Novel Strategies for Attacking the Epidermal Growth Factor Receptor

David Carbone, MD PhD Director, James Thoracic Center

The Ohio State University Columbus, OH USA

Developmental Therapeutics—Clinical Pharmacology and Experimental Therapeutics • Board 225 - Preliminary results of TATTON, a multi-arm phase Ib trial of

AZD9291 combined with MEDI4736, AZD6094 or selumetinib in EGFR-mutant lung cancer. (Abstract 2509) G. R. Oxnard, S. S. Ramalingam, M. Ahn, S. Kim, H. A. Yu, H. Saka, L. Horn, K. Goto, Y. Ohe, M. Cantarini, P. Frewer, M. Lahn, J. C. Yang

• Board 227 - Phase I expansion of S-222611, a reversible inhibitor of EGFR and HER2, in advanced solid tumors, including patients with brain metastases. (Abstract 2511) S. Deva, R. D. Baird, N. Cresti, J. Garcia-Corbacho, L. Hogarth, E. P. Frenkel, K. Kawaguchi, A. Arimura, K. Donaldson, J. Posner, D. Sarker, D. I. Jodrell, R. Plummer, J. F. Spicer

• Board 226 - ABT-414 in patients with advanced solid tumors likely to overexpress the epidermal growth factor receptor (EGFR). (Abstract 2510) G. D. Goss, E. E. Vokes, M. S. Gordon, L. Gandhi, K. P. Papadopoulos, D. W. Rasco, M. Pedersen, J. S. Fischer, K. Chu, W. Ames, H. Xiong, H. Lee, J. Zeng, L. Roberts-Rapp, P. Ansell, E. Reilly, K. D. Holen, A. W. Tolcher

EGFR • Receptor discovered by Stanley

Cohen, for which he received the Nobel prize in 1986.

The ErbB Family and Ligands EGF

TGF-α Amphiregulin

β-cellulin HB-EGF

Epiregulin Heregulins HB-EGF

Heregulins β-cellulin

Tyrosine Kinase Domain

ErbB-1 HER1 EGFR

ErbB-2 HER2 neu

ErbB-3 HER3

ErbB-4 HER4

Extracellular

Intracellular

No Known Ligands

The ErbB Family and Ligands

LIG

ANDS

RECE

PTO

RDI

MER

SAD

APTO

RS

& EN

ZYM

ES

p21-GDP

p21-GTP

INPUTLAYER

HIDDENLAYERS

LIG

ANDS

RECE

PTO

RDI

MER

S

1 1 1 4 4 4 3 43 3

NRG1(3,4)

α β

NRG3(4)

AMPHI-REGULIN

(1)

HB-EGF(1,4)

BET A-CELLULIN

(1)

EPIREGULIN(1,4)

TGF α(1)

LP AThrombinET, etc.

CYT OKINESNRG2

(4)βα

SRCCBL

PLC γPI3K SHP2 GAP NCK

GRB7CRK

JAKSHC

GRB2

SOS ADAP

TOR

S&

ENZY

MES

CASCADES

TRANSCRIPTIONFACT ORS

AKTS6KBAD

PAK

JNKJNKK

RAF

MAPKMEK ABLPKC

SP1 EGR1MYC ELK STATJUN

FOS

OUTPUTLAYER MIGRA TIONAPOPT OSIS GROWTH DIFFERENTIA TIONADHESION

3 22 21 2

1 3

EGF(1)

NRG4(4)

p21-GDP

p21-GTP

VAV

RAC

4 2

Yarden and Sliwkowski

A complex pathway made more so • Cancers tell us that a pathway is important

by clonally tweaking it • HER2 amplification • VIII mutation • Exon 19 deletion, L858R

2/20/01 4/23/01

Then tweaking it again to acquire resistance to our drugs: T790M !!

In this section we have • EGFR TKIs designed to target acquired

resistance mutations • EGFR TKIs in combination with other targeted

inhibitors • Drugs targeting multiple HER-family members

and with better brain penetration • Activation-specific EGFR antibody-drug

conjugate

Optimizing targeting of patients with EGFR mutant tumors • With 1st generation inhibitors, response rates

are high, but benefit is generally transient. • Clinical benefit may be improved by:

– Anticipating resistance mechansisms (Met, MEK) – Combination with other therapeutics (anti-PDL1)

• Can these be safely combined?

TATTON

AZD9291 + Selumetinib

AZD9291 + MEDI4736

AZD9291 + Savolitinib

Dose 2 AZD9291 (80 mg OD) + MEDI4736 (10 mg/kg Q2W)

Asia + ROW Dose 1

AZD9291 (80 mg OD) + MEDI4736 (3 mg/kg Q2W) Asia + ROW

Dose 2 – continuous AZD9291 (80 mg OD) + Selumetinib (50 mg BD)

Asia Dose 1 – continuous

AZD9291 (80 mg OD) + Selumetinib (25 mg BD) Asia

Dose 2 – continuous AZD9291 (80 mg OD) + Selumetinib (75 mg BD)

ROW Dose 1 – continuous

AZD9291 (80 mg OD) + Selumetinib (50 mg BD) ROW

Dose 2 – intermittent: 4 days on/3 days off AZD9291 (80 mg OD) + Selumetinib (75 mg BD)

ROW Dose 1 – intermittent: D1&D4/week

AZD9291 (80 mg OD) + Selumetinib (75 mg BD) ROW

Dose 2 AZD9291 (80 mg OD) + Savolitinib (800 mg OD)

Asia + ROW Dose 1

AZD9291 (80 mg OD) + Savolitinib (600 mg OD) Asia + ROW

Part A – Dose escalation Part B – Dose expansion

EGFR-mutant NSCLC dose escalation: locally confirmed T790M mutation status dose expansion: centrally confirmed T790M mutation status); progression on any prior EGFR-TKI

Innovative Phase I design allows continuous enrollment!

Best percentage change from baseline in target lesion size in patients* receiving AZD9291/MEDI4736 (anti-PDL1) by T790M status

-100%

-80%

-60%

-40%

-20%

0%

20%

40%

60%

80%

Neg

Neg

Neg

Neg

Pos

Pos

Pos

Neg

Pos

Neg

Pos

Pos

Pos

Neg

*Population: All patients dosed who had a baseline and 6-week RECIST assessment †Patients ongoing treatment at data cut off PD, progressive disease; PR, partial response; PRc,, confirmed partial response; RECIST, Response Evaluation Criteria In Solid Tumors; SD, stable disease

Unknown Positive Negative

PD

SD†

SD†

SD†

SD†

PR† PR†

PR PRc† PRc†

PRc†

PR†

PRc†

CR†

Best percentage change from baseline in target lesion size in patients* receiving AZD9291/selumetinib (MEKi) by T790M status

-100%

-80%

-60%

-40%

-20%

0%

20%

40%

60%

80%

Pos

Neg

Pos

Neg

Pos

Pos

Pos

Neg

Neg

Pos

Neg

Pos

UKN

Neg

Pos

Pos

Pos

Pos

Neg

Pos

Neg

Pos

Pos

*Population: All patients dosed who had a baseline and 6-week RECIST assessment †Patients ongoing treatment at data cut off PD, progressive disease; PR, partial response; PRc,, confirmed partial response; RECIST, Response Evaluation Criteria In Solid Tumors; SD, stable disease

Unknown Positive Negative

PD

SD† PD

PD

SD† SD†

SD† SD† SD† SD† SD† SD†

SD† SD†

PRc† PR PRc† PRc† PRc† PR† PRc†

PRc† PR†

Best percentage change from baseline in target lesion size in patients* receiving AZD9291/savolitinib (METi) by T790M status

-100%

-80%

-60%

-40%

-20%

0%

20%

40%

60%

80%

Pos

Neg

Pos

Pos

Neg

UK

Neg

Pos

Neg

Neg

Neg

*Population: All patients dosed who had a baseline and 6-week RECIST assessment †Patients ongoing treatment at data cut off PD, progressive disease; PR, partial response; PRc,, confirmed partial response; RECIST, Response Evaluation Criteria In Solid Tumors; SD, stable disease

c

AZ9291 combinations • Low intrinsic toxicity enables combinations • These rational combinations all have tolerable

toxicity profiles • High levels of activity observed • Remains to be seen if clinical benefit is more

durable, if resistance mechanisms are altered, and whether up-front combinations better than “reactive” ones.

Phase I expansion of S-222611, a reversible inhibitor of EGFR and HER2, in advanced solid tumors, including patients

with brain metastases. S Deva1, A Italiano2, R Baird3, N Cresti4, J Garcia Corbacho3, L Hogarth4, E Frenkel5, K Kawaguchi6, A. Arimura6, K Donaldson6, J Posner6, D Sarker1, D Jodrell3, R Plummer4 & J Spicer1

1King’s College London, Guy’s Hospital, London, UK; 2Institute Bergonie, FR; 3University of Cambridge, Department of Oncology, Cambridge, UK; 4Northern Centre for Cancer Care, Newcastle upon Tyne, UK; 5University of Texas Southwestern Medical Center, Dallas, TX, USA; 6Shionogi & Co. Ltd., Osaka, Japan

Abstract No. 2511

Summary • S-222611 is a potent and selective reversible tyrosine

kinase inhibitor of EGFR and HER2. • Greater potency of anti-tumor activity than lapatinib. • Higher brain penetration. • Maximum tolerated dose (MTD) was not established. • 800 mg daily was selected as a dose for the expansion

phase. • This study included patients with tumors often expressing

EGFR and/or overexpressing HER2.

Adverse drug reactions Incidence (%) of all grades of ADRs in ≥10% subjects [N= 76] No grade 4 or 5 ADRs

Events All grades Grade 3 Diarrhea 57 (75) 9 (12) Rash 36 (47) 0 Nausea 27 (36) 2 (3) Fatigue 23 (30) 2 (3) Vomiting 22 (29) 1 (1) Bilirubin ↑ 21 (28) 5 (7) Appetite ↓ 20 (26) 1 (1) Anemia 9 (12) 3 (4)

2 out of 76 patients (2.6%) withdrawn due to treatment-related AEs Blood bilirubin increased (G3) Nausea, Vomiting (G3)

Similar to erlotinib/lapatinib

HER2-positive breast and upper GI cancer

Patients

～ ～ ～ ～ 200

Primary tumor ORR: N (%) CBR: N (%)

Breast (N=25) 4 (16%) 7 (28%)

Upper GI (N=13) 2 (15%) 2 (20%)

Brain metastases from HER2-positive BC

Baseline Cycle 4 (16 w)

Heavily pre-treated with HER2-based therapies including lapatinib/capecitabine

Pts # HER2 IHC

Brain mets

Best overall response

# 1 3+ Target lesion

PR

# 2 3+ SD (≥12M)

# 3 3+ SD (6.0 M)

# 4 3+ Non-target lesion

SD (4.7M)

# 5 3+ SD (3.3M)

# 6 3+ NE

Pts #1

NOT similar to erlotinib/lapatinib!

Conclusions • A daily dose of 800 mg S-222611 was generally well-tolerated. 20% of patients

required dosage reduction (usually to 400 mg daily).

• Of 25 patients with HER2-positive breast cancer, the RR was 16%, and the CBR was 28%. 6 had brain metastases: 1 intracranial response and 2 prolonged SD (≥ 6 months) were observed.

• The majority of these patients were heavily pre-treated and had received prior HER2-directed therapy.

• Of 13 patients with HER2-positive upper GI cancers, the RR was 15%. • This Phase I study suggests S-222611 is well-tolerated with efficacy against

HER2-positive tumors, including breast cancer metastatic to brain. • It would be interesting to test this agent in non- T790M “brain sanctuary”

relapse patients with EGFR mutant lung cancer

Targeting aberrant EGFR protein • ABT-414 is an antibody-drug conjugate

composed of the antibody ABT-806, targeting an epitope exposed in active EGFR/mutant EGFRvIII (better than cetuximab), linked to the anti-microtubule agent monomethylauristatin

• This is a phase I/II open label study in patients with advanced solid tumors likely to overexpress EGFR

Phase I study of ABT-414 mono- or combination therapy with temozolomide in recurrent GBM (abstract 2016,

Monday afternoon posters)

• 28 patients treated as mono-therapy – 1 CR and 1 PR

• 18 patients with TMZ – 1 CR and 4 PR

Study Design and Primary Objectives

MTD, maximum tolerated dose; q3week, every 3 weeks; RPTD, recommended phase 2 dose; SPECT, single-photon emission computed tomography.

Results • Transient microcystic keratopathy observed • Also G3/4 keratitis, hyponatremia, blurred vision,

dyspnea, and pneumonia • One PR in TNBC • Signal of activity in GBM, ? H&N/BC • Striking difference in overall efficacy and toxicity

compared to that seen when targeting kinase mutant EGFR

Targeting the erbB family • We continue to optimize ErbB targeting:

– Targeting gatekeeper mutations – Inhibiting bypass pathways – Studying combinations with immunotherapies – Improving brain penetration – Targeting chemotherapeutics with ADCs

• In general activated “drivers” are better targets • Understanding and overcoming mechanisms of

escape/PK issues improves clinical efficacy