Mehdi Brahmi, MD
The p53-MDM2 inhibitor siremadlin given with the CDK4/6 inhibitor ribociclib showed activity in a subset of patients with well-differentiated/dedifferentiated liposarcomas enrolled in the biology-driven adaptive phase II MEGAMOST Ribociclib/HDM201 basket trial.1 MEGAMOST was 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 and Cancer Research Center of Lyon in France, presented the results of the cohort who received siremadlin and ribociclib.
“Siremadlin plus ribociclib demonstrated a manageable safety profile with encouraging efficacy in patients with advanced MDM2/CDK4-amplified liposarcoma,” Dr. Brahmi said, reporting a median overall survival for this cohort of 23 months. The results in other cancers characterized by different molecular alterations were “modest,” he said.
MDM2 has long been considered an attractive anticancer target. Siremadlin (NVP-HDM201) is an orally bioavailable and highly specific p53-MDM2 interaction inhibitor. In vitro, it has been shown to disrupt both human and murine TP53-MDM2 interactions, blocking TP53 degradation.
“It is not uncommon in cancers to detect genetic abnormalities of the cell cycle. We now have several drugs that can target the cell cycle. This double inhibition seems to be a relevant therapeutic approach, especially in MDM2/CDK4-amplified liposarcoma and in other cancers that share the same genetic abnormalities,” Dr. Brahmi explained.
Study Details
Patients had advanced solid tumors of any histologic type harboring amplification of CDK6 and/or CDK4, and/or CDKN2A homozygous deletion, and/or amplification of CCND1 and/or CCND3; no deletions or losses beyond a single copy of RB1 by copy number; and P53 wild-type. They were treated with 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. For the whole population of 49 patients, 20 (41.2%) remained progression-free at 3 months. The median progression-free survival was 2.8 months, and median overall survival was 10.7 months.
“We found this combination is feasible in terms of toxicity, with not much more toxicity than with an MDM2 inhibitor alone,” Dr. Brahmi said. The incidence of grade ≥ 3 adverse events was 42%, mostly thrombopenia (12%), anemia (8%), and nausea (6%).
Outcomes among the 17 patients with liposarcoma, however, were “quite impressive,” he reported, 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, and median overall survival was 23.0 months. Although objective responses were uncommon, two patients responded late in treatment and remain in response 2 years later.
EXPERT POINT OF VIEW
Joanna Szkandera, MD
The invited discussant of the MEGAMOST trial, Joanna Szkandera, MD, of the Medical University of Graz in Austria, shared these comments: “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.”
With current first-line treatments of this cancer, response rates have ranged from 9% to 12%, median progression-free survival has been about 4 months and median overall survival has ranged from 15 and 19 months. In the second-line setting, with either trabectedin or eribulin, median progression-free survival was about 2 months and median overall survival 18 months. It now seems that with attention paid to molecular targets, these outcomes can be improved upon, she said.
In well-differentiated and dedifferentiated liposarcomas, 97% of patients have amplification of MDM2, which acts as a negative regulator of p53, potentially promoting the oncogenesis of the tumor. Encouraging results for the phase I trial of the MDM2-p53 antagonist brigamadlin (BI 907828) were reported in 2023, with a response rate of 19% and a median progression-free survival of 7.2 months.2 However, results for another single MDM2 inhibitor, milademetan, were not replicated in the phase III MANTRA trial comparing milademetan and trabectedin; the response rate was less than 5%, median progression-free survival was 3.6 months, and median overall survival was less than 10 months.3
Closer Look at MEGAMOST Findings
“Targeting the MDM2-p53 axis alone does not seem sufficient” in this tumor type, suggested Dr. Szkandera; 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.
In the phase II MEGAMOST trial, patients with at least one prior treatment were selected based on molecular alterations involved in CDK4/6 and MDM2. The 3-month progression-free survival rate was 41.2%, which was almost doubled—nearly 80%—in the cohort with well-differentiated or dedifferentiated liposarcomas. The median progression-free survival was also significantly higher—8.3 months, with a median overall survival more than doubled—23.0 months, vs 10.7 months for the whole cohort, Dr/ Szkandera noted.
These results were clearly “more advantageous” than those reported for milademetan and for the currently approved options trabectedin and eribulin, in terms of overall response rate, median progression-free survival, and median overall survival, she said. Siremadlin plus ribociclib also proved to be tolerable, with “uncomplicated toxicity management,” underlining the fact that “selecting the right combination of targeted therapies involves a careful choice of agents, dosage, and schedule to prevent overlapping toxicity.”
DISCLOSURE: Dr. Brahmi reported personal financial relationships with Bayer, Boehringer Ingelheim, Mundipharma, and Deciphera. Dr. Szkandera reported personal financial relationships with PharmaMar, Bayer, Roche, Lilly, Amgen, Merck, and Bristol Myers Squibb.
REFERENCES
1. Brahmi M, Tredan O, Gomez-Roca CA, et al: Siremadlin and ribociclib in patients with advanced well-differentiated/dedifferentiated liposarcomas and other molecularly selected cancers: Final analysis of MEGAMOST ‘Ribociclib/HDM201’ basket study. ESMO Congress 2024. Abstract LBA80. Presented September 13, 2024.
2. Yamamoto N, Tolcher A, Hafez N, et al: Efficacy and safety of the MDM2–p53 antagonist BI 907828 in patients with advanced biliary tract cancer: Data from two phase Ia/Ib dose-escalation/expansion trials. 2023 ASCO Gastrointestinal Cancers Symposium. Abstract 543. Presented January 19, 2023.
3. Chen TW, Sanfilippo R, Jones RL, et al: Efficacy and safety findings from MANTRA: A global, randomized, multicenter, phase III study of the MDM2 inhibitor milademetan vs trabectedin in patients with dedifferentiated liposarcomas. et al: ESMO Asia Congress 2023. Abstract 76MO. Presented December 1, 2023.
