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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,
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
▪ 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)
Rugo. ASCO 2019. Abstr 1000.
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)
Rugo. ASCO 2019. Abstr 1000.
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
Rugo. ASCO 2019. Abstr 1000.
Rugo. ASCO 2019. Abstr 1000.
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)
Rugo. ASCO 2019. Abstr 1000.
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)
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 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
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