importancia de las mutaciones driver y su inhibición en el ... · phase iii studies: braf + mek...
TRANSCRIPT
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Importancia de las mutaciones driver y su
inhibición en el melanoma metastásico Dr. Javier Medina
Servicio de Oncología Médica, Hospital Virgen de la Salud, Toledo
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Standard therapy Personalized medicine
Adapted from Sloane et al. Cancer 2017;123:2130-42.
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Adapted from Sloane et al. Cancer 2017;123:2130-42.
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• promote cancer progression Driver
mutations:
• confer little or no advantage to tumor growth
Passenger mutations
Adapted from Lim et al. Cancer 2017;123:2118-29.
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Genomic Classification of Cutaneous Melanoma
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BRAF NRAS
KIT GNA11
or GNAQ
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ADVANCED DISEASE
BRAF
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1. Hauschild A, et al. Lancet Oncol. 2012;380:358-365.
Single-Agent BRAF Inhibition vs Dacarbazine in Advanced Melanoma: PFS
10
0
80
60
40
20
0
10
0
80
60
40
20
0
Vemurafenib[2] Dabrafenib[1]
HR: 0.30 (95% Cl: 0.18-0.51;
P < .0001)
Dabrafenib (n = 187)
Dacarbazine (n = 63)
HR: 0.26 (95% Cl: 0.20-0.33;
P < .001)
Vemurafenib (n = 275)
Dacarbazine (n = 274)
0 1 2 3 4 5 6 7 8 9 0 2 4 6 8 10 12
PF
S (
%)
PF
S (
%)
Mos Mos
ORR: 50% vs 6% with
dacarbazine ORR: 48% vs 5% with
dacarbazine
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2. Chapman PB, et al. N Engl J Med. 2011;364:2507-2516.
Single-Agent BRAF Inhibition vs Dacarbazine in Advanced Melanoma: PFS
10
0
80
60
40
20
0
10
0
80
60
40
20
0
Vemurafenib[2] Dabrafenib[1]
HR: 0.30 (95% Cl: 0.18-0.51;
P < .0001)
Dabrafenib (n = 187)
Dacarbazine (n = 63)
HR: 0.26 (95% Cl: 0.20-0.33;
P < .001)
Vemurafenib (n = 275)
Dacarbazine (n = 274)
0 1 2 3 4 5 6 7 8 9 0 2 4 6 8 10 12
PF
S (
%)
Mos Mos
ORR: 50% vs 6% with
dacarbazine ORR: 48% vs 5% with
dacarbazine
PF
S (
%)
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Overall Survival BRIM3
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OS: LDH normal vs elevated
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MAPK REACTIVATION
Adapted from Lim et al. Cancer 2017;123:2118-29.
BRAF-specific alterations overexpression of alternate MAP kinases
additional mutations activating MAPK
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Combination of BRAF and MEK
Inhibitors
Combination of PI3K/AKT
Inhibitors and MAPK Inhibitors
Combination of BRAF/MEK
Inhibitors With Immunotherapy
CURRENT APPROACHES TO OVERCOMING RESISTANCE TO TARGETED THERAPY FOR BRAF-MUTANT MELANOMA
Adapted from Lim et al. Cancer 2017;123:2118-29.
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Combination of BRAF and
MEK Inhibitors
CURRENT APPROACHES TO OVERCOMING RESISTANCE TO TARGETED THERAPY FOR BRAF-MUTANT MELANOMA
Adapted from Lim et al. Cancer 2017;123:2118-29.
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Phase III Studies: BRAF + MEK Inhibition in Previously Untreated Adv Melanoma
1. Robert C, et al. N Engl J Med. 2015;372:30-39.
2. Larkin J, et al. N Engl J Med. 2014;371:1867-1876.
Vemurafenib 960 mg PO BID +
Cobimetinib 60 mg PO QD
3 wks on, 1 wk off
(n = 247)
Vemurafenib 960 mg PO BID +
Placebo BID
3 wks on, 1 wk off
(n = 248)
Primary endpoint (both trials): OS
Dabrafenib 150 PO BID +
Trametinib 2 mg PO QD
(n = 352)
Vemurafenib 960 mg PO BID
(n = 352)
Pts with stage IIIc/IV
unresectable melanoma with
BRAF V600E/K,
ECOG PS 0/1
(N = 704)
Pts with stage IIIc/IV unresectable
melanoma with BRAF V600
mutation, ECOG PS 0/1
(N = 495)
coBRIM[2]
Combi-V[1]
Until disease
progression or
unacceptable
toxicity
Until disease
progression or
unacceptable
toxicity
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Combination BRAF/MEK Inhibition vs Single-Agent BRAF Inhibition: PFS
1. Robert C, et al. N Engl J Med. 2015;372:30-39.
0
20
40
60
80
100
0 22 20 18 16 14 12 10 8 6 4 2
Vemurafenib
(n = 352)
Dabrafenib + trametinib
(n = 352)
Mos
PF
S (
%)
0
20
40
60
80
100
PF
S (
%)
0 15 13 11 9 7 5 3 1
Mos
Vemurafenib +
cobimetinib (n = 247)
Vemurafenib +
placebo (n = 248)
HR: 0.51 (95% CI: 0.39-0.68; P < .001) HR: 0.56 (95% CI: 0.46-0.69; P < .001)
Combi-V[1] coBRIM[2]
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Combination BRAF/MEK Inhibition vs Single-Agent BRAF Inhibition: PFS
2. Larkin J, et al. N Engl J Med. 2014;371:1867-1876.
0
20
40
60
80
100
0 22 20 18 16 14 12 10 8 6 4 2
Vemurafenib
(n = 352)
Dabrafenib + trametinib
(n = 352)
Mos
PF
S (
%)
0
20
40
60
80
100
PF
S (
%)
0 15 13 11 9 7 5 3 1
Mos
Vemurafenib +
cobimetinib (n = 247)
Vemurafenib +
placebo (n = 248)
HR: 0.51 (95% CI: 0.39-0.68; P < .001) HR: 0.56 (95% CI: 0.46-0.69; P < .001)
Combi-V[1] coBRIM[2]
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Combi-V Study of Dabrafenib + Trametinib vs Vemurafenib: OS
D+T (n = 352)
Vemurafenib (n = 352)
Median, mos (95% CI) NR
(18.3-NR) 17.2
(16.4-NR)
Adjusted HR (95% CI) 2-sided P value (stopping boundary)
0.69 (0.53-0.89) .005 (< .0214)
100
80
60
40
20
0 12 0 2 4 6 8 10 14 18 16 20
Mos
OS
(%
)
Dabrafenib + trametinib Vemurafenib
1. Robert C, et al. N Engl J Med. 2015;372:30-39.
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CoBRIM Study of Vemurafenib ± Cobimetinib: OS
100
80
60
40
20
0 0 1 3 5 7 9 11 15 13 17
Mos
OS
(%
)
Vemurafenib + cobimetinib (N = 247)
Vemurafenib + placebo (N = 248)
HR: 0.65 (95% CI: 0.42-1.00; P = .046)
2. Larkin J, et al. N Engl J Med. 2014;371:1867-1876.
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THREE POOLED ANALYSIS OF FACTOR ASSOCIATED WITH CLINICAL OUTCOMES ACROSS DABRAFENIB AND TRAMETINIB
CONMINATION THERAPY PHASE 3 RANDOMISED TRIALS
Dirk Schadendorf, Georgina V.Long, Daniil Stroiakovski, Boguslawa Karaszewska, Axel Hauschild, Evgeny Levchenko, Vanna Chiarion-Sileni, Jacob
Schachter, Claus Garbe, Caroline Dutriaux, Helen Gogas, Mario Mandalà,
John B.A.G. Haanen, Céleste Lebbé, Andrzej Mackiewicz, Piotr Rutkowski,
Jean-Jacques Grob, Paul Nathan, CarolineRobert
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PFS
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PFS
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PFS by RECIST response
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OS
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OS by RECIST response
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14th International Congress of the Society for Melanoma Research/9th World Congress of Melanoma; October 18–21, 2017.
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ADVANCED DISEASE
RETREATMENT BRAF
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RECHALLENGE WITH BRAF-DIRECTED TREATMENT IN METASTATIC MELANOMA: A
MULTI-INSTITUTIONAL RETROSPECTIVE STUDY.
Valpione S, Carlino MS, Mangana J, Mooradian MJ, McArthur G, Schadendorf D, Hauschild A, Menzies AM, Arance A, Ascierto PA, Di Giacomo A, de Rosa F,
Larkin J, Park JJ, Goldinger SM, Sullivan RJ, Xu W, Livingstone E, Weichenthal M, Rai R, Gaba L, Long GV, Lorigan P.
Eur J Cancer. 2018 Mar;91:116-124
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Adapted from Sloane et al. Cancer 2017;123:2130-42.
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Patients demographics and disease characteristics at rechallenge.
Patient N 116
Age, years (range) 51.9 (28.6-80.3)
Metastatic organs number (range) 3 (1-8)
Brain metastases 51 (44%)
Stage
•M1a 14 (12%)
•M1b 6 (5%)
•M1c 96 (83%)
LDH
•<UNL 45 (41%)
•UNL 64 (59%)
•Missing 7 (6%)
PS
•0 34 (35%)
•1 37 (39%)
•2 20 (21%)
•3-4 5 (5%)
•Missing 20 (17%)
BRAFi rechallenge drugs
•Dabrafenib 19 (16%)
•Dabrafenib + trametinib 54 (47%)
•Encorafenib 1 (1%)
•Encorafenib + binimetinib 14 (12%)
•Encorafenib + binimetinib + ribociclib 2 (2%)
•Vemurafenib 19 (16%)
•Vemurafenib + cobimetinib 7 (6%)
First BRAFi regimen and median duration: 9.4 months
•68 (58.6%) single-agent BRAFi
•41 (35.3%) BRAFi + MEKi
•5 (4.3%) combination of single BRAFi and immunotherapy;
Brain metastases were present in 51 (44%) patients at BRAFi retreatment.
Reasons for stopping treatment was:
•disease progression 83 (71.6%)
•toxicity in 16 (13.8%),
•treatment break after CR 9 (7.8%)
Immunotherapy was the most commonly administered treatment between first and rechallenge BRAFi treatment (71.5%)
Valpione S et al. Eur J Cancer. 2018 Mar;91:116-124
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Prognostic factors for PFS
Valpione S et al. Eur J Cancer. 2018 Mar;91:116-124
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Prognostic factors for OS
Valpione S et al. Eur J Cancer. 2018 Mar;91:116-124
•Low tumour burden (less than 3 metastatic sites),
•The combination of BRAFi plus MEKi
•Low LDH
Better OS:
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Combination of PI3K/AKT
Inhibitors and MAPK Inhibitors
CURRENT APPROACHES TO OVERCOMING RESISTANCE TO TARGETED THERAPY FOR BRAF-MUTANT MELANOMA
Adapted from Lim et al. Cancer 2017;123:2118-29.
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SY Lim et al Mechanisms and Strategies to Overcome Resistance to Molecularly Targeted Therapy for Melanoma. Cancer 2017;123:2118-29.
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1) escape mechanisms confer resistance to these targeted therapies
2) mutations may not be the principal drivers of tumor survival
3) therapy may not adequately suppress pathway activity.
SY Lim et al Mechanisms and Strategies to Overcome Resistance to Molecularly Targeted Therapy for Melanoma. Cancer 2017;123:2118-29.
promising preclinical data ≠ real clinical data
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Combination of BRAF/MEK
Inhibitors With Immunotherapy
CURRENT APPROACHES TO OVERCOMING RESISTANCE TO TARGETED THERAPY FOR BRAF-MUTANT MELANOMA
Adapted from Lim et al. Cancer 2017;123:2118-29.
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Interaction of molecular alterations with immune response
in melanoma
Adapted from S. Sloane R et al Cancer. 2017;123:2130-2142.
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ADVANCED DISEASE
NRAS
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Adapted from Lim et al. Cancer 2017;123:2118-29.
guanosine triphosphate antagonists and farnesylate inhibitors
pan-RAF inhibitors
MEK inhibitors
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BINIMETINIB VERSUS DACARBAZINE IN PATIENTS WITH ADVANCED NRAS-MUTANT
MELANOMA (NEMO): A MULTICENTRE, OPEN-LABEL, RANDOMISED, PHASE 3 TRIAL
Reinhard Dummer, Dirk Schadendorf, Paolo A Ascierto, Ana Arance, Caroline Dutriaux, Anna Maria Di Giacomo, Piotr Rutkowski, Michele Del Vecchio, Ralf
Gutzmer, Mario Mandala, Luc Thomas, Lev Demidov, Claus Garbe, David Hogg, Gabriella Liszkay, Paola Queirolo, Ernesto Wasserman, James Ford, Marine
Weill, L Andres Sirulnik, Valentine Jehl, Viviana Bozón, Georgina V Long, Keith Flaherty.
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Randomised, open-label phase 3 study done in 26 countries.
• previously untreated
• had progressed on or after previous immunotherapy
Patients with advanced, unresectable, IIIC or stage IV
NRAS-mutant melanoma who were:
• binimetinib 45 mg orally twice daily
• dacarbazine 1000 mg/m² intravenously every 3 weeks. were randomised (2:1) to
receive:
Randomisation was stratified by stage, performance status, and
previous immunotherapy.
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The primary endpoint was progression-free survival assessed by blinded central review in the intention-to-treat population.
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Overall survival
Progression-free survival
2·8 months VS 1·5 months
11·0 months VS 10·1 months
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Progression-free survival in prespecified subgroups
5·5 months VS 1·6 months
2·8 months VS 1·5 months
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ADVANCED DISEASE
KIT
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low frequencies (<10%)
mucosal or acral lentiginous
surfaces
• Durable responses aprox. 20%
• mutations in exon 11 and 13 of c-KIT were associated with the highest response rate.
Phase II trials
Carvajal RD, Antonescu CR, Wolchok JD, et al. KIT as a therapeutic target in metastatic melanoma. JAMA 2011;305:2327–34. Guo J, Si L, Kong Y, et al. Phase II, imatinib mesylate in patients with metastatic melanoma harboring c-Kit mutation or amplification. J Clin Oncol 2011;29:2904–9.
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ADVANCED MELANOMA
CONCLUSIONS
Targeted therapy is a major advance in the treatment of melanoma
understanding molecular alterations and mechanisms that contribute to evasion ( including immune) will allow us better and more effective treatment strategies
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• ¿Cuál es la mutación driver más importante en el desarrollo del melanoma?
A. BRAF
B. NRAS
C. KIT
D. GNA11
PREGUNTA
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• ¿Cuál es la mutación driver más importante en el desarrollo del melanoma?
A. BRAF
B. NRAS
C. KIT
D. GNA11
PREGUNTA