Abemaciclib Poised to Be New Standard of Care in Aggressive Liposarcoma

CHICAGO — Treatment with the CDK4/6 inhibitor abemaciclib (Verzenio) offered a dramatic survival uptick in a highly aggressive soft-tissue cancer that rarely responds to chemotherapy, according to the SARC041 trial.

Patients (n=108) in the phase IIII study had recurrent or metastatic dedifferentiated liposarcoma (DDLS) that had been treated with any number of prior lines of therapy. Those who received abemaciclib demonstrated a median progression-free survival (PFS) of 9.7 months versus 1.5 months with placebo (HR 0.38, 90% CI 0.25-0.59, P<0.001), reported Mark A. Dickson, MD, of Memorial Sloan Kettering Cancer Center in New York City, at a press briefing at the American Society of Clinical Oncology (ASCO) annual meeting.

The 6-month PFS rates were 60% in the abemaciclib arm versus 22% in the placebo arm, while the 12-month PFS rates were 39% versus 13%, respectively. Median PFS after crossover from placebo to abemaciclib was 3.44 months (95% CI 2.66-6.84).

Dickson said that median overall survival (OS) was not reached in the abemaciclib arm versus 25.5 months with placebo (HR 0.55, 95% CI 0.28-1.07). At 12 months, 85% of patients in the abemaciclib arm were alive versus 71% in the placebo arm, and the corresponding OS rates at 24 months were 72% and 51%, respectively. The difference in OS emerged despite the allowance for crossover. The median OS after crossover was 24.0 months.

SARC041 represents “the first positive phase III clinical trial ever in DDLS,” Dickson stated.

Rodrigo Munhoz, MD, of the Oncology Center-Hospital Sírio-Libanês of São Paulo, Brazil, commented that by “meeting its primary endpoint and demonstrating an improvement in PFS, abemaciclib may become a new standard of care for patients with recurrent events.” Munhoz was not involved in the study.

DDLS accounts for roughly 15-20% of all liposarcomas diagnosed nationwide. Standard of care is surgery followed by surveillance. Trabectedin (Yondelis) and eribulin mesylate (Halaven) are FDA approved as second-line treatment of advanced DDLS. But the response rate is modest and this combination adds only about 2 months to median PFS, Dickson said.

CDK4 is amplified in almost all cases of DDLS, driving progression through the cell cycle and tumor growth, so testing CDK4 inhibitors in this setting was therefore a rational strategy, he noted.

In a phase II study by Dickson and colleagues, patients with DDLS saw a median PFS of 7.7 months with abemaciclib treatment, “which seemed encouraging,” he said, noting that abemaciclib’s selectivity for CDK4 allows for daily dosing, with little need for treatment interruption caused by hematologic toxicity, which is observed more commonly with less selective CDK4/6 inhibitors.

Patients in the current nine-center trial were randomized to abemaciclib, 200 mg orally twice daily, or matching placebo. Crossover to abemaciclib was permitted in the placebo arm at disease progression; 85% of patients randomized to placebo crossed over to abemaciclib.

“About half the patients had no prior therapy and about half the patients had one or more prior therapies. We did an exploratory analysis looking at PFS in those two different groups,” said Dickson. “Median PFS in patients who received abemaciclib as a first-line therapy was over 16 months, and the median PFS for patients who received it as a later line therapy, was 5.4 months.”

The objective response rate (ORR) was 9.3% for abemaciclib versus 0% for placebo (P=0.057). The ORR after crossover was 4.3% (95% CI 0.53%-15%).

The authors reported that grade 3/4 adverse events (AEs), mostly hematologic, were recorded in 30%; 7% experienced grade 3 diarrhea. Grade 3/4 AES were managed successfully with dose reduction and supportive care, they stated, and some 39% on abemaciclib required dose reduction.

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