Trabectedin/Radiation Fails to Yield Robust Responses in Myxoid Liposarcoma

Although trabectedin (Yondelis) plus radiotherapy demonstrated tolerability and was effective in terms of pathologic response in patients with myxoid liposarcoma, the regimen did not produce a satisfactory overall response rate (ORR), according to findings from a phase 2 trial published in JAMA Oncology.

"Trabectedin plus [radiotherapy] might be viewed as a treatment option at least when tolerability is of concern, but further evidence should be generated in this setting," according to the study authors.

Per investigator assessment, the partial response (PR) rate was 19%, and 81% of patients had stable disease. Additionally, patients had a PR rate of 22% based on central review. Based on Choi criteria, the PR rate was 83%, and 17% of patients had stable disease.

The median viable residual tumor was 10% (range, 0%-90%), with 51% of patients having a viable residual tumor of 10% or less and 85% having a viable residual tumor of less than 50%. Of those with an evaluable centralized pathologic response, 13% had complete pathologic responses.

Seven of 42 patients experienced disease recurrence, with a median time to recurrence of 15 months (range, 8-51). Of those with disease recurrence, 1 experienced local recurrence, and 6 had distant metastases. The 4-year overall survival (OS) and distant-free survival (DFS) rates, respectively, were 100% and 84%.

Investigators noted that the trial did not meet the primary end point of overall response by RECIST criteria in at least 70% of patients.

“At study design, a threshold of 70% of [PRs] was chosen to support an enhanced activity of the combination of trabectedin and [radiotherapy] over [radiotherapy] alone based on preclinical models,” the study investigators noted. “In this sense, this study was not confirmative.”

Investigators of this international, open-label, phase 2 study evaluated trabectedin in combination with radiotherapy in 46 patients with myxoid liposarcoma. Patients received treatment in 4 centers in Spain, 1 center in Italy, and 2 centers in France. All patients received 1.5 mg/m2 of trabectedin intravenously every 21 days for a total of 3 cycles plus 25 fractions of radiation for a total of 45 Gy.

Secondary end points of the trial included relapse-free survival, disease-free survival, OS, ORR, and pathologic response rate.

Patients 18 to 70 years old with histologically confirmed and centrally reviewed localized resectable myxoid liposarcoma arising from an extremity or the trunk wall were eligible for enrollment on the trial. Additional eligibility criteria included having an ECOG performance status of 0 or 1 and adequate baseline bone marrow function.

The median patient age was 43 years (range, 18-77), and the median tumor size was 11 cm (range, 3-25). In the phase 2 population, most patients were male (67%), had an ECOG performance status of 0 (87%), high-grade disease (52%), and disease located in the thigh (59%). All patients underwent surgery, with 79% receiving an R0 resection and 21% receiving an R1 resection.

The most common any-grade non-hematologic adverse effects (AEs) included fatigue (50.0%), nausea (47.8%), and alanine aminotransferase level increases (47.8%), with low-grade hematologic AEs including neutropenia (39.1%) and leukopenia (15.2%).

Frequent grade 3/4 hematologic AEs included neutropenia (26.1%) and leukopenia (4.3%), and high-grade non-hematologic AEs included alanine aminotransferase elevation (21.7%), aspartate aminotransferase elevation (13.1%), and increases in gamma-glutamyl transferase levels (10.9%). Investigators reported no deaths related to the study treatment.

“Trabectedin plus [radiotherapy] might be viewed as a treatment option at least when tolerability is of concern, but further evidence should be generated in this setting,” the study authors concluded. “For low-risk [myxoid liposarcoma], prospective studies could assess whether the combination of preoperative [radiotherapy] and trabectedin has an added value when function preservation is a goal.”

Reference

Sanfilippo R, Hindi N, Jurado JC, et al. Effectiveness and safety of trabectedin and radiotherapy for patients with myxoid liposarcoma a nonrandomized clinical trial. JAMA Oncol. Published online March 30, 2023. doi:10.1001/jamaoncol.2023.0056