A 2008 Lifetime Television
movie,
directed
by
Dan
Ireland, starring Harry Connick,
Jr. The film is based on the true
life story of Dr. Dennis Slamon.
New York (NY): Random House, 1998. 214 pp., illus.
ISBN 0-679-45702-X
Targeted Agents
for HER2+
Breast Cancer
10.1200/JCO.2011.40.2545
Pertuzumab
Trastuzumab
Pertuzumab
Fisher, et al. J. Mol. Biol. 2010;402:217-229.
OS
(after an additional year of follow-up)
Lancet Oncol 2013; 14: 461–71 Published Online April 18, 2013
FDA
On June 8, 2012, the U. S. Food and Drug Administration approved
pertuzumab
injection (PERJETA, Genentech, Inc.) for use in combination with
trastuzumab and docetaxel for the treatment of patients with HER2-positive
metastatic breast cancer who have not received prior anti-HER2 therapy or
chemotherapy for metastatic disease. Pertuzumab is a recombinant humanized
monoclonal antibody that targets the extracellular dimerization domain (Subdomain
II) of HER2, and thereby blocks ligand-dependent heterodimerization of HER2 with
other HER family members, including EGFR, HER3 and HER4.
EMA
march 4, 2013
The European Medicines Agency (EMA) has approved Roche’s PERJETATM
(pertuzumab) RG1273 for patients with previously untreated HER2-positive
metastatic breast cancer (mBC). PERJETA is approved in combination with
Herceptin® (trastuzumab) and docetaxel in adult patients with HER2-positive
metastatic or locally recurrent unresectable breast cancer, who have not received
previous anti-HER2 therapy or chemotherapy for their metastatic disease
EMILIA
OS: Second Interim Analysis
85.2% (95% CI: 82.0-88.5)
100
OS (%)
80
Median, Mos
Events, n
Cap + Lap
25.1
182
T-DM1
30.9
149
Stratified HR: 0.68 (95% CI: 0.55-0.85; P = .001)
Efficacy stopping boundary P = .0037 or HR: 0.73
64.7% (95% CI: 59.3-70.2)
78.4% (95% CI: 74.6-82.3)
60
40
T-DM1
51.8% (95% CI: 45.9-57.7)
Lapatinib-capecitabine
20
0
0
2
4
6
8 10 12 14 16 18 20 22 24 26 28 30 32 34 36
Mos
Pts at Risk, n
496 471 453 435 403 368 297 240 204 159 133 110 86 63
Lapatinibcapecitabine
495 485 474 457 439 418 349 293 242 197 164 136 111 86
T-DM1
Data cutoff July 31, 2012; median follow-up: 18.6 mos.
45 27 17
7
4
62 38 28 13 5
Verma S, et al. N Engl J Med. 2012;367:1783-1791.
FDA
On Feb. 22, 2013, the U. S. Food and Drug Administration approved approved
Kadcyla (ado-trastuzumab emtansine), a new therapy for patients with
HER2-positive, late-stage* (metastatic) breast cancer.
This application is currently under review by the EMA
Phase III MARIANNE Study:
T-DM1 ± Pertuzumab in HER2+ MBC
PD
Trastuzumab + Taxane
(n=364)
Patients with HER2+,
previously untreated MBC
T-DM1 + Pertuzumab
(n=364)
(N=1092)
T-DM1 + Placebo
(n=364)
• Primary endpoints: PFS as assessed by IRF, AEs
– Superiority design with a noninferiority analysis
– Interim futility analysis: option to drop experimental arm
• Secondary endpoints: OS, TTF by IRF, ORR, CBR, DOR
ClinicalTrials.gov. NCT01120184.
MM-302
Nanotherapeutic encapsulation of liposomal doxorubicin with an
anti-HER2 antibody fragments coupled to its surface.
Upon administration of MM-302, the immunoliposome allows for
specific delivery of doxorubicin to tumors overexpressing the
HER2 receptor. Once inside the cancer cell, the liposome breaks
down and releases doxorubicin intracellularly,
promoting cell death.
Cancer Res 2012;72(24 Suppl):Abstract nr P5-18-09.
Recombinant antibody fragments
IgG 150 KDa
Fv
Fab
scFv
50 KDa
Fc
MM-302
MM-302
MM-302
Targeted Agents
for HER2+
Breast Cancer
10.1200/JCO.2011.40.2545
ARRY-380
ARRY-380 is an orally active, small molecule, reversibleselective inhibitor of the HER-2 tyrosine kinase receptor
with antitumor activity in HER2-positive breast cancer in
vitro and in vivo .
In multiple preclinical tumor models, ARRY-380 was well
tolerated and demonstrated significant dose-related
tumor growth inhibition that was superior to
trastuzumab and lapatinib.
http://www.arraybiopharma.com/_documents/Publication/PubAttachment430.pdf
http://www.arraybiopharma.com/_documents/Publication/PubAttachment462.pdf
ARRY-380
These findings led to a phase I trial which found ARRY-380 to be
well tolerated, with rash and diarrhea as the most frequent
adverse effects
http://www.arraybiopharma.com/_documents/Publication/PubAttachment462.pdf
http://www.arraybiopharma.com/_documents/Publication/PubAttachment462.pdf
http://www.arraybiopharma.com/_documents/Publication/PubAttachment506.pdf
Inhibitors of EGFR-receptors
Neratinib (HKI-272)
oral, multitargeted, irreversible inhibitor of HER1, HER2 and HER4
Neratinib
Gajria D Chandarlapaty S. Expert Rev Anticancer Ther. 2011;11(2):263-75
Randomized Phase II: Neratinib vs Lapatinib +
Capecitabine in Locally Advanced or MBC
Response
n
Median Survival, Mos
95% CI
Neratinib
117
4.5
3.1-5.7
L+C
116
6.8
5.9-8.2
Neratinib
117
19.7
18.2-NE
L+C
116
23.6
18.0-NE
P Value
PFS
.231
OS
• Most commonly observed severe AEs: diarrhea and hand–foot
syndrome
– 28% in the neratinib arm vs 10% of the patients in the L + C arm
experienced grade 3/4 diarrhea
Martin M, et al. SABCS 2011. Abstract S5-7.
.280
AFATINIB
Afatinib has demonstrated preclinical activity in HER2-positive and
triple-negative xenograft models of breast cancer, and clinical
activity in phase I studies.
The most common treatment-related adverse events of EGFR-TKIs in
general, and afatinib in particular, are gastrointestinal and cutaneous
side effects, specifically diarrhea and rash
The recommended phase II dose of afatinib is 50 mg orally daily
based on phase I trials in patients with advanced solid tumor
malignancies
Afatinib is in Phase III clinical development in breast cancer, NSCLC
and head and neck cancer
OncoTargets and Therapy 2013:6
This study is ongoing, but not recruiting participants.
Cancer Res 2012;72(24 Suppl):Abstract nr OT1-1-16.
Novel Monoclonal Antibodies
Anti HER2 mAbs
MGAH22
TrasGEX
Ertumaxomab
Anti HER3 mAbs
……….
Novel Monoclonal Antibodies
Anti HER2 mAbs
MGAH22
TrasGEX
Ertumaxomab
Anti HER3 mAbs
……….
MGAH22
www.macrogenics.com
MGAH22
Chimeric IgG1 anti-HER2 antibody based on mouse clone 4D5,
the precursor to trastuzumab.
Engineered to maintain the antigen-binding properties of the
original antibody while optimizing its interactions with human
FcϒRs.
The optimized Fc domain confers enhanced ADCC against all
HER2+ tumor cells tested, including cells resistant to
trastuzumab’s anti-proliferative activity or expressing low HER2
levels.
MGAH22
Novel Monoclonal Antibodies
Anti HER2 mAbs
MGAH22
TrasGEX
Ertumaxomab
Anti HER3 mAbs
……….
TrasGEX
Biosimilar or biobetter?
Significantly improved ADCC-activity promising a significantly
better therapeutic outcome for all patients eligible for treatment
with Trastuzumab.
Simultaneously, the fully human nature of Tras-GEX’ host cell lines
avoids the common immunogenic reactions against host-derived
non-human components.
Biosimilars are structural imitations of the originator, whereas
biobetters are improvements to the originator biological molecule
TrasGEX
TrasGEX Phase II is estimated to start in Q3 / 2013.
Novel Monoclonal Antibodies
Anti HER2 mAbs
MGAH22
TrasGEX
Ertumaxomab
Anti HER3 mAbs
……….
Ertumaxomab
Bispecific Trifunctional mAb
IgG
Fab
Fv
IgG
Anti-HER2
Fc
Anti-CD3
Fc
“An antibody which behaves like a man with a wife and a mistress”
Rev. Med. Virol. 2009; 19: 181–183
Clin Cancer Res 2006;12:3085-3091
Ertumaxomab
Porin mediated lysis
T cells
Tumor cells
CD3
HER2
Cytokine activation and
coreceptor activation
Phagocytosis
ADCC
Fcγ receptor
I/III
Accessory cell
(macrophage, dendritic cell, NK
cell…)
Clin Cancer Res 2006;12:3085-3091
Phase II Study of Single Agent Trifunctional Antibody Ertumaxomab
(Anti-HER-2 & Anti-CD3) in HER-2 Low Expressing HormoneRefractory Advanced Breast Cancer Patients (ABC). Cardoso F et al.
Results: Of the planned 40 pts, 28 were enrolled. Recruitment was
prematurely terminated due to a strategic change in the sponsor's
clinical development program.
Eight of 26 evaluable patients (30.8%) had SD at day 70.
The median TTP in the evaluable population was 65.5 days (95%,
CI: 43-98).
The most frequently observed AEs were pyrexia (74.1%),
headache (40.7%), chill (33.3%), and vomiting (29.6%). AEs were
mostly of mild or moderate intensity and the majority (73.8%)
resolved within one day.
http://www.abstracts2view.com/sabcs10/view.php?nu=SABCS10L_1066&terms=
Novel Monoclonal Antibodies
Anti HER2 mAbs
MGAH22
TrasGEX
Ertumaxomab
Anti HER3 mAbs
……….
HER2:HER3 Dimers May Provide an Escape
Mechanism From Trastuzumab
Homodimers
HER2:HER2
HER3:HER3
Heterodimers
HER4:HER4
HER1:HER2
HER1:HER3
HER1:HER4
HER2:HER3
HER2:HER4
HER1:HER1
+
HER3:HER4
+
+
+
+
+
+
+
+
+
+
+
+
+
+
Signaling activity
Tzahar E., et al. Mol Cell Biol. 1996. Sergina NV, et al. Nature. 445:437-441.
U3-1287 (AMG-888)
The maximum administered dose was 20 mg/kg q2w. The most frequent
AEs related to U3-1287 were fatigue (21.1%), diarrhea (12.3%), nausea
(10.5%), decreased appetite (7.0%), and dysgeusia (5.3%). No patient
developed anti-U3-1287 antibodies. In these heavily pretreated patients,
stable disease was maintained ≥ 9 weeks in 19.2% in part 1 and ≥ 10
weeks in 25.8% in part 2.
CONCLUSIONS:
U3-1287 treatment was well tolerated, and some evidence of disease
stabilization was observed. PK data support U3-1287 dosing of 9 to 20
mg/kg every 2 to 3 weeks. Combination studies of U3-1287 are ongoing.
MM-121
A Phase 1/2 study evaluating MM-121 in combination with
erlotinib is ongoing in patients with non-small cell lung
cancer, as well as a Phase 1 dose escalation trial testing the
safety and pharmacokinetics of MM-121.
MM-121
Recombinant antibody fragments
Domain VH - 15 KDa
IgG
Domain VL - 15 KDa
Fv
scFv 28 KDa
Fab
Intrabody
Intracellular
Localization
Domain
Fc
Cytosol
Nucleus
Recombinant antibody fragments
Tandem antibody
“TandAb”
IgG
Fv
Fab
Flexibody
Fc
Triabody 75 KDa
Tetrabody 100 KDa
Recombinant antibody fragments
IgG 150 KDa
Diabody 55 KDa
Fv
Fab
Monospecific
50 KDa
Diabody
Fc
Bispecific
MM-111
MM-111 is a bispecific antibody fusion protein consisting of two
human single-chain variable fragment (scFv) antibodies linked by
modified human serum albumin (HSA).
IgG 150 KDa
50 KDa
modified human
serum albumin
Fv
Fab
Anti-HER2
Anti-HER3
Fc
MM-111
MM-111 can be rationally combined with trastuzumab or lapatinib
for increased antitumor activity and may in the future complement
existing HER2-directed therapies to treat resistant tumors
Mol Cancer Ther 2012 Mar;11(3):582-93.
DEVELOPING A NEW DRUG
On average, it takes between nine and 17 years, and
only one in approximately 19,817 candidate
compounds actually becomes a drug.
http://www.eisai.com/ir/individual/knowledge.html