EVERolimus effectiveness after proGREssion on CDK4/6 inhibitors for ENdocrine receptor-positive/HER2-negative, advanced breast cancer: EVERGREEN quasi-experimental study

BackgroundOptimal sequence of endocrine therapy (ET) for ER+/HER2- advanced breast cancer (ABC) after progression on CDK4/6 inhibitors (CDK4/6i) remains uncertain. We aimed to compare the effectiveness and safety of everolimus-based ET (EVE) with ET alone (ETa) in this setting.MethodsMulticentre, international, retrospective, quasi-experimental study of female patients (pts) with ER+/HER2- ABC who started next line of therapy after progression on CDK4/6i until 31/12/2022 with EVE (EVE-cohort, 9 sites) or ETa in sites where EVE is not standard of care in this setting (ETa-cohort, 5 sites), in Belgium and Portugal. We excluded pts receiving alpelisib as immediate next line. Primary endpoint was real-world progression-free survival (rwPFS); secondary endpoints were time to EVE failure, time to chemotherapy, overall survival (OS) and safety. We compared baseline characteristics and assessed their prognostic/predictive value in univariate/sub-group analyses. Time-to-event endpoints were assessed from start of EVE/ETa and measures of association were determined with 95% confidence interval (CI).ResultsWe included 207 pts (EVE-cohort: 150; ETa-cohort: 57). Baseline characteristics were well balanced, except for visceral disease and number of prior lines (Table). ET was mostly exemestane in EVE-cohort (77%) and fulvestrant in ETa-cohort (61%). Median rwPFS was 5.0 for EVE vs. 4.3 m for ETa (HR 0.75, 95%CI 0.55-1.02), with a numerically higher magnitude of benefit in pts with PIK3CA-AKT1-PTEN pathway alterations (HR 0.56, 0.20-1.61, N=20 EVE: 15, ETa: 5). Secondary efficacy endpoints in the table. Multivariate analysis will be presented at the meeting. No notable safety issues emerged. Table: 355P Main baseline characteristics and secondary time-to-event endpoints EVE (N=150) ETa (N=57) p-value Characteristics Age, median (IQR) 61.0 (53.0, 71.0) 63.0 (50.0, 72.0) 0.61 ECOG, 0-1 (%) 132 (88) 53 (93) 0.68 Charlson Comorbidity Index, 6 (%) 116 (77) 43 (75) 0.63 PR-positive (%) 107 (71) 36 (63) 0.26 Recurrent (%) 108 (72) 38 (68) 0.45 Visceral (%) 97 (65) 43 (75) 0.02 One prior line (%) 86 (57) 45 (79) <0.01 CDK4/6i ≥ 12 m (%) 97 (65) 33 (58) 0.51 Endpoints Time to EVE failure (m) 4.2 Time to chemotherapy (m) 5.8 6.3 HR 1.02, 0.75-1.41 mOS (m) 24.2 20.6 HR 0.81, 0.54-1.20 ConclusionsWe found a non-statistically significant trend for superiority of EVE compared to ETa for unadjusted rwPFS. Pts with PIK3CA-AKT-PTEN pathway alterations, may particularly benefit from the combination.Legal entity responsible for the studyInstitut Jules Bordet.FundingThe study received financial support from Novartis for study set up and data collection from patients treated at Institut Jules Bordet.DisclosureD. Martins Branco: Financial Interests, Personal, Invited Speaker, (03/02/2022 and 23/09/2022): AstraZeneca/DaiichiSankyo; Financial Interests, Personal, Full or part-time Employment: European Society for Medical Oncology; Financial Interests, Institutional, Funding, Institutional funding for observational research projects - role: medical research fellow at Institut Jules Bordet (01/01/2021 - 31/08/2023): Novartis; Financial Interests, Institutional, Funding, Institutional funding for an investigator-initiated clinical trial (NCT05075538) - role: medical research fellow at Institut Jules Bordet (01/01/2021 - 31/08/2023): F. Hoffmann-La Roche Ltd; Financial Interests, Institutional, Other, Two industry-sponsored clinical trials (NCT01358877 and NCT03498716) - role: academic partner medical advisor at Institut Jules Bordet (01/01/2021 - 31/08/2023): F. Hoffmann-La Roche Ltd; Financial Interests, Institutional, Funding, Institutional funding for an investigator-initiated clinical trial (NCT03339843) - role: medical research fellow at Institut Jules Bordet (01/01/2021 - 31/08/2023): Eli Lilly; Non-Financial Interests, Member of Board of Directors: Associação de Investigação e Cuidados de Suporte em Oncologia - Portuguese MASCC affiliate; Non-Financial Interests, Leadership Role, Portuguese Young Oncologists Committee Chair: November 2020 - May 2022: Sociedade Portuguesa de Oncologia. P.G. Aftimos: Financial Interests, Personal, Advisory Board: Boehringer Ingelheim, Macrogenics, Roche, Novartis, Amcure, Servier, G1 Therapeutics, Radius, Deloitte, Menarini, Gilead, Novartis, Eisai, Lilly; Financial Interests, Personal, Invited Speaker: Synthon, Amgen; Financial Interests, Institutional, Research Grant: Roche. B.A. Pereira: Financial Interests, Personal, Invited Speaker: GSK. A.L.V. Matos: Financial Interests, Personal, Invited Speaker: Astrazeneca, Roche, Lilly; Financial Interests, Personal, Advisory Board: Novartis, Grunenthal. L.M. Raposo Fernandes: Financial Interests, Personal, Advisory Board: Novartis, Pfizer; Financial Interests, Personal, Other, Consultancy: Astrazeneca, Pfizer. G. Nader Marta: Other, Meeting/travel grants to attend medical conference.: AstraZeneca. F.P. Duhoux: Financial Interests, Institutional, Advisory Board: Roche, Pfizer, AstraZeneca, Lilly, Novartis, Amgen, Daiichi Sankyo, Pierre Fabre, Gilead, Seagen, MSD, Seagen, Novartis, MSD; Financial Interests, Institutional, Invited Speaker: Novartis, Pfizer, MSD, Roche; Financial Interests, Institutional, Local PI: MSD, Boehringer Ingelheim, Pfizer, Novartis, Lilly, Abbvie, Seagen, Gilead, AstraZeneca, Menarini, Immutep. A.R. Meira Garcia: Financial Interests, Personal, Invited Speaker: Daiichi Sankyo/AstraZeneca; Financial Interests, Personal and Institutional, Local PI: Leopharma. C. Santos: Financial Interests, Personal, Invited Speaker, Speaker: Pfizer; Non-Financial Interests, Principal Investigator, Clinical trial: Msd. E. de Azambuja: Financial Interests, Personal, Advisory Board: Roche/GNE, Novartis, Seagen, MSD; Financial Interests, Personal, Invited Speaker: Zodiac, Libbs, Pierre Fabre, Lilly, AstraZeneca, Gilead Sciences; Financial Interests, Personal, Other, Chair of the Gilead Sciences Research Scholars Program in Solid Tumours: Gilead Sciences; Financial Interests, Institutional, Research Grant: Roche/GNE, AstraZeneca, GSK/Novartis, Servier; Financial Interests, Institutional, Other, Travel Grant: Roche/GNE; Financial Interests, Institutional, Local PI: MSD, ABCSG, Nektar, Gilead, Immunomedics, Synthon, Odonate Therapeutics; Financial Interests, Steering Committee Member, ASCENT 04: Gilead; Financial Interests, Steering Committee Member, Aphinity, Lorelei, Impassion03: Roche; Financial Interests, Steering Committee Member, AURORA: Breast International Group; Financial Interests, Steering Committee Member, Olympia: AstraZeneca; Financial Interests, Personal, Other, Travel grant: AstraZeneca; Non-Financial Interests, Advisory Role, Member of the cardio-oncology council: European Society of Cardiology (ESC); Non-Financial Interests, Advisory Role, Belgium governmental institution for cancer: KCE; Non-Financial Interests, Other, Editorial board member: ESMO Open; Non-Financial Interests, Advisory Role: Anticancer Fund; Non-Financial Interests, Leadership Role, President 2023-2026: Belgian Society of Medical Oncology (BSMO). All other authors have declared no conflicts of interest.