LBA19 - A multicenter, randomized, double-blind, phase II study to evaluate the tolerability of an induction dose escalation of everolimus in patients with metastatic breast cancer (mBC) (DESIREE)

Background

Everolimus added to exemestane improves the outcome of patients (pts) with HR+/HER2- mBC pretreated with nonsteroidal aromatase inhibitors (NSAI). Mucositis is one of the major causes of everolimus discontinuation. To decrease mucositis, DESIREE investigated the use of a dose escalation schedule of everolimus.

Methods

DESIREE is a phase II, multicenter, randomized, double-blind, placebo controlled trial in pts with HR+/HER2- mBC and progression/relapse after NSAI. Pts were randomized to everolimus 10mg/day (EVE-10mg) for 24 weeks (w) or a dose escalation of everolimus (2.5mg/day, w1; 5mg/day, w2; 7.5mg/day, w3; 10mg/day, w4-24) (EVE-esc) plus exemestane. Primary endpoint was the incidence of first episode of mucositis grade (G)≥2 within 12w of treatment start. Secondary endpoints included clinical benefit rate (CBR), relative total dose intensity (RTDI), safety, quality of life (QoL).

Results

160 pts were randomized (June 2015-October 2020), 156 started therapy (n=80 EVE-esc, n=76 EVE-10mg). Median age was 64 years (33-85). At baseline, 56.3% pts in EVE-esc vs 48.7% in EVE-10mg were overweight/obese (p=0.423), 56.3 vs 42.1% had liver M+ (p=0.081), 62.5% vs 51.3% received >1 therapy line for mBC (p=0.196). In EVE-esc, the incidence of mucositis G≥2 within 12w of therapy was significantly lower (28.8 vs 46.1%, p=0.039). This effect maintained statistical significance in multivariate analysis adjusted for age, ECOG PS, BMI, and number of previous therapy lines for mBC (OR=0.41 [95%CI 0.20-0.82], p=0.012). There was no impact on other non-hematologic toxicities as pneumonitis or rash. Median RTDI was 91.1 vs 80.0% (p=0.329). Discontinuations in the first 3w were more frequent in EVE-10mg (6.3 vs 15.8%, p=0.073). CBR did not significantly differ (32.5% vs 44.7% p=0.139). Prospectively captured QoL was not significantly different.

Conclusions

DESIREE met its primary objective and showed that a dose escalation schema of everolimus over three weeks can be successfully used in pts with HR+/HER2- mBC to prevent the onset of mucositis G≥2 without affecting efficacy.

Clinical trial identification

NCT02387099.

Editorial acknowledgement

Legal entity responsible for the study

German Breast Group (GBG Forschungs GmbH).

Funding

Novartis.

Disclosure

S. Loibl: Other, Institutional, Advisory Board, Medical Writing: Novartis; Other, Institutional, Advisory Board: AbbVie; Other, Institutional, Advisory Board, Medical Writing: Amgen; Non-Financial Interests, Institutional, Advisory Board: AstraZeneca; Other, Institutional, Advisory Board: Bayer; Non-Financial Interests, Institutional, Advisory Board, Medical Writing: BMS; Non-Financial Interests, Institutional, Advisory Board, Medical Writing: Celgene; Financial Interests, Personal, Invited Speaker: Chugai; Non-Financial Interests, Institutional, Advisory Board: Daiichi Sankyo; Other, Institutional, Advisory Board: Eirgenix; Other, Institutional, Advisory Board: GSK; Other, Institutional, Other: Immunomedics/Gilead; Other, Institutional, Other: Ipsen; Other, Institutional, Advisory Board: Lilly; Other, Institutional, Advisory Board: Merck; Non-Financial Interests, Institutional, Advisory Board, Medical Writing: Pfizer; Other, Institutional, Advisory Board: Pierre Fabre; Other, Institutional, Advisory Board: Prime/Medscape; Other, Institutional, Advisory Board: Puma; Non-Financial Interests, Institutional, Research Grant: Roche; Other, Institutional, Invited Speaker: Samsung; Other, Institutional, Advisory Board: Seagen; Non-Financial Interests, Institutional, Writing Engagements: Vifor; Other, Personal and Institutional, Other, patent issued: EP18209672.7; Other, Personal and Institutional, Other, patent issued: EP21152186.9; Other, Personal and Institutional, Other, patent issued: EP15702464.7; Other, Institutional, Licensing Fees: VM Scope GmbH. M. Schmidt: Other, Personal, Research Grant: Pierre-Fabre; Non-Financial Interests, Personal and Institutional, Research Grant: Roche; Non-Financial Interests, Personal and Institutional, Research Grant: Pfizer; Other, Personal, Research Grant: Novartis; Other, Personal, Research Grant: AstraZeneca; Other, Personal, Research Grant: Eisai; Other, Personal, Other: Amgen; Non-Financial Interests, Personal and Institutional, Research Grant: Pantarhei; Non-Financial Interests, Personal and Institutional, Research Grant: BioNTech; Other, Institutional, Research Grant: Genentech; Other, Personal, Other: Seagen; Other, Personal and Institutional, Other, Patent issued,: EP2951317; Other, Personal and Institutional, Other, patent issued: EP2390370 . K. Lübbe: Other, Personal, Advisory Board: Roche; Other, Personal, Advisory Board: Novartis; Other, Personal, Invited Speaker: Pfizer; Other, Personal, Advisory Board: Exact Sciences; Other, Personal, Advisory Board: Lilly; Other, Personal, Advisory Board: Eisai; Other, Personal, Advisory Board: MSD. T. Decker: Other, Personal, Advisory Board: Novartis; Other, Personal, Advisory Board: Roche. V. Müller: Other, Personal, Invited Speaker, consultancy honoraria: Amgen; Other, Personal, Invited Speaker: AstraZeneca; Other, Personal, Invited Speaker, consultancy honoraria: Daiichi Sankyo; Other, Personal, Invited Speaker, consultancy honoraria: Eisai; Other, Personal, Invited Speaker: Pfizer; Other, Personal, Invited Speaker, consultancy honoraria: MSD; Other, Personal, Invited Speaker, consultancy honoraria: Novartis; Other, Personal, Invited Speaker, consultancy honoraria: Roche; Other, Personal, Invited Speaker: Teva; Other, Personal, Invited Speaker: Seattle Genetics; Other, Personal, Speaker’s Bureau: Genomic Health; Other, Personal, Speaker’s Bureau: Hexal; Other, Personal, Speaker’s Bureau: Pierre Fabre; Other, Personal, Speaker’s Bureau: ClinSol; Other, Personal, Speaker’s Bureau: Lilly; Other, Personal, Speaker’s Bureau: Tesaro; Other, Personal, Speaker’s Bureau: Nektar; Other, Institutional, Research Grant: Genentech. T. Link: Other, Personal, Other: Tesaro; Other, Personal, Other: MSD; Non-Financial Interests, Personal, Other: Roche; Other, Personal, Other: Novartis; Non-Financial Interests, Personal, Other: Pfizer; Other, Personal, Other: Amgen; Non-Financial Interests, Personal, Other: Clovis; Non-Financial Interests, Personal and Institutional, Other: Celgene; Other, Personal, Other: Lilly; Other, Personal, Other: Myriad; Other, Personal, Other: Esai; Other, Personal, Other: GSK. S. Kümmel: Non-Financial Interests, Personal and Institutional, Other: Roche; Other, Personal, Other: Genomic Health; Other, Personal, Other: Seagen; Other, Personal, Other: Novartis; Other, Personal, Other: Amgen; Other, Personal, Other: Celgene; Non-Financial Interests, Personal and Institutional, Other: Daiichi Sankyo; Other, Personal, Other: AstraZeneca; Other, Personal, Other: Somatex; Other, Personal, Other: MSD; Other, Personal, Other: Pfizer; Other, Personal, Other: PFM medical; Non-Financial Interests, Institutional, Other: Lilly; Non-Financial Interests, Institutional, Other: Sonoscape. O. Hoffmann: Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Invited Speaker, Advisory Board: Roche; Financial Interests, Personal, Invited Speaker, Advisory Board: MSD; Financial Interests, Personal, Invited Speaker: Amgen; Financial Interests, Personal, Invited Speaker, Advisory Board: Daiichi Sankyo; Financial Interests, Personal, Invited Speaker: Hexal; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Invited Speaker: Rhiemser; Financial Interests, Personal, Advisory Board: SEAGAN; Non-Financial Interests, Institutional, Full or part-time Employment: University Hospital of Essen, Germany; Financial Interests, Institutional, Principal Investigator: WSG, GBG. L. Müller: Financial Interests, Personal, Speaker’s Bureau: Roche; Financial Interests, Personal, Speaker’s Bureau: Janssen Cilag. C. Denkert: Other, Institutional, Research Grant: European Commission H2020; Other, Institutional, Research Grant: German Cancer Aid Translational Oncology; Financial Interests, Personal, Other: Novartis; Financial Interests, Personal, Other: Roche; Financial Interests, Personal, Other: MSD Oncology; Financial Interests, Personal, Other: Daiichi Sankyo; Financial Interests, Personal, Other: AstraZeneca; Financial Interests, Personal, Other: Molecular Health; Other, Institutional, Research Grant: Myriad; Other, Institutional, Research Grant: Merck; Other, Personal and Institutional, Ownership Interest, Cofounder/shareholder until 2016: Sividon diagnostics; Financial Interests, Personal and Institutional, Royalties: VMScope digital pathology software; Financial Interests, Personal and Institutional, Other, patent pending: WO2020109570A1 - cancer immunotherapy; Financial Interests, Personal and Institutional, Other, patent issued: WO2015114146A1 and WO2010076322A1- therapy response. M. van Mackelenbergh: Financial Interests, Personal, Speaker’s Bureau: Amgen; Financial Interests, Personal, Speaker’s Bureau: AstraZeneca; Financial Interests, Personal, Speaker’s Bureau: Novartis; Financial Interests, Personal, Speaker’s Bureau: Pfizer; Financial Interests, Personal, Speaker’s Bureau: Mylan; Financial Interests, Personal, Speaker’s Bureau: Pierre Fabre; Financial Interests, Personal, Speaker’s Bureau: Genomic Health; Financial Interests, Personal, Speaker’s Bureau: Roche. P.A. Fasching: Financial Interests, Personal, Other: Novartis; Other, Institutional, Research Grant: Biontech; Financial Interests, Personal, Other: Pfizer; Financial Interests, Personal, Other: Daiichi Sankyo; Financial Interests, Personal, Other: AstraZeneca; Financial Interests, Personal, Other: Eisai; Financial Interests, Personal, Other: Merck Sharp & Dohme; Other, Institutional, Research Grant: Cepheid; Financial Interests, Personal, Other: Lilly; Financial Interests, Personal, Other: Pierre Fabre; Financial Interests, Personal, Other: Seagen; Financial Interests, Personal, Other: Roche; Financial Interests, Personal, Other: Hexal; Financial Interests, Personal, Other: Agendia. All other authors have declared no conflicts of interest.