Do MEK Inhibitors Have a Role as Single...
Transcript of Do MEK Inhibitors Have a Role as Single...
Do MEK Inhibitors Have a Role
as Single Agents?
Kevin B. Kim, M.D.
Disclosures
• Received research grant from Roche/Genentech, GSK,
BMS, AstraZeneca, Esai (no personal compensation).
• Compensated consultant/advisor to Genentech and BMS
• Received honoraria from Genentech
Selective MEK inhibitors
• CI-1040
• PD325901
• Selumetinib (AZD6244)
• Trametinib (GSK1120212)
• MEK162
• GDC-0973
• E6201
• AS703026
• TAK-733
When are MEK inhibitors clinically useful?
• BRAF-mutant melanomas?
• NRAS-mutant melanomas?
• GNAQ/GNA11-mutant (uveal) melanomas?
• BRAF/NRAS/GNAQ/GNA11 Wild-type melanomas?
BRAF-mutant Melanomas
Phase II study of Trametinib:
(Pts with no prior BRAFi therapy; n=57)
Confirmed Response Rate: 25% (95% CI, 14.1, 37.8) Median PFS: 4.0 months (95% CI, 3.6, 5.6)
M1c M1a M0 M1b M-Stage at screening
256%
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Kim, Kefford, Pavlick et al. J Clin Oncol. 2013
METRIC: Phase III Melanoma Study
BRAF mutation status
Using allele-specific PCR at RGI
Stratification factors
LDH (> ULN vs. < ULN) and
Prior chemotherapy (Yes vs. No)
Populations
ITT (all randomized patients) n=322;
Primary efficacy (subset of ITT) n=273
Primary endpoint
Progression-Free Survival (PFS) in BRAFV600Epositive melanoma
Secondary endpoints
PFS in ITT
Overall Survival, Response rate and Safety
Robert, Flaherty, Hersey et al. Annual ASCO meeting 2012; Flaherty et al. N Eng J Med 2012
V600E/K mutation (n=322)
Chemotherapy (n=108)
Trametinib 2mg QD (n=214)
Trametinib 2mg QD
PFS Cross-over*
Screened (N=1059)
Chemotherapy = DTIC or paclitaxel
*Allowed after independent confirmation of progression
METRIC Investigator-Assessed PFS – ITT
0 1 2 3 4 5 6 7 8 9
Number at risk
Trametinib 214 205 163 100 88 28 22 5 0 0
Chemotherapy 108 87 43 24 21 10 6 1 0 0
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Time From Randomization (Months)
Events n (%)
Median (months)
HR (95%CI) P-value
Trametinib 118 (55) 4.8 0.45 (0.33, 0.63) <0.0001
Chemotherapy 77 (71) 1.5
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Robert, Flaherty, Hersey et al. Annual ASCO meeting 2012; Flaherty et al. N Eng J Med 2012
METRIC Best Response and ORR - ITT
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Chemotherapy (n=108) Confirmed RR = 8%; 95% CI (3.9, 15.2)
Disease stage
–100
–80
–60
–40
–20
0
Trametinib (n=214)
Confirmed RR = 22%; 95% CI (16.6, 28.1)
20
40
60
80
100
M1c
M1b
M1a
IIIC
Unknown
39%
15%
100
80
60
40
20
0
–20
–40
–100
–60
–80
Robert, Flaherty, Hersey et al. Annual ASCO meeting 2012; Flaherty et al. N Eng J Med 2012
METRIC – Overall Survival – ITT P
rop
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ion
A
live
Time From Randomization (Months)
0 1 2 3 4 5 6 7 8 9 10
Number at risk
Trametinib 214 208 203 192 170 105 53 24 5 0 0
Chemotherapy 108 96 94 90 72 47 28 15 4 1 0
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Events, n (%)
Median (months)
HR (95% CI)
P-value
6 Month OS
(95% CI)
Trametinib 35 (16) -- 0.54 (0.32, 0.92)
0.0136
81 (73, 86)
Chemotherapy 29 (27) -- 67 (55, 77)
47% of the patients in the chemotherapy arm crossed over to trametinib
Robert, Flaherty, Hersey et al. Annual ASCO meeting 2012; Flaherty et al. N Eng J Med 2012
METRIC – Adverse Events (>15% of patients)
Preferred Term (>15% of subjects) Trametinib n=211
Chemotherapy n=99
Rash 121 (57%) 10 (10%)
Diarrhea 91 (43%) 16 (16%)
Oedema peripheral 54 (26%) 3 (3%)
Fatigue 54 (26%) 27 (27%)
Dermatitis acneiform 40 (19%) 1 (1%)
Nausea 38 (18%) 37 (37%)
Alopecia 36 (17%) 19 (19%)
Hypertension 32 (15%) 7 (7%)
Constipation 30 (14%) 23 (23%)
Vomiting 27 (13%) 19 (19%)
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MEKi known events with Trametinib:
• Decreased Ejection Fraction / Ventricular dysfunction = 14 (7%)
• Chorioretinopathy = 1 (<1%)
No reported case of cutaneous SCC or hyperproliferative skin lesions
Robert, Flaherty, Hersey et al. Annual ASCO meeting 2012; Flaherty et al. N Eng J Med 2012
Single-agent MEK162 in advanced BRAF-
or NRAS-mutant melanoma patients
Patients with advanced cutaneous melanoma
AJCC stage IIIB-IV
NRAS or BRAF mutation
WHO PS 0-2
No prior MEKi therapy
Prior BRAF inhibitor permitted
Prior therapy permitted
BRAFV600 - mutant
n = 41 pts MEK162 45 mg BID
*as of 29 Feb 2012.
Ascierto, Berking, Agarwala et al. ASCO 2012
Phase II study of MEK162: Best percentage change from baseline and best overall response (BRAF pts)
*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 SD UNK PD SD UNK
Progressive Disease (PD)
Stable Disease (SD)
Partial Response (PR)
Unconfirmed PR
Unknown (UNK)
45 mg BRAFV600E
Denotes pre-treated with BRAF inhibitor.
Ascierto, Berking, Agarwala et al. ASCO 2012
Response rate: 23% (8 of 35 pts) Disease control rate: 60%
Most frequent AEs suspected to be MEK162-related
Preferred term
NRAS* 45mg n = 30
BRAFV600*
45 mg n = 41
All grades n (%)
Grade 3/4
n (%)
All grades n (%)
Grade 3/4 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 retention
Edema, 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-related
Diarrhea 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 Ascierto, Berking, Agarwala et al. ASCO 2012
However, Trametinib not effective in patients who
had prior BRAFi Tx
Confirmed Response Rate (RR):
0 response, 11 SD
* Discontinued prior BRAFi due to toxicity
K V600K
Scans unavailable for 5 patients: 2 died and 1 withdrew before first scan,
2 had incomplete scan
M1c M1a M1b M-Stage at screening
266% 155%
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Kim, Kefford, Pavlick et al. J Clin Oncol. 2013
(n = 40) K
Part C Randomized Phase II Study Design
Combination D+T 150mg BID/2mg QD
N= 54
Combination D+T 150mg BID/1mg QD
N= 54
RANDOMI Z E
•BRAF V600E/K metastatic melanoma •No prior BRAFi or MEKi •Up to 1 prior treatment •Treated and stable brain mets N=162
*cross over to Combination D+T 150/2
after progression allowed
Objectives
• PFS, ORR, duration of response, rate of cuSCC
• OS, safety
Monotherapy D 150mg BID*
N= 54
Long G et al. ESMO 2012; Flaherty KT, et al. N Eng J Med 2012
BRAFi vs. MEKi in BRAF-mutant melanoma
• BRAF inhibitors appear to have higher response rates and longer PFS than trametinib
• Both classes of drug have shown survival advantage over chemotherapy in randomized phase III studies.
• Patients whose disease progresses on a prior selective RAF inhibitor do not respond to trametinib alone*
– 0% confirmed response rate among 40 patients in phase II study
• Trametinib can be useful as an alternate to a selective RAF inhibitor when pts cannot tolerate a RAF inhibitor.
• Combination of RAF inhibitor and MEK inhibitor can overcome BRAFi resistance?
*Kim, Kefford, Pavlick et al. SMR meeting 2011
NRAS-mutant Melanomas
Single-agent MEK162 in advanced BRAF-
or NRAS-mutant melanoma patients
Patients with advanced cutaneous melanoma
AJCC stage IIIB-IV
NRAS or BRAF mutation
WHO PS 0-2
No prior MEKi therapy
Prior BRAF inhibitor permitted
Prior therapy permitted
NRAS-mutant
n = 30 pts MEK162 45 mg BID
*as of 29 Feb 2012.
Ascierto, Berking, Agarwala et al. ASCO 2012
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
Ascierto, Berking, Agarwala et al. ASCO 2012
Response rate: 21% (6 of 28 pts) 3 confirmed PR Disease control rate: 68%
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 (ongoing)
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.
Ascierto, Berking, Agarwala et al. ASCO 2012
PFS – NRAS- /BRAF-mutant P
FS
(%
)
0 61 122
0
20
60
40
80
100
365 183 274
Time (days) Number of patients at risk
43 All 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
Ascierto, Berking, Agarwala et al. ASCO 2012
PFS – NRAS- /BRAF-mutant P
FS
(%
)
0 61 122
0
20
60
40
80
100
365 183 274
Time (days) Number of patients at risk
43 All 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
Ascierto, Berking, Agarwala et al. ASCO 2012
• There were 0 responses and 2 SD among 7 patients with NRAS mutation (phase I study of trametinib)
• Responses to Selumetinib or other MEK inhibitors are not available.
However, clinical benefit of MEK inhibitor as a class in NRAS-mutant melanomas is not clear.
Falchook, Lewis, Infante et al. Lancet Oncol 2012
GNAQ/GNA11-mutant (Uveal)
Melanomas
• GNAQ or GNA11 mutations alter MAPK pathway activation and are likely key mediators of oncogenesis in this disease.
• Phase I study of trametinib:
– 2 (1 of which had GNAQ mutation) of 16 uveal melanoma pts had 24% tumor reduction & 4 had SD > 16 weeks
– Of 6 pts with GNAQ or GNA11 mutation, 3 had SD and 3 PD.
• Phase II study of Selumetinib (??)
GNAQ/GNA11 mutant melanomas (Uveal)
Falchook, Lewis, Infante et al. Lancet Oncol 2012
• Non-V600E/K BRAF-mutant melanomas
– 1 (L597V) of 2 pts with non-V600 mutation had PR (L597V).
– 2 of 2 pts with either K601E or V600K/V600R had PR (phase II trametinib)
• MEK inhibitors in BRAF/NRAS WT melanoma
– 4 responses among 20 pts (phase I trametinib)
Other Genotypes of melanomas
Falchook, Lewis, Infante et al. Lancet Oncol 2012
Kim, Kefford, Pavlick et al. J Clin Oncol. 2013
Do MEK inhibitors have a role as single agents?
(as of March 2013)
• BRAF-mutant melanomas? (Yes, for proportions of patients) – OS / PFS advantage over chemotherapy
– Lower response rates than BRAF inhibitors
– Alternate treatment option for BRAFi-intolerant patients
– Likely more useful as combination with BRAF inhibitors
Do MEK inhibitors have a role as single agents?
(as of March 2013)
• NRAS-mutant melanomas? (Potential, but not optimal) – Potential benefit as a single agent; Need larger trials to confirm.
– Durable clinical benefit less likely as single agents
– A number of combination trials at works (+CDK4i / + AKTi, etc.)
Do MEK inhibitors have a role as single agents?
(as of March 2013)
• BRAF/NRAS- Wild type melanomas? (???) – A limited clinical data, but less likely be useful as single agent
Do MEK inhibitors have a role as single agents?
(as of March 2013)
• GNAQ/GNA11-mutant (uveal) melanomas? (???) – Await the results of phase II study of Selumetinib vs. Temozolomide
• Which MEK inhibitors are most efficacious?
• Selumetinib vs. Trametinib vs. MEK162 vs. others
• MEK inhibitor in other mutations?
– MEK mutations?
• Combination strategy
– Which combinations for which genomic profile groups?
• BRAF mutation: BRAFi + MEKi
• NRAS mutation or WT/WT: MEKi + PI3Ki
MEKi + AKTi
MEKi + CDK4i
MEKi + cMETi??
• GNAQ/GNA11 mutation: MEKi + demethylating agents??
• MEK inhibitor vs. ERK inhibitors ??
MEK inhibitors: Potential issues / directions