MEK Inhibitors and their potential role in relapsed NSCLC

Ranee Mehra, MDFox Chase Cancer Center

Philadelphia, PA

Disclosures

• Consulting – Novartis, Bristol Myers Squib

• Spouse is employee of GSK

• Acknowledgment: J. Weiss

Ras-Raf-MEK-ERK1/2 MAP kinase pathway

Frémin and Meloche Journal of Hematology & Oncology 2010 3:8 doi:10.1186/1756-8722-3-8

MEK inhibitors in the ClinicAgents Targets Phase/Disease ToxicitiesSelumetinib (AZD6244)

MEK1 II/NSCLC, Melanoma Nausea, rash, xerostomia

MEK162 (ARRY-162)

MEK 1/2 I, II/NSCLC, NRAS melanoma, pancreatic cancer

Rash, dermatitis, CPK elevation

Trametinib (GSK112212)

MEK 1/2 III/melanoma, colon cancer Rash, diarrhea, retinopathy

Refametinib (BAY-869766)

MEK 1/2 II/HCC, melanoma, colon cancer

rash

PD-0325901 MEK 1/2 I/melanoma, NSCLC rash, fatigue, blurry vision, diarrhea

Plimasertib MEK 1/2 Nausea, rash, visual disturbance, asthenia

Colon cancer, myeloma

TAK-733 MEK 1/2 I/NSCLC, melanoma, colon cancer, breast cancer

Modified from Akinleye et al. J Hematol Oncol 2013, 6:27

Numerous Molecular Changes Drive Lung Cancer

Kris, et al. J Clin Oncol 2011;29:Suppl(Abstr 7506).

Double3%

No mutation detected KRAS

22+%

EGFR 17% EML4-ALK 7%BRAF

MEK1

NRAS

AKT1

PIK3CAHER2MET AMP

KRAS Mutation Subtypes in NSCLCCOSMIC

From J Weiss: ASCO 2013

• Selumetinib is potent and selective allosteric inhibitor of MEK 1/21

• Tendency for greater sensitivity to selumetinib in BRAF/RAS mutant cell lines2

Cell

viab

ility

inhi

bitio

n IC

50 (µ

M)

Cell line1Yeh, et al. Clin Cancer Res 2007

2Davies, et al. Mol Cancer Ther 2007

Selumetinib

Selumetinib

• Phase I study showed that selumetinib plus docetaxel had a manageable tolerability profile

• Preclinically, the combination of selumetinib and docetaxel demonstrated tumor regression in a KRAS-mutant cancer

Hainsworth J et al. J Thorac Oncol 2010;5:1630–6Holt et al. Br J Cancer 2012;106:585–66Kim et al. Mol Can Ther 2011;10:B225

HCT-116 human tumor xenografts (KRAS-mutant)

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

0 2 4 6 8 10 12 14

Mea

n tu

mou

r vol

ume

(cm

3) +

/-s.

e.m

ControlSelumetinib-25mg kg-1 per qdDocetaxel-15mg kg-1Combo

Pre-clinical Activity in TKI resistance

British Journal of Cancer (2011) 105, 382–392

• Following completion of patient enrollment, the primary endpoint was changed from PFS to OS, without changing the sample size‡ – OS analysis was planned for after approximately 58 events

Selumetinib 75 mg BD + docetaxel 75 mg/m2

(day 1 of every 21-day cycle)†

Placebo BD + docetaxel 75 mg/m2

(day 1 of every 21-day cycle)†

*Mutation status determined either by central laboratory (Esoterix, ARMS) or an approved local laboratory†SEL/PBO given until disease progression/intolerable toxicity/other discontinuation criteria met‡To allow decisions to be made based on OS data without breaking study blinding at the earlier endpoint of PFS

EndpointsPrimary• OS

Secondary•PFS•ORR•Duration of response•Change in tumor size•Alive and progression-free at 6 months•Safety and tolerability

Randomization(1:1 ratio)

Patients

•Locally advanced or metastatic NSCLC (stage IIIB-IV) that has failed first-line therapy

•Confirmed KRAS mutant tumor*

•WHO PS 0-1

Selumetinib study

Janne, et al. Lancet Oncol 2013; 14: 38–47

Baseline Patient Characteristics

*Including adenocarcinoma: bronchoalveolarNOS, not otherwise specified

CharacteristicSelumetinib + docetaxel

n=44Placebo + docetaxel

n=43

Gender, number (%) – male/female 21 (47.7) / 23 (52.3) 20 (46.5) / 23 (53.5)

Age, median (range), years 59.5 (26–79) 59 (37–76)

Smoking status, number (%)

Former/current smoker 39 (88.6) 38 (88.4)

Never-smoker 5 (11.4) 5 (11.6)

AJCC classification, number (%) – IIIB/IV 5 (11.4) / 39 (88.6) 1 (2.3) / 42 (97.7)

WHO PS, number (%) – 0/1 21 (47.7) / 23 (52.3) 21 (48.8) / 22 (51.2)

Histological type, number (%)

Adenocarcinoma* 36 (81.8) 33 (82.5)

Squamous carcinoma 3 (6.8) 6 (14.0)

Adenosquamous carcinoma 2 (4.5) 1 (2.3)

Large cell carcinoma (NOS) 2 (4.5) 0 (0.0)

Other 1 (2.3) 3 (7.0)

• There was a numerical increase in OS, hazards non-proportional– 56/83 deaths (67% maturity): selumetinib + docetaxel 29/43, placebo+docetaxel 27/40

Median OSSelumetinib + docetaxel, N=44 9.4 moPlacebo + docetaxel, N=43 5.2 moHR 0.80; 80% CI 0.56, 1.14; 1-sided p=0.2069

Symbols represent censored observations

Primary end-point: OS

Janne, et al. Lancet Oncol 2013; 14: 38–47

Median PFSSelumetinib + docetaxel, N=44 5.3 moPlacebo + docetaxel, N=43 2.1 moHR 0.58; 80% CI 0.42, 0.79; 1-sided p=0.0138

• There was a statistically and clinically significant improvement in PFS– 71/85 events: selumetinib + docetaxel 35/43, placebo+docetaxel 36/40

Symbols represent censored observations

Secondary end-point: PFS

Janne, et al. Lancet Oncol 2013; 14: 38–47

CR, complete response; PR, partial response; SD, stable diseasePD, progressive disease; DoR, duration of response; APF6, alive and progression-free at 6 months

*11 confirmed, 5 unconfirmed†Fisher’s exact 2-sided mid p value; ‡1-sided p value

Selumetinib + docetaxel

N=44

Placebo + docetaxel

N=43

Best overall response, number (%)

CR 0 0

PR 16 (37.2)* 0

SD ≥6 weeks 19 (44.2) 20 (50.0)

PD 8 (18.6) 18 (45.0)

Not evaluable 0 2 (5.0)

Median DoR, days 182 -

p<0.0001† p<0.0158‡

%

Janne, et al. Lancet Oncol 2013; 14: 38–47

Response

Safety and tolerability

Selumetinib + docetaxelN=44

Placebo + docetaxelN=42

Any SAESAE with outcome of death

26 (59.1)4 (9.1)

13 (31.0)3 (7.1)

AE leading to hospitalisation* 21 (47.7) 8 (19.1)AE leading to discontinuationSelumetinib/placeboDocetaxel

8 (18.2)6 (13.6)

5 (11.9)7 (16.7)

AE leading to dose reduction of selumetinib or placebo 16 (36.4) 0AE leading to dose interruptionof selumetinib or placebo 24 (54.5) 4 (9.5)

*Main causes of hospitalization were febrile neutropenia/neutropenic infections,respiratory infections and respiratory disorders

Janne, et al. Lancet Oncol 2013; 14: 38–47

Selumetinib + docetaxel N=44 Placebo + docetaxel N=42Most frequent AEs* All grades Grade 3 & 4 All grades Grade 3 & 4Diarrhea 32 (72.7) 0 7 (16.7) 0Nausea 19 (43.2) 1 (2.3) 12 (28.6) 0Vomiting 19 (43.2) 1 (2.3) 9 (21.4) 1 (2.4)Peripheral edema 18 (40.9) 1 (2.3) 7 (16.7) 0Dermatitis acneiform 17 (38.6) 3 (6.8) 2 (4.8) 0Stomatitis 16 (36.4) 0 8 (19.0) 0Decreased appetite 15 (34.1) 0 11 (26.2) 1 (2.4)Constipation 14 (31.8) 0 8 (19.0) 0Asthenia 14 (31.8) 4 (9.1) 11 (26.2) 0Alopecia 13 (29.5) 0 9 (21.4) 0Fatigue 12 (27.3) 0 14 (33.3) 3 (7.1)Pyrexia 12 (27.3) 0 5 (11.9) 0Hematological changes

Low neutrophil count† 37 (86.0) (30) 67.4 33 (78.6) 23 (54.8)Anemia† 18 (41.9)‡ 1 (2.3) 15 (35.7) 1 (2.4)Febrile neutropenia‡ 8 (18.2) 8 (18.2) 0 0

*AEs defined as most frequent were those having an incidence of ≥25% in either study arm†Taken from laboratory values, n=43‡CTC grade ≥2; protocol allowed inclusion of patients with grade 1 anaemia to enrol‡ Including neutropenic infection

Frequently reported AEs

Janne, et al. ASCO 2012

Two parallel randomized Phase II studies of Selumetinib and Erlotinib in NSCLC selected by KRAS mutations

Carter, ASCO 2013, 8026

Mutated KRAS39 patients

Monotherapyselumetinib

75 mg PO bid

Combination therapy

erlotinib 100 mg PO daily

+selumetinib

150 mg PO daily

77 patients

30 pts

KRAS Wild Type38 patients

MonotherapyErlotinib

150 mg POqdd

Combination therapy

erlotinib 100 mg PO daily

+selumetinib

150 mg PO daily

9 pts 19 pts 19 pts

ResultsKRAS mutated

RR PFS OS

Selumetinib (n=9)

0% 3.8 m 12.8

selumetinib plus erlotinib (n=30)

10% 2.3 m NR

P=0.61 0.86

Carter, ASCO 2013, 8026

KRAS Wild-Type

RR PFS OS

Erlotinib (n=19)

11% 2.1 m 12.9

selumetinib plus erlotinib (n=19)

5% 2.1 m 13.7

P=0.98 0.65

Phase I Trial of GSK1120212 (Trametinib) with Expanded Cohort

• Phase I trial to establish MTD• Toxicity• Pharmacokinetics

Expanded cohort:BRAF-mutant melanomaPancreatic cancerKRAS-mutant NSCLC

MTD, maximum tolerated dose

1. Falchook, et al. ESMO; 2010; 2. Jing, et al. Mol Cancer Ther. 2012;11(3):720-972.

• GSK1120212: a potent reversible inhibitor of MEK1/2

• RAF/RAS mutation a strong predictor of sensitivity in cell lines

• GSK1120212 2 mg daily the recommended dose for phase II trials

19

PFS in KRAS-Mutant NSCLC, Trametinib vs. Docetaxel

• In patients with KRAS-mutant NSCLC, no statistically significant difference in PFS was observed between trametinib and docetaxel

Trametinib (n = 86)

Docetaxel (n = 43)

PFS events, n (%) 61 (71) 31 (72)

Median PFS, weeks (95% CI)

11.7 (7.0,12.4) 11.4 (6.1,18.3)

Hazard ratio (95% CI);2-sided P value

1.14 (0.75, 1.75)P = .5197

Blumenschein et al, ASCO 2013, abstract 8029Slide courtesy of J. Weiss.

Trametinib (GSK212) + Docetaxel in Advanced KRAS mutant and WT NSCLC

CONFIDENTIAL – DO NOT DISTRIBUTE

Study Design

from Gandara et al: ASCO 2013, abstract 8028

N

Objective Response

CR + PR (%)

Disease Control (CR + PR + SD)

(%)

PFS (mos)

All NSCLC patients 47 32% 64% 3.5 (2.6, 6.3

KRAS Mutation+ KRAS+ (G12C) KRAS+ (non-G12C)

251015

28%40%20%

64%80%47%

3.4 (1.5, 6.3)4.8 (3.4,

13.3)2.6 (1.2, 4.2)

KRAS WT 22 32% 68% 4.2 (2.2, 7.6)

Trametinib (GSK212) + Docetaxel in Advanced KRAS mutant and WT NSCLC

updated from Bennouna et al: IASLC WCLC 2013Gandara, Santa Monica 2014

C KRAS G12C‡ Squamous histology§ Best response was CR, single target lymph node <10mm Best response PD

Seven patients did not have a post-baseline disease assessment.

Series1

-100

-80

-60

-40

-20

0

20

40

60

80

100

Perc

ent C

hang

e at

Max

imum

Red

uctio

n fr

om

Bas

elin

e M

easu

rem

ent

C‡ C C C C C CC‡ ‡ ‡ ‡ § *******

*

Maximum Tumor Reduction by Mutation Type

RR, Response rate (CR+PR),includes confirmed and unconfirmed response; DCR, Disease control rate (CR+PR+SD)CR, complete response; PR, partial response; SD, stable disease; PFS, Progression free survival

**

KRAS Mut+

KRAS WTEGFR Mut+ALK+

updated from Bennouna et al: IASLC WCLC 2013; Gandara Santa Monica 2014

Trametinib (GSK212) + Docetaxel in Advanced KRAS mutant & WT NSCLC

N (evaluable)

CR + PR, n (%)

PR, n (%)

Minor Response

,a n (%)SD,

n (%)

Disease Control

(CR + PR + SD), n (%)

Trametinib+ Pemetrexed KRAS+ 23 (22) 4 (17) 4 (17) 2 (9) 11 (48) 15 (65)

Trametinib + Docetaxel

KRAS+ (all mutation subtypes)

25 (21) 7 (28) 7 (28) 5 (20) 8 (32) 15 (60)

CONFIDENTIAL – DO NOT DISTRIBUTE

Trametinib plus pemetrexed in kRAS Mutant+

Kelly et al., ASCO 2013, abstract 8027Gandara et al, ASCO 2013Modified from slide courtesy of J. Weiss.

PD-0325901

• 44 patients treated – advanced NSCLC• PR 0%• PFS 1.8 months• OS 7.8 months• Diarrhea, fatigue, rash

Haura et al. CCR 2010

MEK162: Summary of PK data

• Rapid absorption, plasma Tmax ~1.5 hrs

• Cmax and AUC at 45mg BID was comparable to historical data

• Metabolite < 25% of MEK162 exposure

• Moderate inter-patient variability of exposure

• Modest accumulation on Day 15

Concentration profiles on Day 15 (45 mg BID)

Ascierto et al ASCO 2012 Oral Presentation Abstract #8511

Preliminary Results• Standard 3+3 Design

– 30 mg BID– 45 mg BID– 60 mg BID– 80 mg BID

• N: 19 pts• 2 DLTs at 80 mg BID

– Central serous-like retinopathy (n = 1; G3)– Dermatitis acneiform (n = 1; G3 despite maximal treatment measures)

• Initial: MTD 60 PO BID

Bendell et al. AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics--Nov 12-16, 2011; San Francisco, CA

Preliminary Results• Main AEs: GI, rash, elevated CK, and retinal

Disorders• 1/15 pts with PR• MEK 162 demonstrated desirable PK properties • Evidence of PD changes.• Study expanded in KRAS and Braf mutant tumors.• All DLTs resolved with drug interruption and

patients tolerated re-challenge at a lower dose

Bendell et al. AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics--Nov 12-16, 2011; San Francisco, CA

Summary in KRAS MutantsStudy N RR PFS OS Conclusion

Selumetinib+Docetaxelvs. Docetaxel (Janne 2012)

4443

37%0%

5.32.1

9.45.2

Selumetinib + Doce worthy of phase III study

Trametinib + DocetaxelAbstract 8028

21 28% NR NR Trametinib + Doce worthy of phase II study

Trametinib + PemetrexedAbstract 8027

22 17% 4.1-----------

Trametinib + pem worthy of phase II study

Selumetinib + Erlotinibvs. SelumetinibAbstract 8026

309

10%0%

2.33.8

12.8Not reached

Single-agent selumetinib active, but selumetinib + erlotinib not worthy of further study

Trametinibvs. DocetaxelAbstract 8029

8643

12%12%

2.92.9 -----------

Single-agent trametinib active, but not more so than standard cytotoxic therapy

MEK inhibition in KRAS WT

Study N RR PFS OS ConcErlotinib + Selumetinibvs. ErlotinibAbstract 8026

38 5%11%

2.12.1

13.712.9

Selumetinib does not add to Erlotinib in kRAS WT pts.

Trametinib + DocetaxelAbstract 8029

21 32% --------- -------- Trametinib + Docetaxel is active in kRAS WT.

Trametinib + PemetrexedAbstract 8027

15 16% 5.8--------

Trametinib + Pemetrexed is worthy of phase II testing.