SAR-096: Phase II clinical trial of ribociclib in combination with everolimus in advanced dedifferentiated liposarcoma (DDL) and leiomyosarcoma (LMS) Journal Article
| Authors: | Movva, S.; Matloob, S.; Handorf, E. A.; Choy, E.; Merriam, P.; Flieder, D. B.; Cai, K. Q.; Zhou, Y.; Tetzlaff, E. D.; Pagan, C.; Barker, E.; Veggeberg, R.; Zumpano, D.; Rink, L.; von Mehren, M.; George, S. |
| Article Title: | SAR-096: Phase II clinical trial of ribociclib in combination with everolimus in advanced dedifferentiated liposarcoma (DDL) and leiomyosarcoma (LMS) |
| Abstract: | Purpose: Dedifferentiated liposarcoma (DDL) and leiomyosarcoma (LMS) are two common subtypes of soft-tissue sarcoma, a rare group of diseases for which new treatments are needed. Chemotherapy remains the standard option for advanced disease. Targeting cyclin-dependent kinase 4 and 6 (CDK4/6) in DDL and mTOR in LMS is of biologic interest. When combined, the CDK4 inhibitor ribociclib and the mTOR inhibitor everolimus have shown synergistic growth inhibition in multiple tumor models, suggesting that this combination could be beneficial in patients. Patients and Methods: This was a single arm, open label, multicenter phase II study of the combination of ribociclib and everolimus. Patients were enrolled into one of two cohorts: DDL or LMS with intact Rb. The primary endpoint was progression-free rate (PFR) at 16 weeks. Secondary endpoints included progression-free survival (PFS) and overall survival, safety and biomarker analyses. Results: In the DDL cohort, 33.3% [95% confidence interval (CI), 15.6%–55.3%] of patients were progression-free at 16 weeks. Median PFS in this cohort was 15.4 weeks (95% CI, 8–36 weeks) with 2 partial responses. In the LMS cohort the PFR at 16 weeks was 29.2% (95% CI, 12.6%–51.1%). Median PFS in this cohort was 15.7 weeks (95% CI, 7.7–NA). Most common toxicities included fatigue (66.7%), anorexia (43.8%), and hyperglycemia (43.8%). Concordance between Rb testing methodologies was poor. Conclusions: The combination of ribociclib and everolimus demonstrates activity in DDL with prolonged stable disease (≥16 weeks) meeting the primary endpoint. Notably partial responses were observed. The primary endpoint was not reached in the LMS cohort. The combination was well tolerated with expected side effects. © 2023 American Association for Cancer Research. |
| Keywords: | immunohistochemistry; adult; cancer survival; clinical article; controlled study; protein expression; treatment outcome; aged; overall survival; clinical trial; fatigue; advanced cancer; dose response; drug dose reduction; drug efficacy; drug safety; antineoplastic agent; anorexia; cancer immunotherapy; progression free survival; phase 2 clinical trial; antineoplastic combined chemotherapy protocols; cohort analysis; antineoplastic activity; pathology; hyperglycemia; correlation analysis; multicenter study; mammalian target of rapamycin; phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase; therapy delay; open study; purines; purine derivative; leiomyosarcoma; retinoblastoma protein; everolimus; liposarcoma; cyclin dependent kinase 4; cyclin dependent kinase 6; molecularly targeted therapy; tor serine-threonine kinases; target of rapamycin kinase; dedifferentiated liposarcoma; combination drug therapy; humans; human; male; female; article; rna sequencing; aminopyridines; ribociclib; aminopyridine derivative |
| Journal Title: | Clinical Cancer Research |
| Volume: | 30 |
| Issue: | 2 |
| ISSN: | 1078-0432 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2024-01-15 |
| Start Page: | 315 |
| End Page: | 322 |
| Language: | English |
| DOI: | 10.1158/1078-0432.Ccr-23-2469 |
| PUBMED: | 37967116 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
