A Phase 1 Study of MM-302, a HER2- targeted PEGylated liposomal doxorubicin, in Patients with HER2-positive Metastatic Breast Cancer (MBC)

(1)

P LoRusso1_{, I Krop}2_{, K Miller}3_{, C Ma}4_{, BA Siegel}4_{, AF Shields}5_{, I Moln}_ár6_,

T Wickham6_{, J Reynolds}6_{, K Campbell}6_{, B Hendriks}6_{, T McClure}6_,

V Moyo6_{, P Munster}7

A Phase 1 Study of MM-302, a

HER2-targeted PEGylated liposomal doxorubicin,

in Patients with HER2-positive Metastatic

Breast Cancer (MBC)

1_{Yale Cancer Center, New Haven, CT;}2_{Dana-Farber Cancer Institute, Boston, MA;}3_{Indiana University}

Melvin and Bren Simon Cancer Center, Indianapolis, IN, 4_{Washington University School of Medicine,}

St. Louis, MO; 5_{Karmanos Cancer Institute, Detroit, MI;}6_{Merrimack Pharmaceuticals, Cambridge, MA;} 7_{Helen Diller Family Comprehensive Cancer Center, San Francisco, CA}

(2)

Background

• HER2-positive breast cancer affects ~20% of all breast cancer

and represents a particularly aggressive form of the disease

• Despite recently approved agents like pertuzumab and T-DM1,

HER2-positive MBC remains a high unmet medical need

• Anthracyclines are particularly effective in HER2-positive BC;

however use has declined due to several reasons

• Microtubule targeting agents are heavily used in all lines

(3)

MM-302

:

HER2-targeted PEGylated liposomal doxorubicin

anti-HER2 scFv

• Targets liposome to HER2-overexpressing cells • Promotes internalization

• Binds to a different epitope than trastuzumab • Does not bind to cardiomyocytes

Doxorubicin Crystals

• Effective cytotoxic agent in breast cancer • DNA intercalator, TOP2A inhibitor, free

radical generator

anti-HER2 scFv

radical generator Lipid Membrane PEG 75-110 nm anti-HER2 scFv

Liposome

• Extended half-life

• Stably encapsulates doxorubicin • Passive accumulation in tumors

• Size precludes delivery to cardiac tissue

radical generator Lipid Membrane PEG 75-110 nm anti-HER2 scFv

Liposome

• Extended half-life

• Stably encapsulates doxorubicin • Passive accumulation in tumors

• Size precludes delivery to cardiac tissue

(4)

2 MM-302 Doxorubicin HER2

HER2-positive tumor

Cancer Cell Death 2 2 2 Extravasation via leaky

vasculature _{Binding and} internalization

capillary

MM-302 Proposed Mechanism of Action

4 control MM-302 PLD doxorubicin SUM190 cells (HER2-positive)

(5)

2

X

Does not bind to cardiomyocytes Tight vasculature

MM-302 Proposed Mechanism of Action

H e a r t C e lls 0 5 0 1 0 0 1 5 0 2 0 0 0 1 0 0 0 2 0 0 0 3 0 0 0 4 0 0 0 5 0 0 0 In c u b a t io n t im e ( m in ) to ta l c e ll a s s o c ia te d d o x o r u b ic in (f e m to g r a m s /c e ll ) d o x o r u b ic in P L D M M - 3 0 2 2 MM-302 Doxorubicin HER2

Cardiac tissue

capillary

X

Human stem cell-derived

cardiomyocytes

5

(6)

Preclinical

data supporting MM-302 development

2 0 3 0 4 0 5 0 6 0 0 5 0 0 1 0 0 0 1 5 0 0 2 0 0 0 2 5 0 0 3 0 0 0 D a y s a f t e r i n o c u l a t i o n T u m o r V o l u m e ( m m 3 ) *** * 3 0 4 0 5 0 6 0 7 0 8 0 9 0 0 5 0 0 1 0 0 0 1 5 0 0 2 0 0 0 D a y s a f t e r i n o c u l a t i o n T u m o r V o l u m e ( m m 3 ) ** trastuzumab MM-302 HER2

MM-302 binds to a different epitope than trastuzumab

BT474-M3-breast

NCI-N87-gastric

6 Control MM-302 3 mg/kg weekly trastuzumab 3.5 mg/kg q3d MM-302 & trastuzumab

(7)

Use of Cyclophosphamide Pretreatment to Enhance

MM-302 Tumor Deposition (

BT474-M3

)

N o C y c l o + C y c l o ( - 4 d ) 0 5 1 0 1 5 2 0 % i . d . / g t i s s u e Tumor Deposition N o C y c l o + C y c l o ( - 4 d ) 0 1 0 2 0 3 0 4 0 5 0 6 0 % D O X P O S N u c l e i Nuclear Doxorubicin 2 0 3 0 4 0 5 0 0 1 0 0 2 0 0 3 0 0 4 0 0 5 0 0 6 0 0 7 0 0 8 0 0 9 0 0 C T L M M - 3 0 2 a lo n e M M - 3 0 2 + C y c lo C y c lo 9 6 h r D a y p e r c e n t c h a n g e f r o m d a y 1 4 Tumor Shrinkage No Cyclo + Cyclo MM-302 doxorubicin 7

(8)

MM-302 Phase 1 Study

a_{: 6 mg/kg trastuzumab loading dose,}b_{: 8 mg/kg trastuzumab loading dose}

Patients with locally advanced/unresectable or metastatic HER2-positive breast cancer (N=69) Arm 2 Arm 3 Arm 4 Arm 1 30 & 40 mg/m2_{MM-302, q4w} + 4 mg/kg trastuzumaba_{, q2w}

10

30 mg/m2_{MM-302, q3w} + 6 mg/kg trastuzumabb_{, q3w} + 64_Cu-MM-302

12

30 mg/m2_{MM-302, q3w} + 6 mg/kg trastuzumabb_{, q3w} + 450 mg/m2_{cyclophosphamide, q3w} + 64_Cu-MM-302

13

8, 16, 30, 40 & 50 mg/m2_{MM-302, q4w}

₃₄

patients 8

(9)

Key Study Objectives

• Primary Objective

:

–

To assess the safety and tolerability of:

• MM-302 alone

• MM-302 plus trastuzumab

• MM-302 plus trastuzumab and cyclophosphamide

–

To determine the Phase 2 dose

• Key Secondary Objectives

:

–

Describe dose limiting toxicities

–

Objective response rate

–

Clinical benefit rate (CR + PR + SD at 24 weeks)

–

Duration of response

–

Median progression free survival

–

Pharmacokinetics

(10)

Key Inclusion and Exclusion Criteria

• Inclusion

:

–

Locally advanced/unresectable or MBC HER2 positive

• HER2+ = HER2 IHC 3+ or HER2 ICH 2+ and FISH/CISH-positive

–

Measurable disease (RECIST v1.1)

–

ECOG 0 or 1

• Exclusion

:

–

Received



300 mg/mg

2

_{of anthracycline}

–

NYHA Class III or IV CHF or LVEF



50%

–

History of:

• Coronary artery disease

• Myocardial infarction within the last 12 months

• Severe and/or uncontrolled ventricular arrhythmias

• Clinically significant valvular heart disease

• Angina pectoris requiring medication

• Prolonged QTc interval

(11)

Demographics

TOTAL

N 69

Age

Median Years (range) 55.0 (31-75)

Race

Asian, n (%) 1 (1.4)

Black or African American, n (%) 4 (5.8)

Caucasian, n (%) 64 (92.8)

Prior Regimens for Metastatic Disease

Median (range) 4 (0-11)

Prior Exposure to, n (%)

Anthracycline 37 (53.6) Taxane 64 (92.8) Trastuzumab 68 (98.6) Ado-trastuzumab emtansine (T-DM1) 35 (50.7) Pertuzumab 17 (24.6) Lapatinib 42 (60.9) Hormonal Therapy 33 (47.8) 11

(12)

MM-302 Pharmacokinetics

8 mg/m2 16 mg/m2 30 mg/m2 40 mg/m2 50 mg/m2 8 mg/m2 16 mg/m2 30 mg/m2 40 mg/m2 50 mg/m2

MM-302 Monotherapy

MM-302 plus trastuzumab

t

_1/2

= ~2 days in patients receiving 30 mg/m

2

_{MM-302 +/- trastuzumab}

(13)

AEs occurring in ≥20% of population (any grade)

MM-302 alone MM-302 + trastuzumab MM-302 + trastuzumab + cyclo TOTAL Adverse Event1_{, n (%)} _(N=34) _(N=22) _(N=13) _(N=69) Fatigue 21 (61.8) 10 (45.5) 3 (23.1) 34 (49.3) Nausea 19 (55.9) 9 (40.9) 6 (46.2) 34 (49.3) Constipation 7 (20.6) 9 (40.9) 4 (30.8) 20 (29.0) Decreased Appetite 13 (38.2) 5 (22.7) 2 (15.4) 20 (29.0) Vomiting 9 (26.5) 5 (22.7) 4 (30.8) 18 (26.1) Cough 8 (23.5) 7 (31.8) 2 (15.4) 17 (24.6) Diarrhea 7 (20.6) 5 (22.7) 4 (30.8) 16 (23.2) Neutropenia 9 (26.5) 3 (13.6) 3 (23.1) 15 (21.7) Stomatitis 8 (23.5) 6 (27.3) 1 (7.7) 15 (21.7) Dyspnea 5 (14.7) 5 (22.7) 4 (30.8) 14 (20.3) 13

(14)

Grade 3/4 Treatment Emergent

1

AEs (TEAEs)

1 _{Events determined by investigator to be “possibly”, “probably” or “definitely” related to study drug treatment} 2 _{MedDRA preferred terms}

MM-302 alone MM-302 + trastuzumab MM-302 + trastuzumab + cyclo TOTAL (N=34) (N=22) (N=13) (N=69)

Patients with related Grade 3/4 TEAE, n (%)

9 (26%) 1 (10%) 2 (15%) 12 (17%) Adverse Events2_{, n (%)} Neutropenia 6 (17) - 1 (7) 7 (10.1) Leukopenia 2 (6) - - 2 (2.9) Lymphopenia 1 (3) - 1 (7) 2 (2.9) Mucosal Inflammation 2 (6) - - 2 (2.9) Anemia 1 (3) - - 1 (1.4) Dyspnea 1 (3) - - 1 (1.4) Febrile Neutropenia - 1 (10) - 1 (1.4) Hematocrit decreased 1 (3) - - 1 (1.4) Neutropenic Infection - 1 (10) - 1 (1.4) PPE 1 (3) - - 1 (1.4) Thrombocytopenia 1 (3) - - 1 (1.4) WBC decreased 1 (3) - - 1 (1.4) 14

(15)

_{SAEs and AEs Leading to Treatment Discontinuation}

There were no treatment related deaths on study

N=69

# of patients experiencing SAE 3 (4.3)

Individual SAEs2 _{6 (8.7)}

Febrile Neutropenia 1 (1.4)

Anemia 1 (1.4)

White blood cell count decreased 1 (1.4)

Neutropenia 1 (1.4)

Thrombocytopenia 1 (1.4)

Palmar-plantar erythrodysesthesia 1 (1.4)

Adverse Events2_{Leading to Treatment Discontinuation} _{6 (8.7)}

Aphasia/face edema 1 (1.4) Peripheral neuropathy 1 (1.4) Cardiac failure 1 (1.4) Neutropenia 1 (1.4) Hypoxia 1 (1.4) Thrombocytopenia 1 (1.4) 15

1 _{Events determined by investigator to be “possibly”, “probably” or “definitely” related to study drug treatment} 2 _{MedDRA preferred terms}

(16)

AEs of Special Interest

Adverse Event1 _(N=69) Neutropenia 15 (21.7) Stomatitis 15 (21.7) Mucositis 12 (17.4) Alopecia 7 (10.1) Infusion Reaction 6 (8.7) LVEF changes 6 (8.7) PPE 3 (4.3) Cardiac failure 1 (1.4) Neutropenic fever 1 (1.4)

PPE: palmar-plantar erthrodysesthesia syndrome

There were no severe infusion reactions

16

(17)

Cardiac Safety

• No cardiac events with MM-302 monotherapy (34 pts)

• Infrequent cardiac events with no SAEs in combination arms

– 6 had protocol defined asymptomatic declines in LVEF

• 4 Pts reversible declines - consistent with trastuzumab-induced changes

• 1 Pt decline to 47% noted at off-study assessment

• 1 Pt noted twice to have a range of 45-50% LVEF (off study – unchanged)

• One patient described above discontinued treatment due to LVEF

changes experienced Grade 1 Heart Failure

• 11 patients have cumulative anthracycline exposure >550 mg/m

2

– 7 monotherapy pts, 4 in combination with trastuzumab

(18)

MM-302 Phase 1 Efficacy

Patients Receiving ≥30 mg/m

2

_MM-302

- 1 0 0 - 7 5 - 5 0 - 2 5 0 2 5 5 0 7 5 1 0 0 b e s t c h a n g e i n t a r g e t l e s i o n ( % f r o m b a s e l i n e )

# prior regimens for metastatic disease

Median 4

prior exposure to, n (%)

Anthracycline 37 (60) Trastuzumab 61 (98) Lapatinib 38 (61) Taxane 57 (92) Ado-trastuzumab emtansine (T-DM1) 34 (55) Pertuzumab 17 (27) Hormonal therapy 30 (48) ORR: 11% (7/62) CBR: 21% (13/62) * * * 0 6 1 2 1 8 2 4 3 0 p r o g r e s s i o n f r e e s u r v i v a l ( m o n t h s ) mPFS (95% CI) 7.6 months (3.6-10.9) + trastuzumab _{● ● ● ● ● ●} _{● ●} _● _{● ●} _{● ● ● ● ● ● ● ● ● ● ● ● ●} _{● ●} _{● ●} _{● ●} _{● ● ● ● ●} + cyclophosphamide ● ● ● ● ● ● ● ● ● ● ● ● ●

(19)

Enhanced Efficacy in Anthracycline Naïve Patients

Patients Receiving ≥30 mg/m

2

_MM-302

- 1 0 0 - 7 5 - 5 0 - 2 5 0 2 5 5 0 7 5 1 0 0 b e s t c h a n g e i n t a r g e t l e s i o n ( % f r o m b a s e l i n e ) 0 6 1 2 1 8 2 4 3 0 p r o g r e s s i o n f r e e s u r v i v a l ( m o n t h s ) * * * Anthracycline naive Anthracycline exposed ORR: 11% (7/62) CBR: 21% (13/62) mPFS (95% CI) 7.6 months (3.6-10.9) + trastuzumab _{● ● ● ● ● ●} _{● ●} _● _{● ●} _{● ● ● ● ● ● ● ● ● ● ● ● ●} _{● ●} _{● ●} _{● ●} _{● ● ● ● ●} + cyclophosphamide ● ● ● ● ● ● ● ● ● ● ● ● ●

(20)

- 1 0 0 - 7 5 - 5 0 - 2 5 0 2 5 5 0 7 5 1 0 0 b e s t c h a n g e in t a r g e t le s io n ( % f r o m b a s e l i n e ) 0 6 1 2 1 8 2 4 3 0 p r o g r e s s i o n f r e e s u r v i v a l ( m o n t h s )

Enhanced Efficacy in Anthracycline Naïve Patients

Patients Receiving ≥30 mg/m

2

_MM-302

20 20 - 1 0 0 - 7 5 - 5 0 - 2 5 0 2 5 5 0 7 5 1 0 0 0 6 1 2 1 8 2 4 3 0 + trastuzumab ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● + cyclophosphamide ● ● ● ● ● ● ● ● ● ● ● ● ●

*: patients still on study, ORR: Overall Response Rate, CBR: Clinical Benefit Rate (CR, PR and Stable Disease (SD) at 24 weeks)

*

* *

Anthracycline naive Anthracycline exposed

ORR: 24% (6/25) CBR: 28% (7/25) ORR: 3% (1/37) CBR: 16% (6/37) mPFS: (95% CI) 11.0 months (1.8-13.1) _{(95% CI)}mPFS: 5.7 months _(3.6-8.7) 20

(21)

Enhanced PFS in Anthracycline Naïve Patients

Patients Receiving ≥30 mg/m

2

_MM-302

0 6 1 2 1 8 2 4 3 0 0 2 5 5 0 7 5 1 0 0 p r o g r e s s i o n f r e e s u r v i v a l ( m o n t h s ) P e r c e n t s u r v i v a l a n t h r a c y c l i n e n a i v e a n t h r a c y c l i n e e x p o s e d

Prior Anthracycline: Naïve Exposed

n= 25 37 # of Events, n (%) 16 (64.0) 19 (51.4) # Censored, n (%) 9 (36.0) 18 (48.6) mPFS (months) (95% CI) 11.0 (1.8-13.1) 5.7 (3.6-8.7) median # of prior regimens for MBC 2 5 21 anthracycline naive anthracycline exposed

(22)

22

Bone Brain Brain

Sternal Mass Liver

Breast & Skin

24 h 25 h

45 h

19 h 44 h 19 h

PET/CT 64

_{Cu-MM-302 Localizes to Brain and Bone Metastases}

(23)

Chemotherapy of Physician’s Choice

(capecitabine, gemcitabine or vinorelbine)

+ trastuzumab

6mg/kg*, Q3W

* 8 mg/kg trastuzumab loading dose

HER2-positive

locally advanced/metastatic BC

Anthracycline naive

Prior metastatic treatment with pertuzumab and T-DM1

Prior treatment with trastuzumab (N=250) MM-302 30 mg/m2_{, Q3W} + trastuzumab 6 mg/kg*, Q3W 1 1