Importancia de las mutaciones driver y su inhibición en el ... · Phase III Studies: BRAF + MEK...

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

Standard therapy Personalized medicine

Adapted from Sloane et al. Cancer 2017;123:2130-42.

Adapted from Sloane et al. Cancer 2017;123:2130-42.

• 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.

Genomic Classification of Cutaneous Melanoma

BRAF NRAS

KIT GNA11

or GNAQ

ADVANCED DISEASE

BRAF

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

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 (

%)

Overall Survival BRIM3

OS: LDH normal vs elevated

MAPK REACTIVATION

Adapted from Lim et al. Cancer 2017;123:2118-29.

BRAF-specific alterations overexpression of alternate MAP kinases

additional mutations activating MAPK

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.

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.

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

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]

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]

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.

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.

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

PFS

PFS

PFS by RECIST response

OS

OS by RECIST response

14th International Congress of the Society for Melanoma Research/9th World Congress of Melanoma; October 18–21, 2017.

ADVANCED DISEASE

RETREATMENT BRAF

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

Adapted from Sloane et al. Cancer 2017;123:2130-42.

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

Prognostic factors for PFS

Valpione S et al. Eur J Cancer. 2018 Mar;91:116-124

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:

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.

SY Lim et al Mechanisms and Strategies to Overcome Resistance to Molecularly Targeted Therapy for Melanoma. Cancer 2017;123:2118-29.

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

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.

Interaction of molecular alterations with immune response

in melanoma

Adapted from S. Sloane R et al Cancer. 2017;123:2130-2142.

ADVANCED DISEASE

NRAS

Adapted from Lim et al. Cancer 2017;123:2118-29.

guanosine triphosphate antagonists and farnesylate inhibitors

pan-RAF inhibitors

MEK inhibitors

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.

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.

The primary endpoint was progression-free survival assessed by blinded central review in the intention-to-treat population.

Overall survival

Progression-free survival

2·8 months VS 1·5 months

11·0 months VS 10·1 months

Progression-free survival in prespecified subgroups

5·5 months VS 1·6 months

2·8 months VS 1·5 months

ADVANCED DISEASE

KIT

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.

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

• ¿Cuál es la mutación driver más importante en el desarrollo del melanoma?

A. BRAF

B. NRAS

C. KIT

D. GNA11

PREGUNTA

• ¿Cuál es la mutación driver más importante en el desarrollo del melanoma?

A. BRAF

B. NRAS

C. KIT

D. GNA11

PREGUNTA