Next Generation EGFR Inhibitors

Tony Mok MD

Li Shu Fan Medical Foundation Professor of Clinical Oncology

Dept. of Clinical Oncology

The Chinese University of Hong Kong

EGFR TKIs

First Generation

-Gefitinib

-Erlotinib

-Icotinib

Second Generation

-Afatinib

-Dacomitinib

Third Generation Fourth Generation?

EGFR TKI

First Generation

-Gefitinib

-Erlotinib

-Icotinib

Second Generation

-Afatinib

-Dacomitinib

Third Generation Fourth Generation?

ATP Erlotinib Erlotinib +T790M

EGFR Exon 20 T790M

1st generation

gefitinib, erlotinib

2nd generation

Afatinib, dacomitinib

T790M

WT

L858R/

X19 del

IC5

0

Clinical

tolerable

dose

Cross D, et al. Cancer Discov. 2014;4:1046-1061.

3rd-generation EGFR TKI

Mutation selective + irreversible binding + EGFR WT sparing

(30–100× more potent against T790M and 100× less potent against EGFR WT)

Irreversible binding occurs due to covalent bond with C797.

Pyrimidine-based TKI

Zhou and Janne Nature 2009

0

20

40

60

80

100

1000

2000

3000

4000Gefitinib

CL-387,785

HKI-272

WZ3146

WZ4002

WZ8040

H1975

IC5

0 (

nM

)

0

20

40

60

80

100

1000

2000

3000

4000Gefitinib

CL-387,785

HKI-272

WZ3146

WZ4002

WZ8040

PC9 GR

IC5

0 (

nM

)

De

l19

/T7

90

M

0w Vehicle 2w

0w WZ4002 2w

L8

58

R/T

79

0M

0w WZ4002 2w

0w Vehicle 2w

0

50

100

150

200

250

Vehicle WZ-4002 Vehicle WZ-4002

Rela

tive T

um

or

Vo

lum

e %

p = 0.018p = 0.001

L858R/T790MDel19/T790M

Zhou et al. Nature 2009

0 3 7 10 14 17 21 24 280

200

400

600

800

1000

Vehicle

WZ4002

Erlotinib

Day

Tu

mo

r S

ize

(m

m3)

A431 Cells

EGFR WT & amplified

A New Generation of T790M inhibition

AZD9291

HM61713

CO1686

Avitinib

AZD9291

(Osimertinib)

AURA: Phase I dose expansion study

Escalation

Expansion

Phas

e I

Cohort 1

20 mg

Negative

Cohort 2

40 mg

Cohort 5

240 mg

Rolling six design

Cytology

Tablet

Negative

Cohort 3

80 mg

Negative

Cohort 4

160 mg

Positive Positive PositivePositive Positive

Biopsy Biopsy

First-line First-line

Patients with T790M positive advanced NSCLC

whose disease has progressed following either

one prior therapy with an EGFR-TKI or following

treatment with both EGFR-TKI and other

anticancer therapy

AURA: RR of osimertinib in T790M

positive patients

RR: 64%

Janne et al NEJM 372:1689, 2015

Impact of dose on RR

PFS in T790M +ive and –ive populations

Median

PFS at 9.6

months

AURA2: Phase II, open-label, single-arm study on osimertinib

*Mitsudomi et al WCLC 2015

Primary objective

To investigate the efficacy of AZD9291 by assessment of ORR (RECIST 1.1 BICR)

Patients with confirmed

EGFRm locally advanced or

metastatic NSCLC who have

progressed following prior

therapy with an approved

EGFR-TKI

Central T790M mutation

testing* of biopsy sample

collected following confirmed

disease progression

T790M

positive

(n=210)

T790M

negative

AZD9291 80 mg once daily

Not eligible for enrollment

Key inclusion criteria

•Aged ≥18 (≥20 in Japan)

•Confirmation of tumor EGFR mutation associated with EGFR-TKI

•At least one lesion suitable for accurate repeated measurements

•WHO performance status 0 or 1

•Acceptable organ function

•Stable brain metastases allowed

NOTE: Investigator-assessed ORR was also 71% (95% CI 64, 77)

Data cut-off: May 1, 2015. Population: evaluable for response set (n=199). *Represents imputed values: if it is known that the patient has died, has new lesions or progression of non-target lesions, has withdrawn due to disease progression, and

has no evaluable target lesion (before or at progression) assessments, best change will be imputed as 20%; †ORR defined as the number (%) of patients with at least one visit response of complete response or partial response that was confirmed

at least 4 weeks later; ‡Response required confirmation after 4 weeks; §Stable disease ≥6 weeks included the RECIST visit window (±7 days) CI, confidence interval; DCR, disease control rate (complete response + partial response + stable disease)

Tumor response by independent central review

Confirmed objective response Total

ORR† 71% (95% CI 64, 77)

Complete response,‡ n (%)

Partial response,‡ n (%)

Stable disease ≥6 weeks,§ n (%)

Progressive disease, n (%)

2 (1)

139 (70)

41 (21)

15 (8)

DCR92%

(95% CI 87, 95)

Best percentage change from baseline in target lesion – all patients

Complete response

Partial response

Stable disease

Progressive disease

Not evaluable

100

80

60

20

-20

-40

-60

-80

-100

40

0

Duration of response and progression-free survival

Data cut-off: May 1, 2015. *Green dotted lines represent 95% CI; †Calculated using the Kaplan-Meier technique; ‡Population: evaluable for response analysis set; §Population: full analysis set (n=210); ¶DoR is the time from the first documentation

of complete/partial response (that is subsequently confirmed) until the date of progression or death in the absence of disease progression; **PFS is the time from date of first dosing until the date of objective disease progression or death; ††Median

PFS (months) by investigator assessment§was NC (95% CI 9.3, NC). Maturity: 37%

DoR, duration of response; KM, Kaplan-Meier; NC, not calculable; PFS, progression-free survival

KM-based estimated† Total§

Median PFS,** months (95% CI)†† 8.6 (8.3, 9.7)

Maturity: 38%

Remaining alive and progression free,

% (95% CI)

6 months

9 months

70 (63, 76)

48 (36, 58)

Median follow-up for PFS 6.7 months

Progression-free survival* (BICR)

KM-based estimated† Total‡

Median DoR,¶ months (95% CI)7.8 (7.1, NC)

Maturity: 27%

Remaining in response, % (95% CI)

6 months

9 months

75 (65, 82)

NC (NC, NC)

Range of DoR, months 1.3–8.4

Duration of response* (BICR)

Number of patients

at risk:

1.0

0.9

0.8

0.7

0.5

0.4

0.3

0.2

0.0Pro

bab

ility

of

pro

gre

ssio

n-f

ree s

urv

ival

129630

Month

0.6

0.1AZD9291 80 mg

210 172 115 15

Censored observations

1.0

0.9

0.8

0.7

0.5

0.4

0.3

0.2

0.0

Pro

bab

ility

of

resp

on

se

129630

Month

0.6

0.1

Number of patients

at month:

AZD9291 80 mg

141 123 43

Censored observations

Osimertinib approved by FDA on Nov 13, 2015

(2.5 years since the first patient enrollment)

AURA2 (n=210)

Osimertinib 80 mg

QD

T790M

positiveT790M

negative

Central T790M mutation testing* of biopsy

sample collected following confirmed

disease progression

Patients with confirmed EGFRm locally

advanced or metastatic NSCLC who have

progressed following prior therapy with an

approved EGFR-TKI

Pooled analysis of AURA 1+2

Escalation

Expansion

Ph

ase

I

AURA Phase II Extension (n=201)

Osimertinib 80 mg QD

T790M

cohorts

Cohort 1

20 mg

Negative

Cohort 2

40 mg

Cohort 5

240 mg

Rolling six design

Cytology

Tablet

Negative

Cohort 3

80 mg

Negative

Cohort 4

160 mg

Positive Positive PositivePositive Positive

Biopsy Biopsy

First-line First-line

AURA Ph I/II AURA2 Ph II

Not eligible

for enrollment

Patients with T790M positive advanced NSCLC whose disease has

progressed following either one prior therapy with an EGFR-TKI or

following treatment with both EGFR-TKI and other anticancer therapy

AURA Ph I data cut-off 4 January, 2016; AURA pooled Ph II data cut-off 1 November, 2015.

*The EGFR T790M mutation status of the patient’s tumour was prospectively determined by the designated central laboratory using the

cobas™ EGFR Mutation Test (Roche Molecular Systems) by biopsy taken after confirmation of disease progression on the most recent treatment regimen.

Data from cohorts in grayed out boxes are not included in the analyses reported here.

QD, once daily

Pooled Phase IIRR and PFS on 411 patients with T790M mutation

Largest cohort (n=411) of T790M +ive

population on osimertinib 80mg

Yang et al ELCC 2016

Median PFS: 11 months

AURA 3 Study Design

P

T790M+

(n=470)

T790M- Not eligible for enrolment

AZD9291 (80 mg p.o.

qd) (n=407)

Platinum-based doublet

chemotherapy* every

3 weeks (n=203)

Central

testing of

~ 1540

biopsy

samples

Randomise ~470 patients 2:1

*Pemetrexed 500 mg/m2 + carboplatin AUC5 or

Pemetrexed 500 mg/m2 + cisplatin 75 mg/m2AUC5, area under the plasma concentration–time curve 5 mg/mL−1 per minute;

EGFRm+, EGFR mutation-positive; EGFR-TKI, EGFR tyrosine kinase inhibitor;

NSCLC, non-small cell lung cancer; p.o., orally; qd, once daily;

T790M+, T790M mutation-positive; T790M-, T790M mutation-negative

Primary endpoint:

PFS

PI: T Mok YL Wu

Best timing for osimertinib?

Dx of EGFR

mutation

positive lung

cancer

(+/- T790M)

Presence of

T790M in

plasma

cfDNA

Clinical

progression

and T790M

+ive

Supported by

AURA 1/2/3

To be supported

by FLAURA? ?

EGFR TKI

Potential study concept:

Osimertinib for molecular progression

Monthly

cfDNA for

T790M for

patient on

first line TKI

Continue

the same

TKI till

radiologic

progression

Osimertinib

Plasma positive for

T790M without

radiologic

progression

osimertinib

Time to osimertinib Failure (TTF)

Time to osimertinib Failure (TTF)

Primary

endpoint:

TTF or OS

Rociletinib (CO-1686)

Phase I/II dose escalation study

T790M positive T790M negative

Sequist et al NEJM 2015

Confirmed RR by central

review in 46 pts = 59%

Toxicity signal: hyperglycemia

M502

625mg BID

500mg BID

TIGER-X: Phase 1/2 Trial of RociletinibKey eligibility criteria

• Advanced or recurrent NSCLC with a documented activating EGFR mutation

• Prior treatment with EGFR-directed therapy

• Recent biopsy available or willing to undergo a new on-study biopsy; plasma samples collected

• Phase 2 only

– Disease progression while on treatment with EGFR-directed therapy

– T790M-positive biopsy at the time of entering study

– Treated stable CNS metastases are allowed

26

Phase 1 (Dose Escalation) Phase 2 Expansion Cohorts

CO-1686 Treatment

750mg BID

2nd-line patients

PD upon 1 immediate prior TKI

>2nd-line patients

PD upon ≥2 TKI or chemotherapy

21-day cycles; escalate to MTD

Key outcome measures

• Safety

• Tolerability

• PK profile

• ORR

Best Response to Rociletinib (All Doses) in 256 Centrally Confirmed Tissue T790M+ Patients

100

80

60

40

20

0

−20

−40

−60

−80

−100

SL

D C

han

ge f

rom

Baseli

ne (

%)

500mg 625mg 750mg1000

mgTotal

N 50 124 78 4 256

ORR (%) 60 54 46 75 53

DCR (%) 90 84 82 100 85

27

+ Ongoing

500mg BID HBr

625mg BID HBr

750mg BID HBr

1000mg BID HBr

SLD, sum of longest diameters

*3 patients currently have no evaluable baseline lesions per database and are omitted from this analysis

Nov 2015:

FDA denied the fast track

application

May 2016:

Cessation of future

development of Rociletinib

Olmutinib

(HM61713)

HM61713 = BI 1482694

Phase I/II study in patients with EGFR TKI

pre-treated NSCLC

1. Park K, et al Santa Monica 2016.

Dose escalation (N=66)1

75 mg

100 mg

150 mg

200 mg

250 mg

300 mg

400 mg

500 mg

650 mg

800 mg

1200 mg

Expansion Part 2 (N=76; ongoing)

Expansion Part 1 (N=83)1

T790M-positive (central test)

Progression on ≥1 prior EGFR TKI

T790M positive or negative

Progression on prior EGFR TKI

T790M-positive or negative

Progression on ≥2 prior therapies,

including EGFR TKI

ORR and tumor shrinkage in T790M+

patients (independent review)

PR (n=43)

SD (n=20)

PD (n=3)NE (n=3)

Confirmed PR (n=32)

–100

–50

0

40T

um

or

vo

lum

e c

ha

ng

e (%

)

• DoR is immature; in patients with confirmed OR, response duration ranged between 6 and 31

weeks at data cut-off

Evaluable patients (n=69)

OR (confirmed and unconfirmed), n (%) 43 (62)

Disease control, n (%)

Confirmed OR, n (%)

SD, n (%)

63 (91)

32 (46)

31 (45)

PD, n (%) 3 (4)

NE, n (%) 3 (4)

DoR, duration of response; OR, objective response; ORR, objective response rate; NE, not evaluable; PD, progressed disease; PR, partial

response; SD, stable disease

Most frequent treatment-related adverse

events at 800 mg QDBI1482694 (HM61713) 800 mg QD (n=76)

AE, n (%) All grades Grade 3

Diarrhea 42 (55) 0

Rash 29 (38) 4 (5)

Nausea 28 (37) 0

Pruritus 27 (36) 1 (1)

Dry skin 22 (29) 1 (1)

Palmar-plantar erythrodysesthesia syndrome 22 (29) 2 (3)

Decreased appetite 20 (26) 0

Skin exfoliation 16 (21) 0

Vomiting 12 (16) 2 (3)

Abdominal pain 11 (14) 0

ALT increased 11 (14) 2 (3)

Abdominal pain upper 10 (13) 0

Constipation 10 (13) 0

Pyrexia 9 (12) 0

AST increased 9 (12) 2 (3)

Platelet count decreased 9 (12) 0

Dyspepsia 8 (11) 0

Fatigue 8 (11) 0

AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase

LUX Lung Program

ELUXA Lung Program

• ELUXA 1: Phase II trial in ≥second-line patients with

EGFRT790M+ NSCLC

• ELUXA 2: Phase III trial of second-line BI 1482694 vs platinum-

doublet chemotherapy in patients with EGFRT790M+ NSCLC

• ELUXA 3: Phase III trial of first-line BI 1482694 vs afatinib

in EGFR M+ NSCLC

• ELUXA 4: Phase I/II trial of BI 1482694 in Japanese

patients with EGFRT790M+ NSCLC

EGF816

Phase I/II study design

Tan et al ASCO 2015

Tumor response (n=53)

Tan et al ASCO 2015

Skin rash

Avitinib (AC0010)

3-6 3-6 3-63-63-6

Phase I dose Escalation/Expansion (BID) in T790M+

NSCLC Patients (NCT02330367)

3-6

40

20 20 202020

41

Best Change in Target Lesion and Objective Response Rate (N=36)

• All doses level (N=36)

ORR: 36%; DCR (PR+SD): 97% (35/36)

• Therapeutic doses level (200 mg to 300 mg, N=19)

ORR: 58%; DCR (PR+SD): 95% (18/19)

Wu YL Santa Monic 2016

EGFR TKI

First Generation

-Gefitinib

-Erlotinib

-Icotinib

Second Generation

-Afatinib

-Dacomitinib

Third Generation Fourth Generation?

Erlotinib

OsimertinibT790M+

EGFR

activating

mutation

T790M-

T790M – plus

unknown

resistance

“Loss of T790M”

T790M+ plus

unknown

resistance

T790M+ plus

C797S

Evolution of resistance mechanisms in EGFR mutant lung

cancer following successive EGFR TKI therapy

= resistance mechanism due to

activation of bypass or downstream

signaling pathway

= EGFR C797S

= EGFR T790M

Oxnard et al. IASLC 2015, and Planchard et al. Ann Oncol 2015

EGFR C797S

Zhou et al. Nature, 2009; Thress et al, Nature Medicine, 2015; 2Oxnard et al. IASLC 2015; 3Song et al. JTO 2016

EGFR C797 – Covalent binding site of all mutant

selective EGFR Inhibitors

Normalize of All Cells

-6 -4 -2 0 20

50

100

150121 pt - GEF

121 pt - WZ

121 Res # 1- GEF

121 Res # 1 - WZ

[TKI] log (uM)

Rela

tive C

ell N

um

be

r %

Co

ntr

ol

Figure 1

A)

Actin

ERK

pERK

pEGFR

- + - + 1 uM WZ

121 Pt Res # 1 C)

D)

MGH121 Res # 1 MGH121 pt

Figure 1 – A WZ4002-resistant cell line acquires a C797S mutation and maintains EGFR activity in the

presence of TKI. A) MGH121 parental (pt) and MGH121 WZ4002 Resistant # 1 (Res # 1) cells were

treated with the indicated concentrations of the 1st generation EGFR TKI gefitinib (GEF) or the 3rd generation

EGFR TKI WZ4002 (WZ) for 72 hours. Cell viability was measured by CellTiter-Glo. Experiments were

performed in quadruplicate and error bars depict standard error of the mean. B) MGH121 pt and Resistant

# 2 cells were treated with the indicated concentrations of WZ4002 (nM) for 1 week and then stained with

crystal violet. C) Lysates from MGH121 pt and MGH121 Resistant # 1 cells treated with DMSO or 1μM

WZ4002 for 6 hours were probed with the indicated antibodies. D) Chromatograms depicting the acquired

C797S mutation present in MGH121 Resistant # 2, but not MGH121 parental cells. The arrow is pointing to

the mutated base (G is WT-Cys, C is mt–Ser).

0

B)

10 30

100 300 1000

0 10 30

100 300 1000

MGH121 pt MGH121 Res # 1

G G C T G/C C C T C

Gly 796

Cys/Ser

797 Leu 798

G G C T G C C T C

Gly 796 Cys 797 Leu 798

EGFR

pS6

S6

C797S/T790M21%

T790M Maintained (No additional

resistance mechanism identified)

35%

T790M "Lost"29%

MET Amp/T790-wt3%

Her2 Amp/T790-wt3%

SCLC/T790-wt9%

Reported Resistance Mechanisms to Rociletinib and Osimertinib (n=34)

Thress KS, Paweletz CP, Felip E, et al, Nat Med. 2015;21(6):560-562.

Piotrowska Z, Niederst MJ, Karlovich CA, et al, Cancer Discov. 2015;5(7):713-722.

Yu HA, Tian SK, Drilon AE, et al, JAMA Oncol. 2015;1(7):982-984.

Planchard D, Loriot Y, André F, et al, Ann Oncol. 2015;26(10):2073-2078.

Kim TM, Song A, Kim DW, et al, J Thorac Oncol. 2015. Courtesy Zofia Piotrowska

EGFR L798I

αD helix

PNAS, 1991, 88, 5317-5320 Jeabong Jang and Nathanael Gray

Chabon et al ASCO 2016

The first report of a potential

molecule targeting C797S

EGFR Allosteric Inhibitor:

EAI-045

Limited activity as an single agent

• EAI045 binds the C-

Helix, which can be

displaced by

dimerization of EGFR

• Prevention of

dimerization may

improve the potency

of EAI045 in C797S

mutation.

Summary• AZD9291 (Osimertinib)

– Approved therapy for T790M+ disease

– RR at 64%, PFS 9.6month

• CO1686 (Rociletinib)

– RR is not confirmed at the FDA submission

– Hyperglycemia from active metabolite

• HM61713 (Olmutinib)

– Enter into phase III study after a partnership with BI

• EGF816

– Phase I response rate at 75%

– Unusual maculopapular rash

• Fourth Generation?

– Targeting C797S

– Allosteric molecule EAI045

I am so confused!!