6ER-004 Preliminary clinical response of ribociclib as a single agent in advanced breast cancer: in search of new therapeutic indications

Background and importance Ribociclib, an orally bioavailable CDK4/6 inhibitor, is currently approved in combination with anaromatase inhibitor for the treatment of pre/perimenopausal women with HR positive, HER2 negative advanced breast cancer. Alterations in the CDK4/6-Rb-E2F pathway, which promotes cell proliferation, usually occur in human tumours. Thus ribociclib remains as an attractive therapeutic strategy for the treatment of other neoplasms in which this pathway is significantly dysregulated. Aim and objectives To evaluate the preliminary clinical response of ribociclib as a single agent, in terms of best overall response (BOR) and progression free survival (PFS) in patients with Rb+ advanced solid tumours (AST) and lymphomas. Material and methods A literature review was carried out of studies published during 2016–2019 in the electronic databases Medline, Embase and Cochrane Library. No restrictions in terms of language or publication year were applied. Search strategy terms were: ‘Ribociclib’, ‘clinical response’, ‘single agent’ and ‘advanced cancer’. Boolean operators were used to connect specific search keywords for each database and other free text terms. Results Five clinical trials were found. A phase I study of single agent ribociclib in 132 patients from Europe and USA with Rb+ AST and lymphomas showed preliminary signs of clinical activity (NCT01237236): 3 patients achieved a partial response (PR), 43 a BOR of stable disease (SD) and 8 had PFS for >6 months. In another phase I trial in 17 Japanese patients with advanced oesophageal, breast, peritoneum and soft tissue tumours (NCT01898845), ribociclib exhibited a limited response, as no patient achieved a complete response (CR) or PR, and 4 achieved BOR on SD. In a phase I study in 32 paediatric patients with neuroblastoma and malignant rhabdoid tumours treated with single agent ribociclib (NCT01747876), BOR was SD in 9 patients and 5 achieved SD for more than 6, 6, 8, 12 and 13 cycles, respectively. The results of phase 0 and phase Ib studies that assessed the clinical response of ribociclib as monotherapy in glioblastoma (NCT02933736, NCT02345824), showed limited clinical efficacy and ineffectiveness, respectively. Both studies mentioned the presence of a significant increase in cells mTOR/PI3K signalling pathway activity. Conclusion and relevance Inhibition of the CDK4/6-Rb-E2F pathway by ribociclib showed preliminary limited clinical response in patients with AST and lymphomas. However, the observation of prolonged SD support further investigation of ribociclib in combination with other agents, especially mTOR/PI3K inhibitors. References and/or acknowledgements No conflict of interest.