352TiP - Neoadjuvant chemo-immunotherapy plus/minus fasting-like approach in stage II-III triple-negative breast cancer patients: The phase II randomized BREAKFAST-2 trial

Background

Despite remarkable improvements in early-stage Triple-Negative Breast Cancer (TNBC) treatment with neoadjuvant chemoimmunotherapy (CT-IO), a considerable proportion of TNBC patients (pts) still experience tumor relapse after surgery. Preclinical studies indicate that TNBC is exquisitely sensitive to fasting-like approaches (FLAs), and we have recently shown that cyclic FLA boosts systemic and intratumor immunity in cancer patients. We hypothesize that combining FLA with preoperative CT-IO can increase pathologic complete response (pCR) rates in pts with stage II-III TNBC.

Trial design

BREAKFAST-2 (NCT05763992) is an open-label, multicentric, randomized, phase 2 trial aimed at investigating the antitumor activity of experimental FLA in combination with standard preoperative CT-IO in pts with treatment-naïve, localized (T1c and N1-2, or T2-4 and N0-2) TNBC. Pts will be randomized in a 1:1 ratio to: a) control arm (standard CT-IO), consisting of 12 administrations of weekly paclitaxel + carboplatin concomitant with 4 triweekly cycles of Pembrolizumab, followed by 4 triweekly cycles of doxorubicin/epirubicin + cyclophosphamide + Pembrolizumab every three weeks; b) experimental arm, consisting of CT-IO + 5-day FLA every three weeks, up to 8 FLA cycles. Then pts will undergo surgery. Key eligibility criteria are: age of 18-75 years, ECOG PS 0-1, BMI > 19 kg/m², absence of malnutrition, diabetes, uncontrolled autoimmune disorders, or severe comorbidities. The primary study endpoint is pCR. Hypothesizing that the experimental treatment is able to increase the pCR rate from 65% (historical data with CT-IO alone) to 85%, and assuming an α error of 5% and a power of 85%, a total of 145 patients will be enrolled. Secondary endpoints include: safety and tolerability, compliance, Event-Free Survival (EFS) and Overall Survival (OS). We will combine plasma metabolomics and bulk/single cell RNA-seq analyses to explore the impact of the experimental treatment on systemic and intratumor immunometabolic pathways, as well as to assess the association between immunometabolic changes and clinical outcomes. The trial has started to enroll pts on May 2^nd, 2023.

Clinical trial identification

NCT05763992.

Editorial acknowledgement

Legal entity responsible for the study

Fondazione IRCCS Istituto Nazionale dei Tumori, Milan.

Funding

Giuliani Foundation – Fondazione Gianmaria e Sabrina Giuliani; Fondazione IRCCS Istituto Nazionale dei Tumori; AIRC.

Disclosure

C. Vernieri: Financial Interests, Personal, Advisory Board: Novartis, Pfizer, Lilly, Daiichi Sankyo, Lilly, Istituto Gentili; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Institutional, Research Grant: Roche. M.V. Dieci: Financial Interests, Personal, Invited Speaker: Eli Lilly, Exact sciences, Gilead, Seagen, Daiichi Sankyo, Novartis; Financial Interests, Personal, Advisory Board: Novartis, Eli Lilly, Seagen, Exact Science, Daiichi Sankyo, Gilead; Financial Interests, Personal, Other, Consultancy: Pfizer; Financial Interests, Personal, Other, Consultancy on educational project: Roche. M. Lambertini: Financial Interests, Personal, Advisory Board: Roche, AstraZeneca, Lilly, Novartis, Pfizer, Exact Sciences, MSD, Seagen, Gilead; Financial Interests, Personal, Invited Speaker: Takeda, Sandoz, Ipsen, Libbs, Knight, Daiichi Sankyo, Lilly, Pfizer, Novartis, Roche; Financial Interests, Personal, Other, Travel grant to attend ASCO 2022: Gilead; Financial Interests, Institutional, Coordinating PI, 2-year research grant paid to my Institution: Gilead. C. De Angelis: Financial Interests, Personal, Advisory Board: Roche, Eli Lilly, GSK, Novartis, Pfizer, AstraZeneca; Financial Interests, Institutional, Funding: Novartis. G.V. Bianchi: Financial Interests, Personal, Advisory Board: Novartis, Eli Lilly, Daiichi Sankyo, AstraZeneca, Roche, MSD, Seagen. D. Generali: Financial Interests, Personal, Other, Educational events: Novartis, Lilly, Pfizer, Daiichi Sankyo, Roche; Financial Interests, Personal and Institutional, Research Grant: AstraZeneca , Novartis , LILT. L. Del Mastro: Financial Interests, Personal, Invited Speaker, Educational meeting: Novartis, Symposia, Andromeda E20, Vyvamed srl; Financial Interests, Personal, Invited Speaker, Lecture: Ipsen; Financial Interests, Personal, Advisory Board, Her2+ and TN breast cancer: Roche; Financial Interests, Personal, Writing Engagement, Consultancy for TNBC text: Roche; Financial Interests, Personal, Advisory Board, denosumab: Amgen; Financial Interests, Personal, Advisory Board, Early and metastatic BC: Eli Lilly; Financial Interests, Personal, Invited Speaker, CDK4-6 inhibitors: Eli Lilly; Financial Interests, Personal, Advisory Board, tucatinib: Seagen Int; Financial Interests, Personal, Advisory Board, Oncotype dx: Exact sciences, Havas life; Financial Interests, Personal, Advisory Board, Neratinib: Pierre Fabre; Financial Interests, Personal, Invited Speaker, Internal training: MSD; Financial Interests, Personal, Invited Speaker, Educational meetings: Accademia Nazionale Medicina; Financial Interests, Personal, Writing Engagement, Author for BC text: Pensiero Scientifico Editore; Financial Interests, Personal, Advisory Board, Breast cancer: Uvet; Financial Interests, Personal, Other, Author slide kits and interviews: Think2it; Financial Interests, Personal, Advisory Board, Palbociclib: Pfizer; Financial Interests, Personal, Invited Speaker, Breast cancer: Aristea, Meeting SrL; Financial Interests, Personal, Other, Author slide kits: Forum service; Financial Interests, Personal, Other, Author text about biosimilars: Edizioni Minerva Medica; Financial Interests, Personal, Other, consultant: Kardo srl; Financial Interests, Personal, Invited Speaker, Breast cancer meetings: Delphi international, Over srl; Financial Interests, Personal, Invited Speaker: Prex Srl, Editree; Financial Interests, Personal, Advisory Board: Uvet, Collage SpA, Daiichi Sankyo, AstraZeneca, Agendia, Gilead; Financial Interests, Personal, Other, Interview: Infomedica srl; Financial Interests, Personal, Other, Consultant: Sharing progress in cancer care - Switzerland; Financial Interests, Personal, Other, Consultancy: Eli lilly; Financial Interests, Institutional, Funding, National coordinating PI: Roche; Financial Interests, Institutional, Funding, Local PI: AstraZeneca, Roche, Eli Lilly, Daiichi Sankyo, Novella Clinical, Novartis; Non-Financial Interests, Institutional, Product Samples, Genomic Test: FoundationOne. V. Guarneri: Financial Interests, Personal, Invited Speaker: Eli Lilly, Novartis, Amgen, GSK; Financial Interests, Personal, Advisory Board: Eli Lilly, Novartis, MSD, Gilead, Eli Lilly, Sanofi, Merck Serono, Exact Sciences, Eisai, Olema Oncology; Financial Interests, Institutional, Local PI: Eli Lilly, Roche, BMS, Novartis, AstraZeneca, MSD, Synton Biopharmaceuticals, Merck, GSK, Daiichi Sankyo, Nerviano; Non-Financial Interests, Member: ASCO. G. Pruneri: Financial Interests, Personal and Institutional, Advisory Role: Roche, Bayer, AstraZeneca. F.G.M. De Braud: Financial Interests, Personal, Advisory Board: Roche, EMD Serono, NMS Nerviano Medical Science, Sanofi, MDS, Incyte, BMS, Menarini, AstraZeneca, Pierre Fabre, Mattioli 1885 , MCCann Health, Taiho, IQVIA; Financial Interests, Personal, Speaker’s Bureau: BMS, Healthcare Research & Pharmacoepidemiology, Merck Group, MSD, Pfizer, Servier, Sanofi, Roche, Amgen, Incyte , Dephaforum, Seagen, Nadirex, Ambrosetti, Itanet; Financial Interests, Personal and Institutional, Sponsor/Funding: Novartis, F Hoffmann-LaRoche Ltd, BMS, Ignyta Operating INC, Merck Sharp&Dohme Spa, Kymab, Pfizer, Tesaro, MSD, MedImmune LCC, Exelis Inc., LOXO Oncology Incorporated, Daiichi Sankyo, Basilea Pharmaceutica International AG, Janssen-Cilag International NV, Merck KGAA. All other authors have declared no conflicts of interest.