Background

Venous thromboembolic events (VTE), elevated aminotransferases (EAT) and interstitial lung disease (ILD) are adverse events (AEs) for abemaciclib (oral CDK4 & 6 inhibitor). In monarchE, patients (pts) receiving abemaciclib+endocrine therapy (ET) as adjuvant treatment (txt) of HR+, HER2- high-risk early breast cancer (EBC) reported these AEs more frequently vs ET alone pts.

Methods

The safety population (pop) comprised 5591 treated (tx) pts (median duration of abemaciclib: 17 months). The protocol included management guidance for AEs. Pts with history of VTE were not eligible. Risk factors for VTE (Khorana risk score) and adjuvant radiotherapy (95.4% pts) were well balanced across arms.

Results

In abemaciclib tx pts: Most VTEs were G≥3 (1.3%), primarily pulmonary embolism (0.9%) (Table). Of pts experiencing VTE, 94% received anti-coagulants and 19.4% discontinued abemaciclib or all txt due to VTE. VTEs were increased with tamoxifen txt; G≥3 VTEs were higher in pts with body mass index (BMI)> 25 (1.8%) vs BMI<25 (0.6%). 85% of G≥3 EAT were single occurrences; incidence was highest early on txt (∼3 months). Of pts experiencing G≥3 EAT, 71% had dose hold/reduction and 16% discontinued due to EAT. All G≥3 alanine aminotransferase (ALT) increases, per central lab, were reversible with dose modification or discontinuation. No pts had drug-induced liver injury (no Hy’s law cases). Most ILD events were G1 (1.4%). Of pts experiencing ILD, 52% were tx with steroids/antibiotics and 23% discontinued abemaciclib or all txt due to ILD. ILD was higher in Asians (6.6%; G1: 4.9%; G≥3: 0.3%; 13% of Asian pts with ILD discontinued (0.9% of pop)). Table: 44O

Characteristics of VTEs, EAT and ILD

Conclusions

VTE, EAT and ILD were manageable with dose adjustments and comedications in pts with EBC; results were consistent with the known safety profile of abemaciclib. Although ILD was higher in Asian pop, G≥3 AEs and discontinuations were similar. Most pts experiencing these AEs could continue abemaciclib.

Clinical trial identification

NCT03155997.

Editorial acknowledgement

Eglantine Julle-Daniere.

Legal entity responsible for the study

Eli Lilly.

Funding

Eli Lilly.

Disclosure

M. Toi: Honoraria (self), Research grant/Funding (self), Research grant, Lecture honoraria: Chugai, Takeda, Pfizer, Taiho, Eisai, AstraZeneca, Shimadzu, Yakult; Honoraria (self), Advisory/Consultancy, Research grant/Funding (self), Research grant, Lecture honoraria, Advisory role for a drug development: Kyowa-Kirin, Daiichi Sankyo; Research grant/Funding (self): JBCRG association, Astellas; Advisory/Consultancy, Research grant/Funding (self): Eli Lilly; Honoraria (self), Lecture Honoraria: MSD, Exact Science, Novartis; Honoraria (self), Advisory/Consultancy, Honoraria for an advisory meeting: Konica Minolta, BMS; Honoraria (self), Research grant/Funding (self), Research Fund and Honoraria for lecture: Nippon Kayaku; Research grant/Funding (self): AFI Technologies; Advisory/Consultancy: Athenex Oncology, Bertis, Terumo, Kansai Medical Net; Advisory/Consultancy, Research grant/Funding (self): Luxonus; Research grant/Funding (self): Shionogi, GL Science; Officer/Board of Directors: JBCRG association, Organisation for Oncology and Translational Research, Kyoto Breast Cancer Research Network. N. Harbeck: Shareholder/Stockholder/Stock options: West German Study Group; Honoraria (self): Roche, Novartis, Amgen, Pfizer, Genomic Health, AstraZeneca, Zodiac Pharma, Pierre Fabre; Advisory/Consultancy: Roche/Genentech, Novartis, Celgene, Pfizer, Eli Lilly, Sandoz, Daiichi Sankyo, Agendia, AstraZeneca, Merck Sharp & Dohme, Odonate Therapeutics, Seattle Genetics, West German Study Group, Pierre Fabre; Research grant/Funding (institution): Roche/Genentech (Inst), Novartis (Inst), Pfizer (Inst), Lilly (Inst), Merck Sharp & Dohme (Inst). J.M. Puig: Honoraria (self), Personal fees: Protocol JPCF. J. Cruz: Honoraria (self), Advisory/Consultancy, Lectures, Travel, Advisory: PharmaMar, Roche, Novartis, Pfizer; Honoraria (self), Advisory/Consultancy, Lectures, Advisory: Eli Lilly, AstraZeneca; Advisory/Consultancy: Daiichi, Seagen, Glaxo; Honoraria (self), Advisory/Consultancy: Eisai; Honoraria (self), Lectures: Bayer. M. Takahashi: Honoraria (self): Eli Lilly; Honoraria (self): AstraZeneca; Honoraria (self): Pfizer; Honoraria (self), Research grant/Funding (self): Eisai; Research grant/Funding (self): Kyowa Kirin; Research grant/Funding (self): Taiho. M. Hulstijn, E.A. Twum, A. Regev, B. San Antonio: Full/Part-time employment: Eli Lilly. D.M. Median: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Institutional research funding, Honoraria, Lecture fee, Consulting/Advisory role: Eli Lilly; Advisory/Consultancy, Non-remunerated activity/ies, Educational, Lecture fee, Consulting/Advisory role: AstraZeneca; Research grant/Funding (self), Lecture fee: A&D Pharma; Honoraria (self): Clovis; Advisory/Consultancy, Travel/Accommodation/Expenses: Genekor; Honoraria (self), Advisory/Consultancy, Lecture fee, Honoraria, Advisory role: Novartis; Advisory/Consultancy, Travel/Accommodation/Expenses, Lecture fee, Advisory, Travel, Educational: Pfizer; Honoraria (self), Honoraria (institution), Advisory/Consultancy, Research grant/Funding (self), Travel/Accommodation/Expenses, Lecture fee, Honoraria, Travel, Educational: Roche; Honoraria (self): Samsung Bioepis. M. Campone: Honoraria (institution), Advisory/Consultancy, Consulting/advisory/fees to the Institution: AstraZeneca, Sanofi, Servier, AbbVie, Accord, Pfizer, Seagen; Advisory/Consultancy: Daiichi Sankyo; Honoraria (self), Advisory/Consultancy: Eli Lilly; Advisory/Consultancy, Speaker Bureau/Expert testimony: Novartis; Advisory/Consultancy: GT1. All other authors have declared no conflicts of interest.

Background

Leptomeningeal metastasis (LM) is a rare complication of metastatic breast cancer (MBC), with high rates of morbidity/mortality. Large cohorts are scarce. Our study aimed to describe the largest-to-date real-life population of MBC patients treated with intrathecal (IT) therapy and to evaluate prognostic models.

Methods

ESME MBC database (NCT03275311) includes all consecutive patients having started treatment for MBC since 2008. Overall survival (OS) of patients treated with IT therapy was estimated using the Kaplan-Meier method. Prognostic models were constructed using Cox proportional hazards models. Performance was evaluated using C-index and calibration plots.

Results

Of 22,266 female patients included in the ESME database covering 2008-2016, 312 were IT-treated with methotrexate, cytarabine or thiotepa and included in our analysis (15 patients have been excluded because of lack of data on the treatment line). Compared with non-IT treated ones, these were younger at MBC relapse (median age 52 years vs 61 years) and had more often lobular histology (23.4% vs 12.7%) or triple-negative subtype (24.7% vs 13.3%) (all p<0.001). Median OS was 4.5 months (95% CI 3.8-5.6) and 1-year survival rate was 25.6%. In case of IT therapy, significant prognostic factors associated with worse outcome by multivariable analysis were triple-negative subtype (HR=1.81 [95%CI 1.32-2.47]), treatment line ≥ 3 (HR=1.88 [95% CI 1.30-2.73]), ≥ 3 other metastatic sites (HR=1.33 [95%CI 1.01-1.74]), and IT cytarabine or thiotepa vs methotrexate (HR=1.68 [95%CI 1.28-2.22]), while concomitant systemic therapy was associated with better OS (HR=0.47 [95%CI 0.35-0.62]) (all p<0.001). We validated two previously published prognostic scores, the Curie score and the breast graded prognostic assessment, both with C-index of 0.57.

Conclusions

MBC patients with LM treated with IT therapy have a poor prognosis. However, in this large series, we could identify a subgroup of patients with better prognosis, when concomitant systemic therapy and IT methotrexate were used.

Clinical trial identification

NCT03275311.

Legal entity responsible for the study

UNICANCER.

Funding

UNICANCER. The ESME MBC database receives financial support from an industrial consortium (Roche, Pfizer, AstraZeneca, MSD, Eisai and Daiichi Sankyo). Data collection, analysis and publication are managed entirely by R&D UNICANCER independently of the industrial consortium.

Disclosure

M. Campone: Honoraria (self): Lilly; Advisory/Consultancy, Speaker Bureau/Expert testimony: Novartis; Advisory/Consultancy: GT1. All other authors have declared no conflicts of interest.

Background

Genetic mutations on breast cancer (BC) susceptibility genes such as BRCA 1 or 2, are well known risk factors for BC development. 5-10% of BC are associated with a gBRCAm, which can impact tumor characteristics and management of the associated BC. Using the French prospective ongoing CANTO cohort (NCT01993498) we conducted a retrospective analysis focusing on clinical characteristics and patterns of care of eBC by gBRCA status.

Methods

Data from 9368 women diagnosed with stage I to IIIa BC from 2012 to 2017 were analysed by BRCA status. Demographics, medical and family history, disease characteristics and BC treatment were examined overall and per subgroup populations.

Results

In this cohort, 169 (1.8%) patients (pts) had a gBRCAm (92 gBRCA1m and 77 gBRCA2m), 2226 (28%) were gBRCA wild type (wt) and 6573 (70.2%) gBRCA unknown (uk). Women with gBRCAm were younger than gBRCAwt or uk (mean age 43.7 years [95% CI: 42.0–45.4] versus (vs) 53.7 [53.2 - 54.1] vs 58.2 [57.9 - 58.5] respectively) at BC diagnosis. Tumours of pts with gBRCAm were characterized by higher proportion of triple negative (TN) subtype (44% [36.7-52.2] vs 13.3% [12.1 - 14.7] vs 7.9% [7.3 - 8.6]), higher stage II/IIIa (65.1% [57.4-72.2] vs 52.0% [50.0-53.9] vs 49.0% [47.8-50.2], higher histological grade 3 (67.9% [60.2-74.8] vs 32.9% [31.1-34.8] vs 25.5% [24.5-26.6]) when compared to gBRCAwt and uk pts. gBRCAm pts were more likely to undergo radical mastectomy (46.2% [35.0-50.4] vs 24.9% [23.3-26.6] vs 22.5% [21.5-23.6] ) with more axillary dissection (51.5% [43.7-59.2] vs 40.5% [38.4-42.2] vs 34.5% [33.4-35.7]) compared to gBRCAwt and uk pts. gBRCAm pts were also more likely to receive chemotherapy 92.9% [87.9-96.3] vs 56.4% [54.5-58.4] vs 49.4% [48.2-50.6] especially in the neo adjuvant setting (39.1% [31.6-46.8] vs 16.4% [15.0 -17.8] vs 11.5% [10.7-12.3]).

Conclusions

In our cohort, 30% of eBC pts had their gBRCAm status tested; of them 7.1% had gBRCAm 1 or 2. Consistent with prior research, women with gBRCAm had a substantial proportion of higher stage TN tumours and were treated with aggressive chemotherapy. Further studies on clinical outcomes of eBC pts with gBRCAm are warranted.

Clinical trial identification

NCT01993498.

Legal entity responsible for the study

UNICANCER.

Funding

This research was conducted with support from ANR (Agence Nationale de la Recherche) under the Call for Cohort Project - Investment of the Future reference ANR-10-COHO-04. The study was sponsored by AstraZeneca.

Disclosure

B. Pistilli: Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Puma Biotechnology; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Novartis; Advisory/Consultancy, Speaker Bureau/Expert testimony: Myriad Genetics; Advisory/Consultancy, Speaker Bureau/Expert testimony: Pierre Fabre; Honoraria (self), Research grant/Funding (institution): AstraZeneca; Honoraria (self): MSD Oncology; Honoraria (self), Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): Daiichi; Research grant/Funding (institution): Merus. C.C. Jouannaud: Honoraria (self): Daiichi; Honoraria (self): Sankyo; Honoraria (self), Speaker Bureau/Expert testimony: Pfizer; Travel/Accommodation/Expenses: Novartis. F. Lerebours: Honoraria (self), Advisory/Consultancy: Genomic Health; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony: Eli Lilly; Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Novartis; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Pierre Fabre; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Eisai; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: AstraZeneca; Travel/Accommodation/Expenses: Roche; Travel/Accommodation/Expenses: Pfizer. M. Campone: Honoraria (self), Speaker Bureau/Expert testimony: Lilly; Honoraria (self), Speaker Bureau/Expert testimony: Accord; Honoraria (self): GT1; Honoraria (self), Speaker Bureau/Expert testimony: Pfizer; Speaker Bureau/Expert testimony: AstraZeneca; Speaker Bureau/Expert testimony: Sanofi; Speaker Bureau/Expert testimony: Servier; Speaker Bureau/Expert testimony: AbbVie; Speaker Bureau/Expert testimony: Novartis. I. Vaz-Luis: Honoraria (institution): AstraZeneca; Honoraria (institution): Amgen; Honoraria (institution): Pfizer. All other authors have declared no conflicts of interest.