A Matching-Adjusted Indirect Comparison of Trabectedin and Pazopanib for the Treatment of Advanced, Metastatic, Leiomyosarcomas

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. Legal entity responsible for the study: Janssen Scientific Affairs, LLC, Pharma Mar S.A., LLC Funding: Janssen Scientific Affairs, LLC, Pharma Mar S.A., LLC Disclosure: R.L. Jones: Consultant for: Adaptimmune, Blueprint, Eisai, Epizyme, Daichii, Deciphera, Janssen Scientific Affairs, LLC, Immunedesign, Lilly, Merck, Pharmamar. J-Y. Blay: Research Funding and honoraria from Novartis, GSK and Pharmamar. A. Lecesne: Honoraria: Pfizer, Novartis, Pharmamar, Amgen, Lilly. J. Martin-Broto: Advisory boards for Novartis, Lilly, PharmaMar, Eisai, Bayer. M.J. Pontes, J.M. Fernandez Santos, B. García San Andrés: Employee of Pharma Mar S.A. and own stock in Pharma Mar S.A. G. Wang, S. Wang, C.R. Shin: Employee of Janssen and own stock in Johnson & Johnson. R. Maki: Consulting or advisory role: SARC, ASCO, AADX, ARCUS, Bayer, GSAI, GEM, Novartis, GSK, Immune Design, Janssen, Kyropharm, Lilly Tracon and Presage. Research Funding, travel and accommodations, expenses: Tracon, Immune Design, Lilly and SARC. S. Patel: Consultant to: Janssen, Eisai, Novartis, CytRx, Epizyme, Bayer, Eli Lilly. Grants for clinical trial from: Janssen, Eisai, Morphotek. G.D.S. Demetri: Consulting: Novartis, Janssen, PharmaMar, Daiichi-Sankyo, Adaptimmune, Eisai Patent licensed to Novartis from Dana-Farber with royalty paid to Dana-Farber. Research support to Dana-Farber: Novartis, Janssen.