Cardiac safety of trabectedin monotherapy or in combination with pegylated liposomal doxorubicin in patients with sarcomas and ovarian cancer

Abstract

Background: As with other alkylating agents, cardiac dysfunction can occur with trabectedin therapy for advanced soft tissue sarcomas (STS) or recurrent ovarian cancer (ROC) where treatment options for advanced disease are still limited. Cardiac safety for trabectedin monotherapy (T) for STS or in combination with pegylated liposomal doxorubicin (T+PLD) for ROC was evaluated in this retrospective postmarketing regulatory commitment.

Methods: Patient data for multiple cardiac-related treatment-emergent adverse events (cTEAEs) were evaluated in pooled analyses of ten phase 2 trials, one phase 3 trial in STS (n = 982), and two phase 3 trials in ROC (n = 1231).

Results: Multivariate analyses on pooled trabectedin data revealed that cardiovascular medical history (risk ratio [RR (95% CI)]: 1.90 [1.24-2.91]; p = 0.003) and age ≥65 years (RR [95% CI]: 1.78 [1.12-2.83]; p = 0.014) were associated with increased risk for cTEAEs. Multivariate analyses showed increased risk of experiencing cTEAEs with T+PLD compared to PLD monotherapy (RR [95% CI]: 2.70 [1.75-4.17]; p < 0.0001) and with history of prior cardiac medication (RR [95% CI]: 1.88 [1.16-3.05]; p = 0.010).

Conclusions: For patients with STS or ROC who still have limited treatment options, trabectedin may be initiated after carefully considering benefit versus risk. Trial Registration (ClinicalTrials.gov): NCT01343277; NCT00113607; NCT01846611.

Keywords: anthracycline; cardiac toxicity; chemotherapy; patient outcomes; soft tissue sarcomas.

Conflict of interest statement

Robin L. Jones: Honoraria and consulting fees from Adaptimmune, Blueprint, Clinigen, Eisai, Epizyme, Daiichi Sankyo, Deciphera, Immune Design, Johnson & Johnson, Lilly, Merck, PharmaMar, Pfizer, Tracon, UpToDate. Thomas J. Herzog: Scientific Advisory Boards for AZ, Caris, Clovis, Genentech, GSK, Johnson & Johnson, Merck. Shreyaskumar R. Patel: Clinical trial funding from Janssen, personal fees from PharmaMar (travel for the advisory board), and personal fees from M.J. Hennessey/OncLive (presentation at an educational meeting) and has acted as a paid consultant for Bayer, Daiichi Sankyo, Eli Lilly, Epizyme, Immune Design, Janssen, and Novartis Oncology; has received grants from Blueprint Medicines; and has received personal fees from CytRx and EMD Serono. Margaret von Mehren: Support to Fox Chase Cancer Center for the conduct of SAR‐3007; member of the scientific steering committee for the study; honoraria from Janssen in the past for scientific advisory board participation. Research funding from Novartis; paid consulting for Blueprint, Deciphera, Exelixis. Scott M. Schuetze: Honoraria and travel support from Janssen for participation in scientific advisory boards; research funding to the institution for support of clinical trials of trabectedin in sarcoma. Brian A. Van Tine: Basic Science Grant Funding from Pfizer, Tracon, and Merck; consulting fees from Epizyme, Lilly, CytRX, Janssen, Immune Design, Daiichi Sankyo, Bayer, Plexxikon, and Adaptimmune; speaking fees from Caris, Janssen, and Lilly; travel support from Lilly, GSK, and Adaptimmune. Robert Coleman: Grants from NIH (2P50 CA109298; P30CA016672), Gateway Foundation, and V Foundation during the conduct of the study and grants and personal fees (research support, consulting) from AstraZeneca, Clovis, Genmab, Roche/Genentech, Janssen; grants (research support) from Merck; and personal fees (consulting) from Tesaro, Medivation, Gamamab, Agenus, Regeneron, and OncoQuest outside the submitted work. Roland Knoblauch: Employee of Janssen Oncology. Spyros Triantos: Currently employed by Janssen Research and Development. Peter Hu: Employee of Janssen Research and Development. Waleed Shalaby: Employee of Janssen Scientific Affairs, LLC; stock in Johnson and Johnson, of which Janssen is a wholly owned subsidiary. Tracy McGowan: Employee of Janssen Scientific Affairs, LLC; stock in Johnson and Johnson, of which Janssen is a wholly‐owned subsidiary. Bradley Monk: Personal fees (honorarium/consultant) from Abbvie, Advaxis, Agenus, Amgen, Aravive, Asymmetric Therapeutics, Boston Biomedical, Chemo Care, ChemoID, Circulogene, Conjupro, Easai, Geistlich, Genmab/Seattle Genetics, GOG Foundation, ImmunoGen, Immunomedics, Incyte, Laekna Health Care, Mateon (formally OXiGENE), Merck, Mersana, Myriad, Nucana, OncoMed, Oncoquest, Oncosec, Perthera, Pfizer, Precision Oncology, Puma, Regeneron, Samumed, Takeda, VBL, and Vigeo; personal fees (honorarium/consultant/speaker) from AstraZeneca, Clovis, Janssen/Johnson & Johnson, Roche/Genentech, and Tesaro/GSK. George D. Demetri: Grants, personal fees, and non‐financial support from PharmaMar—including travel to a research meeting—and from Janssen; grants from AbbVie, Adaptimmune, Bayer, Daiichi‐Sankyo, Epizyme, GlaxoSmithKline, Ignyta, Loxo Oncology, Novartis, Pfizer, and Roche; personal fees from AbbVie, Adaptimmune, Bayer, Blueprint Medicines, Daiichi‐Sankyo, Caris Life Sciences, Champions Oncology, EMD‐Serono, Epizyme, G1 Therapeutics, Ignyta, Loxo Oncology, Mirati Therapeutics, Merrimack Pharmaceuticals, M.J. Hennessey/OncLive, Novartis, Pfizer, Polaris Pharmaceuticals, Roche, Sanofi, WIRB Copernicus Group, Translate BIO, ZioPharm, RELAY Therapeutics; non‐financial support from AbbVie, Daiichi‐Sankyo, Epizyme, Novartis, and Roche; travel to present at an educational meeting for M.J. Hennessey/OncLive, Novartis, and Pfizer; travel to an advisory board meeting for Bayer, Caris Life Sciences, Daiichi‐Sankyo, EMD‐Serono, Loxo Oncology, Roche, and WIRB Copernicus Group; travel to FDA meeting for Epizyme; travel to research meeting for Adaptimmune; service as a member of the Board of Directors with support for travel to board meetings for Blueprint Medicines, Merrimack Pharmaceuticals and Translate BIO; equity for Blueprint Medicines and G1 Therapeutics; equity options for Bessor Pharmaceuticals, Caris Life Sciences, Champions Oncology, Erasca Pharmaceuticals, G1 Therapeutics, Translate BIO, and RELAY Therapeutics; a patent, issued and licensed to PharmaMar, for trabectedin use for cancer (patent from PharmaMar; no funds from this and no license to Dana Farber Cancer Center or to Dr. Demetri); and patent, issued and licensed to Novartis from Dana‐Farber Cancer Institute (DFCI), for imatinib use in gastrointestinal stromal tumor, and royalties from DFCI for that patent.

© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Figures

FIGURE 1

Cumulative Incidence of Cardiac‐Related Adverse Events Over Treatment Duration for Treated Patients (Pooled Studies ET743‐OVC‐3006 and ET743‐OVA‐301). PLD, pegylated liposomal doxorubicin

FIGURE 2

Multivariate Analysis on Incidence of Cardiac‐Related TEAEs (Logistic Regression) for Treated Patients (Trabectedin – Pooled Phase 2 and 3 Studies). Dependent variable: incidence of cardiac‐related TEAEs. CI, confidence interval; TEAEs, treatment‐emergent adverse events

FIGURE 3

Multivariate Analysis on Incidence of Significant LVEF Decrease (Logistic Regression) for Treated Patients (Pooled Studies OVC‐3006 and OVA‐301). Dependent variable: incidence of significant LVEF decrease. CI, confidence interval; LVEF, left ventricular ejection fraction; PLD, pegylated liposomal doxorubicin