Overall survival and histology-specific subgroup analyses from a phase 3, randomized controlled study of trabectedin or dacarbazine in patients with advanced liposarcoma or leiomyosarcoma

Abstract

Background: We performed a randomized phase 3 study of trabectedin versus dacarbazine in previously-treated patients with liposarcoma/leiomyosarcoma (LPS/LMS).

Methods: Patients were randomized 2:1 to trabectedin (n = 384) or dacarbazine (n = 193) administered intravenously every 3 weeks. The primary objective was overall survival (OS). Secondary objectives were progression-free survival, objective response rate, safety, and patient-reported outcomes, all previously reported and demonstrating superior disease control with trabectedin. Results of the final OS analysis in preplanned subgroups of patients with LPS/LMS are presented.

Results: At the time of the final OS analysis, 577 patients had been assigned randomly, including 423 (73%) with LMS and 154 (27%) with LPS. The median duration of treatment exposure was higher in the trabectedin arm compared with the dacarbazine arm (4 vs 2 cycles), as was the proportion of patients receiving an extended number of therapy courses (≥6 cycles: 42% vs 22%). This pattern was consistent across histological subgroups: the median number of treatment cycles (4 vs 2 for both subgroups) and proportion of patients with ≥6 treatment cycles (LMS, 43% vs 24%; LPS, 40% vs 16%). Despite improved disease control by trabectedin, no improvement in OS was observed; the final median OS for trabectedin versus dacarbazine was 13.7 versus 13.1 months (P = .49). Sensitivity analyses of OS suggest confounding by post-study anticancer therapies, which were utilized in most patients in both treatment arms (71% vs 69%, respectively).

Conclusion: The final OS results demonstrated comparable survival between LPS/LMS patients receiving trabectedin or dacarbazine, which is consistent with the interim analysis results. Both LPS and LMS demonstrated improved disease control with trabectedin.

Trial registration: ClinicalTrials.gov NCT01343277.

Keywords: dacarbazine; leiomyosarcoma; liposarcoma; soft tissue sarcoma; trabectedin.

Conflict of interest statement

Shreyaskumar Patel has received grants and personal fees from Janssen; personal fees from PharmaMar and M.J. Hennessey/OncLive; grants from Blueprint Medicines; and personal fees from CytRx, Eli Lilly, EMD Serono, Epizyme, Immune Design, and Novartis Oncology. Margaret von Mehren received support paid to Fox Chase Cancer Center for conduct of the study and received consultant fees from Janssen and personal fees for advisory board participation; was a member of the trial's scientific steering committee; and has been a paid consultant and data and safety monitoring board member for Eisai. Damon R. Reed has served on advisory boards for Epizyme, Janssen, Loxo, and Shire Pharmaceuticals; has been a web site consultant for Epizyme; has been on a speaker's bureau for OncLive; and has received clinical trial support from Janssen associated with the ET743‐SAR‐3007 trial. Pamela Kaiser reports contracting (per patient placed on trial) between Johnson & Johnson (Janssen) and Lutheran General/Oncology Specialists. John Charlson has received clinical trial support for the ET743‐SAR‐3007 and ET743‐SAR‐3002 trials (institutional support to Medical College of Wisconsin) as well as from Blueprint, CytRx, Deciphera, Lilly, Novartis, and Threshold and has participated on advisory boards for CytRx, Immune Design, Lilly, and Threshold. Christopher W. Ryan has received clinical trial research funding from Janssen Research & Development, LLC; has received grants from Argos Therapeutics, Bayer, Bristol‐Myers Squibb, CytRx Corporation, Daiichi Sankyo, Eisai, Exelixis, Genentech, GlaxoSmithKline, Janssen, Karyopharm Therapeutics, MabVax, Merck, Morphotek, Novartis, OSI Pharmaceuticals, Pfizer, Threshold Pharmaceuticals, and TRACON Pharmaceuticals; and has received personal consulting fees from Eisai, EMD Serono, Exelixis, Genentech, Novartis, and Pfizer. Daniel Rushing has received grant funding from Sarcoma Alliance for Research through Collaboration and OncLive; has received personal fees from Janssen; and has received institutional payments from Janssen for the conduct of the trial as well as possible reimbursement from Eli Lilly and Eisai for a physician advisory panel. Michael Livingston has received clinical trial support (institution received money from Janssen to defray the cost of the study) through Blumenthal Cancer Center (now Levine Cancer Center). Arun Singh has served on advisory boards for Eli Lilly, Daiichi Sankyo, and Roche; has served on speaker's bureaus for Eisai, Eli Lilly, Novartis, and OncLive; has received consulting fees from Eisai; has been on the Board of Directors for Certis Oncology Solutions and also holds stock in the company; and has received clinical trial support from Janssen associated with the ET743‐SAR‐3007 trial. Rahul Seth has received clinical trial support (ie, institutional fees) from Janssen. Charles Forscher has received research support from Janssen and Karyopharm and has served on a medical advisory board for Janssen, Epizyme, and Blueprint. Gina D'Amato has served on speaker's bureaus and advisory boards for Eisai, Eli Lilly, Janssen, Novartis, and OncLive and has served on an advisory board for Epizyme. Sant P. Chawla has served as a consultant and/or advisor for, has served on speakers’ bureaus for, and has received honoraria and research funding from Amgen, CytRx Corporation, GlaxoSmithKline, Ignyta, Immune Design, Janssen, Karyopharm Therapeutics, Roche, Sarcoma Alliance for Research through Collaboration, Threshold Pharmaceuticals, and TRACON Pharma. George Wang, Trilok Parekh, Roland Knoblauch, and Sharon McCarthy are all employees of Janssen (a subsidiary of Johnson & Johnson). Martee L. Hensley has received institutional research support from Janssen for the conduct of the study; was a faculty speaker for Research to Practice; served on a faculty expert panel for OncLive; has served on advisory boards for Janssen, Lilly/Lilly Oncology, and Tesaro; and reports chapter author royalties for UpToDate, advisory and market research roles for Tesaro, ongoing research support to Memorial Sloan Kettering Cancer Center from Bristol‐Myers Squibb, research honoraria from Comsort, and a spouse's ongoing employment with Sanofi. Robert G. Maki has received grants from PharmaMar; has received personal consulting fees and clinical trial support (ie, institutional grants) from Janssen while conducting trabectedin studies between 1998 and 2017; has received consultant fees from Arcus, Bayer, Foundation Medicine, Janssen/PharmaMar, Presage Biosciences, and Tracon Pharmaceuticals; has received honoraria from the American Association for Cancer Research and the American Society of Clinical Oncology; has served on the data safety monitoring board for AADi, Deciphera, and Karyopharm; is a member of the Medical Oncology Exam Committee for the American Board of Internal Medicine; has received clinical trial support from Daiichi‐Sankyo, Genentech, Immune Design, Immunocor, Janssen/PharmaMar, Lilly/Imclone, Presage Biosciences, Regeneron, Sarcoma Alliance for Research through Collaboration, and Tracon Pharmaceuticals; has received royalties from Springer, Wiley, and UpToDate; and has received a grant from Fondazione Enrico Pallazzo. George D. Demetri has received grants, personal fees, and nonfinancial support from PharmaMar—as well as travel expenses for a research meeting—and from Janssen in relation to the submitted work. In addition, he has received grants from AbbVie, Adaptimmune, Bayer, Daiichi‐Sankyo, Epizyme, GlaxoSmithKline, Ignyta, Loxo Oncology, Novartis, Pfizer, and Roche; has received personal fees from AbbVie, Adaptimmune, Bayer, Blueprint Medicines, Daiichi‐Sankyo, Caris Life Sciences, Champions Oncology, EMD‐Serono, Epizyme, G1 Therapeutics, Ignyta, Loxo Oncology, Mirati Therpeutics, Merrimack Pharmaceuticals, M.J. Hennessey/OncLive, Novartis, Pfizer, Polaris Pharmaceuticals, Roche, Sanofi, WIRB Copernicus Group, ZioPharm; has received nonfinancial support from AbbVie, Daiichi‐Sankyo, Epizyme, Novartis, and Roche; has received travel expenses for an educational meeting for M.J. Hennessey/OncLive, Novartis, and Pfizer; has received travel expenses for an advisory board meeting for Bayer, Caris Life Sciences, Daiichi‐Sankyo, EMD‐Serono, Loxo Oncology, Roche, and WIRB Copernicus Group; has received travel expenses for an FDA meeting for Epizyme; has received travel expenses for a research meeting for study for Adaptimmune; has received travel expenses for board meetings for Blueprint Medicines and Merrimack Pharmaceuticals; has equity for Blueprint Medicines and G1 Therapeutics; has equity options for Bessor Pharmaceuticals, Caris Life Sciences, Champions Oncology, Erasca Pharmaceuticals, G1 Therapeutics, and Merrimack Pharmaceuticals; reports a patent that is issued and licensed to PharmaMar for trabectedin use for cancer (patent from PharmaMar [for which he receives no funds and no license to Dana‐Farber Cancer Center or to Dr. Demetri]); and reports a patent that is issued and licensed to Novartis for imatinib use for gastrointestinal stromal tumors as well as royalties stemming from the patent.

© 2019 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.

Figures

Figure 1

CONSORT diagram. LMS, leiomyosarcoma; LPS, liposarcoma; OS, overall survival.

Figure 2

Kaplan‐Meier estimate of overall survival (OS) at the final analysis. (A) OS for total patient population. (B) OS for patients with leiomyosarcoma. (C) OS for patients with liposarcoma. The median OS (95% confidence interval [CI]) for patients with leiomyosarcoma was 14.1 (12.2‐16.5) versus 13.6 (9.1‐17.2) months (P = .37) for patients in the trabectedin versus dacarbazine arms; for those with liposarcoma, the median OS was 13.1 (7.0‐25.6) versus 12.6 (9.3‐17.8) months (P = .83).

Figure 3

Time to post‐study anticancer therapy utilization in trabectedin versus dacarbazine. CI, confidence interval.

Figure 4

Kaplan‐Meier estimate of progression‐free survival (PFS) at final analysis. (A) PFS for patients with leiomyosarcoma. (B) PFS for patients with liposarcoma. CI, confidence interval.