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Efficacy and safety of oral MEK162 in
patients with locally advanced and
unresectable or metastatic cutaneous
melanoma harboring BRAFV600 or
NRAS mutations
Paolo 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-KIT
Q61NRAS
NRAS wt
BRAF wt
Ascierto P, et al. J Transl Med. 2012 May 2;10(1):83
Survival of patients with BRAF- or
NRAS-mutant melanoma (n = 313)
N
Median
OS (y)
P
WT
94
1.3
------
BRAF with
inhibitor
41
NR
.02
BRAF without
inhibitor
112
0.9
.10
NRAS
66
0.7
.003
Inhibitors: PLX-4032;GSK-2118436;GSK-1120212;AZD-6244
OS for NRAS vs WT
NRAS: Candidate as a new prognostic marker for stage IV?
Jakob JA , et al., Cancer 2011: epub
MEK inhibitors: targeting RAS and
BRAF mutations in cancer
70-90% pancreatic cancer
RAS
30-40% colon cancer
~30% lung cancer
~20% melanoma
MEK162
50-60% melanoma
BRAF
36% thyroid cancer
12% ovarian cancer
8- 12% colorectal cancer
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
8 cell lines
Mean Tumor Volume
Log(10) EC50 (μM)
18 cell lines
Effect of MEK162 on the Growth of the A-375
B-RAFV600E Melanoma Model In Vivo
SEM (mm3)
EC50 of MEK162 in 26 B-RAFV600E
Melanoma Cell Lines
Time on Treatment (days)
MEK162
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
EC50 of MEK162 in 6 N-RAS Mutant
Melanoma Cell Lines
Mean Tumor Volume
Log(10) EC50 (μM)
4 cell lines
SEM (mm3)
2 cell lines
Effect of MEK162 on the Growth of the
Q61K N-RAS Mutant Melanoma Model In Vivo
Time on Treatment (days)
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 BRAFor NRAS-mutant melanoma patients
Patients with advanced
cutaneous melanoma
BRAFV600 - mutant
n = 41 pts
MEK162 45 mg BID
AJCC stage IIIB-IV
NRAS or BRAF mutation
WHO PS 0-2
No prior MEKi therapy
Prior BRAF inhibitor permitted
Prior therapy permitted
*as of 29 Feb 2012.
NRAS-mutant
n = 30 pts
MEK162 45 mg BID
Study centers
Germany
N=19
Essen
Kiel
Munich
The Netherlands
N=15
Amsterdam
Nijmegen
USA
N=10
Bethlehem, PA
Fayetteville, AR
Portland, OR
Switzerland
N=5
Zurich
Italy
N=22
Genoa
Naples
Patient characteristics
NRAS*
n = 30
BRAF*
n = 41
56.0 [15.0]
53.7 [14.6]
66.7/33.3
53.7/46.3
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)
2(6.6)
2 (4.9)
9 (30.0)
10 (24.4)
Age
Mean [SD]
Gender
Male/Female, %
WHO performance status, n (%)
Other
Radiotherapy (yes)
*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
NRAS*
n =30
BRAF*
n =41
Median
1.0
1.0
Min
0.0
0.0
Max
6.0
4.0
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)
Number of prior medications
n, (%)
*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)
N=28*
45 mg NRAS
Progressive Disease (PD)
Stable Disease (SD)
Partial Response (PR)
Unconfirmed PR
*Patients with missing best % change from baseline and unknown overall response are not included.
Ongoing pts
Best percentage change from baseline and best
overall response (BRAF)
45 mg BRAFV600E
N=35*
Progressive Disease (PD)
Stable Disease (SD)
Partial Response (PR)
Unconfirmed PR
Unknown (UNK)
 
SD PD SD UNK PD SD UNK
*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.
Denotes pre-treated with BRAF inhibitor.
Clinical activity
NRAS*
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
6
2
0
0
0
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
35
Complete response (CR)
0
0
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)
Total partial responses (PR) (confirmed + unconfirmed)
*as of
29 Feb 2012
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.
11
Time to response and duration of response
in patients with NRAS- and BRAF-mutant
melanoma who achieved confirmed PRs*
Mutation
Time to
response**
(weeks)
Duration of
Response***
(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-mutant
100
NRAS mt
PFS (%)
80
Median (months) [95% CI]: 3.65 [2.53, 5.39]
Median (days) [95% CI]: 111 [77, 164]
BRAF mt Median (months) [95% CI]: 3.55 [2.00, 3.81]
Median (days) [95% CI]: 108 [61, 116]
60
40
20
0
0
61
122
Number of patients at risk
All 71
43
14
183
Time (days)
2
274
365
0
0
Most frequent adverse events suspected
to be MEK162-related
BRAFV600*
45 mg
n = 41
NRAS*
45mg
n = 30
Preferred term
All grades
n (%)
29 (96.7)
Grade
3/4
n (%)
14 (46.7)
All
grades
n (%)
39 (95.1)
Grade
3/4
n (%)
18 (43.9)
6 ( 20.0)
18 ( 60.0)
7 (23.3)
5 (16.7)
1 ( 3.3)
1 ( 3.3)
0 (0.0)
0 (0.0)
16 (39.0)
15 (36.6)
2 (4.9)
1 (2.4)
0 (0.0)
3 (7.3)
0 (0.0)
0 (0.0)
10( 33.3)
6 (20.0)
4 (13.3)
1 (3.3)
0 (0.0)
1 (3.3)
14( 34.1)
3 (7.3)
5 (12.2)
1 (2.4)
0 (0.0)
0 (0.0)
8 (26.7)
7 (23.3)
6 (20.0)
2 (6.7)
0 (0.0)
0 (0.0)
15 (36.6)
7 (17.1)
3 ( 7.3)
1 (2.4)
0 (0.0)
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)
Total
Skin-related
Rash
Dermatitis acneiform
Pruritis
Dry skin
Fluid retention
Edema, peripheral
Edema, periorbital
Edema, facial
Gastrointestinal-related
Diarrhea
Nausea
Vomiting
*as of 29 Feb 2012..
There were no treatment related deaths
Central serous retinopathy-like events*
MEK 162
45 mg BID, n=71
Retinal Events**
Grade 1
Grade 2
Grade 3/4
Total
Patients, n (%)
7 (10%)
6 (8%)
0 (0%)
13 (18%)
** as of 29 Feb 2012.
•
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.
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