management of metastatic her-2 + bc: state of the art and ......são paulo, junho 2019. management...
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São Paulo, Junho 2019
Management of Metastatic HER-2 + BC:State of the Art and New Agents
Carlos H. Barrios, M.D.
Centro de Pesquisa em Oncologia, HSL-PUCRSLatin American Cooperative Group, LACOG
Grupo OncoclínicasPorto Alegre, Brazil
POTENTIAL CONFLICTS OF INTEREST 2019
• Clinical Research: AbbVie, Amgen, Astellas Pharma, AstraZeneca, Bristol-Myers Squibb, Celgene, Covance, Lilly, Medivation, Merck Serono, Merck Sharp Dohme (MSD), Novartis, Pfizer, PharmaMar, Roche/Genentech.
• Academic Research Projects: CPO, PUCRS, LACOG, GBECAM, INCA-Brazil.
• Advisory Boards and Consulting: Boehringer-Ingelheim, GSK, Novartis, Pfizer, Roche/Genentech, Eisai.
• No financial conflicts to declare.
Carlos H. Barrios, [email protected]
Conflict of Interest Statement
This presentation reflects my personal opinion, and not that of my employer or the sponsor of this activity. Its main objective is to stimulate independent scientific discussion and does not intend to promote a specific product or indication. The information presented may be different from the local/regional label of some of the medications. Please refer to your local label for further clarification.
Carlos H. Barrios, [email protected]
Carlos Barrios MD
Key Phase III HER2 Positive MBC Trials
1. Swain S, et al. ASCO 2019; 2. Diéras V, et al. Lancet Oncol 2017; 3. Krop I, et al. Lancet Oncol 2017; 4. Blackwell K, et al. J Clin Oncol 2012
Table adapted from: Rugo H, 2019
First Line Second Line Third Line 3rd/4th Line
Trial CLEOPATRA1 EMILIA2 TH3RESA3 EGF1049004
Number of Patients 808 991 602 291
Treatment
ComparisonsTHP vs TH T-DM1 vs XL T-DM1 vs TPC HL vs L
Gain in OS16.3m
(40.8 vs. 57.1)
4m
(25.9 vs. 29.9)
6.9m
(15.8 vs. 22.7)
4.5m
(9.5 vs. 14)
Side effectsMinimally
increased
Less with
T-DM1
Less with
T-DM1
Minimally
increased
Prior
Trastuzumab (anti-
HER2 Rx)
Only 10% and
interval of ≥12m
required
100% (16% with
adjuvant, disease
free interval <6m)
Prior
Trastuzumab and
Lapatinib
100%(≥ 3
regimens)
Current Approach for Advanced HER2+ Breast Cancer
First
Line
Second
Line
Third and
Further Lines
Trastuzumab +
Pertuzumab +
Taxane (CT)
TDM1
Cap + Lapatinib
Chemo + Trastuzumab
Lapatinib + Trastuzumab
Endocrine Rx + anti-HER2 Rx (HR+)
Pertuzumab or TDM1 if not received earlier
Anti-HER2 directed TKIs in Development
Pernas S, Tolaney SM. Ther Adv Med Oncol 2019, Vol. 11: 1–16DOI: 10.1177/1758835919833519
• Orally bioavailable• Selective HER2 inhibitor
(HER2>EGFR)• Decreased potential for EGFR-
related toxicities (GI, skin)• Penetrates CNS• Two phase I combination trials
HER2+ MBCTucatinib + T-DM1:
mPFS 8.2 m; RR 47%a
Tucatinib + capecitabine + trastuzumab: mPFS 7.8 m, RR 61%b
Moulder et al. AACR-NCI-EORTC 2011.Koch et al, AACR 2011.
Borges et al, AACR.
Tucatinib in HER2 positive BC
a. Dinkel, et al. AACR 2012. b. Hamilton, et al SABCS 2017.
Murthy R, et al. The Lancet Oncology, 19(7), 880-888. doi:10.1016/s1470-2045(18)30256-0
Tucatinib in HER2 positive BC
HER2CLIMB: Tucatinib + trastuzumab/capecitabineRegistrational Study
Double blinded randomized
ClinicalTrials.gov. NCT02614794
• Metastatic
HER2+ breast
cancer with
progression after
pertuzumab,
trastuzumab, a
taxane and T-
DM1
• Patients +/-
stable brain
metastases
• No prior tx w/
capecitabine for
MBC
Tucatinib +
Capecitabine +
Trastuzumab
2:1
Placebo +
Capecitabine +
Trastuzumab
Primary Endpoint
PFS(BICR* per RECIST
1.1)
Secondary
Endpoints
PFS in pts with
brain mets (BICR*
per RECIST 1.1)
OS, DOR, CBRN= 600
*BICR: Blinded independent central review
Analysis for primary endpoint planned by end of 2019
Anti-HER2 directed Antibody Drug Conjugates in Development
Pernas S, Tolaney SM. Ther Adv Med Oncol 2019, Vol. 11: 1–16DOI: 10.1177/1758835919833519
Ponde M, et al. Curr Treat Options Oncol 2019 Apr 1;20(5):37. doi: 10.1007/s11864-019-0633-6.
Optimizing ADCs in Breast Cancer
DS-8201a (Deruxtecan): HER2 directed ADC
• High potency payload• Different MOA• Short systemic T1/2• Bystander effect• Tumor selective
cleavable linker• High drug-to-antibody
ratio (8 vs. 3.5 for TDM1)
Iwata H, et al. ASCO 2018
Phase 1 Deruxtecan:Toxicity
Tamura K, et al. Lancet Oncol 2019 Published Online April 29, 2019http://dx.doi.org/10.1016/
Phase I Deruxtecan: Responses
Best percentage change in tumor size from baseline in individual patients with HER2-positive
breast cancer treated with trastuzumab deruxtecan (5·4 mg/kg or 6·4 mg/kg doses; n=110)
Dotted lines denote 20% increase or 30% reduction in tumor size. For this plot, one subject
was excluded due to no post-baseline sum of diameters.
Tamura K, et al. Lancet Oncol 2019 Published Online April 29, 2019http://dx.doi.org/10.1016/
Phase I Deruxtecan: Responses
Tamura K, et al. Lancet Oncol 2019 Published Online April 29, 2019http://dx.doi.org/10.1016/
Phase I Deruxtecan: PFS
Progression-free survival for trastuzumab deruxtecan (5·4 mg/kg
or 6·4 mg/kg) in patients with HER2-positive breast cancer
Tamura K, et al. Lancet Oncol 2019 Published Online April 29, 2019http://dx.doi.org/10.1016/
Trastuzumab Deruxtecan
Iwata H, et al. ASCO 2018; Modi S , et al. SABCS 2018Confirmed Overall RR: 49.3%
Deruxtecan: Ongoing and Phase III Trials
DESTINY-Breast01 (NCT03248492), a pivotal, phase 2, multicenter, open label trial, is further characterizing the activity and safety of trastuzumab deruxtecan in patients with HER2-positive unresectable or metastatic breast cancer previously treated with TDM1. (THIRD LINE)
DESTINY-Breast02 (NCT03523585) will assess the efficacy and safety of trastuzumab deruxtecan versus investigator’s choice of treatment (trastuzumab plus capecitabine or lapatinib plus capecitabine) in patients whose disease progressed on TDM1. (THIRD LINE)
DESTINY-Breast03 (NCT03529110) will assess the efficacy and safety of trastuzumab deruxtecan compared with TDM1. (SECOND LINE)
In August, 2017, the US Food and Drug Administration granted breakthrough therapy designation to trastuzumab deruxtecan for treatment of patients
with advanced HER2-positive breast cancer previously treated with trastuzumab and pertuzumab, and whose disease progressed after TDM1.
OTHER ANTI-HER2 ANTIBODIES
Hope S. Rugo, MD
Abstract #1000
1. Nordstrom JL, et al. Breast Cancer Res. 2011;13(6):R123;
2. Stavenhagen JB, et al. Cancer Res. 2007;67(18):8882-8890.
Margetuximab: Fc-engineered to Activate Immune Responses
20
Fab: •Same specificity and affinity1
•Similarly disrupts signaling
Fc engineering:2
•↑ Affinity for activating FcgRIIIA (CD16A)•↓ Affinity for inhibitory FcgRIIB (CD32B)
Margetuximab
Fab:•Binds HER2 with high specificity• Disrupts signaling that drives
cell proliferation and survival
Trastuzumab
Fc:• Wild-type immunoglobulin G1 (IgG1)
immune effector domains• Binds and activates immune cells
Margetuximab Binding to FcγR Variants:2
Receptor Type Receptor
Allelic Variant
Relative Binding
Affinity Fold-Change
Activating
CD16A158F Lower 6.6x ↑
158V Higher 4.7x ↑
CD32A131R Lower 6.1x ↓
131H Higher ↔
Inhibitory CD32B CD32B Equivalent 8.4x ↓
Hope S. Rugo, MD
Abstract #1000
PFS Analysis in ITT Population24% Risk Reduction of Disease Progression
Central Blinded Analysis (Primary Endpoint)30% Risk Reduction of Disease Progression
Investigator Assessed (Secondary Endpoint)
• PFS analysis was triggered by last randomization on October 10, 2018, after 265 PFS events occurred
ITT population: N=536. CI=confidence interval.
Margetuximab + Chemotherapy
(n=266)
Trastuzumab + Chemotherapy
(n=270)
# of events 160 177
Median PFS (95% CI)
5.6 months(5.06–6.67)
4.2 months(3.98–5.39)
HR by stratified Cox model, 0.70(95% CI, 0.56–0.87)
Stratified log-rank P=0.001
Margetuximab + Chemotherapy
(n=266)
Trastuzumab + Chemotherapy
(n=270)
# of events 130 135
Median PFS (95% CI)
5.8 months (5.52–6.97)
4.9 months (4.17–5.59)
HR by stratified Cox model, 0.76(95% CI, 0.59–0.98)
Stratified log-rank P=0.033
Hope S. Rugo, MD
Abstract #1000
Planned Exploratory PFS Analysis by CD16A Genotype, by CBA
FF or FV, n=437 of 506 (86%) VV, n=69 of 506 (14%)
506 patients genotyped (94%)
Margetuximab + Chemotherapy
(n=37)
Trastuzumab + Chemotherapy
(n=32)
# of events 21 13
Median PFS(95% CI)
4.8 months (2.46–5.65)
5.6 months (2.86–11.04)
HR by unstratified Cox model, 1.78(95% CI, 0.87–3.62)
Unstratified log-rank P=0.110
Margetuximab + Chemotherapy
(n=221)
Trastuzumab + Chemotherapy
(n=216)
# of events 103 112
Median PFS(95% CI)
6.9 months (5.55–8.15)
5.1 months (4.14–5.59)
HR by unstratified Cox model, 0.68(95% CI, 0.52–0.90)
Unstratified log-rank P=0.005
TAKE HOME MESSAGES
EGFR,
HER2 and
ErbB4,3
collaborate
within a
framework
of a
layered
signalling
network
Yarden and Sliwkowski (2001) Nature Rev. Mol. Cell Biol, 2:127-137.
Proposed Mechanisms of Resistance toHER2-targeted Therapy
△16HER2 splice isoform
(Mitra et al. Mol Cancer Ther, 2009)
Activation of EPO receptor by rHuEPO
(Liang et al. Cancer Cell 2010)
Upregulation of IGF-IR receptor
(Gail Phillips, AACR, 2009)
Activation of AXL
(Liu et al, Cancer Res, 2009)
Upregulation of MET receptor
(Shattuck et al, Cancer Res, 2008)
Expression of ER
(Xia et al, PNAS, 2006)
Shedding of ERBB2
(Scalitriti et al, J Nat Cancer Inst, 2007)
Loss of PTEN and PIK3CA mutations
(Eichhorn et al, Cancer Res, 2009)
MUC4/MUC1 steric hindrance of binding
(Nagy et al. Cancer Res. 2005)
Increase in p-ERBB3
(Sergina et al, Nature, 2007)
Cyclin E amplification/overexpression
(Scaltriti et al. PNAS 2011)
Upregulation of miR-21(Gong, et al, J Biol Chem, 2011)
△16HER2homodimers
Updated/Adapted from: Chen et al. Clin Cancer Res; 2008
naive
To address in animals the ability of 3XmAbs to overcome resistance to osimertinib, we inoculated PC9ER-AZDR cells in CD1-nu/nu mice, which were later treated with either osimertinib or antibodies.As expected, neither erlotinib nor osimertinib inhibitedgrowth of the corresponding tumors in animals. On the contrary, treatment with 3XmAbs strongly and persistently reduced tumor volumes, and no relapses were observed > 90 days after ending all antibody treatments. Immunohistochemical staining of xenografts confirmed the ability of 3XmAbs, unlike osimertinib, to arrest cell proliferation.
Overcoming Resistance to EGFR Inhibitors
Mancini M, et al. EMBO Mol Med (2018) 10: 294–308
• Cetuximab
• Trastuzumab
• mAB33
number
Targeting HER3: Current Agents Under Study
Mishra R, et al. Oncol Rev. 2018;12:355.
Carlos Barrios MD
Real World Data on OS in MBC
Delaloge S, et al. ASCO 2017.
Year of Diagnosis
OS (m) 2008 2009 2010 2011 2012 2013
HR+ HER2-
(N=9.908)
43.7
(40.2-46.6)
42.0
(38.9-44.6)
40.9
(38.0-43.4)
42.0
(39.2-45.0)
44.5
(41.8-47.3)
40.3
(37.8-ND)
HER2+
(N=2.861)
38.6
(33.6-44.6)
42.3
(38.3-50.8)
40.1
(35.2-45.6)
42.3
(36.5-49.8)
51.1
(46.5-ND)Not Reached
HR- HER2-
(N=2.317)
15.1
(12.7-16.4)
15.1
(13.0-17.4)
14.7
(13.2-17.0)
14.0
(11.4-15.9)
13.9
(11.4-15.9)
14.1
(12.5-15.5)
positive
ACKNOWLEDGEMENTS
• CPO
Ana Gelatti
Fernanda Damian
Fernanda Pruski
• LACOG
Gustavo Werutsky
Tomas Reinert
Paulo Nunes
• CHO
Sergio Azevedo
Sergio Roithmann
Luiz Bruno
Gabriel Prolla
Stephen Stefani
• SOP
André Fay
Matheus Ferla
Luciana Viola
Fabiana Viola
Helena Andrade
Caroline Albuquerque
São Paulo, Junho 2019
Carlos H. Barrios, M.D.
Centro de Pesquisa em Oncologia, HSL-PUCRSLatin American Cooperative Group, LACOG
Grupo OncoclínicasPorto Alegre, Brazil
Management of Metastatic HER-2 + BC:State of the Art and New Agents