Abemaciclib markedly improved PFS vs placebo in patients with advanced dedifferentiated liposarcoma.
Abemaciclib (Verzenio) significantly improved progression-free survival (PFS) compared with placebo in patients with advanced or metastatic dedifferentiated liposarcoma (DDLS), delivering the first positive phase 3 trial results ever reported in this disease setting, according to data from the phase 3 SARC041 study (NCT04967521) presented at the
Patients who received abemaciclib (n = 54) achieved a median PFS of 9.7 months compared with 1.5 months with placebo (n = 54; HR, 0.38; 90% CI, 0.25-0.59; P < .001), representing a 62% reduction in the risk of progression or death. The median overall survival (OS) was not reached in the abemaciclib arm vs 25.5 months with placebo (HR, 0.55; 95% CI, 0.28-1.07; P = .07), despite 85% of patients in the placebo arm crossing over to receive abemaciclib after disease progression. The median PFS after crossover to abemaciclib was 3.4 months.
“PFS was significantly improved with abemaciclib compared with placebo, even though most patients in the placebo group crossed over to receive abemaciclib; OS was better with abemaciclib,” Mark A. Dickson, MD, a sarcoma medical oncologist and associate attending physician at Memorial Sloan Kettering Cancer Center in New York, New York, said during the presentation. “This result, together with the fact that PFS and response rate after crossover were lower than for those who received abemaciclib first, suggests that early treatment with abemaciclib improves patient outcomes.”
SARC041 was a randomized, double-blind study that enrolled adult patients with recurrent or metastatic DDLS.1,2 Patients were required to have an ECOG performance status 0 or 1 and documented disease progression per RECIST 1.1 criteria within 6 months prior to study entry and were eligible regardless of number of prior systemic therapies, including treatment-naive patients. Those with extensive disease that required immediate treatment were excluded.
Patients were randomly assigned 1:1 to abemaciclib at 200 mg orally twice daily or matching placebo. Stratification was performed according to number of prior systemic treatments (0 vs ≥ 1 prior lines).1 CT imaging was performed every 6 weeks for 36 weeks, then every 12 weeks. Crossover from placebo to abemaciclib was permitted at disease progression.
The primary end point was PFS. Secondary end points included overall response rate (ORR), PFS after crossover, OS, and safety.
At baseline, most patients in both the investigational and control arms were male (54% vs 69%) and had tumors located in the abdomen/retroperitoneum (80% vs 92%). The median age was 67 years in both the investigational (range, 41-84) and control (range, 19-84) arms. Patients received 0 (52% vs 50%) or 1 or more prior lines of therapy (48% vs 50%).
The 6-month PFS rate was 60% with abemaciclib vs 22% with placebo, and the 12-month PFS rates were 39% vs 13%, respectively. The 12-month OS rates were 85% and 71%, respectively; the respective 24-month OS rates were 72% and 51%.
Overall, the ORR was 9% with abemaciclib vs 0% with placebo. The ORR after crossover to the investigational arm was 4%. Despite the modest ORR, tumor control was broadly observed, consistent with CDK4/6 inhibition producing predominantly disease stabilization rather than shrinkage, Dickson noted. “Although responses were relatively rare, they were profound and durable,” he said.
Dickson added that treating patients with abemaciclib earlier in their disease course may be more beneficial. This is supported by a pre-planned exploratory analysis within the abemaciclib arm, which demonstrated a median PFS of 16.4 months in patients with no prior systemic therapy exposure (n = 27) vs 5.3 months in those who had received 1 or more prior lines (n = 27; log-rank P = .029).
In terms of safety, dose reductions were required in 39% of patients in the abemaciclib arm vs 2% in the placebo arm. The most common adverse effects (AEs) in the abemaciclib arm included diarrhea (grade 2, 28%; grade 3, 7%), anemia (22%; 4%, respectively), decreased neutrophil count (9%; 11%; grade 4, 2%), white blood cell count decreased (13%; 7%), and increased creatinine levels (20%; 6%). Grade 4 decreased lymphocyte count was observed at a rate of 2% in the abemaciclib arm. No comparable grade 3 or 4 AEs were observed in the placebo arm for most hematologic and gastrointestinal parameters.
“Ongoing correlative work includes analysis of archival tumor tissue to evaluate potential predictive biomarkers and mechanisms of resistance,” Dickson said. “We should advocate for inclusion of abemaciclib in treatment guidelines for liposarcoma worldwide. Given the benefit of early treatment with abemaciclib, it makes sense to evaluate abemaciclib in the neoadjuvant or adjuvant setting next.”
Disclosures: Dickson received research funding from AADi (Inst), Lilly (Inst), and Sumitomo Dainippon Pharma Oncology (Inst).
