Phase II trial of CDK4/6 inhibitor palbociclib in advanced sarcoma based on mRNA expression of CDK4/ CDKN2A.

Cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors demonstrated activity in terms of progression-free survival (PFS) in advanced dedifferentiated liposarcoma (DD-LPS), a sarcoma with CDK4 amplification. CDK4 overexpression is by far more common than amplification in sarcomas and it might be a rational target for CDK inhibitors. Preclinical investigators of this study found that CDK4 overexpression, while not of CDKN2A, was the most consistent predictive factor for palbociclib efficacy in sarcomas. Advanced adult-type soft-tissue sarcoma, excluding DD-LPS, or bone sarcoma patients, progressing after at least one systemic line, whose tumors overexpressed CDK4, but not CDKN2A at baseline biopsy, were accrued in this single-arm phase II trial (EudraCT number: 2016-004039-19). With the main endpoint of a 6-month PFS rate, 40% was considered promising in this population. Palbociclib was administered orally at 125 mg/day for 21 days in 28-day cycles. A total of 214 patients with 236 CDK4/CDKN2A determinations were assessed for prescreening, archival material (141), and screening, baseline biopsy (95). There were 28 (29%) with favorable mRNA profiles from 95 screened patients at baseline. From 23 enrolled patients, 21 evaluable, the 6-month PFS rate was 29% (95% CI 9-48), and there were 6 patients out of 21 with a PFS longer than 6 months. The median PFS and overall survival were 4.2 (95% CI 3.6-4.8) and 12 (95% CI 8.7-15.4) months, respectively. Translational research showed a significant correlation between CDK4 mRNA and protein expression. Palbociclib was active in a variety of sarcoma subtypes, selected by CDK4/CDKN2A, and deserves further investigation in the sarcoma context.

A phase II trial of weekly nab-paclitaxel for progressive and symptomatic desmoid tumors.

Desmoid fibromatosis (DF) are mesenchymal neoplasms, with potential aggressive course and relevant clinical impact. New systemic therapy modalities are needed in this symptomatic/progressive population. In this multicenter, phase II trial (NCT03275818), patients with symptomatic/progressing DF received three cycles of weekly nab-paclitaxel. Brief pain inventory short form (BPI-SF) was collected at baseline and in every visit. MRI was performed every 3 months. Primary composite endpoint was RECIST 1.1 overall response rate (ORR) and/or clinical response (improvement ≥ 2 points in BPI-SF). If 40% of patients achieved clinical/radiological response, further investigation would be warranted. Toxicity, progression-free survival (PFS), pattern of response and its correlation with clinical best response and BPI, variation of physical function, and analgesic consumption were secondary endpoints. The translational research reported was not a pre-specified secondary outcome. Forty eligible patients started therapy, being 35 radiologically and clinically evaluable. The study achieved its primary endpoint, as 7(20%) patients obtained RECIST partial response, whereas 31(89%) experienced pain reduction of ≥2 points in BPI-SF worst pain. Therapy was well tolerated. With a median follow-up of 30(14-44) months, median 12 and 24-months PFS rates were 91%(CI 95%, 82-100) and 84%(CI 95%, 71-97). For clinical progression, 12 and 24-months PFS rates were 85% (CI 95%, 73-97) and 74% (CI 95%, 58-90) respectively. Short course of nab-paclitaxel is active, safe and achieves quick and durable responses in progressing/symptomatic DF patients.