A. Urruticoechea (Donostia, Spain)

Onkologikoa

Author Of 2 Presentations

 On-Demand ePoster Display

14P - Immunomodulatory effect of denosumab in early breast cancer: preliminary results of a randomized window-opportunity clinical trial D-Biomark (NCT03691311).

Abstract

Background

Most breast cancers (BC) exhibit low immune infiltration and are unresponsive to immunotherapy. Hence, the urgency to find new mechanisms of immune activation, postulating receptor activator of nuclear factor kappa-Β ligand (RANKL) and its receptor RANK as potential immunomodulator. Our previous data demonstrated that RANK pathway inhibitors, such as denosumab, used for the treatment of bone metastasis, could also prevent and/or treat BC and regulate the tumour immune crosstalk. However, the population of breast cancer patients who may benefit from denosumab remains to be identified.

Methods

Patients with early-stage HER2-negative BC, candidates to tumour excision as first therapeutic approach are included. Patients are randomized 2:1 to denosumab: control (no treatment); experimental arm received 2 doses of 120 mg subcutaneous denosumab (once per week) before surgery (2-4 weeks later). Putative changes in tumour cell proliferation by Ki67 immunohistochemistry (IHC), cell survival by cleaved caspase 3 IHC (primary endpoints) and stromal tumour infiltrating lymphocytes (TILs) quantified in the haematoxylin and eosin by between baseline (biopsy sample) and surgery are evaluated. Specific antibodies will be used to characterize infiltrating immune populations. Denosumab driven gene expression changes in tumour samples will be analysed and tools such as CIBERSORT will be used to characterize the immune infiltrate.

Results

We present results from the first 36 patients enrolled out of 60. Clinical and tumour characteristics were well balanced between the groups. No relevant toxicities were reported. No clinically significant differences in Ki67 and cleaved caspase-3 were observed after denosumab treatment. Interestingly, a statistically significant increase in TILs was observed in the denosumab treated group (p=0.03, Paired t test) but not in the control group (p=0.80). A 33% of patients treated denosumab showed a ≥10% increase in TILs vs 0% in the control group (p =0.05).

Conclusions

Short term neoadjuvant denosumab increases TILs in early BC.

Clinical trial identification

NCT03691311.

Legal entity responsible for the study

The authors.

Funding

Amgen Juan de la Cierva. Postdoctoral contract. IJCI-2017-31564 Río Hortega (CM19/00148) Instituto de Salud Carlos III / Ministerio de Ciencia, Innovación y Universidades. ERC-Consolidator grant PLEIO-RANK European Research Council.

Disclosure

All 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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