subanalysis based on BRAF status [abstract 9030]. Poster presentation at: Annual Meeting of the American Society of Clinical Oncology
2013; May 31-June 4; Chicago, IL.
39
EFECTO
VACUNA
I
P
I
L
I
M
U
M
A
B
TEMOZOLAMIDA1
DACARBACINA3
FOTEMUSTINA2
TRO 30%
SLP a 6 meses 45%
SG 1 año 68%
Fase 2 random (+/- DTIC)
TRO 5,4 vs 14,3%
SG a 3 años 9 vs 20%
TRO 29%
TRO 40% M1 cerebrales
Mediana SG 13,3 meses
Patel 20121 Di Giacomo 20122 Hersh 20113 ABRAXANE???
CONCLUSIONES
• MM tradicionalmente considerado poco quimiosensible
• A pesar de agentes antidiana e inmuno, una mayoría de pax con MM recibirá QT en algún momento
• PoliQT y bioQT incrementa TRO pero no impacto SG
• 2 estudios randomizados positivos de monoQT frente a DTIC: fotemustina y nab-paclitaxel
• Nab-paclitaxel nueva alternativa terapéutica en MM, mejora SLP (en espera de datos maduros de SG)
• Estrategias de combinación QT+ inmuno pueden potenciar efectos (sinergia)