Mecanismos de resistencia a terapia anti-HER2 Experiencia investigadora del C.I.C. de

SalamancaRepercusión en la práctica clínica

Alberto OcañaHospital Clínico San Carlos

MadridCentro Regional de Investigaciones Biomédicas. Universidad de

Castilla La Mancha, Albacete

Summary

• Mechanisms to overcome trastuzumabresistance: Our experience

• Mechanisms to overcome trastuzumabresistance TDM1 resistance: by standereffect

• Other vulnerabilities

SRC p95

dasatinibChemical library

A phase II trial of Dasatinib in combination with trastuzumab and

paclitaxel in the first line treatment of HER2 positive Metastatic Breast

Cancer (MBC) patients: GEICAM/2010-04

A. Ocana1, M. Ruiz Borrego2, M. Gil Martin3, S. Antolin4, M. Atienza2, A. Montaño2, N. Ribelles5, A. Guerrero6, M. Muñoz7,

I. Fernández-Pérez8, A. Urruticoechea9, A. Falcon Gonzalez10, S. Pernas Simon3, J. Prato Varela11, M.J. Escudero12, S. Benito13, R. Caballero14,

E. Carrasco15, F. Rojo16, A. Pandiella17

1Clinical Oncology, Complejo Hospitalario Universitario de Albacete, Albacete, ES, 2Medical Oncology, Hospital Virgen del Rocío, Sevilla, ES, 3Medical Oncology, Institut

Català d'Oncologia (ICO)-Hospitalet, Barcelona, ES, 4Clinical Oncology, Complejo Hospitalario U A Coruña, Coruña, ES, 5Medical Oncology, Hospital Clínico

Universitario Virgen de la Victoria, Malaga, ES, 6Medical Oncology, Instituto Valenciano de Oncología, Valencia, ES, 7Clinical Oncology, H Clinic i Provincial de

Barcelona, Barcelona, ES, 8Medical Oncology, Hospital Alvaro Cunqueiro, Vigo, ES, 9Clinical Oncology, Fundación Onkologikoa, San Sebastián, ES, 10Medical

Oncology, Hospital Universitario Virgen del Rocio, Sevilla, ES, 11Medical Oncology, Complejo Hospitalario Universitario A Coruña, A Coruna, ES, 12Statistics, GEICAM,

San Sebastian De Los Reyes, ES, 13Operations, GEICAM, San Sebastian De Los Reyes, ES, 14Traslational Research Director, GEICAM, San Sebastian De Los Reyes,

ES, 15Scientific Director, GEICAM, Madrid, ES, 16Cancer Institute, Hospital Universitario Fundación Jimenez Diaz, GEICAM, CIBERONC-ISCIII, Madrid, ES, 17Oncology,

Centro de Investigación del Cáncer and CIBERONC, CSIC-Universidad de Salamanca, Salamanca, ES

Background

Study design

▪ Activation of SRC is a described mechanism of resistance to trastuzumab (T)1-2. The addition of the

SRC kinase inhibitor dasatinib (D) to T increases its antitumor activity and synergies with taxanes in

preclinical models2.Table 1. Patient and Tumor Characteristics n=29

Median age, years (range) 49 (32-81)

Menopausal Status, n (%)

Postmenopausal 17 (59)

Premenopausal 12 (41)

Metastatic locations, n (%)

Visceral 23 (79)

Non-visceral 12 (41)

Previous Trastuzumab (neo/adjuvant), n (%)

No 19 (66)

Yes 10 (34)

Previous Chemotherapy (neo/adjuvant)1, n (%)

No 14 (48)

Yes 15 (52)

Histologic Grade (G), n (%)

G2 13 (45)

G3 5 (17)

Unknown 11 (38)

Hormone Receptor (HR), n (%)

HR-positive 22 (76)

HR-negative 7 (24)

Tumour evaluated in HER2 central screening, n (%)

Primary Tumour 13 (45)

Metastatic Tumour 16 (55)

▪ Single-arm, multicentre, open-label study (NCT01306942).

▪ 27 patients included from Jun2013 to Dec2015 (plus 2

additional patients with measurable disease from the Phase

I part of this study).

Figure 1. Treatment schedule

28-day cycle

Dasatinib 100mg

Trastuzumab 2mg/kg*

Paclitaxel 80mg/m2

Week 1 Week 2 Week 3 Week 4

Daily

*Loading dose of 4mg/kg for the first cycle. Treatment until progression,

unacceptable toxicity or withdrawal of informed consent.

▪ We assessed pharmacodynamic changes of p-

SRC and p-AKT in sequential Peripheral Blood

Mononuclear Cells (PBMCs) samples (0h and 8h)

at Cycle 1 Day 1 by ELISA and Western Blot.

1. Zhang S, et al. Nat Med 2011 Apr;17(4):461-9.

2. Seoane S, et al. J Natl Cancer Inst 2010 Sep 22;102(18):1432-46.

Results

Table 2. Main Adverse Events (AE) per patient regardless

causality (NCI-CTCAE v4.0) (n=29)

AE G1, n (%) G2, n (%) G3, n (%)

Alopecia 7 (24.1) 13 (44.8) -

Anorexia 6 (20.7) 1 (3.4) -

Diarrhoea 13 (44.8) 5 (17.2) 1 (3.4)

EF decrease - 7 (24.1) 4 (13.8)

Fatigue 18 (62.1) 5 (17.2) 2 (6.9)

Hypertension 5 (17.2) 7 (24.1) 2 (6.9)

Mucositis oral 8 (27.6) - -

Nausea 7 (24.1) 1 (3.4) -

Sensory neuropathy 13 (44.8) 6 (20.7) 2 (6.9)

Vomiting 7 (24.1) 1 (3.4) -

Weight gain 4 (13.8) 7 (24.1) -

aPTT prolonged 2 (6.9) 6 (20.7) -

ALT increase 17 (58.6) 6 (20.7) -

AP increased 9 (31.0) 2 (6.9) -

AST increased 20 (69.0) 1 (3.4) -

Hypocalcaemia 2 (6.9) 7 (24.1) 1 (3.4)

Hypomagnesemia 8 (27.6) 2 (6.9) -

Hyponatremia 4 (13.8) - 2 (6.9)

Hypophosphatemia 4 (13.8) 4 (13.8) 1 (3.4)

Anaemia 13 (44.8) 12 (41.4) -

RBC count decreased 27 (93.1) 1 (3.4) -

WBC count decreased 12 (41.4) 5 (17.2) -

Neutropenia 16 (55.2) 7 (24.1) 2 (6.9)

▪ No grade 4 AE were reported.

▪ Related Serious Adverse Events reported:

G3 pneumonitis, G3 diarrhoea, G2 angor pectoris, overdose,

and sudden death.

Treatment administration:

Table 3. No. cycles & RDI n=29

Number of cycles –Median (range) 12 (1 – 35)

RDI (%) of T – Mean (range) 99.8 (88.1 – 124.1)

RDI (%) of P – Mean (range) 89.8 (53.7 – 104.1)

RDI (%) of D – Mean (range) 98.3 (81.4 – 100.3)

Results

Conclusions:

• The combination showed a high efficacy rate (with an ORR that reached almost 80% of treated

patients) and a good long-term tolerability.

• Target inhibition was demonstrated by decreased levels of p-SRC and p-AKT in PBMCs in patients

treated with dasatinib, as previously described in preclinical models.

▪ p-SRC was significantly reduced in PBMCs after 8h (p<0.0001, 4.4 folds) of D administration in C1D1

in 16 (55%) assessed patients. p-AKT was reduced 1.9 folds (p=0.131).

▪ The ORR was 79.3% (95% Confident Interval (CI) 60.3 – 92.0) and the CBR was 82.8% (95% CI 64.2-94.2).

Median TTP: 23.9 months (95% CI 14.9-NR)

Median PFS: 23.9 months (95% CI 10.3-NR)

Figure 2. Kaplan-Meier Plot for TTP Figure 3. Kaplan-Meier Plot for PFS

NR: Not Reached. NR: Not Reached.

Summary

• Mechanisms to overcome trastuzumabresistance: Our experience

• Mechanisms to overcome trastuzumabresistance TDM1 resistance

• Better HER2 binding

• Other vulnerabilities

MECHANISMS

OF ACTION

MECHANISMS

OF RESISTANCE

RELATED TO TRASTUZUMAB

T-DM1 EXCLUSIVE

RELATED TO DM1

Mitotic arrest

Apoptosis

Mitotic catastrophe

Intracellular trafficking

disruption

High

[DM1]

Low

[DM1]

1. Bystandard effect

2. Masking of the epitope

3. Shedding of HER2

4. High p95HER2

5. NRG-HER3 signaling

6. Cell survival pathways

1. Drug efflux pumps

2. Alterations in tubulins

3. Tubulin isoforms (β3)

1. Defective internalization

2. Defective trafficking

3. Excessive recycling

4. Impaired lysosomal

processing

5. Induction of cyclin B

HER2 signaling inhibition

ADCC stimulation

HER2 shedding blockade

1 2

4

3

5

61

2 3

45

1

2

3

4

LYSOSOMAL

DEGRADATION

PAYLOAD

RELEASE

BINDING

TO HER2

INTERNALIZATION

G1

S

G2

M

Tumor heterogeneity in HER2 expression

• T-DM1 is only effective against cells expressing HER2; there is no

bystander effect

• Even if HER2 is expressed widely in breast tumors, selection of clones with a no or a limited expression of HER2 could become the prominent population after exposure to T-DM1.

• These cells could still be targeted by conventional chemotherapy but not by cytotoxic catabolites derived from T-DM1.

• The combination of T-DM1 and chemotherapy has been explored, and although there is acceptable efficacy in early phase trials, this approach seems highly toxic.

$7 billion investment for a share of Japan-based Daiichi Sankyo's

To buy into the Daiichi Sankyo drug, AstraZeneca had to go to the public market in March for the first time. It raised $3.5 billion in a public stock offering, which Bloomberg described as a "painful experience."

It is predicted that trastuzumab deruxtecan could reach $5 billion in drugsales globally for AstraZeneca and Daiichi. Herceptin generated about $7 billion in 2018.

DS-8201a

Summary

• Mechanisms to overcome trastuzumabresistance

• Mechanisms to overcome trastuzumabresistance TDM1 resistance

• Better HER2 binding

• Other vulnerabilities

BET inhibitors

BET-PROTACS

Univ TorontoIan TannockEitan AmirGary Bader

CIC_SalamancaAtanasio PandiellaJuan Carlos MontalvoAzucena Esparís Ogando

Oncología SalamancaJuan Jesús Cruz-Hernández

Yale UniversityLajos PusztaiGabriel Santpere

Bostjan SerugaArnoud TempletonSaroj NiraulaG Balazs- HungaryEduardo Osinaga-Uruguay

GEICAMMiguel Martin

Thanks for your attention