cco melanoma

Targeted Therapy for BRAF V600–Mutant Melanoma

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Faculty

Keith T. Flaherty, MDDirector of Temeer Center for Targeted TherapyMassachusetts General Hospital Cancer CenterBoston, Massachusetts

Keith T. Flaherty, MD has disclosed that he has received consulting fees from GlaxoSmithKline, Novartis, and Roche/Genentech.


Incidence of Key Driver Oncogenes in Melanoma BRAF ~ 50%

NRAS ~ 20%

CKIT ~ 1%

– Primarily mucosal and acral lentiginous

GNAQ/GNA11 ~ 1%

– Almost exclusively uveal

Nikolaou VA, et al. J Invest Dermatol. 2012;132:854-863. Smalley KS, et al. Semin Oncol. 2012;39:204-214.


BRAF Mutations: Biology and Practice

BRAF mutations

Stable across primary to metastatic melanoma

Detectable in formalin-fixed, paraffin-embedded tumor samples

BRAF Mutation, % N = 677

All BRAF mutations 47

V600E 72

V600K 23

V600R/L 4

Non-V600 2

Jakob J, et al. ASCO 2011. Abstract 8500.

NRAS

CRAFBRAF

MEK

ERK


BRAF Mutation Testing

BRAF mutations are present throughout melanoma disease progression

– If metastasis biopsy not available, most recent melanoma surgery sample adequate (eg, lymph node)

BRAF mutation testing is commercially available

– FDA-approved tests

– Cobas 4800 BRAF V600 Mutation Test (vemurafenib)

– THxID BRAF Kit (dabrafenib with or without trametinib)

NCCN. Clinical practice guidelines in oncology: melanoma. v.1.2014.


BRAF “Inhibitors” Only Inhibit in the Context of BRAF Mutation

CRAFBRAF

MEK

ERK

P

P

CRAF

MEK

ERK

P

P

CRAF

Heidorn SJ, et al. Cell. 2010;140:209-221. Poulikakos PI, et al. Nature. 2010; 464:427-430. Hatzivassiliou G, et al. Nature. 2010;464:431-435.

RAS-GTP


BRAF-Mutant Melanoma Initial Therapy


Key Target Selectivity of Raf Inhibitors

Target Kinase IC50 (nM)

Vemurafenib Dabrafenib

BRAF-V600E 31 0.6

CRAF 48 5

BRAF 100 12

Bollag G, et al. Nature. 2010;467:596-599. Kefford R, et al. ASCO 2010. Abstract 8503.


Sosman J, et al. N Engl J Med. 2012;366:707-714.

Tumor regression: ~ 90% of patients

8 confirmed CRs

BRIM-2 Phase II Study of Vemurafenib in Metastatic Melanoma: Tumor Regression

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Patients Treated With Vemurafenib

Disease StageM1aM1bM1c


1. Chapman PB, et al. N Engl J Med. 2011;364:2507-2516. 2. McArthur G, et al. ECCO-ESMO 2011. Abstract LBA28. 3. Hauschild A, et al. Lancet. 2012;380:358-365. 4. Robert C, et al. ASCO 2012. Abstract LBA8509. 5. Flaherty KT, et al. N Engl J Med. 2012;367:107-114.

Phase III Trials in BRAF V600E–Mutant MelanomaTrial Name NCT Identifier N Treatment Arms

BRIM-3[1,2] NCT01006980 675 Vemurafenib 960 mg PO BID (n = 337)Dacarbazine 1000 mg/m2 IV q3w

(n = 338)

BRF113683[3] NCT01227889 250 Dabrafenib 150 mg PO BID (n = 187)Dacarbazine 1000 mg/m2 IV q3w (n = 63)

METRIC[4,5] NCT01245062 322 Trametinib 2 mg PO QD (n = 214)Dacarbazine1000 mg/m2 IV q3w or paclitaxel 175 mg/m2 q3w (n = 108)


Chapman PB, et al. N Engl J Med. 2011;364:2507-2516.

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Patients Treated With Vemurafenib

Unresectable stage IIIc

M1a M1b M1c

Disease Stage 100

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00 2 4 6 8 10 12

Mos

PF

S (

%)

HR: 0.26 (95% Cl: 0.20-0.33; P < .001)

Vemurafenib (n = 275)

Dacarbazine (n = 274)

BRIM-3 Phase III Study of Vemurafenib vs DTIC in Melanoma: Response and PFS


Mos

Vemurafenib (n = 337)Est 6-mo survival: 83%Median follow-up: 6.2 mos

Dacarbazine (n = 338)Est 6-mo survival: 63%Median follow-up: 4.5 mos

OS

(%

)

HR: 0.44 (95% CI: 0.33-0.59)

Dacarbazine median OS: 7.9 mos

McArthur G, et al. ECCO-ESMO 2011. Abstract LBA28.

BRIM-3 Phase III Study of Vemurafenib vs Dacarbazine in Melanoma: OS

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00 1 2 3 4 5 6 7 8 9 10 11 12 13 14


Phase III Study of Dabrafenib vs DTIC in Melanoma: Response and PFS

Hauschild A, et al. Lancet Oncol. 2012;380:358-365.

Unresectable IIC

M1A

M1B

M1C

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FS

(%

)0 1 2 3 4 5 6 7 8 9

DabrafenibDacarbazine

Mos


Trametinib (n = 214)

Confirmed RR: 22% (95% CI: 16.6-28.1)

Single-Agent MEKi (Trametinib) in BRAF-Mutant/BRAFi-Naive Metastatic Melanoma

Robert C, et al. ASCO 2012. Abstract LBA8509.

Disease Stage

39%

M1cM1bM1aIIIC

Unknown

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Phase III METRIC: Trametinib (MEKi) vs Dacarbazine or Paclitaxel

Flaherty KT, et al. N Engl J Med. 2012;367:107-114.

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FS

HR: 0.45 (95% Cl: 0.33-0.63; P < .001)

Trametinib(n = 214)

Chemotherapy(n = 108)

Pro

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f O

S

1.0

0.8

0.6

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Trametinib(n = 214)

Chemotherapy(n = 108)

HR: 0.54 (95% Cl: 0.32-0.92; P = .01)

Mos Since Randomization


Most Common AEs With Approved Targeted Agents in Advanced MelanomaAE (≥ Grade 2), % Vemurafenib[1] Dabrafenib[2] Trametinib[3]

Arthralgia 21 5 NR

Rash 18 NR 27

Fatigue 13 6 9

Cutaneous SCC/ keratoacanthoma

12/8 6 (combined) NR

Hyperkeratosis 6 13 NR

Pyrexia NR 11 NR

Headache 5 5 NR

Photosensitivity (any grade) 12 3 NR

Hypertension NR NR 12

1. Chapman PB, et al. N Engl J Med. 2011;364:2507-2516. 2. Hauschild A, et al. Lancet. 2012;380:358-365. 3. Flaherty KT, et al N Engl J Med. 2012;367:107-114.


Vemurafenib + Ipilimumab: Hepatotoxicity

Phase I study in patients with BRAF V600–mutant melanoma

– Dose-limiting grade 3 aminotransferase elevation in 4 pts

– Lowering dose of vemurafenib still produced elevated aminotransferase levels

– Hepatic adverse events asymptomatic and reversible

– Other adverse events of the combination: grade 2 temporal arteritis, grade 3 rash

– Study has been closed to further accrual

Ribas A, et al. N Engl J Med. 2013;368:1365-1366.


Resistance to BRAF Inhibitors


Sosman J, et al. N Engl J Med. 2012;366:707-714.

BRIM-2 Phase II Study of Vemurafenib in Metastatic Melanoma: PFS

Ind

ivid

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Pat

ien

ts T

reat

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Wit

h V

emu

rafe

nib

TTPTime to responseDiedAlive with response

Mos0 202 4 6 8 10 12 14 16 18


Molecular Characteristics of Disease Progression Variable restoration of signaling through ERK

No new activating mutations in BRAF

– BRAFV600E persists at progression

300

250

200

150

100

50

0

H-S

core

BL Day 15 DP

pERK

Time

N = 23 n = 12


Bypassing BRAF Inhibitor Blockade

Nazarian R, et al. Nature. 2010;468:973-977. Johannessen CM, et al. Nature. 2010;468:968-972. Villanueva J, et al. Cancer Cell. 2010;18:683-695. Wagle N, et al. J Clin Oncol. 2011;29:3085-3096. Shi H, et al. Nat Commun. 2012;3:724. Poulikakos PI, et al. Nature. 2011;480:387-390. Straussman R, et al. Nature. 2012;487:500-504. Whittaker SR, et al. Cancer Discov. 2013;3: 350-362. Maertens O, et al. Cancer Discov. 2013;3:338-349.

CRAFBRAF

MEK

ERK

P

P

BRAF BRAF

BRAF

BRAF

NRAS

COT

MEK

Alternative splicing

Amplification

PI3K

NF1


Single-Agent MEKi (Trametinib) in BRAF-Mutant/BRAFi-Naive Metastatic Melanoma

Robert C, et al. ASCO 2012. Abstract LBA8509.

Disease Stage

39%

Trametinib (n = 214)

Confirmed RR: 22% (95% CI: 16.6-28.1)

M1cM1bM1aIIIC

Unknown

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Single-Agent MEK Inhibitor Has Minimal Activity in BRAFi-Refractory Patients

Unconfirmed RR: 5% (95% CI: 0.6-16.9) 1 CR, 1 PR, 11 SD

*Discontinued prior BRAFi due to toxicityK = V600K

M1cM1a M1bM Stage at Screening

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*

Kim KB, et al. J Clin Oncol. 2013;31:482-489.

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Tumor Regression With BRAF/MEK Combination in BRAFi-Refractory Patients

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Mos Since Prior BRAFi

PRSDPD

Best Response on Prior BRAFiRR: 19%

M = Prior MEKi

Flaherty KT, et al. SMR 2011. Abstract LBA1-4.

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1.0 0.4 0 0.6 4.2 -- 0.3 2.1 4.3 2.6 7.7 0.5 0.2 1.0 -- 6.2 0.5 1.0 0.2 7.4 9.21.1 1.1

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Dabrafenib + Trametinib Combination in BRAF Inhibitor–Naive Patients

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Best Confirmed Response

CR

PRPD

SD

Dabrafenib 150 mg BID/Trametinib 2 mg QD

Long G et al. ESMO 2012. Abstract LBA27_PR.

10080604020

0-20-40-60-80

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Dabrafenib Monotherapy


Delayed Resistance With BRAF/MEK Combo vs Single-Agent BRAF Inhibition


Full-dose BRAF/MEKFull-dose BRAF/half-dose MEKFull-dose BRAF

Full-Dose BRAF/MEK Full-Dose BRAFMedian PFS, mos 9.4 5.8HR 0.39 (P < .001)1.0

0.8

0.6

0.4

0.2

00 3 6 9 12 15 18

Mos Since Randomization

Pro

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S


Grade 3† All Grades Grade 3† All Grades Grade 3† All Grades

Cutaneous SCCa‡ 9 (17) 10 (19) 1 (2) 1 (2) 3 (5) 4 (7)

Skin papilloma 0 8 (15) 0 4 (7) 0 2 (4)

Hyperkeratosis 0 16 (30) 0 3 (6) 0 5 (9)

Decreased EF 0 0 1 (2) 2 (4) 0 5 (9)

Cardiac failure 0 0 1 (2) 1 (2) 0 0

Hypertension 0 2 (4) 0 2 (4) 1 (2) 5 (9)

Chorioretinopathy 0 0 0 0 1 (2) 1 (2)

BRAF/MEK vs BRAF Inhibition: AEs


Adverse Event, n (%)

Dabrafenib Monotherapy(n = 53)*

Grade 3/4 All Grades

Combination 150/1(n = 54)


Combination 150/2(n = 55)*


Any event 23 (43) 53 (100) 26 (48) 53 (98) 32 (58) 55 (100)

Pyrexia 0 14 (26) 5 (9) 37 (69) 3 (5) 39 (71)

Chills 0 9 (17) 1 (2) 27 (50) 1 (2) 32 (58)

Fatigue 3 (6) 21 (40) 1 (2) 31 (57) 2 (4) 29 (53)

Nausea 0 11 (21) 2 (6) 25 (46) 1 (2) 24 (44)

Vomiting 0 8 (15) 2 (4) 23 (43) 1 (2) 22 (40)

Diarrhea 0 15 (28) 0 14 (26) 1 (2) 20 (36)

*1 patient assigned to monotherapy received combination 150/2 and was included in the combination 150/2 safety analyses.†No grade 4 adverse events reported for these categories.‡ Includes keratoacanthoma .



CRAFBRAF

MEK

ERK

P

P

CRAF

MEK

ERK

P

P

CRAF

RAS-GTP

Heidorn SJ, et al. Cell. 2010;140:209-221. Poulikakos PI, et al. Nature. 2010;464:427-430. Hatzivassiliou G, et al. Nature. 2010;464:431-435.


CRAFBRAF

MEK

ERK

P

P

CRAF

MEK

ERK

P

P

CRAF

RAS-GTP

BRAF inhibitor BRAF

inhibitor

MEKinhibitor MEK

inhibitor

Heidorn SJ, et al. Cell. 2010;140:209-221. Poulikakos PI, et al. Nature. 2010;464:427-430. Hatzivassiliou G, et al. Nature. 2010;464:431-435.



Conclusions

For 50% of patients with melanoma, BRAF and MEK inhibition have been validated as new therapies

Building on BRAF or BRAF/MEK inhibition will proceed in 2 directions:

– Further optimizing MAPK-targeted therapy

– Combination targeted therapy antagonizing pathways essential for melanomagenesis

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