Resistencias en cáncer de mama HER2 positivo, Hay margen para la mejora?

Transcription

1 Resistencias en cáncer de mama HER2 positivo, Hay margen para la mejora? Salamanca, 2018

2 Un 20% de los tumores son HER2 positivos Alteración molecular fundacional: necesaria, pero no suficiente

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4 Cruz JJ, et al. Annals of Oncology 2007

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11 Summary Mechanisms to overcome trastuzumab resistance TDM1 resistance Trastuzumab + pertuzumab resistance

12 SRC p95

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

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17 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/ A. Ocana 1, M. Ruiz Borrego 2, M. Gil Martin 3, S. Antolin 4, M. Atienza 2, A. Montaño 2, N. Ribelles 5, A. Guerrero 6, M. Muñoz 7, I. Fernández-Pérez 8, A. Urruticoechea 9, A. Falcon Gonzalez 10, S. Pernas Simon 3, J. Prato Varela 11, M.J. Escudero 12, S. Benito 13, R. Caballero 14, E. Carrasco 15, F. Rojo 16, A. Pandiella 17 1 Clinical Oncology, Complejo Hospitalario Universitario de Albacete, Albacete, ES, 2 Medical Oncology, Hospital Virgen del Rocío, Sevilla, ES, 3 Medical Oncology, Institut Català d'oncologia (ICO)-Hospitalet, Barcelona, ES, 4 Clinical Oncology, Complejo Hospitalario U A Coruña, Coruña, ES, 5 Medical Oncology, Hospital Clínico Universitario Virgen de la Victoria, Malaga, ES, 6 Medical Oncology, Instituto Valenciano de Oncología, Valencia, ES, 7 Clinical Oncology, H Clinic i Provincial de Barcelona, Barcelona, ES, 8 Medical Oncology, Hospital Alvaro Cunqueiro, Vigo, ES, 9 Clinical Oncology, Fundación Onkologikoa, San Sebastián, ES, 10 Medical Oncology, Hospital Universitario Virgen del Rocio, Sevilla, ES, 11 Medical Oncology, Complejo Hospitalario Universitario A Coruña, A Coruna, ES, 12 Statistics, GEICAM, San Sebastian De Los Reyes, ES, 13 Operations, GEICAM, San Sebastian De Los Reyes, ES, 14 Traslational Research Director, GEICAM, San Sebastian De Los Reyes, ES, 15 Scientific Director, GEICAM, Madrid, ES, 16 Cancer Institute, Hospital Universitario Fundación Jimenez Diaz, GEICAM, CIBERONC-ISCIII, Madrid, ES, 17 Oncology, Centro de Investigación del Cáncer and CIBERONC, CSIC-Universidad de Salamanca, Salamanca, ES

18 Study design 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 models 2. Table 1. Patient and Tumor Characteristics n=29 Single-arm, multicentre, open-label study (NCT ). 27 patients included from Jun2013 to Dec2015 (plus 2 additional patients with measurable disease from the Phase I part of this study). 28-day cycle Dasatinib 100mg Trastuzumab 2mg/kg* Paclitaxel 80mg/m 2 Figure 1. Treatment schedule 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): Seoane S, et al. J Natl Cancer Inst 2010 Sep 22;102(18): 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) 1 Ten patients Metastatic receivedtumour taxanes for early BC. 16 (55)

19 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) G=Grade. EF=Ejection Fraction. aptt=activated Partial Thromboplastin Time. ALT=Alanine Aminotransferase. AP=Alkaline Phosphatase. AST=Aspartate Aminotransferase. RBC=Red Blood Cell. WBC=White Blood Cell. 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 ( ) RDI (%) of P Mean (range) 89.8 ( ) RDI (%) of D Mean (range) 98.3 ( ) RDI=Relative Dose Intensity. Reasons for Treatment Discontinuation: Table 4. Discontinuation of Study Treatment n=29 Progressive Disease 9 (31%) Adverse Event 6 (25%) Investigator/Sponsor Criteria 5 (17%) Other 4 (14%) 5 pts were on study treatment when this analysis was performed. The AEs causing discontinuation of study treatment included: neutropenia (3 patients), and fatigue, neurotoxicity and angor pectoris (1 patient each).

20 Results The ORR was 79.3% (95% Confident Interval (CI) ) and the CBR was 82.8% (95% CI ). Figure 2. Kaplan-Meier Plot for TTP Figure 3. Kaplan-Meier Plot for PFS Median TTP: 23.9 months (95% CI 14.9-NR) Median PFS: 23.9 months (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.

21 After TDM1 trastuzumab+pertuzumab vs trastuzumab+pertuzumab+dasatinib

22 Summary Mechanisms to overcome trastuzumab resistance TDM1 resistance Trastuzumab + pertuzumab resistance

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24 Mechanism of resistance?

25 BINDING TO HER2 MECHANISMS MECHANISMS OF ACTION OF RESISTANCE RELATED TO TRASTUZUMAB 1. Low HER2 levels HER2 signaling inhibition 2. Masking of the epitope ADCC stimulation 3. Shedding of HER2 HER2 shedding blockade 4. High p95her NRG-HER3 signaling 6. Cell survival pathways 4 5 INTERNALIZATION 6 1 T-DM1 EXCLUSIVE Defective internalization LYSOSOMAL DEGRADATION G2 M 5 S G Defective trafficking 3. Excessive recycling 4. Impaired lysosomal processing PAYLOAD RELEASE Mitotic arrest Apoptosis Mitotic catastrophe 4 Intracellular trafficking disruption 2 RELATED TO DM1 5. Induction of cyclin B High [DM1] Low [DM1] Drug efflux pumps 2. Alterations in tubulins 3. Tubulin isoforms (β3)

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27 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.

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29 Anti-HER2 combinations: TDM1 Chemotherapy induces a release of neoantigens therefore augmenting the immune response: combination with immunomodulators Combination with CDK4/6 inhibitors CombinationwithHER2 TK inhibitors

30 PHASE BRAZO EXPERIMENTAL OBJETIVOS I I I I/II I I/II I/II I I Drug: T-DM1 Drug: Pembrolizumab Drug: Utomilumab. Drug: Trastuzumab Drug: Trastuzumab Emtansine Drug: T-DM1 Drug: Pembrolizumab Drug: Ribociclib Drug: T-DM1 Drug: Trastuzumab Drug: Fulvestrant Drug: Atezolizumab. Drug: Carboplatin. Drug: Docetaxel. Drug: Pertuzumab. Drug: Trastuzumab Drug: Trastuzumab emtansine Drug: Doxorubicin. Drug: Cyclophosphamide Drug: Neratinib Drug: T-DM1 Drug: TDM1 Drug: Lapatinib Drug: Abraxane Drug: PI3K inhibitor BYL719 Biological: ado-trastuzumab emtansine Other: pharmacological study Other: laboratory biomarker analysis Primary Outcome Measures : Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] [ Time Frame: 21 days ] The number and type of DLTs as defined in the protocol that occur during the first 21 days of treatment and all maximum grade of all treatment-related adverse events using CTCAE v4.0 will be used to identify a safe and tolerable dose PRIMARY OBJECTIVE: Estimate the maximum tolerated dose (MTD) and determine the recommended dose (RP2D) of utomilumab in combination with adorastuzumab emtansine (T-DM1) or trastuzumab in subjects with HER2 positive advanced breast cancer. Primary Outcome Measures : Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] [ Time Frame: 21 days ] The number and type of DLTs as defined in the protocol that occur during the first 21 days of treatment and all maximum grade of all treatment-related adverse events using CTCAE v4.0 will be used to identify a safe and tolerable dose Primary Outcome Measures : Maximum Tolerated Dose (Mtd) And/Or Recommended Phase2 Dose (RP2D) [ Time Frame: 2 years ] Clinical Benefit Rate (CBR) By RECIST [ Time Frame: 2 years ] Primary Outcome Measures : Percentage of Participants With Dose Limiting Toxicities (DLT) - Cohort 1A, 1B, 1C, 1D, 1F [ Time Frame: Baseline up to Day 21 ] Percentage of Participants With DLT - Cohort 1E [ Time Frame: Baseline up to Day 28 ] Percentage of Participants With Adverse Events (AEs) According to National Cancer Institute Common Terminology Criteria for AEs, Version 4.0 (NCI CTCAE Primary Outcome Measures : Safety and tolerability of T-DM1 and neratinib to determine the recommended Phase II dose (RP2D) [ Time Frame: Day 1, 8, and 15 of cycle 1. ] If 1 of 3 patients in this cohort experiences a dose limiting toxicity (DLT), 3 more patients will be added at the same dose level. If 0 of 3 initial patients or 1 of 6 patients in an expanded cohort experiences a DLT, the dose for the next cohort will be escalated to dose level 2; otherwise, the combination will be considered too toxic. Overall response rate (ORR) by measurement of target Secondary Outcome Primary Outcome Measures : Maximum Tolerable Dose [ Time Frame: approximately 16 weeks ] Maximum tolerated dose (MTD) of Trastuzumab Emtansine in combination with Lapatinib plus Abraxane in metastatic Her2 overexpressed breast cancer. PRIMARY OBJECTIVES: I. Determine safety, tolerability, feasibility, and the maximum-tolerated dose (MTD) of dose-escalating BYL719 in combination with adotrastuzumab emtansine (T-DM1) in patients with HER2-positive metastatic breast cancer (MBC) after progression on trastuzumab and taxane-based therapy. Primary Outcome Measures : Incidence and severity of adverse events [ Time Frame: 12 months ] Incidence and severity of clinical lab abnormalities [ Time Frame: 12 months ] Drug: tucatinib (ONT-380) Drug: T-DM1 I Drug: PD and T-DM1 Primary Outcome Measures : Maximum Tolerated Dose (MTD) [ Time Frame: 42 days at the end of Cycle 2 ] A standard 3+3 trial design will be used for PD dose escalation cohorts.the dosing of PD will be divided into 3 cohorts, the subjects will receive PD on days 5-18 of each 21 day cycle.

31 Summary Mechanisms to overcome trastuzumab resistance TDM1 resistance Trastuzumab + pertuzumab

32 TDM1 activity after pertuzumab? There is one ongoing prospective study that will examine the efficacy of T-DM1 specifically in patients who have received prior pertuzumab (Clinicaltrials.gov identifier: NCT ). (SystHERs Registry, NCT ) is also underway to collect information on treatment patterns and treatment sequencing for HER2-positve MBC.

33 Novel approaches

34 Other manners to target HER2 CAR T Cell Therapy

35 Summary Clinical situation- management Mechanisms to overcome trastuzumab resistance: 2-3 lines (trastu+lapatinib o trastu+pertu) TDM1 resistance Trastuzumab + pertuzumab (after 1 line)

36 Thanks for your attention