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228MO - PALOMA-4: Primary results from a phase III trial of palbociclib (PAL) + letrozole (LET) vs placebo (PBO) + LET in Asian postmenopausal women with estrogen receptor–positive/human epidermal growth factor receptor 2–negative (ER+/HER2–) advanced breast cancer (ABC)
- Binghe Xu (Beijing, China)
Abstract
Background
The incidence of breast cancer in Asian women has increased rapidly over the past 40 years. A previous subgroup analysis from PALOMA-2 indicated that PAL + LET may be effective as first-line therapy in postmenopausal Asian women with ER+/HER2– ABC. The PALOMA-4 study assessed the efficacy and safety of PAL + LET in Asian patients (pts).
Methods
PALOMA-4, an international, double-blind, phase 3 trial, randomized postmenopausal Asian women who had not received prior systemic therapy for ER+/HER2– ABC 1:1 to receive PAL (125 mg/d orally; 3 weeks on, 1 week off) + LET (2.5 mg/d orally; continuously) or PBO + LET. The primary endpoint was Kaplan-Meier analysis of investigator-assessed progression-free survival (PFS); between-arms comparisons used a stratified log-rank test. Secondary endpoints included objective response rate (ORR) and safety; between-arms comparisons used the Cochran-Mantel-Haenszel test. Safety was summarized descriptively.
Results
Pts (N=340) were randomized (PAL + LET, 169; PBO + LET, 171). The median duration of follow-up for overall survival was 52.8 mo. Baseline characteristics were generally similar between the 2 groups. At the data cutoff (Aug 31, 2020), the median PFS based on investigator assessment was 21.5 mo for PAL + LET and 13.9 mo for PBO + LET (hazard ratio, 0.68 [95% CI, 0.53–0.87];
Conclusions
PALOMA-4, the largest study to date of a cyclin-dependent kinase 4/6 inhibitor in Asian pts with ABC, confirmed the efficacy and safety of PAL + LET as first-line therapy in postmenopausal Asian women with ER+/HER2– ABC.
Clinical trial identification
NCT02297438.
Editorial acknowledgement
Editorial support was provided by Anny Wu, PharmD, of ICON plc (North Wales, PA, USA) and was funded by Pfizer Inc.
Legal entity responsible for the study
Pfizer Inc.
Funding
Pfizer Inc.
Disclosure
B. Xu: Financial Interests, Personal, Advisory Role, Consultancy: Novartis, Roche; Financial Interests, Institutional, Research Grant: Hengrui; Financial Interests, Institutional, Funding: Hengrui; Financial Interests, Personal, Speaker’s Bureau: AstraZeneca, Pfizer, Roche, Eisai. C. Huang: Financial Interests, Personal, Other, Honoraria: Amgen, AstraZeneca, Novartis, Pfizer, Roche; Financial Interests, Institutional, Research Grant: Amgen, AstraZeneca, Daiichi Sankyo, EirGenix, Lilly, MSD, Novartis, OBI, Pfizer, Roche; Financial Interests, Institutional, Funding: Amgen, AstraZeneca, Daiichi Sankyo, EirGenix, Lilly, MSD, Novartis, OBI, Pfizer, Roche; Financial Interests, Personal, Advisory Role: Amgen, AstraZeneca, Lilly, Novartis, Pfizer, Roche; Financial Interests, Personal, Other, Consultancy: Amgen, AstraZeneca, Lilly, Novartis, Pfizer, Roche; Financial Interests, Personal, Speaker’s Bureau: Roche; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Amgen, Pfizer, Roche. V. Sriuranpong: Financial Interests, Institutional, Research Grant: Roche, MSD, Novartis, Pfizer, AstraZeneca; Financial Interests, Institutional, Funding: Roche, MSD, Novartis, Pfizer, AstraZeneca; Financial Interests, Personal, Advisory Role: Roche, Novartis, Boehringer Ingelheim, MSD, Pfizer, Amgen; Financial Interests, Personal, Other, Consultancy: Roche, Novartis, Boehringer Ingelheim, MSD, Pfizer, Amgen. K.C.R. Ngan: Financial Interests, Institutional, Research Grant: Pfizer; Financial Interests, Institutional, Funding: Pfizer; Financial Interests, Personal, Advisory Role: Pfizer, Novartis, Sanofi, AstraZeneca, Lilly, MSD, Zai Lab, Roche, Eisai; Financial Interests, Personal, Other, Consultancy: Pfizer, Novartis, Sanofi, AstraZeneca, Lilly, MSD, Zai Lab, Roche, Eisai; Financial Interests, Personal, Speaker’s Bureau: Novartis, AstraZeneca, Sanofi, Pfizer, Zai Lab, Eisai, Lilly, MSD; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Pfizer, Astellas, Novartis, MSD, Roche, Eisai, Merck, Sanofi, BMS, Zai Lab. X. Wang: Financial Interests, Personal, Full or part-time Employment: Pfizer; Financial Interests, Personal, Stocks/Shares: Pfizer. H. Zhao: Financial Interests, Personal, Full or part-time Employment: Pfizer. All other authors have declared no conflicts of interest.
229MO - Overall survival (OS) of palbociclib (P) plus endocrine therapy (ET) versus capecitabine (CAP) in hormone-receptor+/HER2- metastatic breast cancer (MBC) that progressed on aromatase inhibitors (AIs): Final results of the PEARL study
- Miguel Martin Jimenez (Madrid, Spain)
Abstract
Background
PEARL study did not show superiority in progression-free survival (PFS) with P+ET versus (vs) CAP in patients (pts) with AI-resistant MBC, but P+ET was better tolerated and showed a significant delay in quality of life deterioration. Final OS data are reported here.
Methods
PEARL had two consecutive cohorts: cohort 1 (C1) with 296 pts randomized to P+exemestane vs CAP, and cohort 2 (C2) with 305 pts randomized to P+fulvestrant (F) vs CAP. Secondary endpoints included OS in C2 and in wild-type (wt) ESR1 (measured in ctDNA at baseline) pts (C1+C2). OS analysis was planned when 152 deaths occurred in C2, in order to have an 80% power to detect an increase of 50% in OS from 22 months (m) with CAP to 33 m with P+F or P+ET in wtESR1 pts. Adjusted hazard ratio (aHR) was calculated using a stratified Cox proportional hazard model with treatment arm, stratification factors and number of involved sites as covariates.
Results
At data cut-off (11Jan2021), the median follow-up of C2 and wtESR1 pts were 28.0 m and 30.3 m, respectively. Median OS in C2 was 31.1 m with P+F vs 32.8 m with CAP (aHR 1.10, 95% CI, 0.81–1.50; p=0.550). Median OS in wtESR1 pts was 37.2 m with P+ET vs 34.8 m with CAP (aHR 1.06, 95% CI, 0.81-1.37; p=0.683). None of the subgroup analyses showed superiority in OS for P+ET vs CAP. Subsequent therapy was given to 79.8% and 82.9% of pts with P+ET and CAP, respectively. The median number of subsequent lines was 3 (1-10) in the P+ET arm and 3 (1-9) in the CAP arm. First subsequent therapy was CDK4/6 inhibitor+ET in 26.1% of pts in the CAP arm and CAP in 36.1% of pts in the P+ET arm. The median PFS2 defined as time from randomization to the end of first subsequent therapy or death, was similar in both arms either in C2, 18.3 m with P+F vs 17.7 m with CAP (aHR 0.95, 95% CI, 0.73-1.25; p=0.728), and in wtESR1 pts, 18.3 m with P+ET vs 18.2 m with CAP (aHR 1.04, 95% CI, 0.83-1.31; p=0.717). PFS and response did not change in this final analysis. No new safety findings were observed with longer follow-up.
Conclusions
Palbociclib + endocrine therapy did not show a statistically superior OS compared to CAP in MBC pts progressing to AIs.
Clinical trial identification
NCT02028507.
Legal entity responsible for the study
GEICAM Spanish Breast Cancer Group.
Funding
Pfizer and AstraZeneca.
Disclosure
M. Martin Jimenez: Financial Interests, Personal, Advisory Role: AstraZeneca. Amgen, Taiho Oncology, Roche/Genentech, Novartis, PharmaMar, Eli Lilly, PUMA, Taiho Oncology, and Pfizer; Financial Interests, Personal, Speaker’s Bureau: AstraZeneca. Amgen, Roche/Genentech, Novartis, Daiichi Sankyo, and Pfizer; contracted research fees from Roche, Novartis, and PUMA; Financial Interests, Institutional, Research Grant: Roche. Novartis. PUMA. C. Zielinski: Financial Interests, Personal, Advisory Role: Roche, Novartis, Bristol Myers Squibb, Merck Sharp & Dohme, Imugene, Ariad, Pfizer, Merrimack, Merck KGaA, Fibrogen, AstraZeneca, Tesaro, Gilead, Servier, Shire, Eli Lilly, and Athenex; Financial Interests, Personal, Speaker’s Bureau: Roche, Novartis, Bristol Myers Squibb, Merck Sharp & Dohme, Imugene, Ariad, Pfizer, Merrimack, Merck KGaA, Fibrogen, AstraZeneca, Tesaro, Gilead, Servier, Shire, Eli Lilly, and Athenex; Financial Interests, Institutional, Research Grant: Bristol Myers Squibb, Merck Sharp & Dohme, Pfizer, AstraZeneca, and Merck KGaA. M. Ruiz-Borrego: Financial Interests, Personal, Advisory Role: Pfizer, Novartis, and Lilly; Financial Interests, Personal, Speaker’s Bureau: Pfizer, Novartis, and Lilly. E. Carrasco: Financial Interests, Personal, Ownership Interest: Lilly; Financial Interests, Personal, Other, Travel, accommodation support: Roche; Other, Institutional, Research Grant: Roche/Genentech, Bristol Myers Squibb, Novartis, Pfizer, Celgene, AstraZeneca, Merck Sharp & Dohme, Pierre Fabre, and Takeda; Financial Interests, Personal, Advisory Board, Her husband: Bristol Myers Squibb, Novartis, Celgene, Roche Pharma, Janssen, Amgen, Incyte, AbbVie, and Pfizer; Financial Interests, Personal, Research Grant, Her husband's institution: from Celgene, Janssen, Bristol Myers Squibb, Novartis, Celgene, Roche/Genentech, Amgen, Pfizer, and AbbVie. E.M. Ciruelos: Financial Interests, Personal, Advisory Board: Lilly, Novartis, MSD, AstraZeneca, Pfizer and Roche; Financial Interests, Personal, Speaker’s Bureau: Roche, Lilly and Pfizer; Financial Interests, Personal, Other, Travel and congress assistance support: Pfizer and Roche. M. Muñoz: Financial Interests, Personal, Other, Travel and Congress assistance support: Roche, Novartis, Pfizer and Eisai. B. Bermejo: Financial Interests, Personal, Advisory Board: Roche, Novartis and MSD; Financial Interests, Personal, Speaker’s Bureau: Roche, Novartis, MSD, Pfizer and Pierre Fabre; Financial Interests, Personal, Other, Travel and Congress assistance support: Pfizer. M. Margeli: Financial Interests, Personal, Advisory Board: Roche, Novartis, Pfizer, and Eisai; Financial Interests, Institutional, Funding: Roche, Pfizer, Novartis, Lilly, AstraZeneca, Eisai, and Kern; Financial Interests, Personal, Other, Travel and Congress assistance support: Roche. A. Anton: Financial Interests, Personal, Advisory Board: Bayer. N. Turner: Financial Interests, Personal, Advisory Board: AstraZeneca, Bristol Myers Squibb, Lilly, Merck Sharpe & Dohme, Novartis, Pfizer, Roche/Genentech, Bicycle Therapeutics, Taiho, Zeno pharmaceuticals, Repare therapeutics; Financial Interests, Institutional, Research Grant: AstraZeneca, BioRad, Pfizer, Roche/Genentech, Clovis, Merck Sharpe & Dohme, and Guardant Health. E. Alba: Financial Interests, Personal, Advisory Board: Roche, Novartis, Pfizer, Lilly, Bristol Myers Squibb, Genomic Health, and Nanostring; Financial Interests, Personal, Other, Travel Support: Celgene; Financial Interests, Institutional, Research Grant: Roche, Pfizer, Sysmex, Merck Sharp & Dohme, and Nanostring. J. De La Haba: Financial Interests, Personal, Speaker’s Bureau: AstraZeneca, Pfizer, Novartis and Lilly. M. Ramos: Financial Interests, Personal, Speaker’s Bureau: Novartis, Roche, and Pfizer. M. Corsaro: Financial Interests, Personal, Stocks/Shares, Employed: Pfizer. Z. Kahan: Financial Interests, Personal, Speaker’s Bureau: Pfizer, Roche, AstraZeneca and Novartis; Other, Personal, Funding, Travel Support: Pfizer, Roche, AstraZeneca and Novartis; Financial Interests, Personal, Advisory Board: Pfizer, Roche, AstraZeneca and Novartis. M. Gil-Gil: Financial Interests, Personal, Funding: Pfizer, Ferrer International and Esteve Pharma. All other authors have declared no conflicts of interest.
Discussion 228MO and 229MO
- Maria Vittoria Dieci (Padova, Italy)
230MO - First in human, modular study of samuraciclib (CT7001), a first-in-class, oral, selective inhibitor of CDK7, in patients with advanced solid malignancies
- Matthew G. Krebs (Manchester, United Kingdom)
Abstract
Background
CDK7 inhibition is a promising therapeutic strategy in cancer. CDK7 is a key kinase, regulating cell division, transcription and nuclear receptor function, particularly the oestrogen receptor.
Methods
Tolerability, pharmacokinetics and efficacy of samuraciclib were assessed; including evaluation of ascending doses (M1A), paired tumour biopsy (PB) samples (M1A), effect of food on bioavailability (M4) and a triple-negative breast cancer (TNBC) expansion cohort (M1B).
Results
M1A recruited 33 patients in 5 cohorts: 120, 240, 360mg and 480 mg once daily (OD), and 180 mg twice daily (BID). 11 further patients were dosed in PB cohorts for pharmacodynamic assessment. M4 recruited 15 patients. M1B recruited 23 patients. At 120 mg, 240 mg and 360mg, most common adverse drug reactions (AE) were: G1-2 nausea, vomiting and diarrhoea. At 480 mg, 3/6 patients experienced a DLT (G3 diarrhoea, G3 oral mucositis, G3 vomiting). At 180mg BD, 1/7 patients experienced a DLT (G4 thrombocytopaenia). 240mg OD and 360 mg OD were determined clinically relevant doses, with 360mg OD as the preliminary recommended phase 2 dose. In fasted patients, median Tmax = 1.5 - 4 hrs and geomean T1/2 ∼ 75 hrs. Steady-state was achieved within 8 - 15 days. Plasma exposure increased dose proportionally; pharmacologically active exposures were achieved throughout the entire dosing period. Food had no clinically significant effect on exposure. 57% (25/44) of RECIST evaluable patients had evidence of disease control at first post baseline scan (FPBS) observed across the ‘all comer’ cohorts in M1A and M4, including a partial response (PR) in a patient with HR+ breast cancer; PSA reductions were observed in the 4 castrate-resistant prostate cancer patients recruited. Preliminary tumour biopsy data supports tumour target engagement. 20 patients with TNBC were evaluable for RECIST assessment: 12/20 had stable disease at FPBS; 3 have been on treatment > 1 year.
Conclusions
Samuraciclib has demonstrated an acceptable safety profile with evidence of anti-tumour activity.
Clinical trial identification
2017-002026-20.
Legal entity responsible for the study
Carrick Therapeutics.
Funding
Carrick Therapeutics.
Disclosure
M.G. Krebs: Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Advisory Board: Janssen; Financial Interests, Personal, Advisory Board: Bayer; Financial Interests, Personal, Advisory Board: Seattle Ger; Financial Interests, Personal, Advisory Board: Om Pharma; Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Speaker’s Bureau: Janssen; Financial Interests, Personal, Other, travel expenses: BerGenBio; Financial Interests, Personal, Other, travel expenses: Immutep; Financial Interests, Institutional, Research Grant: Roche; Financial Interests, Institutional, Research Grant: Bergenbio; Financial Interests, Personal, Advisory Board: Achilles Therapeutics; Financial Interests, Institutional, Principal Investigator: Carrick; Financial Interests, Institutional, Principal Investigator: Turning Point; Financial Interests, Institutional, Principal Investigator: Janssen; Financial Interests, Institutional, Principal Investigator: Roche; Financial Interests, Institutional, Principal Investigator: AstraZeneca; Financial Interests, Institutional, Principal Investigator: Blueprint; Financial Interests, Institutional, Principal Investigator: bergenbio; Financial Interests, Institutional, Principal Investigator: Immutep; Financial Interests, Institutional, Principal Investigator: Astellas; Financial Interests, Institutional, Principal Investigator: Seattle Ger. S. Lord: Financial Interests, Personal, Other: Eisai; Financial Interests, Personal, Other: Prosigna; Financial Interests, Personal, Other: Roche; Non-Financial Interests, Personal, Advisory Board: Shionogi; Non-Financial Interests, Personal, Advisory Board: Sanofi; Financial Interests, Institutional, Research Grant: CRUK; Financial Interests, Institutional, Research Grant: Against Breast Cancer; Financial Interests, Institutional, Research Grant: Pathios Therapeutics; Financial Interests, Personal, Funding: Pfizer; Financial Interests, Personal, Funding: Roche; Financial Interests, Personal, Funding: Synthon; Financial Interests, Personal, Funding: Piqur Therapeutics; Financial Interests, Personal, Stocks/Shares: Mitox Therapeutics; Financial Interests, Personal, Full or part-time Employment: Pfizer. A. Bahl: Financial Interests, Personal, Stocks/Shares: Carrick Therapeutics; Financial Interests, Personal, Full or part-time Employment: Carrick Therapeutics. G. Clack: Financial Interests, Personal, Stocks/Shares, Employee: Carrick Therapeutics; Financial Interests, Personal, Stocks/Shares: Athenex Inc. E. Ainscow: Financial Interests, Personal, Full or part-time Employment: Carrick Therapeutics; Financial Interests, Personal, Stocks/Shares: Carrick Therapeutics; Financial Interests, Personal, Stocks/Shares: Astrazeneca. A.G. Barrett: Financial Interests, Institutional, Full or part-time Employment: Imperial College. P. Dickinson: Financial Interests, Institutional, Full or part-time Employment: Seda Pharma Development Services Ltd . M.J. Fuchter: Financial Interests, Personal, Full or part-time Employment: NK:IO Ltd; Non-Financial Interests, Personal and Institutional, Full or part-time Employment: IMperial College Hospital. M. Lehnert: Financial Interests, Personal, Full or part-time Employment: Carrick Therapeutics; Financial Interests, Personal, Stocks/Shares: Carrick Therapeutics.S. Ali: Financial Interests, Personal, Stocks/Shares: Carrick Therapeutics. S. Mcintosh: Financial Interests, Personal, Stocks/Shares: Carrick Therapeutics; Financial Interests, Personal, Full or part-time Employment: Carrick Therapeutics. R.C. Coombes: Financial Interests, Personal, Stocks/Shares: Carrick Therapeutics; Financial Interests, Personal, Funding: AstraZeneca. All other authors have declared no conflicts of interest.
LBA18 - POSEIDON randomized phase II trial: Tamoxifen (TAM) + taselisib or placebo (PLA) in patients (pts) with hormone receptor positive (HR+)/HER2- metastatic breast cancer (MBC)
- Ana Mafalda Antunes De Melo e Oliveira (Barcelona, Spain)
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
Stratification factors, n(%) Taselisib + TAM N=76 PLA + TAM N=76 Post-menopausal 72 (95) 70 (92) Lobular histology 14 (18) 13 (17) PIK3CAmut Exon 20 Exon 9 Not detected Not tested 11 (14) 8 (11) 25 (33) 32 (42) 10 (13) 15 (20) 19 (25) 32 (42) <6m on prior ET for MBC 25 (33) 24 (32) Prior EVE 25 (33) 19 (25) 0-1 prior CT for MBC 49 (64) 51 (67)
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 Partners; 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, Advisory 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, Other: 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.
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)
- Sibylle Loibl (Neu-Isenburg, Germany)
Abstract
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.
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.
Discussion 230MO, LBA18 and LBA19
- Sung-Bae Kim (Seoul, Korea, Republic of)