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%

K

* *

* * * *

*

* *

*

* *

K K

K K

K

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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

Pro

po

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n A

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an

d P

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ree


METRIC Best Response and ORR - ITT

9

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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


METRIC – Overall Survival – ITT P

rop

ort

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


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%)

11

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


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.


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%

K K

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*


(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.


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


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.


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


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


• 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)


• 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



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


(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.)


(as of March 2013)

• BRAF/NRAS- Wild type melanomas? (???) – A limited clinical data, but less likely be useful as single agent


(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

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