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

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