In a European platform trial (AcSé-ESMART) reported in the Journal of Clinical Oncology, Bautista et al found evidence of activity of the CDK4/6 inhibitor ribociclib plus the mTOR inhibitor everolimus in a population of children with recurrent or refractory malignancies enriched for alterations in the cyclin D–CDK4/6 (cell cycle) or PI3K/AKT/mTOR pathways.
AcSé-ESMART is a proof-of-concept, phase I or II, platform trial designed to investigate targeted agents in molecularly enriched cancer populations.
Study Details
In the study, 32 patients (median age = 13.7 years) enrolled between October 2016 and June 2019 received ribociclib plus topotecan/temozolomide (TOTEM; group A, n = 14) or ribociclib plus everolimus (group B, n = 18). Disease included sarcomas in 44% of patients and brain tumors in 41%; one patient had T-cell acute lymphoblastic leukemia. In group A, 11 patients (79%) had tumors with alterations in the cyclin D–CDK4/6 pathway. In group B, 14 (82%) had alterations in the cyclin D–CDK4/6 (n = 10) or PI3K/AKT/mTOR (n = 10) pathways, or both (n = 6).
Patients received ribociclib once daily for 16 days following TOTEM for 5 days (group A) or for 21 days with everolimus once daily (group B) continuously in 28-day cycles.
Ribociclib in combination with TOTEM or everolimus was well tolerated. The observed activity signals initiated a follow-up study of the ribociclib/everolimus combination in a population enriched with molecular alterations within both pathways.— Bautista et al
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Key Findings
The primary toxicities were leukopenia, neutropenia, and lymphopenia. The recommended phase II doses were ribociclib at 260 mg/m2 once daily with temozolomide at 100 mg/m2 once daily and topotecan at 0.5 mg/m2 once daily (group A) and ribociclib at 175 mg/m2 once daily and everolimus at 2.5 mg/m2 once daily (group B).
No objective responses were observed in either group. In group A, stable disease as best response was observed in 2 of 14 patients (tumor control rate = 14.3%, 95% confidence interval [CI] = 0%–33%). Median progression-free survival was 1.8 months (95% CI = 0.9–3.1 months) and median overall survival was 4.6 months (95% CI = 3.2–8.8 months).
Among 17 evaluable patients in group B, stable disease as best response was observed in 7 (tumor control rate = 41.2%, 95% CI = 18%–65%). The patient with T-acute lymphoblastic leukemia exhibited a > 2-log10 reduction in their white blood cell count during the first treatment cycle. Median progression-free survival was 1.7 months (95% CI = 1.3–3.7 months) and median overall survival was 5.7 months (95% CI = 3.9–8.2 months).
Overall, 8 of the 9 patients with stable disease were among the 25 patients with cyclin D–CDK4/6 or PI3K/AKT/mTOR pathway alterations.
The investigators concluded, “Ribociclib in combination with TOTEM or everolimus was well tolerated. The observed activity signals initiated a follow-up study of the ribociclib/everolimus combination in a population enriched with molecular alterations within both pathways.”
Birgit Geoerger, MD, PhD, of Gustave Roussy Cancer Campus, INSERM, Université Paris-Saclay, Villejuif, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was supported by the Institut National de Cancer, Association Imagine for Margo, Fondation ARC, and Novartis. For full disclosures of the study authors, visit ascopubs.org.
