Ribociclib plus topotecan–temozolomide or everolimus led to stable disease in 29% of patients.

  • Major Finding: Ribociclib plus topotecan–temozolomide or everolimus led to stable disease in 29% of patients.

  • Concept: A patient with T-cell acute lymphoblastic leukemia (T-ALL) had stable disease and blast reduction.

  • Impact: The recommended phase II doses obtained in this work have enabled initiation of two follow-up trials.

The cyclin-dependent kinase 4/6 (CDK4/6) inhibitor ribociclib has been approved for the treatment of HR+ HER2 advanced breast cancer and is currently under investigation for a variety of other malignancies. Based on the high frequency of genetic aberrations affecting cell-cycle pathways regulated by CDK4/6 in many pediatric cancers, Bautista and colleagues initiated a phase I/II clinical trial of ribociclib plus the topoisomerase I inhibitor topotecan and the alkylating agent temozolomide (arm A; 14 patients treated) or the mTOR inhibitor everolimus (arm B; 17 patients treated) in pediatric patients with advanced cancers, mainly brain tumors and sarcomas. Patients were selected for arm A if topotecan–temozolomide was considered an appropriate treatment and their cancer had genetic alterations leading to activation of CDK4/6-regulated pathways, whereas patients were selected for arm B if their cancer had CDK4/6 pathway–activating genetic alterations (as in arm A) or alterations affecting the PI3K–AKT–mTOR pathway. Although there were no objective responses, 14.3% of patients in arm A and 41.2% of patients in arm B experienced stable disease as their best response, with a notable signal in arm B of substantial blast count reduction in one patient with T-cell acute lymphoblastic leukemia. The safety and toxicity profile was mainly as expected given the single-agent profiles of the drugs in pediatric patients and combination-drug profiles obtained in adult patients, with hematologic adverse events (mainly leukopenia, neutropenia, and lymphopenia) predominating. Based on these findings, two further trials examining ribociclib plus topotecan–temozolomide or everolimus, the former using an alternative dosing scheme and the latter enrolling patients with T-cell acute lymphoblastic leukemia and other malignancies that exhibit genetic activating aberrations in both pathways, have been initiated.

Bautista F, Paoletti X, Rubino J, Brard C, Rezai K, Nebchi S, et al. Phase I or II study of ribociclib in combination with topotecan-temozolomide or everolimus in children with advanced malignancies: Arms A and B of the AcSé-ESMART trial. J Clin Oncol 2021 Aug 4 [Epub ahead of print].

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