metastatic triple negative breast cancer: ongoing...
TRANSCRIPT
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Joan AlbanellHospital del Mar, Barcelona
Metastatic Triple Negative Breast Cancer:
Ongoing Trials
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Metastatic Triple Negative Breast Cancer Spectrum
Targeting Growth Factor Receptors
Targeting Signaling Transduction Pathways
Targeting The Androgen Receptor
Immune Checkpoint Modulators
Dynamics of mTNBC
Summary
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Potential Therapeutic Implications of TNBC Subtyping
Abramson et al. Cancer 2015
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ClinicalTrials.Gov (Feb 2015)
• Searching term: Triple Negative Metastatic Breast Cancer; Excluding ad hoc trials based on Chemo or PARPinh
• 31 Ongoing Trials (Active, not recruiting; Recruiting; Not yetrecruiting) with Targeted Therapy or Immunotherapy
• No trials with mandatory specific mutations/amplifications
• TN Subtypes for Elegibility not Observed
• Lots of biomarker exploratory analysis and planned subsets
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ClinicalTrials.Gov (Feb 2015)
• Triple Negative based on traditional ER/PR/HER2 (all comers) (n=23)
– Growth Factor Receptors: Met (ARQ-197, cabozantinib, onartuzumab (+CT, Beva)); EGFR; Nimotuzumab(+CT), Icotinib; FGFR: Lucitanib
– PI3K/Akt/mTOR: BKM120, Ipatasertib + paclitaxel, everolimus (+CT), (n=2)
– MEK: Cometinib + Paclitaxel, Trametinib (andGSK2141795)
– CDK inhibitor: Dinaciclib
– Apoptosis: Abraxane + Tigatuzumab (Death Receptor 5)
– Stemness: CXCR4 POL6326 + ct; Notch/Hedgehog RO4929097 + vismodegiv; LDE225 (+BKM120/CT)
– Glutaminase Inhibitor: CB-839
– Angiogenesis: ENMD-2076, Apatinib
– Immunotherapy (PD-L1+?): Nivolumab + CT; Nivolumab + Ipilimumab, Autologous cMet Redirected T Cells
• Triple Negative and Androgen Receptor Positive (n=5)– Bicalutamide (n=2), Enzalutamide, Orterone, 4 OH testosterone
• Triple Negative and Androgen Receptor Negative (n=1)– PI3K: GDC-0941 + cisplatin
• Triple Negative EGFR Positive: Gefitinib (n=1)
• Triple Negative gpNMB Positive: Glembatunumab vedotin (n=1)
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From C Turner ES
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Metastatic Triple Negative Breast Cancer Spectrum
Targeting Growth Factor Receptors
Targeting Signaling Transduction Pathways
Targeting Stemness
Targeting The Androgen Receptor
Immune Checkpoint Modulators
Dynamics of mTNBC
Summary
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Andre et al. CCR 2013
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A new breast cancer ‘subtype’?
- HER2 Negative (1+ or 2+; FISH negative)- HER3 Positive
- ER + or -
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Phase I Pharmacoynamic andAntitumor Data with RG7116
Proc ASCO 2013
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Mirschberger et al. Cancer Res 2013
RT7160 (anti-HER3) Combined with Anti-EGFR or Pertuzumab
Anti-EGFR + anti-HER3 Pertuzumab + anti-HER3
HER2 1+/2+ and FISH- / HER3+ trial
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Metastatic Triple Negative Breast Cancer Spectrum
Targeting Growth Factor Receptors
Targeting Signaling Transduction Pathways
Targeting Stemness
Targeting The Androgen Receptor
Immune Checkpoint Modulators
Dynamics of mTNBC
Summary
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PIK3CA Mutations in Basal-like Cancerand by Lehmann’s Subtypes
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Dual PI3K/mTOR inhibitors
• Target homologous regions in the catalytic sites of PI3K and downstream components mTORC1 and mTORC23,6
• Targeting two levels of the pathway may provide the potential advantage of stronger inhibition3,6
Pan-PI3K class I inhibitors
• Inhibit all four isoforms of class I PI3K (α, β, γ, δ) and provide the broadest inhibition of PI3K3,6
• May be better suited to combination therapy and in tumour types lacking PIK3CA mutations4
Isoform specific inhibitors
• Characterised by greater and PI3K isoform-specific activity3
• Provide the potential to completely block a specific target while limiting toxicities associated with a broader inhibition5
PI3K Inhibitors in Development• Three generations of PI3K inhibitors have now been developed1–3
1. Akinlele et al, J Haematol Oncol 2013; 2 Porta et al, Front Oncol 2014; 3. Martini et al, Front Oncol 2013; 4. Dienstmann et al, Mol Can Ther 2014;5. Fruman and Rommel, Nat Rev Drug Dis 2014; 6. Rodon et al, Nat Rev Clin Oncol 2013; 7. Engelman et al, Nat Rev Cancer 2009; 8. Courtney et al, J Clin Oncol 2010
First-generation Second-generation Third-generation
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Taselisib, a Selective Inhibitor of PI3Kα and Mutant Variants, Was More Active in PIK3CA-Mutant Breast Cancer
Genentech, data on file.Based on measurable disease. Waterfall chart does not include patients with no post-baseline tumor measurements;Data extracted 15 Aug 2014. Some data not source-verified.
In this Phase Ib study PMT4979g, heavily pretreated patients (>4L) with either wild-type or PI3KCA-mutant BC responded to single-agent taselisib
PIK3CA status ORR, % (cPR)
Mutant 25 (6/24)
Mut, prior fulvestrant 25 (1/4)
Wild-type 0 (0/9)
Taselisib as a single-agent in wild-type and PI3KCA-mutant BC
-100
-50
0
509 mg/G 9 mg/D 9 mg/A 8 mg 5 mg 3 mg 12 mg
72.1PD
101.1PD
51.6PD
31.4PD
31.6PD
81.5SD
51.1PD
41.8PD
63.9SD
1.5SD
45.1SD
42.1PD
52.0PD
82.0PD
41.4PD
83.8SD
83.9SD
88.1SD
58.2SD
83.9SD
21.6PD
117.6SD
81.6PD
35.4SD
22.5SD
46.6PR
34.4PR
615.7PR
56.3PR
137.4PR
6.7+PR
# prior txmo on study
1210 1403 1317 101 1324 301 216 1504 1904 1822 1601 1105 2404 3101 208 1910 1103 1304 209 205 1316 1204 213 1816 214 203 215 218 1313 303 2901 Bestconfirm esp
Bes
t %
SLD
Ch
ange
PIK3CA mutant PIK3CA wild type HER2 expression Prior Fulvestrant Prior Everolimus Prior Letrozole PR+ PR-
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Phase II trial of Everolimus and Carboplatin in TNBC(Sing et al. BCRT 2014)
• Majority of patients had prior chemo,including carboplatin
• 1 CR, 6 PR, 7 SD
• Clinical Benefit 36% (21-57%)
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MEK Inhibitor Trametinib and Akt InhibitorGSK2141795 in Treating Patients With Metastatic
Triple-Negative Breast Cancer
PART 1: Patients receive trametinib PO QD on days 1-28. Patients whoexperience disease progression continue to Part 2.
PART 2: Patients receive trametinib as in Part 1 and also receive Aktinhibitor GSK2141795 PO QD on days 1-28.
Duncan et al. Cell 2012
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HER3 Phosphorylation in TNBC cells in Response to Cetuximab plusAkt or PI3K inhibition (Tao et al. Sci Signal 2015)
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Metastatic Triple Negative Breast Cancer Spectrum
Targeting Growth Factor Receptors
Targeting Signaling Transduction Pathways
Targeting Stemness
Targeting The Androgen Receptor
Immune Checkpoint Modulators
Dynamics of mTNBC
Summary
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Gamma-Secretase Inhibitor (PF-03084014) Clinical Trials
Title Phase Status ID Number
A Phase 1 Trial of
PF-03084014
in patients with advanced
solid tumor malignancy and
T-cell acute lymphoblastic
leukemia/lymphoblastic
lymphoma
1 Closed NCT00878189
A8641014
Phase 1b study of docetaxel +
PF-03084014 in metastatic or
locally recurrent/advanced
triple negative breast cancer
1b Open for
recruitment
NCT01876251
A8641016
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Phase I Trial Results with the Gamma-Secretase Inhibitor PF-03084014 (Messersmith et al. CCR 2014)
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HCC1599cell line xenograft
HCC1599 treated tumors
PF-03084014 + Docetaxel Leads to Enhanced Effect in Triple Negative Breast Cancer Models in Part via CSC Inhibition
Zhang C, et al. Stem Cells Transl Med 2013;2:233–242
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Breast Cancer TN, no more
than 3 previous QT treatment
lines.
Docetaxel IV C3s
LDE225Oral daily
Design 3+3
LDE225400 mg
Docetaxel75 mg/m2
Docetaxel75 mg/m2
Docetaxel75 mg/m2
LDE225400 mg
LDE225400 mg
ND1 (3-6 patients)
TLD
win
do
w 4
2 d
ays
(2 c
ycle
s)
LDE225400 mg
Docetaxel60 mg/m2
ND -1
Tre
atm
en
t ti
ll p
rogr
ess
ion
, un
acce
pta
ble
to
xici
ty o
r IC
F w
ith
dra
w
ND3 (3-6 patients)
ND2 (3-6 patients)
GEICAM/ 2012-12 "EDALINE”Phase Ib Dose Escalation, Open Label, Multicenter Study Evaluating the Hedgehog Inhibitor
LDE225 in Combination With Docetaxel in Triple Negative (TN) Advanced Breast Cancer (ABC) Patients.
Martín M, et al. ESMO 2014
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Metastatic Triple Negative Breast Cancer Spectrum
Targeting Growth Factor Receptors
Targeting Signaling Transduction Pathways
Targeting Stemness
Targeting The Androgen Receptor
Immune Checkpoint Modulators
Dynamics of mTNBC
Summary
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Gucalp et al. CCR 2013
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PIK3CA Mutations in AR-Positive TNBC ConfersSensitivity to Combined PI3K and AR Inhibitors
(Lehmann et al. BCR 2014)
Pan-PI3kinh
Dual PI3K/mTOR
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Metastatic Triple Negative Breast Cancer Spectrum
Targeting Growth Factor Receptors
Targeting Signaling Transduction Pathways
Targeting Stemness
Targeting The Androgen Receptor
Immune Checkpoint Modulators
Dynamics of mTNBC
Summary
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Metastatic Triple Negative Breast Cancer Spectrum
Targeting Growth Factor Receptors
Targeting Signaling Transduction Pathways
Targeting Stemness
Targeting The Androgen Receptor
Immune Checkpoint Modulators
Dynamics of mTNBC
Summary
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Metastatic Triple Negative Breast Cancer Spectrum
Targeting Growth Factor Receptors
Targeting Signaling Transduction Pathways
Targeting Stemness
Targeting The Androgen Receptor
Immune Checkpoint Modulators
Dynamics of mTNBC
Summary
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Summary
1. The majority of trials select patients based on traditional triple negative status.
2. The majority of trials included biomarker endpoints or enrichment of subsets.
3. Androgen receptor is the main biomarker used for subtyping TNBC for anti-androgen trials.
4. Increasing preclinical evidence and the limited activity of single agent data with signaltransduction inhibitor point to drug combinations and biologically-driven patients selectionas an attractive strategy.
5. Targeting stem-like/EMT ongoing. Role of Mesenchymal subtype tbd.
6. Immune checkpoint modulators are promising. Role of Basal/Immune subtypeand PD1/PD-L1 tbd.
7. Tackling the dynamics of TNBC biology in sequential patient specimens is necessary tobetter understand this aggressive disease. Aurora as a big effort.