Phase II trial of the CDK4 inhibitor PD0332991 in patients with advanced CDK4-amplified well-differentiated or dedifferentiated liposarcoma

Abstract

Purpose: CDK4 is amplified in > 90% of well-differentiated (WDLS) and dedifferentiated liposarcomas (DDLS). The selective cyclin-dependent kinase 4 (CDK4)/CDK6 inhibitor PD0332991 inhibits growth and induces senescence in cell lines and xenografts. In a phase I trial of PD0332991, several patients with WDLS or DDLS experienced prolonged stable disease. We performed an open-label phase II study to determine the safety and efficacy of PD0332991 in patients with advanced WDLS/DDLS.

Patients and methods: Patients age ≥ 18 years experiencing disease progression while receiving systemic therapy before enrollment received PD0332991 200 mg orally once per day for 14 consecutive days in 21-day cycles. All were required to have CDK4 amplification by fluorescence in situ hybridization and retinoblastoma protein (RB) expression by immunohistochemistry (≥ 1+). The primary end point was progression-free survival (PFS) at 12 weeks, with 12-week PFS of ≥ 40% considered promising and ≤ 20% not promising. If ≥ nine of 28 patients were progression free at 12 weeks, PD0332991 would be considered active.

Results: We screened 48 patients (44 of 48 had CDK4 amplification; 41 of 44 were RB positive). Of those, 30 were enrolled, and 29 were evaluable for the primary end point. Grade 3 to 4 events included anemia (17%), thrombocytopenia (30%), neutropenia (50%), and febrile neutropenia (3%). At 12 weeks, PFS was 66% (90% CI, 51% to 100%), significantly exceeding the primary end point. The median PFS was 18 weeks. There was one partial response.

Conclusion: Treatment with the CDK4 inhibitor PD0332991 was associated with a favorable progression-free rate in patients with CDK4-amplified and RB-expressing WDLS/DDLS who had progressive disease despite systemic therapy.

Trial registration: ClinicalTrials.gov NCT01209598.

Conflict of interest statement

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Figures

Fig 1.

Diagram showing flow of patients and testing for CDK4 and retinoblastoma protein (RB). DD, dedifferentiated; LPS, liposarcoma; WD, well differentiated.

Fig 2.

Kaplan-Meier curve of progression-free survival. Dashed lines indicate 95% CI.

Fig 3.

Time in study for all evaluable patients. Gold bars represent patients with purely well-differentiated liposarcoma; blue bars represent dedifferentiated tumors. Arrows indicate patients who remained in study at the data cutoff. Star indicates patient with partial response.

Fig 4.

Computed tomography scans at (A) baseline and (B) after 13 months of treatment with PD0332991, demonstrating favorable tumor response (arrows) in dedifferentiated liposarcoma surrounded by well-differentiated liposarcoma.