Genome-Driven Therapy for Chemotherapy-Resistant Metastatic<i>CDK6</i>-Amplified Osteosarcoma

Lazow, Margot A.; Johnson, Sheryl; Johnson, Neil; Breneman, John C.; Dexheimer, Phillip; Szabo, Sara; Pressey, Joseph G.

doi:10.1200/po.20.00032

Cited by 3 publications

(2 citation statements)

References 39 publications

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“…Rb status and CDK4/6 expression of tumors should be evaluated in future trials to correlate with treatment response. For example, in a case study published in JCO Precision Oncology, a patient with refractory osteosarcoma had genomic testing showing CDK6 amplification with no inactivating alterations or loss of RB1, leading the oncology team to choose combination ribociclib and gemcitabine treatment based on our phase I clinical trial( 22 ). The time to progression in this patient was 9 months, which was considerably longer than that of most patients treated with gemcitabine (with or without docetaxel) for relapsed/refractory osteosarcoma (median 2–4 months).…”

Section: Discussionmentioning

confidence: 99%

A Phase I Study of sequences of the CDK4/6 Inhibitor, Ribociclib Combined with Gemcitabine in Patients with Advanced Solid Tumors

Seetharam,

Norman,

Allred

et al. 2024

Preprint

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Background: Based on preclinical data showing addition of CDK4/6 inhibitors to gemcitabine is synergistic, ribociclib was evaluated in combination with gemcitabine to determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLT). Methods: In this single arm multicohort phase I trial, we evaluated the safety and efficacy of Ribociclib plus Gemcitabine in patients with advanced solid tumors. Patients received Gemcitabine intravenously on days 1 and 8 followed by Ribociclib days 8–14, with treatment repeated every 3 weeks. Results: The study enrolled 43 patients between October 2017 and September 2019. The escalation phase (19 patients) determined the MTD and recommended phase II dose (RP2D) to be ribociclib 800mg daily and gemcitabine 1000mg/m2 for the expansion phase (24 patients). One patient experienced Grade 4 thrombocytopenia. Eleven patients experienced Grade 3 adverse events (AE), the most common being neutropenia, thrombocytopenia, and anemia. No partial or complete responses were observed. 15/22 (68%) of efficacy evaluable patients who received the MTD achieved best response of stable disease. Conclusions: The addition of Ribociclib to Gemcitabine was tolerated well and yielded stability of tumors in both cohorts. Ribociclib and gemcitabine could have synergistic activity in certain tumor types, and our data provides support for the combination. Clinical Trial Registration: NCT03237390

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Section: Discussionmentioning

confidence: 99%

A Phase I Study of sequences of the CDK4/6 Inhibitor, Ribociclib Combined with Gemcitabine in Patients with Advanced Solid Tumors

Seetharam,

Norman,

Allred

et al. 2024

Preprint

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“…Similar to CDK4, CDK6 may serve as a biomarker for CDK4/6 inhibitor success and these findings set the foundation for further testing. 20 …”

Section: Clinical Use Of Cdk4/6 Inhibitors In Sarcomamentioning

confidence: 99%

Clinical Utility of CDK4/6 Inhibitors in Sarcoma: Successes and Future Challenges

Hsu

Seligson

Hays

et al. 2022

JCO Precision Oncology

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PURPOSE Soft tissue and bone sarcomas are rare malignancies that exhibit significant pathologic and molecular heterogeneity. Deregulation of the CDKN2A-CCND-CDK4/6-retinoblastoma 1 (Rb) pathway is frequently observed in about 25% of unselected sarcomas and is pathognomonic for specific sarcoma subtypes. This genomic specificity has fueled the clinical evaluation of selective CDK4/6 inhibitors in sarcomas. Here, we highlight successes, opportunities, and future challenges for using CDK4/6 inhibitors to treat sarcoma. MATERIALS AND METHODS This review summarizes the current evidence for the use of CDK4/6 inhibitors in sarcoma while identifying molecular rationale and predictive biomarkers that provide the foundation for targeting the CDK4/6 pathway in sarcoma. A systematic review was performed of articles indexed in the PubMed database and the National Institutes of Health Clinical Trials Registry (ClinicalTrials.gov). For each sarcoma subtype, we discuss the preclinical rationale, case reports, and available clinical trials data. RESULTS Despite promising clinical outcomes in a subset of sarcomas, resistance to CDK4/6 inhibitors results in highly heterogeneous clinical outcomes. Current clinical data support the use of CDK4/6 inhibitors in subsets of sarcoma primarily driven by CDK4/6 deregulation. When dysregulation of the Rb pathway is a secondary driver of sarcoma, combination therapy with CDK4/6 inhibition may be an option. Developing strategies to identify responders and the mechanisms that drive resistance is important to maximize the clinical utility of these drugs in patients with sarcoma. Potential biomarkers that indicate CDK4/6 inhibitor sensitivity in sarcoma include CDK4, CCND, CCNE, RB1, E2F1, and CDKN2A. CONCLUSION CDK4/6 inhibitors represent a major breakthrough for targeted cancer treatment. CDK4/6 inhibitor use in sarcoma has led to limited, but significant, early clinical success. Targeted future clinical research will be key to unlocking the potential of CDK4/6 inhibition in sarcoma.

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Genome-Driven Therapy for Chemotherapy-Resistant MetastaticCDK6-Amplified Osteosarcoma

Cited by 3 publications

References 39 publications

A Phase I Study of sequences of the CDK4/6 Inhibitor, Ribociclib Combined with Gemcitabine in Patients with Advanced Solid Tumors

A Phase I Study of sequences of the CDK4/6 Inhibitor, Ribociclib Combined with Gemcitabine in Patients with Advanced Solid Tumors

Clinical Utility of CDK4/6 Inhibitors in Sarcoma: Successes and Future Challenges

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