Cabazitaxel Impresses in Locally Advanced De-Differentiated Liposarcoma

Progression-free survival (PFS) results with cabazitaxel (Jevtana) in metastatic or inoperable locally advanced de-differentiated liposarcoma (DDLPS) suggest the drug should be studied further in this setting, according to investigators of an international phase II study.

Among 37 patients in the single-arm trial, the PFS rate at 12 weeks was 55%, meeting the study’s primary endpoint, reported Roberta Sanfilippo, MD, of Fondazione IRCCS Istituto Nazionale Tumori in Milan, and colleagues.

“Overall, treatment options for patients with advanced DDLPS remain limited, with a strong need for more effective and tolerable treatment options,” Sanfilippo and colleagues wrote in JAMA Oncology. “Of note, none of the target agents tested in patients with DDLPS in clinical studies reported, until now, a better outcome than cabazitaxel.”

At 21.6 months of follow-up, the median PFS was 6.5 months, median time to progression was 7.4 months, and median overall survival was 21.1 months. The rate of objective tumor response was 8%, with one complete response and two partial responses. Median time to onset of response was 8 months, and 60.5% of patients had stable disease as best response.

“A further phase III study of cabazitaxel is strongly recommended to assess the efficacy of this drug in patients with DDLPS, hopefully improving the armamentarium of the medical oncologist and outcomes for these patients,” the authors concluded.

In a commentary accompanying the study, Christina Roland, MD, MS, of the University of Texas MD Anderson Cancer Center in Houston, noted that the rare nature of soft-tissue sarcoma (an overall incidence of just 7 cases per 100,000, and more than 70 histologic types) “has led to historic challenges in understanding of disease biology and clinical trial conduct.”

Smaller, histology-specific phase II trials provide “strong background data for future phase III trials, [and have] led to numerous histology-specific FDA approvals over the last 10 years, a stark contrast to the preceding decades,” Roland noted. “The early data from the current study demonstrate comparable (if not slightly better) PFS compared with recent, liposarcoma-specific trials that led to FDA approvals.”

For this study, Sanfilippo and team recruited 40 patients at 10 institutions in four European countries from March 2015 to March 2019. Two patients were deemed ineligible after medical review, while a third was still receiving treatment at the clinical cutoff date.

Eligible patients had to have metastatic or locally advanced histologically proven DDLPS with evidence of disease progression within the past 6 months, and had to have received no more than one previous line of chemotherapy.

Median age of study participants was 65 years, 53% were men, and 55% had a performance status of 0. Thirty-six patients had poorly or undifferentiated tumors, 32 had grade 2 disease, and 29 had comorbid conditions at trial entry.

Cabazitaxel was administered at a dose of 25 mg/m² IV infusion over 1 hour every 21 days until intolerance, progression, or withdrawal of consent. Twenty-six of the 40 patients received at least 4 cycles of cabazitaxel, with a median of 5 cycles for all patients.

“Notably, a subgroup of patients, 11 of 38 (30%), received more than 10 cycles of cabazitaxel, with one patient receiving 30 cycles,” Sanfilippo and team noted. “This suggests not only a prolonged benefit of the drug in a subgroup of patients, but even a good tolerability of the treatment.”

Twenty-three patients had a schedule modification, while 13 had a dose modification (four due to hematologic adverse events and nine due to nonhematologic adverse events). Twenty-two patients stopped treatment due to disease progression, while nine stopped due to toxic effects.

The most common cabazitaxel-related adverse events were decreased neutrophil count (52.5%), diarrhea (42.5%), fatigue (40%), anorexia (32.5%), and anemia (30%).

The most frequent grade 3-4 adverse events, regardless of their relationship to cabazitaxel, included decreased neutrophil count (50%) and white blood cell count (42.5%), febrile neutropenia (25%), fatigue (12.5%), and anemia (10%). There were 27 serious adverse events and 20 serious adverse reactions, with no deaths associated with toxic effects.