Rociletinib (CO-1686) · 2015. 4. 14. · Rociletinib (CO-1686) causes tumor regression in front-line L858R transgenic model • No cell line based models with EGFR L858R mutation

Rociletinib (CO-1686)

April, 2015

Lung adenocarcinoma is increasingly treated according to

driver mutation

• Lung cancer incidence

– Worldwide: 1.2M cases per year

– UK: 43K cases per year

• Activating mutations (e.g. del 19,

L858R) in EGFR found in ~15% of

all NSCLC

– Twice as common in East Asian

populations

• Standard of care in mutant EGFR

NSCLC is most often a reversible

EGFR inhibitor as first-line therapy

2

Globocan 2012; CRUK 2011; Blakely & Bivona, Cancer Discov. 2012

T790M is the most common reason for loss of initial benefit

with EGFR inhibitors in newly diagnosed NSCLC patients

• Tumor genetics in 155 mutant EGFR lung cancer patients

undergoing re-biopsy after development of acquired resistance to

erlotinib/gefitinib

3

Yu et al., Clinical Cancer Res. 2013

There are limited options for patients that progress on first

generation EGFR TKIs

• There are no therapies currently available to specifically target

T790M disease

• Current standard treatment is cytotoxic chemotherapy

– Platinum containing doublet chemotherapy (e.g. gemcitabine/cisplatin)

– Single agent chemotherapy (e.g. pemetrexed, docetaxel, gemcitabine)

• New treatment options with improved adverse event profiles and

reduced requirements for hospital care are needed.

4

Yu et al., Clinical Cancer Res. 2013

Rociletinib (CO-1686) nonclinical summary

• Rociletinib (CO-1686)

– Inhibits the T790M EGFR resistance mutation at clinically relevant

exposures

– Oral dosing

– Irreversible (covalent) inhibitor

– Inhibits EGFR activating mutations

– Spares wild-type (WT) EGFR signaling

– Highly selective across the entire kinome

• Rociletinib demonstrates potent activity and EGFR pathway blockade

in cell lines with activating and T790M EGFR mutations

• As a single agent rociletinib causes tumor regressions in front-line

and T790M xenograft models

– Includes subcutaneous, PDX, and transgenic models

5

CO-1686

Walter et al., Cancer Discov. 2013

Rociletinib (CO-1686) binds EGFR covalently

• Irreversible binding results in sustained EGFR pathway suppression

6

Acrylamide forms covalent

bond with C797

Interaction between trifluoromethyl

group and M790 increases potency


Rociletinib (CO-1686) inhibits mutant EGFR, including

T790M, but spares wild-type EGFR

• Growth inhibition of tumor cell lines with rociletinib (CO-1686)

7

GI 5

0 [

CO

-16

86

] n

M

NC

I-H

1975

HC

C827

PC

9

HC

C827-E

PR

A431

NC

I-H

1299

NC

I-H

358

1 0

1 0 0

1 0 0 0

1 0 0 0 0

G e n o ty p e

D e l1 9

L 8 5 8 R

T 7 9 0M

+ ++

+ +

+

-

- -

- --

-

-

-

-- -

-

-

-

Front line model

Second line model (T790M)

EGFR WT


Rociletinib (CO-1686) spares wild type EGFR

• Rociletinib (CO-1686) is uniquely WT EGFR sparing

8

Symbol Compound EC50 (nM)

afatinib 15

gefitinib 107

AZD9291 131

erlotinib 209

CO-1686 3930

0

2 5

5 0

7 5

1 0 0

1 2 5

1 5 0

A 4 3 1 (W T E G F R )

d o s e [n M ]

% v

iab

ilit

y (

me

an

S

EM

)

5 0001 2503137820510 .30 .080 .020 .004

rociletinib (CO-1686)

Clovis Oncology, data on file

Rociletinib (CO-1686) causes tumor regression in front-line

L858R transgenic model

• No cell line based models with EGFR L858R mutation available

• Performed “gold standard” transgenic model

• Conclusion: Xenograft and transgenic models show that rociletinib is

an effective inhibitor of initial activating EGFR mutations (Del19 and

L858R) and T790M

9

Erlotinib CO-1686 Vehicle

*

Me

an

tu

mo

r v

olu

me

(mm

3)

SE

M

0

1 0 0

2 0 0

3 0 0

4 0 0

5 0 0

6 0 0

B a s e l in e

2 1 -d a y s p o s t -d o s in g

V e h ic le E r lo t in ib

5 0 m g /k g Q D

C O -1 6 8 6

5 0 m g /k g B ID

* * * *

L8

58

R

* Diffuse tumor cells in lung


• CO-1686 activity observed in L858R/T790M transgenic model

-1 0 0

-8 0

-6 0

-4 0

-2 0

0

2 0

4 0

6 0

8 0

1 0 0

2 0 0

4 0 0

6 0 0

Ch

an

ge

fro

m B

as

eli

ne

(%

)

P D

S D

P R

C R

A fa tin ib

2 0 m g /k g

C O -1 6 8 6

5 0 m g /k g B ID

CO-1686 : Baseline CO-1686 : 3W

Afatinib: Baseline Afatinib : 3W

Rociletinib WT EGFR sparing profile allows for dosing to

efficacy - not MTD

10


Long-term Rociletinib activity superior to erlotinib in PC-9

(EGFRdel19) front line model

• Inhibition of T790M may improve durability of response

• rociletinib (CO-1686) administration better tolerated

– Impressive anti-tumor response in ~500 mm3 tumors

– No body-weight loss compared to vehicle treated animals

11

0 1 0 2 0 3 0 4 0 5 0 6 0 7 0 8 0 9 0 1 0 0

0

2 0 0

4 0 0

6 0 0

8 0 0

1 0 0 0

1 2 0 0

1 4 0 0

D a y s o f d o s in g

Tu

mo

r v

olu

me

(Me

an

mm

3

SE

M)

V e h ic le

C O -1 6 8 6 (1 5 0 m g /k g B ID )

E rlo t in ib (5 0 m g /k g Q D )

C o n tin u e d o s in g n = 3 m ic e w ith e rlo tin ib

D o s e re m a in in g m ic e w ith C O -1 6 8 6

Clovis Oncology, data on file

TIGER-X Phase 1 identified 625 mg as Phase 2 dose

• TIGER-X, an international phase 1/2 study, examined 2 formulations

and multiple doses/schedules of rociletinib

– Therapeutic doses defined as 900 mg BID (original formulation) or ≥500

mg BID HBr salt tablet (PK optimized formulation)

• Two clinical doses under exploration – 500 mg BID and 625 mg BID

• 625 mg BID of optimized oral formulation (fed state) was identified as

the optimal dose and schedule

– 500 mg BID remains under investigation as step-down dose

– Clinical dose group: patients treated with 625/500 mg BID (n=56)

• Early evidence of activity was observed with durable RECIST

responses, particularly in T790M+ patients

• Wild-type EGFR sparing was confirmed by absence of cutaneous

toxicity (rash, paronychia, stomatitis, etc)

• Breakthrough status was granted by FDA in May 2014

FDA = US Food and Drug Administration; HBr = hydrobromide; RECIST = Response

Evaluation Criteria In Solid Tumors; RP2D = recommended phase 2 dose

12

Soria et al., ENA, 2014

TIGER-X expansion phase in T790M+

Key exclusion criteria:

– Symptomatic brain metastases

– Exon 20 insertion as activating EGFR mutation

• Patients with diabetes or cardiovascular disease were eligible

• Study sites in United States, Europe, and Australia

Key inclusion criteria:

– Advanced or metastatic EGFR mutation+ NSCLC

– At least 1 prior EGFR TKI therapy, with no upper limit or limit

on chemotherapy

– Biopsy within 60 days of study entry – molecular analysis T790M+

13


TIGER-X clinical dose group (T790M+):

baseline characteristics

625 mg BID 500 mg BID Total

N 30 26 56

Median age, years 59 59 59

Female, % 63 77 70

Asian, % 7 15 11

ECOG PS grade 0, % 13 27 20

Median no. of prior Rx 3 3 3

No. of prior TKIs, %

1 43 46 45

2 13 39 25

≥3 27 12 20

Immediate prior TKI, % 73 85 79

History of diabetes, % 3 12 7

History of cardiovascular disease, % 13 15 14

*7 patients started treatment with 900 mg BID free-base formulation and converted to 500 mg HBr salt tablet. The

majority of their treatment was with HBr tablet and they are aggregated with the 500 mg BID HBr tablet group.

ECOG PS = Eastern Cooperative Oncology Group Performance Status.

14


Rociletinib demonstrated linear pharmacokinetics across

efficacious dose range

• Rociletinib was absorbed rapidly with an elimination half-life of 2 – 4

hours, suitable for BID dosing regimen

• High fat breakfast slightly slowed the rate of absorption and

increased the amount absorbed with no change in the peak plasma

concentration of CO-1686

• No accumulation of CO-1686

15

5 0 0 7 5 0 1 0 0 0

0

1 2 5 0 0

2 5 0 0 0

3 7 5 0 0

5 0 0 0 0

6 2 5 0 0

7 5 0 0 0

1 0 0 0 0 0

1 2 5 0 0 0

H B r D o s e v s A U C

B ID D o s e (m g )

6 2 5

CO

-16

86

AU

C0

-24 (

ng

.h/m

L)

P h a s e 1

P h a s e 2

Wakelee et al., ELCC, 2014

TIGER-X clinical dose group responses

67% ORR 67% ORR (per RECIST 1.1)

89% DCR

Best Response for Evaluable T790M+ Patients

Ch

an

ge f

rom

Baselin

e (

%)

100

80

60

40

20

0

-20

-40

-60

-80

-

100

16


TIGER-X clinical dose group: PFS

*Data as of 25 September 2014 reflecting 31% data maturity

PFS = progression-free survival.

Kaplan-Meier Plot of PFS in T790M+ Patients

Su

rviv

al

Pro

bab

ilit

y

PFS (months)

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

+ + + + + + + + +

+

+ + + + + +

+

+

+

+

+ +

56(0) 52(1) 27(4) 21(5) 18(7) 16(8) 14(10) 11(13) 11(13) 7(13) 6(13) 5(14) 5(15) 2(17) 1(17) 1(17) 1(17) 0(17)

At Risk (events)

Median PFS = 10.4 months*

17


TIGER-X clinical dose group: adverse events

Adverse event Frequency, %

Hyperglycemia 32

Diarrhea 25

Nausea 25

Reduced appetite 20

Fatigue 14

Muscle spasm 13

Vomiting 11

Treatment-related adverse events

(all grades) seen in >10% of patients

Adverse event Frequency, %

Hyperglycemia 14

Grade 3/4 treatment-related adverse events

seen in >5% of patients*

*21% of patients had a grade 3/4 treatment-related

adverse event and only hyperglycemia was

observed in ≥5% of patients

18


TIGER-X adverse events of interest

• No grade 3/4 adverse events observed in >1 patient except for

hyperglycemia

– Hyperglycemia readily managed with oral agent (typically metformin)

and, on occasion, dose reduction

• No cutaneous toxicity of note

– Grade 1 rash observed in 2 patients (transient, not acneiform/folliculitis)

– No paronychia or stomatitis

• Grade 3 QTc prolongation observed in 1 patient (625 mg BID)

• Across entire clinical program (>200 patients, all doses, all

genotypes):

– Pneumonitis observed in 4 patients – all quickly reversible; last 2 cases

resumed rociletinib therapy under steroid cover without recurrence of

pneumonitis

– No heart failure observed

19


Observed hyperglycemia relates to metabolite of rociletinib

• Rociletinib metabolite M502 is an inhibitor of IGF1R and accumulates

in humans causing hyperglycemia

– No hyperglycemia observed in toxicology studies of rociletinib

• Like rociletinib, M502 is wild-type EGFR sparing

Assay Rociletinib M502

A431 (IC50, nM) Cellular (wild-type EGFR)

903 907

NCI-H1975 (IC50, nM) Cellular (T790M EGFR)

36 961

IGF1R (IC50, nM) Kinase

477 57

IGF1R (IC50, nM) Cellular

458 58

IC50 = half maximal inhibitory concentration

IGF1R = insulin-like growth factor 1 receptor

20


IGF1R pathway activation may play a role in acquired

resistance to EGFR TKI

• Multiple publications have demonstrated a role for IGF1R signaling in

mediating resistance to EGFR inhibitors in NSCLC models

– Resistance to WZ4002 (a third-generation EGFR inhibitor structurally related to

CO-1686) is mediated by IGF1R signaling and can be reversed by the addition of

an IGF1R inhibitor (data from Janne lab)

100

80

60

40

20

0 0 0.01 0.1 1 10

WZ4002 (μmol/L)

+ DMSO

+ BMS536924

+ DMSO

+ BMS536924

WZR3

WZR4

WZ4002 + IGF1R inhibitor BMS536924 restores activity in resistant cell lines with IGF1R pathway activation

Pe

rce

nta

ge

of

Co

ntr

ol

Cortot et al., Cancer Res. 2013; Sharma et al., Cell 2010; Vazquez-Martin et al., Sci Rep. 2013

21

IGF1R inhibitor can overcome resistance in mutant EGFR

patient derived cell lines

• Cell line models derived from biopsy specimens collected after the

development of acquired resistance to EGFR inhibitors

• IGF1R inhibitor combination restores activity in 3/11 patient cell lines

Crystal et al., Science 2014

22

Cell line Patient

IGF1R

Combined responses from TIGER-X Phase 1/2 C

han

ge f

rom

Baselin

e (

%)

Best Response for All Patients (Any T790M

Status) on Therapeutic Doses (n=179)

ORR = 46% DCR = 84%

100

80

60

40

20

0

-20

-40

-60

-80

-

100

DCR = disease control rate; ORR = overall response rate.

23


Striking Activity in T790M-negative Patients

24

*Database as of January 2nd 2015

• RECIST ORR = 42% overall

• RECIST ORR = 50% in patients treated

with 625mg BID immediately off prior TKI

• mPFS = 7.5mo

Best Response for Target Lesions Centrally Confirmed T790M Negative 1686-008 Pts at 500 or 625mg BID

(Clinical Dose Group)

Comprehensive Monotherapy Development Program

TIGER-X (Ph 2) TIGER-X (Ph 2) • Single arm – expansion cohorts

• ≥2nd-line mutant EGFR NSCLC, T790M+

TIGER-1 (Ph 2/3) TIGER-1 (Ph 2/3) • Randomized rociletinib vs erlotinib

• 1st-line, treatment-naïve

TIGER-2 (Ph 2) TIGER-2 (Ph 2)

• Single-arm

• 2nd-line mutant EGFR NSCLC, T790M+

• Patients progressing on 1st-line EGFR TKI

• Now adding T790M– cohort

TIGER-3 (Ph 3) TIGER-3 (Ph 3) • Randomized rociletinib vs chemotherapy

• >2nd-line mutant EGFR NSCLC, T790M+

and T790M– (sequential analysis)

25


Qiagen’s existing therascreen® EGFR test is being developed as a

tissue companion diagnostic (CDx) for rociletinib

• Qiagen therascreen EGFR test for FFPE specimens

– Detects 29 mutations in EGFR

– Uses allele-specific PCR

– FDA-approved (with Afatanib)

• Clinical validation required for approval with rociletinib

26

FFPE = formalin-fixed paraffin-embedded

Combination studies to begin

• Rociletinib to be combined with several targeted therapeutics and

checkpoint inhibitors

• Collaborations established with multiple partner

companies/physicians

• Initial combination with:

27

Target Drug

PDL1 mAb

PD1 Pembrolizumab (Merck)

MEK Trametinib (GSK)

Aurora kinase small molecule inhibitor


Conclusions

• Rociletinib (CO-1686) is an oral, potent, irreversible inhibitor of

activating EGFR mutations and T790M

• Compelling and durable activity was demonstrated with clinical

doses in T790M+ patients

– 67% objective response rate

– Median (immature) PFS estimated at 10.4 months

• Wild-type sparing was confirmed, with no cutaneous toxicity

• The only grade 3/4 adverse event observed in >5% of patients

was hyperglycemia, readily managed with oral Rx

• Encouraging activity was observed in T790M– patients

• Comprehensive pivotal trial program is advancing rapidly

• NDA and MAA filings planned for mid 2015

28

Differentiation and areas of interest

• Rociletinib (CO-1686) has a unique tolerability and efficacy profile

– No evidence of WT EGFR inhibition observed in patients

– Evidence of activity in T790M- patients

– Moderately short plasma half-life allows for flexibility in dosing regimens

and management of potential combination AEs

• Clovis is interested in performing combination studies beyond those

mentioned with rociletinib, for example:

29

Combination Rationale

Anti-angiogenesis PFS increase in mutant EGFR patients treated with EGFR TKI and bevacizumab

Anti-EGFR antibody Dual inhibition of EGFR; block dimerization; potential lack of overlapping toxicity

Met inhibitor Activating and T790M EGFR pathway blockade may drive bypass pathway

activation

PARP inhibitor Platinum sensitivity and HRD signature observed in NSCLC

Mathematical based

alternative dosing strategies Use mathematical evolutionary modeling to delay the onset of acquired resistance

Radiotherapy Radio-sensitizing potential; lack of overlapping toxicity

Documents

Rociletinib (CO-1686) · 2015. 4. 14. · Rociletinib (CO-1686) causes tumor regression in front-line L858R transgenic model • No cell line based models with EGFR L858R mutation