ABSTRACT
Background: Taselisib is an oral inhibitor of class I α, δ, and ϒ isoforms of PI3K that has demonstrated clinical activity in combination with TAM (Baird R et al, CCR 2019). Methods: POSEIDON is an international, multicenter, randomized (1:1) phase II trial of TAM + taselisib or PLA in pts with HR+/HER2- MBC after prior endocrine treatment (ET). Cross-over was allowed. Primary endpoint: unstratified progression-free survival (PFS;local assessment). Secondary endpoints: safety, RECIST 1.1 overall response rate (ORR;complete response [CR] + partial response [PR]), clinical benefit rate (CBR;CR + PR + stable disease >6 months) and overall survival (OS). 180 pts were required to detect a PFS constant hazard ratio (HR) of 0.64 (ß=90%, 2-sided α=0.2). Accrual closed prematurely due to Covid-19, decreasing the power to 83%. Results: 152 pts (median age 63) enrolled (Table), median follow-up 26.4 months (m). Addition of taselisib to TAM increased median PFS from 3.2 to 4.8m (unstratified HR 0.62, 95%CI 0.43-0.93, p=0.02;stratified HR 0.68, 95%CI 0.4-1.2, p=0.16), independently of PIK3CA status. In taselisib arm, ORR 11.8% (95%CI 5.6- 21.3) and CBR 22.4% (95%CI 13.6-33.4);in PLA arm, ORR 2.6% (95%CI 0.3- 9.2) and CBR 14.5% (95%CI 7.5-24.4). Reasons for stopping taselisib / PLA: toxicity 22% / 4%, progressive disease 55% / 67%, other (mainly Covid-19) 23% / 29%. Common adverse events (AEs) in taselisib arm: diarrhea (36%), nausea (35%), hyperglycemia (28%). Common AEs in PLA arm: nausea (21%), fatigue (16%). G3-5 AEs were more common with taselisib (44% vs 5%, p<0.01), mainly diarrhea (11%), hyperglycemia (5%) and transaminitis (5%). OS will be presented. [Formula presented] Conclusions: Addition of taselisib to TAM increased PFS in pts with HR+/HER2-neg MBC but the tolerability of the regimen was poor. Combining ET and PI3K-AKT pathway inhibition using drugs with a better therapeutic index warrants additional study in breast cancer subgroups most likely to benefit. Clinical trial identification: EudraCT 2013-003947-51;NCT02301988. Legal entity responsible for the study: The Netherlands Cancer Institute (NKI). Funding: POSEIDON is a European investigator-initiated trial, funded by the EU FP7 RATHER consortium (project ID: 258967) and EurocanPlatform (project ID: 260791), with additional support from an unrestricted research grant from Genentech, and led by the Netherlands Cancer Institute (Amsterdam, the Netherlands), Cambridge Cancer Centre (Cambridge, UK), and Vall d’Hebron Institute of Oncology (Barcelona, Spain). Disclosure: M. Oliveira: Financial Interests, Personal, Advisory Board: Roche;Financial Interests, Personal, Advisory Board: GSK;Financial Interests, Personal, Advisory Board: PUMA Biotechnology;Financial Interests, Personal, Advisory Board: AstraZeneca;Financial Interests, Personal, Invited Speaker: Roche;Financial Interests, Personal, Invited Speaker: Seattle Genetics;Financial Interests, Personal, Invited Speaker: Novartis;Financial Interests, Personal, Invited Speaker: MSD;Financial Interests, Personal, Invited Speaker: Guardant Health;Financial Interests, Personal, Invited Speaker: Pfizer;Financial Interests, Institutional, Invited Speaker: Roche;Financial Interests, Invited Speaker: Roche;Financial Interests, Personal, Invited Speaker: AstraZeneca;Financial Interests, Institutional, Invited Speaker: AstraZeneca;Financial Interests, Institutional, Invited Speaker: Genentech;Financial Interests, Institutional, Invited Speaker: Novartis;Financial Interests, Institutional, Invited Speaker: Immunomedics;Financial Interests, Institutional, Invited Speaker: Seattle Genetics;Financial Interests, Institutional, Invited Speaker: GSK;Financial Interests, Institutional, Invited Speaker: Boehringer-Ingelheim;Financial Interests, Institutional, Invited Speaker: Zenith Epigenetics;Financial Interests, Personal, Invited Speaker: AstraZeneca;Non-Financial Interests, Invited Speaker: SOLTI Breast Cancer Research. R.D. Baird: Financial Interests, Institutional, Other, Honoraria: Molecular P rtners;Financial Interests, Institutional, Advisory Role: Shionogi;Financial Interests, Institutional, Advisory Role: Daiichi Sankyo;Financial Interests, Institutional, Advisory Role: Molecular Partners;Financial Interests, Institutional, Advisory Role: Roche/Genentech;Financial Interests, Institutional, Advisory Role: Novartis;Financial Interests, Institutional, Advisory Role: AstraZeneca;Financial Interests, Institutional, Research Grant: AstraZeneca;Financial Interests, Institutional, Research Grant: Genentech;Financial Interests, Institutional, Research Grant: Shionogi;Financial Interests, Institutional, Research Grant: Molecular Partners;Financial Interests, Institutional, Research Grant: Sanofi;Financial Interests, Institutional, Research Grant: Boehringer Ingelheim;Financial Interests, Institutional, Research Grant: Roche;Financial Interests, Institutional, Research Grant: Biomarin;Financial Interests, Institutional, Research Grant: G1 Therapeutics;Financial Interests, Institutional, Research Grant: Carrick Therapeutics;Financial Interests, Personal, Other: Shionogi;Financial Interests, Personal, Other: AstraZeneca;Financial Interests, Personal, Other: Molecular Partners;Financial Interests, Personal, Other: Daiichi Sankyo. C. Saura Manich: Financial Interests, Personal, Advisory Role: AstraZeneca;Financial Interests, Personal, Advisory Role: Daiichi Sankyo;Financial Interests, Personal, Advisory Role: Eisai;Financial Interests, Personal, Advisory Role: Exact Sciences;Financial Interests, Personal, Advisory Role: F. Hoffmann - La Roche Ltd;Financial Interests, Personal, Advisory Role: MediTech;Financial Interests, Personal, Advisory Role: Merck Sharp & Dome;Financial Interests, Personal, Advisory Role: Novartis;Financial Interests, Personal, Advisory Role: Pfizer;Financial Interests, Personal, Advisory Role: Philips;Financial Interests, Personal, Advisory Role: Pierre Fabré;Financial Interests, Personal, Advisory Role: Puma Biotechnology;Financial Interests, Personal, Advisory Role: Roche Farma;Financial Interests, Personal, Advisory Role: Sanofi-Aventis;Financial Interests, Personal, Advisory Role: SeaGen;Financial Interests, Personal, Advisory Role: Zymeworks;Financial Interests, Personal, Sponsor/Funding: Daiichi Sankyo;Financial Interests, Personal, Sponsor/Funding: Novartis;Financial Interests, Personal, Sponsor/Funding: Pfizer;Financial Interests, Personal, Sponsor/Funding: Roche;Financial Interests, Personal, Sponsor/Funding: Sanofi;Financial Interests, Institutional, Research Grant: AstraZeneca;Financial Interests, Institutional, Research Grant: Daiichi Sankyo;Financial Interests, Institutional, Research Grant: Eli Lilly and Company;Financial Interests, Institutional, Research Grant: Genentech;Financial Interests, Institutional, Research Grant: Immunomedics;Financial Interests, Institutional, Research Grant: Macrogenics;Financial Interests, Institutional, Research Grant: Merck Sharp and Dhome España S.A.;Financial Interests, Institutional, Research Grant: Novartis;Financial Interests, Institutional, Research Grant: Pfizer;Financial Interests, Institutional, Research Grant: Piqur Therapeutics;Financial Interests, Institutional, Research Grant: Puma;Financial Interests, Institutional, Research Grant: Roche;Financial Interests, Institutional, Research Grant: Synthon;Financial Interests, Institutional, Research Grant: Zenith Epigenetics. C. Mather: Financial Interests, Full or part-time Employment, Immediate family member: Clovis Oncology;Financial Interests, Stocks/Shares, Immediate family member: Clovis Oncology. J. Cortés: Financial Interests, Personal, Advisory Role: Roche;Financial Interests, Personal, Advisory Role: Celgene;Financial Interests, Personal, Advisory Role: Cellestia;Financial Interests, Personal, Advisory Role: AstraZeneca;Financial Interests, Personal, Advisory Role: Biothera Pharmaceutical;Financial Interests, Personal, Advisory Role: Merus;Financial Interests, Personal, Advisory Role: SeaGen;Financial Interests, Personal, Ad isory Role: Daiichi Sankyo;Financial Interests, Personal, Advisory Role: Erytech;Financial Interests, Personal, Advisory Role: Athenex;Financial Interests, Personal, Advisory Role: Polyphor;Financial Interests, Personal, Advisory Role: Lilly;Financial Interests, Personal, Advisory Role: Servier;Financial Interests, Personal, Advisory Role: MSD;Financial Interests, Personal, Advisory Role: GSK;Financial Interests, Personal, Advisory Role: Leuko;Financial Interests, Personal, Advisory Role: Bioasis;Financial Interests, Personal, Advisory Role: Clovis Oncology;Financial Interests, Personal, Advisory Role: Boehringer Ingleheim;Financial Interests, Personal, Advisory Role: Kyowa Kirin;Financial Interests, Personal, Invited Speaker: Roche;Financial Interests, Personal, Invited Speaker: Novartis;Financial Interests, Personal, Invited Speaker: Celgene;Financial Interests, Personal, Invited Speaker: Eisai;Financial Interests, Personal, Invited Speaker: Pfizer;Financial Interests, Personal, Invited Speaker: Samsung Bioepis;Financial Interests, Personal, Invited Speaker: Lilly;Financial Interests, Personal, Invited Speaker: Merck Sharp&Dohme;Financial Interests, Personal, Invited Speaker: Daiichi Sankyo;Financial Interests, Institutional, Research Grant: Roche;Financial Interests, Institutional, Research Grant: Ariad Pharmaceuticals;Financial Interests, Institutional, Research Grant: AstraZeneca;Financial Interests, Institutional, Research Grant: Baxalta GMBH/Servier Affaires;Financial Interests, Institutional, Research Grant: Bayer Healthcare;Financial Interests, Institutional, Research Grant: Eisai;Financial Interests, Institutional, Research Grant: F.Hoffman La Roche;Financial Interests, Institutional, Research Grant: Guardant Health;Financial Interests, Institutional, Research Grant: Merck Sharp&Dohme;Financial Interests,Institutional, Research Grant: Pfizer;Financial Interests, Institutional, Research Grant: Piqur Therapeutics;Financial Interests, Institutional, Research Grant: Puma;Financial Interests, Institutional, Research Grant: Quenn Mary University of London;Financial Interests, Personal, Stocks/Shares: MedSIR;Financial Interests, Personal, Proprietary Information: MedSIR;Financial Interests, Personal, Other: Roche;Financial Interests, Personal, Other: Novartis;Financial Interests, Personal, Other: Eisai;Financial Interests, Personal, Other: Pfizer;Financial Interests, Personal, Other: Daiichi Sankyo. C. Caldas: Financial Interests, Personal, Advisory Board: AstraZeneca's iMED External Science Panel;Financial Interests, Personal, Advisory Board: Illumina;Financial Interests, Institutional, Research Grant: AstraZeneca;Financial Interests, Institutional, Research Grant: Genentec;Financial Interests, Institutional, Research Grant: Roche;Financial Interests, Institutional, Research Grant: Servier. S.C. Linn: Financial Interests, Personal, Advisory Board: Cergentis;Financial Interests, Personal, Advisory Board: IBM;Financial Interests, Institutional, Research Grant: Agendia;Financial Interests, Institutional, Research Grant: AstraZeneca;Financial Interests, Institutional, Research Grant: Eurocept-pharmaceuticals;Financial Interests, Institutional, Research Grant: Pfizer;Financial Interests, Institutional, Research Grant: Genentech;Non-Financial Interests, Institutional, Other: Genentech;Financial Interests, Institutional, Research Grant: Merck;Non-Financial Interests, Institutional, Other: Merck;Financial Interests, Institutional, Research Grant: Novartis;Non-Financial Interests, Institutional, Other: Novartis;Financial Interests, Institutional, Research Grant: Roche;Non-Financial Interests, Institutional, Other: Roche;Financial Interests, Institutional, Research Grant: Tesaro;Non-Financial Interests, Institutional, Other: Tesaro;Financial Interests, Institutional, Research Grant: Immunomedics;Non-Financial Interests, Institutional, Other: Immunomedis;Non-Financial Interests, Institutional, Other: AstraZeneca;Non-Financial Interests, Institutional, Oth r: Pfizer;Non-Financial Interests, Institutional, Other: Cergentis;Non-Financial Interests, Institutional, Other: Daiichi Sankyo;Non-Financial Interests, Institutional, Other: IBM;Non-Financial Interests, Institutional, Other: Bayer. All other authors have declared no conflicts of interest.
ABSTRACT
INTRODUCTION: In breast cancer, local tumour control is thought to be optimised by administering higher local levels of cytotoxic chemotherapy, in particular doxorubicin. However, systemic administration of higher dosages of doxorubicin is hampered by its toxic side effects. In this study, we aim to increase doxorubicin deposition in the primary breast tumour without changing systemic doxorubicin concentration and thus without interfering with systemic efficacy and toxicity. This is to be achieved by combining Lyso-Thermosensitive Liposomal Doxorubicin (LTLD, ThermoDox, Celsion Corporation, Lawrenceville, NJ, USA) with mild local hyperthermia, induced by Magnetic Resonance guided High Intensity Focused Ultrasound (MR-HIFU). When heated above 39.5°C, LTLD releases a high concentration of doxorubicin intravascularly within seconds. In the absence of hyperthermia, LTLD leads to a similar biodistribution and antitumour efficacy compared with conventional doxorubicin. METHODS AND ANALYSIS: This is a single-arm phase I study in 12 chemotherapy-naïve patients with de novo stage IV HER2-negative breast cancer. Previous endocrine treatment is allowed. Study treatment consists of up to six cycles of LTLD at 21-day intervals, administered during MR-HIFU-induced hyperthermia to the primary tumour. We will aim for 60 min of hyperthermia at 40°C-42°C using a dedicated MR-HIFU breast system (Profound Medical, Mississauga, Canada). Afterwards, intravenous cyclophosphamide will be administered. Primary endpoints are safety, tolerability and feasibility. The secondary endpoint is efficacy, assessed by radiological response.This approach could lead to optimal loco-regional control with less extensive or even no surgery, in de novo stage IV patients and in stage II/III patients allocated to receive neoadjuvant chemotherapy. ETHICS AND DISSEMINATION: This study has obtained ethical approval by the Medical Research Ethics Committee Utrecht (Protocol NL67422.041.18, METC number 18-702). Informed consent will be obtained from all patients before study participation. Results will be published in an academic peer-reviewed journal. TRIAL REGISTRATION NUMBERS: NCT03749850, EudraCT 2015-005582-23.