Efficacy and safety of oral MEK162 in patients with locally advanced and

unresectable or metastatic cutaneous melanoma harboring BRAFV600 or

NRAS mutationsPaolo A. Ascierto,* Carola Berking, Sanjiv S. Agarwala,

Dirk Schadendorf, Carla van Herpen, Paola Queirolo,Christian U. Blank, Axel Hauschild, J. Thaddeaus Beck,

Angela Zubel, Faiz Niazi, Simon Wandel, Reinhard Dummer*National Cancer Institute, Naples

Italy

Disclosures• Employment or Leadership Position: None

• Advisory Role: Bristol-Meyers Squibb, Merck Sharp & Dohme, Roche-Genentech, Glaxo Smith-Kline, Amgen, Celgene, Medimmune, Novartis

• Consultant: Merck Sharp & Dohme

• Stock Ownership: None

• Honoraria: Bristol-Meyers Squibb, Merck Sharp & Dohme, Roche-Genentech

• Research Funding: None

• Expert Testimony: None

• Other Remuneration: None

Advanced melanoma: different approaches according to mutational status

BRAFV600E/K

c-KITQ61NRAS

NRAS wtBRAF wt

Ascierto P, et al. J Transl Med. 2012 May 2;10(1):83

NMedian OS (y) P

WT 94 1.3 ------

BRAF with inhibitor 41 NR .02

BRAF without inhibitor 112 0.9 .10

NRAS 66 0.7 .003Inhibitors: PLX-4032;GSK-2118436;GSK-1120212;AZD-6244

Survival of patients with BRAF- or NRAS-mutant melanoma (n = 313)

NRAS: Candidate as a new prognostic marker for stage IV?

OS for NRAS vs WT

Jakob JA , et al., Cancer 2011: epub

MEK inhibitors: targeting RAS and BRAF mutations in cancer

70-90% pancreatic cancer70-90% pancreatic cancer

30-40% colon cancer30-40% colon cancer

~30% lung cancer~30% lung cancer

~20% melanoma~20% melanoma

50-60% melanoma50-60% melanoma

8- 12% colorectal cancer8- 12% colorectal cancer

12% ovarian cancer12% ovarian cancer

36% thyroid cancer36% thyroid cancer

RAS

BRAF

MEK162

Frémin C, Meloche S. J Hematol Oncol. 2010;3:8; Pratilis CA, Solit DB. Clin Cancer Research, 2010;16:3329

MEK162 is active against BRAFV600E

mutant melanoma cell lines in vitro/in vivo

18 cell lines

8 cell lines

Log(

10) E

C50

(μM

)

EC50 of MEK162 in 26 B-RAFV600E

Melanoma Cell Lines

MEK162

Mea

n Tu

mor

Vol

ume

SEM

(mm

3 )

Time on Treatment (days)

Effect of MEK162 on the Growth of the A-375 B-RAFV600E Melanoma Model In Vivo

SEM, standard error of the mean; T/C tumor growth inhibition ratio.

MEK162 is active against NRAS mutant melanoma cell lines in vitro/in vivo

Mea

n Tu

mor

Vol

ume

SEM

(mm

3 )

Time on Treatment (days)

Effect of MEK162 on the Growth of the Q61K N-RAS Mutant Melanoma Model In Vivo

4 cell lines

2 cell lines

Log(

10) E

C50

(μM

)

EC50 of MEK162 in 6 N-RAS MutantMelanoma Cell Lines

MEK162

SEM, standard error of the mean.

Open-label phase II study

• Primary objective of the study was to estimate the ORRs of MEK162 in patients with BRAFV600

and NRAS-mutant advanced cutaneous melanoma at a dose of 45mg BID

• Secondary objectives included PFS, duration of response, safety and tolerability

BID, twice daily.

Single-agent MEK162 in advanced BRAF-or NRAS-mutant melanoma patients

Patients with advanced cutaneous melanoma

AJCC stage IIIB-IVNRAS or BRAF mutation

WHO PS 0-2No prior MEKi therapy

Prior BRAF inhibitor permittedPrior therapy permitted

BRAFV600 - mutantn = 41 pts

MEK162 45 mg BID

NRAS-mutantn = 30 pts

MEK162 45 mg BID

*as of 29 Feb 2012.

USAN=10

Bethlehem, PAFayetteville, AR

Portland, OR

GermanyN=19Essen

KielMunich

SwitzerlandN=5

Zurich

Study centers

The NetherlandsN=15

AmsterdamNijmegen

ItalyN=22

Genoa Naples

Patient characteristics NRAS*n = 30

BRAF*n = 41

Age

Mean [SD] 56.0 [15.0] 53.7 [14.6]

GenderMale/Female, % 66.7/33.3 53.7/46.3

WHO performance status, n (%)

0-1 27 (90.0) 41 (100.0)

2 3 (10.0) 0 (0.0)

Stage IV, n (%) 30 (100.0) 39 (95.1)

No. pts with prior anticancer therapy, n (%) 23 (76.6) 27 (65.9)

BRAF inhibitor 0 (0.0) 7 (17.1)

Chemotherapy 16 (53.3) 16 (39.0)

Immunotherapy 14 (46.7) 19 (46.3)

Other 2(6.6) 2 (4.9)

Radiotherapy (yes) 9 (30.0) 10 (24.4)

*as of 29 Feb 2012; SD, standard deviation.Note: patients with more than one prior line of therapy are counted more than once.

Number of prior antineoplastic therapies

Number of prior medications NRAS*n =30

BRAF*n =41

Median 1.0 1.0

Min 0.0 0.0

Max 6.0 4.0

n, (%)

0 7 (23.3) 14 (34.1)

1 12 (40.0) 10 (24.4)

2 6 (20.0) 11 (26.8)

3 3 (10.0) 4 (9.8)

4 0 (0.0) 2 (4.9)

5 1 (3.3) 0 (0.0)

6 1 (3.3) 0 (0.0)

*as of 29 Feb 2012.Note: patients with more than one prior line of therapy are counted more than once.

Best percentage change from baseline and best overall response (NRAS)

*Patients with missing best % change from baseline and unknown overall response are not included.

N=28*Progressive Disease (PD)Stable Disease (SD)Partial Response (PR)Unconfirmed PR

45 mg NRAS

Ongoing pts

Best percentage change from baseline and best overall response (BRAF)

*Patients with missing best % change from baseline and unknown overall response are not included.denotes a missing best % change from baseline.

UNK indicates patients not qualifying for confirmed CR or PR and without SD after more than 6 weeks or early progression within the first 12 weeks.

N=35*

SD PD SDUNK PD SDUNK

Progressive Disease (PD)Stable Disease (SD)Partial Response (PR)Unconfirmed PRUnknown (UNK)

45 mg BRAFV600E

Denotes pre-treated with BRAF inhibitor.

Clinical activityNRAS*45 mg

BRAF*45 mg

Patients enrolled 30 41 Patients without efficacy assessment(only baseline available)

- too early in the study- patient death- discontinuation due to AEs- discontinuation due to withdrawn consent

2

2000

6

0 2 35

1

Patients with at least 2 scans(BL and at least one evaluation on treatment) 28 35

Best overall response, n (%)* 28 35Complete response (CR) 0 0

Total partial responses (PR) (confirmed + unconfirmed) 6 (3 + 31) (21%) 8 (2 + 62) (23%)

Stable disease (SD) 13 (46) 13 (37)

Progressive disease 9 (32) 12 (34)

Unknown3,4 0 (0) 2 (6)

Overall respone rate (CR+PR) 6 (21) 8 (23)

Disease control rate (CR+PR+SD) 19 (68) 21(60)

*as of 29 Feb 2012 11 patient PD, 1 AE and 1 too early; 2 3 patients PD, 3 AE; 3 Unknown resposponse in non-target lesion; 4 Unknown due to target lesions not measured; 5 Femur fracture Gr 3, Gr 3 bilateral pain in hands, Gr3 reduction in performance status.

Time to response and duration of response in patients with NRAS- and BRAF-mutant melanoma who achieved confirmed PRs*

MutationTime to

response**(weeks)

Duration ofResponse***

(weeks)

NRAS 7.6 16.3

NRAS 7.0 7.1

NRAS 8.0 17.3

BRAF 10.7 15.6

BRAF 8.0 16.1

*as of 29.02. 2012.

**Time to response was calculated as the time between the first day of treatment until the date of first documented response.***Duration of response was calculated as the time from the date of first documented response to the date of event/censoring for PFS.

PFS – NRAS- /BRAF-mutantP

FS (%

)

0 61 1220

20

60

40

80

100

365183 274Time (days)

Number of patients at risk

43All 71 14 2 0 0

Median (months) [95% CI]: 3.55 [2.00, 3.81]Median (days) [95% CI]: 108 [61, 116]

Median (months) [95% CI]: 3.65 [2.53, 5.39]Median (days) [95% CI]: 111 [77, 164]NRAS mt

BRAF mt

Most frequent adverse events suspected to be MEK162-related

Preferred term

NRAS*45mgn = 30

BRAFV600*

45 mgn = 41

All gradesn (%)

Grade 3/4

n (%)

All gradesn (%)

Grade3/4

n (%)Total 29 (96.7) 14 (46.7) 39 (95.1) 18 (43.9)Skin-related

Rash 6 ( 20.0) 1 ( 3.3) 16 (39.0) 0 (0.0)Dermatitis acneiform 18 ( 60.0) 1 ( 3.3) 15 (36.6) 3 (7.3)Pruritis 7 (23.3) 0 (0.0) 2 (4.9) 0 (0.0)Dry skin 5 (16.7) 0 (0.0) 1 (2.4) 0 (0.0)

Fluid retentionEdema, peripheral 10( 33.3) 1 (3.3) 14( 34.1) 1 (2.4)Edema, periorbital 6 (20.0) 0 (0.0) 3 (7.3) 0 (0.0)Edema, facial 4 (13.3) 1 (3.3) 5 (12.2) 0 (0.0)

Gastrointestinal-relatedDiarrhea 8 (26.7) 2 (6.7) 15 (36.6) 1 (2.4)Nausea 7 (23.3) 0 (0.0) 7 (17.1) 0 (0.0)Vomiting 6 (20.0) 0 (0.0) 3 ( 7.3) 0 (0.0)

Blood creatine phosphokinase increased 11( 36.7) 7 ( 23.3) 9 ( 22.0) 7 (17.1)

Fatigue 4 (13.3) 0 ( 0.0) 10 (24.4) 2 (4.9)Dysgeusia 0 (0.0) 0 ( 0.0) 8 (19.5) 0 (0.0)*as of 29 Feb 2012.. There were no treatment related deaths

Central serous retinopathy-like events*

• Retinal events were reversible without interruption of treatment in the majority of patients

*Central serous retinopathy-like retinal events included: retinal detachment, retinal pigment epitheliopathy, retinoschisis, retinal oedema, chorioretinopathy, retinopathy and retinal exudates.

MEK 162 45 mg BID, n=71

Retinal Events** Grade 1 Grade 2 Grade 3/4 TotalPatients, n (%) 7 (10%) 6 (8%) 0 (0%) 13 (18%)

** as of 29 Feb 2012.

Conclusions

• MEK162 showed clinical activity in patients with either BRAF- or NRAS-mutant advanced melanoma

• Acceptable safety profile at 45 mg BID with manageable side effects

• MEK162 is the first targeted therapy to show activity in patients with NRAS-mutant melanoma

Acknowledgements

• The author would like to thank: – Patients and their families – Investigators, co-investigators and the study teams at

each participating center– Unit of Medical Oncology and Innovative Therapies,

National Cancer Institute, Naples, Italy• The study was sponsored by Novartis Pharma

AG, Basel, Switzerland