Outcomes in the dedifferentiated liposarcoma cohort of SAR-096, a phase II trial of ribociclib in combination with everolimus in advanced dedifferentiated liposarcoma (DDL), and leiomyosarcoma (LMS).

Abstract

11515 Background: Dedifferentiated liposarcoma (DDL) is characterized by ring chromosomes of chromosone12, which includes amplification of MDM2 and CDK4. Exposure to CDK4 inhibitors in Rb+ leiomyosarcoma (LMS) cell lines leads to decreased cell proliferation, and increased senescence, and G0/G1-phase arrest. When combined, ribociclib a CDK4 inhibitor and everolimus, an mTOR inhibitor show synergistic growth inhibition in multiple tumor models. We hypothesized that this combination could lead to increased disease control in patients with DDL. Methods: This study enrolled patients (pts) into one of two cohorts: DDL or Rb+ LMS. LMS pts were required to have 1 prior line of therapy; DDL pts required no prior therapy. There were no limits to prior therapies in either group. Measurable disease by RECIST 1.1 was also required. Ribociclib was given at 300 mg daily for 21/28 days and everolimus was given continuously at 2.5 mg daily in 28 day cycles. The primary endpoint was progression free rate at 16 weeks. A Simon two-stage design was utilized and if at least 8 out of 24 pts were progression free at 16 weeks, the treatment was declared promising for the cohort. Here in we present data on the DDL cohort. Results: To date, 21 DDS pts, median age of 63 (range 40-79), of which 43% (n = 9) female were treated. Median prior lines of therapy was 1 (range 0-6). Of 19 pts with complete data, 8 (42%) met the primary endpoint of non-progression at 16 weeks. Confirmed partial response was seen in 2 pts (10%). Median PFS was 16 weeks, and stable disease occurring as best response in 11 (55%) pts. Grade 3-4 toxicities were uncommon except for lymphopenia (24%) and neutropenia (33%); no episode of neutropenic fever were observed. There was one death on study secondary to myocardial infarction, considered possibly related to therapy. Results of optional tissue biopsies pre and on therapy obtained to assess pharmacodynamic changes in PTEN, pAKT, CDK4, Rb and pS6 will be presented. Conclusions: The combination of ribociclib and everolimus demonstrates activity in DDL with prolonged stable disease (>16 weeks) meeting the primary protocol endpoint. Notably partial responses were also observed. The combination was well tolerated with acceptable side effects. Updated outcomes will be presented. Clinical trial information: NCT03114527.