Management of Metastatic HER-2 + BC: State of the Art and ......São Paulo, Junho 2019. Management of Metastatic HER-2 + BC: State of the Art and New Agents. Carlos H. Barrios, M.D

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.


Phase I Deruxtecan: Responses


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


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


(n=266)


(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%)


(n=37)


(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


(n=221)


(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

Documents

Management of Metastatic HER-2 + BC: State of the Art and ......São Paulo, Junho 2019. Management of Metastatic HER-2 + BC: State of the Art and New Agents. Carlos H. Barrios, M.D