M. Capelán (Barcelona, Spain)

Vall d’Hebron Institute of Oncology (VHIO)

Author Of 2 Presentations

 On-Demand ePoster Display

16P - Understanding the biologic determinants of ribociclib efficacy in breast cancer

Abstract

Background

Ribociclib improves survival in hormone receptor-positive (HR+)/HER2-negative (HER2-) advanced breast cancer (BC). Deeper understanding of the biology associated with ribociclib efficacy is needed, especially within the HER2-enriched (HER2-E) subtype given recent analysis of MONALEESA program. Here, we performed gene expression (GE) analysis with/without ribociclib monotherapy in BC patient-derived xenografts (PDX).

Methods

Eighteen PDXs representative of HR+/HER2- (n=11, 61%), HER2+ (n=6, 33%) and triple-negative (n=1, 6%) BC were treated with ribociclib monotherapy (75 mg/kg/day). The % change in tumor volume from baseline was calculated at day 35. RNA was obtained from flash-frozen tumors at baseline and day 12. PAM50 GE was analyzed by nCounter and associated with tumor response (as a continuous variable) using quantitative Statistical Analysis Microarrays (SAM). Differential GE during ribociclib treatment was identified using two-class paired SAM. All SAM used a false-discovery rate<5%.

Results

Baseline PAM50 subtype distribution was Luminal B (44%), HER2-E (33%) and Basal-like (B-L) (22%). HER2-E and Luminal B PDXs showed a statistically significant higher response to ribociclib (mean change in volume >40% and >140%), than B-L (>660%). Baseline GE analysis identified 6 genes highly expressed in responders (FOXA1, ERBB2, GRB7, MLPH, GPR160 and CXXC5), and 7 lower expressed genes (SFRP1, KRT17, MYC, CDH3, KRT5, MIA and KRT14). Paired GE analyses across PDXs identified 12 upregulated genes during treatment, including estrogen activation-related genes (ESR1, PGR, FOXA1, MAPT or BLVRA); and 12 downregulated genes, including proliferation-related genes (MKI67 or KIF2C) and HER2-E-related genes (ERBB2 or TMEM45B). Similar results were obtained with HR+/HER2- PDXs when analyzed separately.

Conclusions

In BC PDXs, B-L biology associates with lower response to ribociclib monotherapy than Luminal or HER2-E. Ribociclib induces a luminal phenotype with high GE of estrogen-regulated genes and low GE of proliferation genes, a biological switch that could explain the better efficacy of ribociclib in the endocrine therapy (ET)-resistant HER2-E subtype observed in clinical trials when combined with ET.

Legal entity responsible for the study

Institut d'Investigacions Biomèdiques August Pi i Sunyer.

Funding

Has not received any funding.

Disclosure

M. Oliveira: Honoraria (self): Roche, Novartis, Seattle Genetics; Advisory/Consultancy: Roche/Genentech, GlaxoSmithKline, Puma Biotechnology, AstraZeneca, Seattle Genetics; Research grant/Funding (institution): Philips Healthcare (Inst), Roche/Genentech (Inst), Novartis (Inst), AstraZeneca (Inst), Immunomedics (Inst), Seattle Genetics (Inst), Boehringer Ingelheim (Inst), GlaxoSmithKline (Inst), Cascadian Therapeutics (Inst), Sanofi (Inst), Celldex Therapeutics; Travel/Accommodation/Expenses: Roche, Novartis, Grünenthal Group, Pierre Fabre, GP Pharm, Eisai. N. Chic: Travel/Accommodation/Expenses: Novartis, Eisai, Pierre Fabre. R. Dienstmann: Advisory/Consultancy, Speaker Bureau/Expert testimony: Roche; Advisory/Consultancy: Boehringer Ingelheim; Speaker Bureau/Expert testimony: Ipsen; Speaker Bureau/Expert testimony: Amgen; Speaker Bureau/Expert testimony: Servier; Speaker Bureau/Expert testimony: Sanofi; Speaker Bureau/Expert testimony: Merck Sharp & Dohme; Research grant/Funding (self): Merck; Research grant/Funding (self): Pierre Fabre. C. Saura Manich: Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: AstraZeneca, Daiichi Sankyo, Merck, Sharp and Dohme España SA, Novartis, Pfizer, Puma, Synthon; Advisory/Consultancy, Travel/Accommodation/Expenses: Celgene, Clovis Oncology, Eisai, F. Hoffmann-La Roche Ltd., Genomic Health, Odonate Therapeutics, Philips Healthwork, Pierre Fabre, prIME Oncology, Sanofi Aventis, Zymeworks; Research grant/Funding (institution): Eli Lilly and Company, Genentech, Immunomedics, Macrogenics, Piqur Therapeutics, Roche, Synthon. A. Prat: Advisory/Consultancy, Research grant/Funding (self): Novartis Farma, SA; Advisory/Consultancy: Lilly Spain; Advisory/Consultancy: Pfizer, SLU; Advisory/Consultancy, Research grant/Funding (self): Roche Farma, SA; Advisory/Consultancy: Bristol-Myers Squibb; Advisory/Consultancy: Amgen, SA; Advisory/Consultancy: Daiichi; Advisory/Consultancy: Oncolytics Bioteck; Research grant/Funding (self): Sysmex Europe GmbH; Research grant/Funding (self): Medica Scientia Inno, Research, SL; Research grant/Funding (self): Celgene, SLU; Research grant/Funding (self): Astellas Pharma, SA; Research grant/Funding (self): NanoString Technologies; Officer/Board of Directors, Member executive Board: Breast International Group (BIG).; Officer/Board of Directors, Member executive Board and Foundation: SOLTI; Research grant/Funding (self): Puma; Research grant/Funding (self): Incyte. V. Serra: Research grant/Funding (self): Novartis, Genentech. All other authors have declared no conflicts of interest.

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129TiP - Metformin (MF) in the prevention of hyperglycemia (HG) in patients (pts) with PIK3CA-mutated, hormone receptor (HR)[+]/HER2[-] advanced breast cancer (ABC) treated with alpelisib (ALP) plus fulvestrant (F): METALLICA

Abstract

Background

ALP is an α-specific PI3K-α inhibitor, that has shown to significantly increase the median progression-free survival (PFS) when combined with F in pts with PIK3CA-mutated, HR[+]/HER2[–] ABC who had failed to an aromatase inhibitor (AI) regimen. HG is an on-target effect of the PI3K inhibition, being the most frequent adverse event (AE) of grade (G)3/4 and the most common AE leading to discontinuation of ALP in the randomized, phase III SOLAR-1 study. MF is approved for pts with diabetes mellitus (DM) and represented the preferred option for treating ALP-induced HG in the SOLAR-1 study. METALLICA is evaluating the effect of MF in the prevention of HG in PIK3CA-mutated, HR[+]/HER2[–] ABC pts under treatment with ALP plus F.

Trial design

This is a multicenter, open-label, two-cohort, Simon’s two-stage design, phase II trial. Main selection criteria include: (1) Pts ≥ 18 years diagnosed with AI-resistant, PIK3CA-mutated, HR[+]/HER2[–] ABC; (2) No prior history of type I/II DM requiring anti-diabetic drugs; (3) ≤1 prior line of chemotherapy for ABC and/or no prior treatment with any PI3K inhibitor and/or F. A total of 68 pts will be enrolled into two study cohorts according to the baseline glycaemia status: (A) 48 pts with fasting glycaemia <100 mg/dL and glycosylated hemoglobin (HbA1c) < 5.7%; (B) 20 pts with fasting glycaemia 100–140 mg/dL and/or HbA1c 5.7–6.4%. Pts will receive ALP (300mg, orally, once daily) plus F (500mg, intramuscular injection on days 1, 15 of cycle 1 and on day 1 thereafter) and MF (500mg, twice a day (BID) on days 1–3 and 1000mg BID thereafter). The primary endpoint is the rate of G3/4 HG over the first 2 cycles in both cohorts as per CTCAE v4.03. The secondary endpoints include PFS, overall response rate, time to progression, clinical benefit rate as per RECIST v1.1, and overall safety as per CTCAE 4.03. The stage II will be conducted if G3/4 HG after the first 2 cycles are observed in ≤3 pts of 23 in cohort A and ≤2 pts of 7 in cohort B. The final analysis will be defined as positive if ≤6 pts of 48 in cohort A and ≤4 pts of 20 in cohort B have G3/4 HG. The Simon two-stage design was planned to attain an 80% power at 5% nominal alpha level.

Clinical trial identification

NCT04300790.

Legal entity responsible for the study

MEDSIR.

Funding

Novartis.

Disclosure

A. Llombart Cussac: Leadership role: Eisai, Celgene, Lilly, Pfizer, Roche, Novartis, MSD; Shareholder/Stockholder/Stock options: MedSIR, Initia-Research; Advisory/Consultancy: Lilly, Roche, Pfizer, Novartis, Pierre Fabre, GenomicHealth, GSK; Speaker Bureau/Expert testimony: Lilly, AstraZeneca, MSD; Research grant/Funding (self): Roche, Foundation Medicine, Pierre Fabre, Agendia; Travel/Accommodation/Expenses: Roche, Lilly, Novartis, Pfizer, AstraZeneca. J.M. Pérez-Garcia: Advisory/Consultancy: Roche, Lilly; Travel/Accommodation/Expenses: Roche; Full/Part-time employment: MedSIR. A. Urruticoechea: Travel/Accommodation/Expenses: Roche/Genentech, Pfizer. J.F. Cueva Banuelos: Honoraria (self): Roche, AstraZeneca, Teva, Celgene, Novartis.; Advisory/Consultancy: Roche, AstraZeneca. J. Cortés: Advisory/Consultancy: Roche, Celgene, Cellestia, AstraZeneca, Biothera Pharmaceutical, Merus, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex, Polyphor, Lilly, Servier, Merck Sharp & Dohme, GSK, Leuko, Bioasis, Clovis Oncology; Honoraria (self): Roche, Novartis, Celgene, Eisai, Pfizer, Samsung Bioepis, Lilly, Merck Sharp & Dohme, Daiichi Sankyo; Research grant/Funding (institution): Roche, Ariad Pharmaceuticals, AstraZeneca, Baxalta GMBH/Servier Affaires, Bayer Healthcare, Eisai, F. Hoffman-La Roche, Guardanth Health, Merck Sharp & Dohme, Pfizer, Piqur Therapeutics, Puma C, Queen Mary University of London; Licensing/Royalties: MedSIR. All other authors have declared no conflicts of interest.

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