A novel combination of the p53-MDM2 inhibitor siremadlin and the CDK4/6 inhibitor ribociclib has demonstrated promising anticancer activity in a subset of patients with well-differentiated/dedifferentiated liposarcomas. These findings come from the biology-driven adaptive phase II MEGAMOST Ribociclib/HDM201 basket trial, designed to evaluate the clinical benefit of molecularly driven treatment matched to molecular alterations in advanced solid tumors.
Mehdi Brahmi, MD, of the Centre Leon Berard, presented the results of the cohort who received siremadlin and ribociclib. The study focused on patients with advanced solid tumors harboring amplification of CDK6 and/or CDK4, and/or CDKN2A homozygous deletion, and/or amplification of CCND1 and/or CCND3, with wild-type P53.
Efficacy and Safety
"Siremadlin plus ribociclib demonstrated a manageable safety profile with encouraging efficacy in patients with advanced MDM2/CDK4-amplified liposarcoma," Dr. Brahmi reported. The median overall survival for this cohort was 23 months. In the overall population of 49 patients, 41.2% remained progression-free at 3 months, with a median progression-free survival of 2.8 months and a median overall survival of 10.7 months. The incidence of grade ≥ 3 adverse events was 42%, mostly thrombopenia (12%), anemia (8%), and nausea (6%).
Outcomes among the 17 patients with liposarcoma were particularly notable, with 14 patients responding at 3 months, yielding a 3-month progression-free survival rate of 78.9% and a median progression-free survival of 8.3 months. At 6 months, 52.9% of patients remained progression-free. Two patients responded late in treatment and remain in response 2 years later.
Expert Commentary
Joanna Szkandera, MD, of the Medical University of Graz, commented on the MEGAMOST trial, stating, "Siremadlin and ribociclib showed promising activity in the treatment of well-differentiated and dedifferentiated liposarcomas and was well tolerated… These results underline the fact that selecting patients with specific genetic profiles based on the combination of different molecular alterations—like the CDK4/6 and MDM2 pathways—appears to be a pioneering approach for future studies on patients with these tumors."
Comparison to Existing Treatments
Dr. Szkandera noted that current first-line treatments for liposarcoma yield response rates ranging from 9% to 12%, with median progression-free survival of about 4 months and median overall survival ranging from 15 to 19 months. Second-line treatments with trabectedin or eribulin show a median progression-free survival of about 2 months and median overall survival of 18 months. The MEGAMOST findings suggest that outcomes can be improved with attention paid to molecular targets.
Rationale for Combination Therapy
In well-differentiated and dedifferentiated liposarcomas, 97% of patients have amplification of MDM2, which acts as a negative regulator of p53. Co-targeting of CDK4/6, which is amplified in more than 90% of these tumors and promotes cell-cycle progression, may be a better approach than targeting the MDM2-p53 axis alone.
In the MEGAMOST trial, the 3-month progression-free survival rate was nearly 80% in the liposarcoma cohort, with a median progression-free survival of 8.3 months and a median overall survival of 23.0 months, compared to 10.7 months for the whole cohort. These results are more advantageous than those reported for milademetan and for trabectedin and eribulin.
Study Details
Patients received oral siremadlin at 120 mg every 3 weeks plus ribociclib at 200 mg for 2 weeks on, 1 week off. Researchers evaluated 49 patients, including 15 with well-differentiated liposarcomas, 2 with de-differentiated liposarcomas, and 32 with other histotypes.
