Pisa, 19 Settembre 2019 Luca Moscetti Modena Cancer Center€¦ · KATE2 trial, vs T-DM1 No benefit in PFS (8,2 vs 6,8 mo) exploratory endpoint demonstrated promising PFS in the PD-L1

Luca MoscettiModena Cancer Center

Università degli Studi di Modena e Reggio EmiliaPoliclinico di Modena, Italy

EMA National expertScientific officer Breast/Prostate/Melanoma

E-PM-EPCEuropean Medicines Agency

Terapia della malattia metastatica

Malattia HER 2 positiva

Pisa, 19 Settembre 2019

Disclosure for the last three years

Consultant

Eisai, Pfizer, Novartis, Roche, Eli Lilly

The views expressed in this presentation are the personal views of the

author and may not be understood or quoted as being made on behalf of

or reflecting the position of the European Medicines Agency or one of its

committees or working parties

Current standard Tx in Her 2 Overexpressed mBCSpecial category

(older, frail, unfit pts)

Fir

st

lin

e

Pertuzumab + Trastuzumab +

docetaxel/paclitaxel(Cleopatra)

Consider HT

maintenance in

ER+

(Pertain)

HT + Trastuzumab

HT + lapatinib

in ER+

Chemo-monotherapy + her

2 blockade

Seco

nd

lin

e

Trastuzumab emtasine T-DM1(Emilia)

Capecitabine

lapatinib

Chemo

monotherapy +

her 2 blockade

>T

hir

d lin

e

Capecitabine Lapatinib(EGF100151)

Other Txs +/- her 2 blockade

Lapatinib

trastuzumab

Pertuzumab

or T-DM1

What happened in the last year?

First line Tx:

CLEOPATRA

final OS results

Courtesy of C. Criscitiello

Courtesy of C. Criscitiello

Mark D. Pegram 2018 ASCO EDUCATIONAL BOOK

Mark D. Pegram 2018 ASCO EDUCATIONAL BOOK

✓ To overcome resistance as a result of PIK3CA mutation,

✓ Novel approaches to enhance antibody-dependent cell-mediated

cytotoxicity (ADCC) of immune effector cells to address resistance

caused by low-affinity activating Fcγ receptor (FcγR) polymorphisms,

✓ Solutions to overcome anatomic resistance by the blood-brain barrier in

HER2+ brain metastasis

✓ De-escalate the therapy overcoming the resistance in HR+/triple positive

disease (i.e.cyclinD1-CDK4 pathway)

Main resistance mechanisms

The use of antibody-drug conjugate (ADC) ado-trastuzumab emtansine

(T-DM1) to overcome resistance as a result of PIK3CA mutation (30% mutation frequency ),

Main resistance mechanism: PI3Kmut

Baselga J, Clin Cancer Res. 2016;22:3755-3763.

EMILIA trial subanalysisPIK3CA DNA sequence analysis (259 pts)

PI3K

status*PFS m’s OS m’s PFS m’s OS m’s

capecitabine plus lapatinib T-DM1

Mutant 4.3 17.3 10.9 NR^

Wild type 6.4 27.8 9.8 NR^

*For exon 1: R88Q; exon 4: N345K; exon 7: C420R; exon 9: E542K, E545X, and Q546X; and exon 20: M1043I, H1047X, and

G1049R

^ NR not reached

Baselga J, Clin Cancer Res. 2016;22:3755-3763.

Novel approaches to enhance antibody-dependent cell-mediated cytotoxicity

(ADCC) of immune effector cells to address resistance caused by low-

affinity activating Fcγ receptor (FcγR) polymorphisms,


FC-engineered HER2 monoclonal antibody: Margetuximab

Augmenting ADCC using agonist antibodies directed against CD137

Margetuximab + CT vs Trastuzumab + CT in Pts with HER2+ MBC After Standard Anti-HER2 Tx (SOPHIA): Background

▪ Margetuximab: HER2-binding antibody with Fc portion engineered to have increased affinity for activating Fcγ receptor CD16A (both lower and higher affinity alleles) and decreased affinity for inhibitory Fcγ receptor CD32B[1]

‒ CD16A-158F allele binds with lower affinity to trastuzumab; discordant studies on association between genotype and efficacy of trastuzumab in EBC and MBC[2,3]

▪ Margetuximab Fc domain has an increased ability to bind the immunoglobulin G fragment C receptor on immune effector cells and to mediate antibody-dependent cellular cytotoxicity

1. Nordstrom. Breast Cancer Res. 2011;13:R123. 2. Musolino. J Clin Oncol. 2008;26:1789.3. Hurvitz. Clin Cancer Res. 2012:18;3478. 6. Rugo. ASCO 2019. Abstr 1000.

• Randomized, open-label phase III trial

SOPHIA: Study Design

Margetuximab 15 mg/kg Q3W + CT*(n = 266)

Patients with HER2+ MBC with ≥ 2 previous anti-HER2 therapies,

including pertuzumab, and 1-3 prior lines of tx for metastatic disease; prior brain metastasis allowed if

treated/stable(N = 536)

CT choice, no. of prior lines of tx (> 2 vs ≤ 2), no. of metastatic sites (> 2 vs ≤ 2)

Trastuzumab + CT*8 mg/kg loading → 6 mg/kg Q3W

(n = 270)

Rugo. ASCO 2019. Abstr 1000.

Sequential primary endpoint: PFS, OS

Secondary endpoints: ORR and investigator assessed PFS

Exploratory endpoints: CBR; DoR; effect of CD16A, CD32A, and

CD32B alleles on efficacy

*Investigators choice of CT: capecitabine, eribulin, gemcitabine, or vinorelbine.

SOPHIA: Previous Therapy

Characteristic, n (%) Margetuximab + CT (n = 266) Trastuzumab + CT (n = 270)

Settings of previous therapy▪ Adjuvant and/or neoadjuvant▪ Metastatic only

158 (59)108 (41)

145 (54)125 (46)

Previous metastatic lines of therapy▪ ≤ 2 lines▪ > 2 lines

175 (66)91 (34)

180 (67)90 (33)

Type of previous anti-HER2 therapy▪ Trastuzumab▪ Pertuzumab▪ T-DM1▪ Lapatinib▪ Other

266 (100)266 (100)242 (91)41 (15)

6 (2)

270 (100)269 (100)247 (92)39 (14)

6 (2)

Type of previous anti-HER2 therapy▪ Taxane▪ Anthracycline▪ Platinum

252 (95)118 (44)34 (13)

249 (92)110 (41)40 (15)

Previous endocrine therapy 126 (47) 133 (49)


Events, n

SOPHIA: PFS in ITT Population by Central Blinded Analysis (Primary Endpoint)

5.8 (5.52-6.97)4.9 (4.17-5.59)


Patients at Risk, n

PFS

(%

)

266270

174158

9474

4533

2113

82

62

41

21

01 1

Mos

Median PFS, Mos (95% CI)

24% Reduction in Risk of Disease Progression

HR: 0.76 (95% CI: 0.59-0.98;P = .033)

Margetuximab + CTTrastuzumab + CT

Margetuximab + CT (n = 266)Trastuzumab + CT (n = 270)

130135

100

80

60

40

20

0

0 5 10 15 20 25

SOPHIA: Response

OutcomeMargetuximab + CT

(n = 262)Trastuzumab + CT

(n = 262)P Value

ORR, % (95% CI) 22.1 (17.3-27.7) 16.0 (11.8-21.0) .060

CBR, % (95% CI) 36.6 (30.8-42.8) 24.8 (19.7-30.5) .003

CR, n (%) 7 (2.7) 4 (1.5) --

PR, n (%) 51 (19.5) 38 (14.5) --

SD, n (%) 149 (56.9) 147 (56.1) --

PD, n (%) 35 (13.4) 46 (17.6) --

Not evaluable/available, n (%)

20 (7.6) 27 (10.3) --

Median DoR, mos (95% CI) 6.1 (4.11-9.13) 6.0 (4.01-6.93) .541



SOPHIA: ConclusionsStrenght

✓ 100% pertuzumab/trastuzumab and 90% T-DM1 pretreated

✓ Adequate design for third line Tx

✓ Enhanced PFS benefit for individuals with the low-affinity CD16A allele in

this setting (HR: 0.68; P = .005): patient selection for genotype?

Weakness

✓ Co primary endpoints: not yet reached

✓ Increase in mPFS 1 month….

Wait for the second interim OS analysis later in 2019

UTOMILUMAB (PF-05082566)

phase IB/II clinical trial of agonist CD137 antibody utomilumab in combination with

trastuzumab (or T-DM1) is currently underway (NCT03364348).

Brand new treatments

Class Compound Conjugate Effect

Antibody-drug

conjugates

Trastuzumab

deruxtecan

(DS-8201

DeruxtecanTopoisomerase I inhibitor

DNA topoisomerase I inhibitor

by a tetrapeptide linker.

Trastuzumab

duocarmazine

(SYD985)

DuocarmazineAlkylator agent

binds to the minor groove of DNA,

alkylates adenine at the N3 position

ARX788 Amberstatin Microtubule inhibitors

Byparatopic/Bispecific

Her 2 antibodies

ZW25Byparatopic

Her 2 antibody

Link two distinct HER 2

epitopes

PRS-343Bispecific Her 2/CD137

(41BB/Her2)

Link to CD137 on immune

cells

Compound Phase# Previous

linesORR% Outcomes Ref.

Trastuzumab

deruxtecan

(DS-8201)

I >464.2

(44 in her low Her2)

mPFS 7.4 mos

in Her 2 low

(IHC 2+/ISH- or IHC 1+)

Iwata H,. J Clin Oncol.

2018;36(15_suppl; abstr 2501)

Trastuzumab

duocarmazine

(SYD985 )

I pretreated33

(30/40 in her low

Her2)

PFS 9.4 mosSaura C, J Clin Oncol.

2018;36(15_suppl; abstr1014)

ZW25 I pretreated NR NRMeric-Bernstam F, J Clin Oncol.

2018;36(15_suppl; abstr2500)

Compound Class drug Comparator

Phase of

development

Trial/Acron/#NCT

# expected pts to

enroll

DS-8201a Conjugated AbT-DM1

(Trastuzumab and Taxanepretreated)

Phase III [DESTINY-Breast03]

NCT03529110500

DS-8201a Conjugated AbSoC

(TDM1 pretreated)

Phase III[DESTINY-Breast02]

NCT03523585600

DS-8201a Conjugated Ab(resistant or refractory

to T-DM1)

Phase II[DESTINY-Breast01]

NCT03248492230

SYD985 Conjugated Ab

SoC(Pretreated at least two

HER2-targeted regimens)

Phase III[TULIP]

NCT03262935345

ARX788 Conjugated AbHER2 ISH positive or

IHC3+ HER2 ISH negative with IHC 2=

Phase I/IINCT03255070

Five sequential dose

escalation cohorts are

planned.

PRS-343Bispecific

Her2/CD137(41BB/Her2)

HER 2+ PretreatedPhase I

NCT0333056178

Overcome anatomic resistance by the blood-brain barrier in HER2+

brain metastasis

Main resistance mechanism

• Increase anti her 2 Abs dose

• Small molecules Her 2 tyrosine kinase inhibitors

Increase anti Her 2 Abs dose

High-dose (6 mg/kg weekly) trastuzumab (in combination with standard dose

pertuzumab for control of extracranial metastasis) for HER2+ CNS

metastasis.

An Open-Label, Single-Arm, Phase II Study of Pertuzumab With High-Dose

Trastuzumab for the Treatment of Central Nervous System Progression

Post-Radiotherapy in Patients With HER2-Positive Metastatic Breast Cancer

(PATRICIA) (NCT02536339)


New irreversible pan HER inhibitor: Neratinib

Strenght

✓ Adequate third line Tx

✓ Similar toxicity to capecitabine lapatinib regimen

✓ Encouraging CNS activity

Weakness

✓ 40% only trastuzumab pretreated

✓ OS as co-primary endpoints: end point not reached

✓ Increase in mPFS 2 month….

✓ Grade 3 Diarrhea in 25% of patients still remains an heavy toxicity for

pretreated patients

Compound Class drug Comparator/Setting

Phase of

development

Trial/Acron/#NCT

# expected pts to

enroll

PyrotinibIrreversible pan-

HER inhibitor

Brain mts,HR+

Trastuzumab resistant

Phase I/II trial ongoing[DESTINY-Breast03]

NCT03529110-

TucatinibIrreversible pan-

HER inhibitor

III lineTucatinib or placebo in combination with

capecitabine and trastuzumab

Phase III[HER2CLIMB]NCT02614794

612

PoziotinibIrreversible pan

HER inhibitor-

I/IINCT02418689NCT03429101NCT02659514

Up to 30

✓ De-escalate the therapy overcoming the resistance in HR+/triple positive

disease (i.e.cyclin D1-CDK4 pathway)


PERTAIN: Tras/Pert/IA

TAnDEM: Trast/Anastrozole

Jonhston’s trial: Lap/letrozole

ALTERNATIVE: Lap/Trast/IA 11 months

18 months

8 months

5 months

better PFS in luminal subtypeby PAM50, vs nonluminal

(12.4 versus 4.1 months, HR0.30, p = 0.025)

Phase II SOLTI-

1303 PATRICIA trial: Palbociclib,

Trastuzumab

Letrozole

Compound Class drug Comparator/SettingPhase of development

Trial/Acron/#NCT

# expected pts

to enroll

Abemaciclib CDK4/6 inhibitor

Ab + Trast +/- Fulv vsSoC/HR+

Trastuzumab resistant

Phase II trial[MonarcHer]

NCT02675231225

Palbociclib CDK4/6 inhibitor

Palb+ Endocrine Therapy vs. Anti-HER2 Therapy +

Endocrine TherapyAfter Induction

Treatment

Phase III[PATINA]

NCT02947685496

PalbociclibCDK4/6 inhibitor

Palb+ Trast+/- letrozole

in heavily pretreated(up to 2–4 prior

lines)

Phase II SOLTI-1303 PATRICIA trial

(NCT02448420), >PFS in luminalby PAM50, vs

nonluminal (12.4 vs 4.1 mos, HR0.30, p = 0.025)

Immunotherapy

Compound Companion drug Phase of

developmentTrial/Acron/

Main results

Avelumab -Phase I trial

[Javelin]No responses in pretreated pts

Pembrolizumab Trastuzumab

Phase Ib/IIPANACEA (IBCSG 45-

13/BIG 4-13/KEYNOTE-

014)

ORR of 15.2% and a median of PFS andOS of 2.7 months and 16 months, respectively, inPD-L1 positive patient, no responses in PD-L1 negative.Most PD-L1+ developed resistant disease

Atezolizumab T-DM! KATE2 trial, vs T-DM1

No benefit in PFS (8,2 vs 6,8 mo)exploratory endpoint demonstratedpromising PFS in the PD-L1 positive (PD-L1IHC expression >1%) and stromal TIL subgroups

Trastuzumab

1998

Lapatinib

2007

T-DM1

2013

Pertuzumab

2012

NeratinibMargetuximab Trastuzumab

Deruxtecan

>2015

25 mos

+5 mos vs CTOS gain

50 mos

+16 mos vs T

9 mos

+3 mos vs CTPFS gain

18 mos

+6 mos vs T

25 mos

0 mos vs CT

PFS gain

31 mos

+6 mos vs LAPOS gain

Fir

st

lin

eS

eco

nd

lin

e>

Th

ird

lin

e

8 mos

+4 mos vs CT

8 mos

+4 mos vs LAP

Trastuzumab

Duocarmazine

PRS-343 ZW-25

Pyrotinib

Tucatinib

ARX788

Grazie

Pisa, 19 Settembre 2019

Documents

Pisa, 19 Settembre 2019 Luca Moscetti Modena Cancer Center€¦ · KATE2 trial, vs T-DM1 No benefit in PFS (8,2 vs 6,8 mo) exploratory endpoint demonstrated promising PFS in the PD-L1