simposio educacional melanoma ¿cuÁl es el … · abraxane phase 3 study of nab® -paclitaxel vs...

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…


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


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


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

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


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


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.


melanoma: a subanalysis based on BRAF status [abstract 9030]. Poster presentation at: Annual Meeting of the American Society or Clinical Oncology



Chemotherapy-Naive Metastatic Melanoma Objective of the Subanalysis

• To evaluate the efficacy and safety of nab-paclitaxel vs

dacarbazine by BRAF mutation status




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.




34


Chemotherapy-Naive Metastatic Melanoma Baseline Patient Characteristics


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.




35


Chemotherapy-Naive Metastatic Melanoma Baseline Patient Characteristics (Cont)

DTIC, dacarbazine; mo, months; nab-P, nab-paclitaxel; PFS, progression-free survival.




36


Chemotherapy-Naive Metastatic Melanoma Results: Independent Assessment of PFS by BRAF Status

DTIC, dacarbazine; mo, months; nab-P, nab-paclitaxel; OS, overall survival.




37


Chemotherapy-Naive Metastatic Melanoma Results: Interim OS by BRAF Status


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.





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


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.




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)

simposio educacional melanoma ¿cuÁl es el … · abraxane phase 3 study of nab® -paclitaxel vs...

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