A matching-adjusted indirect comparison of trabectedin and pazopanib for the treatment of advanced, metastatic, leiomyosarcomas

Abstract

Background: Trabectedin (T) and pazopanib (P) are approved treatments for locally advanced or metastatic leiomyosarcoma (L-mSTS). In the absence of head-to-head randomized controlled trials (RCTs); a matched indirect comparison (MAIC) was performed to assess potential differences in clinical efficacy between the treatment groups. Methods: MAIC was performed by extracting baseline characteristics from two phase III RCTs: SAR 3007 (T) and PALETTE (P): individual patient level data (IPD) was available forT only aggregated was published for P. Excluding those T patients who did not meet inclusion criteria for PALETTE, a sample size of 372 L-mSTS patients (T=263, P=109) was generated. Of all baseline characteristics, only time since diagnosis (≥30 vs. < 30 months), age (≥65 vs. <65 years), and body weight (≥77 vs. < 77 kilograms), were statistically significant outcome predictors with T. The generalized method of moments (GMM) was used to optimally match cohorts for evaluation of differences in overall survival (OS), progression-free survival (PFS), and safety. Statistical analysis was performed using “R”. Results: There was no statistically significant difference in PFS [HR=0.82, (95%CI 0.63-1.06, p=0.13)], or OS [HR=0.86, (95% CI 0.64-1.18, p=0.36)]. The percentage of patients with post-progression therapies was higher in T (74.5%) vs. P (59%) group. In the subgroup with PFS ≥6 months, patients treated with T experienced significantly improved median PFS (11.2 months vs PFS 8.4 months HR: 0.47 (95% CI: 0.3007 - 0.7434), p=0.002 and were significantly more likely to achieve long term survival (OS≥18 months): 45.8% vs. 33.7% (95%CI: 23.5%-48.3%), p=0.025. Increased myelosuppression and hepatotoxicity observed with T whereas diarrhea, hypertension, pulmonary toxicity/pneumothorax, and neurotoxicity were observed with P. Conclusions: The MAIC model warrants further investigation and validation. No differences in mPFS or mOS were noted in a MAIC comparison. Among patients achieving long term disease control (PFS > 6 mo), T significantly increased mPFS and the proportion of patients achieving prolonged overall survival (OS≥18 mo). Differences in the safety profile were highlighted by this indirect comparison.