Carlos López-Jiménez, Medical Oncologist at the Sarcoma Unit of Fundación Jiménez Díaz University Hospital (Madrid) and a PhD candidate in Molecular Biosciences at Universidad Autónoma de Madrid (UAM), shared a post on LinkedIn:
“About liposarcoma, abemaciclib and placebo: SARC041 in context (Part II)
MDM2 inhibitors have been explored more than once in advanced liposarcoma (LPS). The most recent agent was brigimadlin, which, in a bold move, was compared with standard first-line doxorubicin in the ambitious phase III BRIGHTLINE-1 trial. Expectations were high. Both physicians and patients noted that the drug was active. For the first time in years, a treatment was able to challenge anthracyclines.
There is no doubt that brigimadlin is an active drug. It addressed an important unmet need in patients with a rare disease. Some patients still remain on treatment today. However, the results reported in 2024 did not fully match expectations. Although ORR clearly favored brigimadlin (22% vs 8.6%), mPFS did not (8.4 months with brigimadlin vs 7.2 months with doxorubicin). The difference was not statistically significant. Yet brigimadlin demonstrated clinically meaningful benefit for many patients.
Brigimadlin failed to demonstrate superiority over doxorubicin. The primary endpoint was not met. Development of the drug was discontinued. A biologically active therapy for a rare and aggressive disease—one that genuinely changed patients’ lives—was never approved and access is no longer available to new patients with LPS.
Why did brigimadlin fail? There is more than one possible explanation. Such a prolonged PFS had never been reported for doxorubicin in this setting. Doxorubicin performed far better than anticipated. In addition, response assessment using RECIST criteria may not have been the optimal way to capture biological response in LPS.
What would have been the best approach to ensure that brigimadlin reached patients? Would the outcome have been different using Choi criteria for response assessment? A non-inferiority design, perhaps? Testing the drug in a different setting rather than first line? Or even against placebo?
SARC041 took a more pragmatic approach.
In rare diseases, our goal should be to make effective drugs available to patients. Opportunities to conduct clinical trials are scarce, and sometimes you only get one shot. A single misstep can be unforgiving.
SARC041 represents an opportunity to add a new treatment – abemaciclib – to a field where therapeutic options remain limited and their efficacy modest. I am not a fan of placebo-controlled studies—even with crossover allowed. However, from a pragmatic perspective, I understand that placebo may sometimes be the safest way to ensure that an effective drug demonstrates its activity and ultimately reaches patients.
And this time, it did.”
Other articles about Liposarcoma on OncoDaily.