Pharmacokinetics, safety, and activity of trabectedin as first‐line treatment in elderly patients who are affected by advanced sarcoma and are unfit to receive standard chemotherapy: A phase 2 study (TR1US study) from the Italian Sarcoma Group

Abstract

BACKGROUND: Although elderly patients (≥70 years) represent 30% of new diagnoses of soft tissue sarcoma (STS), they are underrepresented in clinical trials and are often unfit to receive standard anthracycline-based chemotherapy. Trabectedin is registered as a second-line treatment for advanced STS and is characterized by a favorable safety profile. METHODS: The aim of this single-arm, phase 2 study was to investigate trabectedin (scheduled dose, 1.3-1.5 mg/m 2) as a first-line treatment in elderly patients with advanced stage STS who are inoperable and are unfit to receive standard anthracycline-based chemotherapy. The coprimary endpoints were progression-free survival at 3 months (PFS3) and the rate of clinically limiting toxicities (CLTs). We also conducted an ancillary study on pharmacokinetics. RESULTS: Twenty-four patients (12 men and 12 women) with a median age of 79 years (interquartile range [IQR], 74-83 years) were enrolled. The histological subtype was leiomyosarcoma in 46%, liposarcoma in 33%, and other histotypes in 21%. The median number of trabectedin courses was 4 (IQR, 3-6), with 7 patients (29%) receiving ≥6 cycles. Eight patients (33%) required dose reductions. The most frequent grade 3/4 adverse events were neutropenia in 9 patients (38%), fatigue in 5 patients (21%), and aminotransferase elevation in 5 patients (21%). PFS3, median PFS, and overall survival were 71% (80% CI, 57%-81%), 4 months, and 12 months, respectively. Ten patients (42% [80% CI, 28%-57%]) experienced CLTs. Trabectedin C max , half-life, clearance, and distribution volume were 1.28 ng/mL (standard deviation [SD], 0.58 ng/mL), 26.70 hours (SD, 9.09 hours), 39.98 L/h/m 2 (SD, 14.08 L/h/m 2), and 1460 L/m 2 (SD, 561 L/m 2), respectively. CONCLUSION: Trabectedin can be administered safely to elderly patients with STS who are unfit to receive anthracyclines. Pharmacokinetics in the elderly population was superimposable to historical data.

Metastasectomy in Leiomyosarcoma: A Systematic Review and Pooled Survival Analysis

“…In addition, gemcitabine and docetaxel also have demonstrated activity in LMS and this combination is used as a first-line therapy in the metastatic setting in some jurisdictions [57,58]. Newer treatments, including trabectedin, pazopanib and eribulin, have shown promising results in metastatic, unresectable LMS in later line settings [59][60][61][62][63][64][65][66][67][68][69][70][71]. It is imperative to evaluate the role of metastasectomy in the era of these modern systemic therapy regimens, even for all STS.…”

Marine Power on Cancer: Drugs, Lead Compounds, and Mechanisms

“…A number of clinical phase I studies have found that it has a good effect on ovarian cancer when used alone or in combination with other chemotherapeutic drugs, such as cisplatin [ 68 , 69 , 70 ]. Phase II and III clinical studies have shown that trabectedin alone or in combination with other anticancer drugs is effective in soft tissue tumors, especially liposarcoma and leiomyosarcoma, and prolongs the survival time of the patients [ 30 , 71 , 72 , 73 ].…”

Current Reality of Treating Advanced Soft Tissue Sarcoma as Illustrated by Case Studies

“…This indication is supported by the phase II Trabectedin First Line Therapy In Unfit Sarcoma (TR1US) study, which enroled 24 patients with advanced STS unsuited to receive standard chemotherapy due to stable arrhythmia, previous myocardial infarction, and/or age ≥80 years. Median PFS was 4 months and the overall disease control rate was 62% [42]. A post-marketing phase IV study involving 218 patients with advanced STS receiving trabectedin in clinical practice, of whom about 10% were unsuited to receive standard first-line therapy, reported a median PFS of 5.9 months, a median OS of 21.3 months, and a manageable safety profile [43].…”