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Tissue/Site-Agnostic Study of Ribociclib for Tumors With Cyclin D-CDK4/6 Pathway Genomic Alterations: A Phase II,
Julio Peguero1, Davendra P S Sohal2, Bert H O'Neil3
1Oncology Consultants PA, Houston, TX.
Purpose:
As part of the Novartis Signature Program, this study evaluated the efficacy of ribociclib (selective cyclin-dependent kinase 4/6 [CDK4/6] inhibitor) in patients with cyclin D-CDK4/6 pathway-aberrant tumors.
Methods:
This was a phase II, single-arm, signal-seeking study in patients with advanced malignancies that had progressed on or after standard treatment. Prior identification of tumor CDK4/6 mutation or amplification, CCND1/3 amplification, or CDKN2A mutation or loss was required. Clinical benefit (defined as the proportion of patients with response or stable disease at ≥ 16 weeks) was the primary end point.
Results:
From 61 centers in the United States, 106 patients (median age, 62.5 years) were enrolled across multiple malignancies. The patient population was heavily pretreated (median number of prior therapies, three; range, 0 to 19). Median progression-free survival was 1.8 months (95% CI, 1.8 to 1.9). In patients with solid tumors, the clinical benefit rate was 18.1% (n = 19 of 105) and the overall response rate was 2.9% (n = 3 of 105); three partial responses occurred in patients with adenocarcinoma (unknown primary), soft tissue sarcoma, and urothelial carcinoma. No tumor cohort met the prespecified criteria for success. The most common adverse events suspected to be related to treatment were neutropenia (30.2%; decreased neutrophils, 15.1%), fatigue (31.1%), and nausea (29.2%). Fatigue and nausea were typically mild. Only one incident of febrile neutropenia was experienced (grade 3).
Conclusion:
No new or unexpected safety signals were observed in this heavily pretreated patient population. Although responses were seen in tumors with CCND1-CDK4/6 amplifications, the primary end point was not met, suggesting additional evaluation of ribociclib, possibly as combination therapy, is needed.
Insights
Ribociclib, a CDK4/6 inhibitor, showed limited clinical benefit in heavily pretreated advanced cancer patients with cyclin D-CDK4/6 pathway aberrations. Further studies, potentially combining ribociclib, are needed.
Area of Science:
- Oncology
- Molecular Biology
- Clinical Pharmacology
Background:
- The cyclin D-CDK4/6 pathway is frequently dysregulated in various cancers.
- Targeting this pathway with inhibitors like ribociclib offers a therapeutic strategy.
- Patient selection based on specific genetic alterations is crucial for targeted therapies.
Purpose of the Study:
- To evaluate the efficacy of ribociclib in patients with advanced malignancies harboring cyclin D-CDK4/6 pathway-aberrant tumors.
- To assess clinical benefit rate and overall response rate as primary endpoints.
- To identify safety signals associated with ribociclib treatment in this population.
Main Methods:
- A phase II, single-arm, signal-seeking study design.
- Enrollment of 106 patients with advanced malignancies progressing on standard treatments.
- Requirement for prior identification of tumor CDK4/6, CCND1/3, or CDKN2A alterations.
Main Results:
- Median progression-free survival was 1.8 months.
- Clinical benefit rate was 18.1% in patients with solid tumors (19/105).
- Common adverse events included neutropenia, fatigue, and nausea; no unexpected safety signals were observed.
Conclusions:
- Ribociclib did not meet the primary endpoint in this heavily pretreated population.
- Responses were observed in tumors with CCND1-CDK4/6 amplifications, warranting further investigation.
- Combination therapy approaches with ribociclib may be necessary for improved efficacy.
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