Malattia HER2 positiva

(1)

Luca Moscetti

Modena Cancer Center

Università degli Studi di Modena e Reggio Emilia Policlinico di Modena, Italy

EMA National expert

Scientific officer Breast/Prostate/Melanoma E-PM-EPC

European Medicines Agency

Terapia della malattia metastatica Malattia HER 2 positiva

Pisa, 19 Settembre 2019

(2)

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

(3)

Current standard Tx in Her 2 Overexpressed mBC Special category (older, frail, unfit pts)

First line

Pertuzumab + Trastuzumab + docetaxel/paclitaxel

(Cleopatra)

Consider HT maintenance in

ER+

(Pertain)

HT + Trastuzumab HT + lapatinib

in ER+

Chemo-monotherapy + her 2 blockade

Secondline

Trastuzumab emtasine T-DM1

(Emilia)

Capecitabine lapatinib

Chemo monotherapy +

her 2 blockade

>Third line

Capecitabine Lapatinib

(EGF100151)

Other Txs +/- her 2 blockade

Lapatinib trastuzumab

Pertuzumab or T-DM1

(4)

What happened in the last year?

First line Tx:

CLEOPATRA

final OS results

(5)

Courtesy of C. Criscitiello

(6)

Courtesy of C. Criscitiello

(7)

(8)

Mark D. Pegram 2018 ASCO EDUCATIONAL BOOK

(9)

Mark D. Pegram 2018 ASCO EDUCATIONAL BOOK

(10)

✓ 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

(11)

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: PI3K

^mut

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

EMILIA trial subanalysis

PIK3CA 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

(12)

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

(13)

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,

Main resistance mechanisms

FC-engineered HER2 monoclonal antibody: Margetuximab

Augmenting ADCC using agonist antibodies directed against CD137

(14)

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.

(15)

• 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.

(16)

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)

(17)

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 (%)

266 270

174 158

94 74

45 33

21 13

8 2

6 2

4 1

2 1

0

1 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 + CT Trastuzumab + CT

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

130 135 10

0 8 0 6 0 4 0 2 0 0

0 5 10 15 20 25

(18)

(19)

(20)

SOPHIA: Response

Outcome Margetuximab + 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

(21)

SOPHIA: Conclusions

Strenght

✓ 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

(22)

UTOMILUMAB (PF-05082566)

phase IB/II clinical trial of agonist CD137 antibody utomilumab in combination with trastuzumab (or T-DM1) is currently underway (NCT03364348).

(23)

Brand new treatments

Class Compound Conjugate Effect

Antibody-drug conjugates

Trastuzumab deruxtecan

(DS-8201

Deruxtecan

Topoisomerase I inhibitor

DNA topoisomerase I inhibitor by a tetrapeptide linker.

Trastuzumab duocarmazine

(SYD985)

Duocarmazine Alkylator agent

binds to the minor groove of DNA, alkylates adenine at the N3 position

ARX788 Amberstatin Microtubule inhibitors

Byparatopic/Bispecific Her 2 antibodies

ZW25 Byparatopic

Her 2 antibody

Link two distinct HER 2 epitopes

PRS-343 Bispecific Her 2/CD137 (41BB/Her2)

Link to CD137 on immune cells

(24)

Compound Phase # Previous

lines ORR% Outcomes Ref.

Trastuzumab deruxtecan

(DS-8201)

I >4 64.2

(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 pretreated

33 (30/40 in her low

Her2)

PFS 9.4 mos Saura C, J Clin Oncol.

2018;36(15_suppl; abstr1014)

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

2018;36(15_suppl; abstr2500)

(25)

Compound Class drug Comparator

Phase of development Trial/Acron/#NCT

# expected pts to enroll

DS-8201a Conjugated Ab T-DM1

(Trastuzumab and Taxane pretreated)

Phase III [DESTINY-Breast03]

NCT03529110

500

DS-8201a Conjugated Ab SoC

(TDM1 pretreated)

Phase III [DESTINY-Breast02]

NCT03523585

600

DS-8201a Conjugated Ab (resistant or refractory to T-DM1)

Phase II

[DESTINY-Breast01]

NCT03248492

230

SYD985 Conjugated Ab

SoC

(Pretreated at least two HER2-targeted

regimens)

Phase III [TULIP]

NCT03262935

345

ARX788 Conjugated Ab

HER2 ISH positive or IHC3+ HER2 ISH negative

with IHC 2=

Phase I/II NCT03255070

Five sequential dose escalation cohorts are

planned.

PRS-343

Bispecific Her2/CD137 (41BB/Her2)

HER 2+ Pretreated Phase I

NCT03330561 78

(26)

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

(27)

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)

(28)

(29)

(30)

(31)

(32)

(33)

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(35)

(36)

(37)

(38)

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

(39)

Compound Class drug Comparator/Setting

Phase of development Trial/Acron/#NCT

# expected pts to enroll

Pyrotinib Irreversible pan- HER inhibitor

Brain mts, HR+

Trastuzumab resistant

Phase I/II trial ongoing [DESTINY-Breast03]

NCT03529110

-

Tucatinib Irreversible pan- HER inhibitor

III line

Tucatinib or placebo in combination with

capecitabine and trastuzumab

Phase III [HER2CLIMB]

NCT02614794

612

Poziotinib Irreversible pan

HER inhibitor -

I/II NCT02418689 NCT03429101 NCT02659514

Up to 30

(40)

✓ De-escalate the therapy overcoming the resistance in HR+/triple positive disease (i.e.cyclin D1-CDK4 pathway)

Main resistance mechanisms

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 subtype by PAM50, vs nonluminal (12.4 versus 4.1 months, HR

0.30, p = 0.025)

Phase II SOLTI-

1303 PATRICIA trial: Palbociclib, Trastuzumab Letrozole

(41)

Compound Class drug Comparator/Setting Phase of development Trial/Acron/#NCT

# expected pts to enroll

Abemaciclib CDK4/6 inhibitor

Ab + Trast +/- Fulv vs SoC/

HR+

Trastuzumab resistant

Phase II trial [MonarcHer]

NCT02675231

225

Palbociclib CDK4/6 inhibitor

Palb+ Endocrine Therapy vs. Anti- HER2 Therapy + Endocrine Therapy

After Induction Treatment

Phase III [PATINA]

NCT02947685

496

Palbociclib CDK4/6 inhibitor

Palb+

Trast+/- letrozole in heavily pretreated

(up to 2–4 prior lines)

Phase II SOLTI- 1303 PATRICIA trial (NCT02448420), >PFS in luminal

by PAM50, vs

nonluminal (12.4 vs 4.1 mos, HR 0.30, p = 0.025)

(42)

Immunotherapy

Compound Companion drug

Phase of development

Trial/Acron/

Main results

Avelumab - Phase I trial

[Javelin] No responses in pretreated pts

Pembrolizumab Trastuzumab

Phase Ib/II PANACEA (IBCSG 45-

13/BIG 4- 13/KEYNOTE-

014)

ORR of 15.2% and a median of PFS and

OS of 2.7 months and 16 months, respectively, in PD-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 demonstrated

promising PFS in the PD-L1 positive (PD-L1 IHC expression >1%) and stromal TIL subgroups

(43)

Trastuzumab 1998

Lapatinib 2007

T-DM1 2013 Pertuzumab

2012

Neratinib

Margetuximab Trastuzumab

Deruxtecan

>2015

25 mos +5 mos vs CT

OS gain ^{50 mos}

+16 mos vs T

9 mos +3 mos vs CT

PFS gain ^{18 mos}

+6 mos vs T

25 mos 0 mos vs CT

PFS gain

31 mos +6 mos vs LAP

OS gain

First lineSecondline>Third line

8 mos +4 mos vs CT

8 mos

+4 mos vs LAP

Trastuzumab Duocarmazine

PRS-343 ZW-25

Pyrotinib Tucatinib

ARX788

(44)

Malattia HER2 positiva

Luca Moscetti

Modena Cancer Center

EMA National expert

Scientific officer Breast/Prostate/Melanoma E-PM-EPC

European Medicines Agency

Terapia della malattia metastatica Malattia HER 2 positiva

Pisa, 19 Settembre 2019

Disclosure for the last three years

What happened in the last year?

First line Tx:

CLEOPATRA

final OS results

Main resistance mechanisms

Main resistance mechanism: PI3K

EMILIA trial subanalysis

Main resistance mechanisms

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

SOPHIA: Study Design

SOPHIA: Previous Therapy

SOPHIA: PFS in ITT Population

SOPHIA: Response

SOPHIA: Conclusions

UTOMILUMAB (PF-05082566)

Brand new treatments

Main resistance mechanism

• Increase anti her 2 Abs dose

• Small molecules Her 2 tyrosine kinase inhibitors

Increase anti Her 2 Abs dose

New irreversible pan HER inhibitor: Neratinib

Main resistance mechanisms

11 months

18 months 8 months 5 months

Immunotherapy

Grazie

Pisa, 19 Settembre 2019