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Home , Dasatinib

Mecanismos de resistencia a terapia anti-HER2 Experiencia investigadora del C.I.C. de Salamanca Repercusión en la práctica clínica

Alberto Ocaña Hospital Clínico San Carlos Madrid Centro Regional de Investigaciones Biomédicas. Universidad de Castilla La Mancha, Albacete Summary

• Mechanisms to overcome resistance: Our experience

• Mechanisms to overcome trastuzumab resistance TDM1 resistance: by stander effect

• Other vulnerabilities SRC p95

Chemical library dasatinib

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

▪ 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

Study design Median age, years (range) 49 (32-81) ▪ Single-arm, multicentre, open-label study (NCT01306942). Menopausal Status, n (%) ▪ 27 patients included from Jun2013 to Dec2015 (plus 2 additional patients with measurable disease from the Phase Postmenopausal 17 (59) I part of this study). Premenopausal 12 (41) Metastatic locations, n (%) Visceral 23 (79) Figure 1. Treatment schedule Non-visceral 12 (41) Previous Trastuzumab (neo/adjuvant), n (%) 28-day cycle Week 1 Week 2 Week 3 Week 4 No 19 (66) Dasatinib 100mg Daily Yes 10 (34) Trastuzumab 2mg/kg* Previous (neo/adjuvant)1, n (%) Paclitaxel 80mg/m2 No 14 (48) Yes 15 (52) *Loading dose of 4mg/kg for the first cycle. Treatment until progression, unacceptable toxicity or withdrawal of informed consent. Histologic Grade (G), n (%) G2 13 (45) ▪ We assessed pharmacodynamic changes of p- G3 5 (17) SRC and p-AKT in sequential Peripheral Blood Unknown 11 (38) Hormone Receptor (HR), n (%) Mononuclear Cells (PBMCs) samples (0h and 8h) HR-positive 22 (76) at Cycle 1 Day 1 by ELISA and Western Blot. HR-negative 7 (24) Tumour evaluated in HER2 central screening, n (%)

1. Zhang S, et al. Nat Med 2011 Apr;17(4):461-9. Primary Tumour 13 (45) 2. Seoane S, et al. J Natl Cancer Inst 2010 Sep 22;102(18):1432-46. Metastatic Tumour 16 (55) Results ▪ No grade 4 AE were reported. Table 2. Main Adverse Events (AE) per patient regardless ▪ Related Serious Adverse Events reported: causality (NCI-CTCAE v4.0) (n=29) G3 pneumonitis, G3 diarrhoea, G2 angor pectoris, overdose, AE G1, n (%) G2, n (%) G3, n (%) and sudden death. Alopecia 7 (24.1) 13 (44.8) - Treatment administration:

Anorexia 6 (20.7) 1 (3.4) - Table 3. No. cycles & RDI n=29 Diarrhoea 13 (44.8) 5 (17.2) 1 (3.4) EF decrease - 7 (24.1) 4 (13.8) Number of cycles –Median (range) 12 (1 – 35) 18 (62.1) 5 (17.2) 2 (6.9) Hypertension 5 (17.2) 7 (24.1) 2 (6.9) RDI (%) of T – Mean (range) 99.8 (88.1 – 124.1) Mucositis oral 8 (27.6) - - 7 (24.1) 1 (3.4) - RDI (%) of P – Mean (range) 89.8 (53.7 – 104.1) Sensory neuropathy 13 (44.8) 6 (20.7) 2 (6.9) RDI (%) of D – Mean (range) 98.3 (81.4 – 100.3) 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) - 16 (55.2) 7 (24.1) 2 (6.9) Results

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

Median TTP: 23.9 months Median PFS: 23.9 months (95% CI 14.9-NR) (95% CI 10.3-NR)

NR: Not Reached. NR: Not Reached.

▪ 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).

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.

Summary

• Mechanisms to overcome trastuzumab resistance: Our experience

• Mechanisms to overcome trastuzumab resistance TDM1 resistance

• Better HER2 binding

• Other vulnerabilities MECHANISMS MECHANISMS OF ACTION OF RESISTANCE

RELATED TO TRASTUZUMAB 1. Bystandard effect HER2 signaling inhibition 2. Masking of the epitope ADCC stimulation 3. Shedding of HER2 BINDING HER2 shedding blockade 4. High p95HER2 TO HER2 3 1 2 5. NRG-HER3 signaling 6. Cell survival pathways 4 5

T-DM1 EXCLUSIVE INTERNALIZATION 6 1 2 3

1. Defective internalization 2. Defective trafficking M LYSOSOMAL G2 G1 3. Excessive recycling S DEGRADATION 5 4. Impaired lysosomal 4 processing 4 RELATED TO DM15. Induction of cyclin B 3 1. Drug efflux pumps Mitotic arrest 2 PAYLOAD High 2. Alterations in tubulins RELEASE [DM1] 3. Tubulin isoforms (β3) Mitotic catastrophe Low [DM1] Intracellular trafficking 1 disruption

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.

DS-8201a

$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 could reach $5 billion in drug sales globally for AstraZeneca and Daiichi. Herceptin generated about $7 billion in 2018.

Summary

• Mechanisms to overcome trastuzumab resistance

• Mechanisms to overcome trastuzumab resistance TDM1 resistance

• Better HER2 binding

• Other vulnerabilities BET inhibitors

BET- PROTACS

CIC_Salamanca Univ Toronto Atanasio Pandiella Yale University Bostjan Seruga GEICAM Ian Tannock Juan Carlos Montalvo Lajos Pusztai Arnoud Templeton Miguel Eitan Amir Azucena Esparís Ogando Gabriel Santpere Saroj Niraula Martin Gary Bader G Balazs- Hungary Oncología Salamanca Eduardo Osinaga-Uruguay Juan Jesús Cruz-Hernández

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