LAUSR

Abstract Background Retreatment with PLD in ROC has raised potential concerns of increased toxicity and diminished response rates. This subgroup analysis examined the safety and efficacy of platinum-sensitive patients (pts) with prior PLD therapy who participated in a randomized, open-label study comparing T+PLD vs PLD alone in line 3 ROC. Methods Women with advanced-relapsed ROC having responded to 2 lines of platinum-based therapy were enrolled. Pts were randomly assigned 1:1 to T+PLD [T: 1.1mg/m2, PLD:30mg/m2, IV, Q3 wks] or PLD [PLD 50mg/m2, IV, Q4 wks]. The primary endpoint was overall survival (OS). Secondary endpoints included progression free survival (PFS) and objective response rate (ORR). Stratification was based on prior PLD use (Y or N), BRCA1/2 mutation, and platinum-free interval (PFI). NCT01846611. Results ET743-OVC-3006 was discontinued (1/18/18) after an interim analysis showed that the futility threshold for OS was exceeded. Up to that point, 576 pts were randomized (T+PLD, n=289; PLD, n=287). The safety and efficacy, stratified by prior PLD (Y or N), are presented in the table. Between treatment arms, prior PLD use did not influence the ORR (OR:2.064; 95% CI:0.479, 9.073; p=0.341), PFS (HR:0.626, 95% CI: 0.265, 1.478; p=0.281), or OS (HR:0.933; 95% CI: 0.335, 2.596; p=0.894). In addition, within each treatment cohort (Table), prior PLD use did not influence ORR, PFS, or OS. While combination T+PLD, as expected, elicited greater grade 3/4 TEAEs than PLD alone, prior PLD therapy did not appear to impact the incidence of grade 3/4 TEAEs within each treatment arm except for thrombocytopenia for T+PLD (Table).Table: 1030PEfficacy and safety of T+PLD vs PLD by prior PLD therapy useTable: 1030PT + PLD [n=289]PLD monotherapy [n=287]EfficacyPrior PLDPrior PLDYes (n=19, 6.6%)No (n=270, 93.4%)HR (95% CI)Yes (n=20, 7%)No (n=267, 93%)HR (95% CI)ORR (%)52.645.61.328 (0.468 – 3.819)35360.959 (0.313 - 2.692)PFS (months)7.17.50.853 (0.435, 1.671)5.67.41.212 (0.688, 2.135)OS (months)34.222.10.844 (0.409, 1.740)28.920.90.713 (0.349, 1.458)SafetyPrior PLDPrior PLDYes (n=19, 6.6%)No (n=267, 92.4%)Yes (n=20, 7%)No (n=262, 91.3%)Grade 3/4 TEAEs, n (%)18 (94.7)225 (84.3)14 (70)166 (63.4)Gastrointestinal5 (26.3)50 (18.7)5 (25)50 (19.1)Nausea3 (15.8)18 (6.7)1 (5)3 (1.1)Vomiting3 (15.8)15 (5.6)1 (5)4 (1.5)Diarrhea2 (10.5)3 (1.1)00Hematologic10 (52.6)152 (56.9)3 (15)75 (28.6)Anemia4 (21.1)57 (21.3)1 (5)19 (7.3)Febrile neutropenia2 (10.5)20 (7.5)1 (5)2 (0.8)Neutropenia7 (36.8)117 (43.8)1 (5)58 (22.1)Leukopenia3 (15.8)38 (14.2)020 (7.6)Thrombocytopenia4 (21.1)39 (14.6)03 (1.1)Skin PPE010 (3.7)2 (10)31 (11.8)Cardiac---3 (1.1)1 (5)1 (0.4)EF decreased001 (5)0Atrial fibrillation---1 (0.4)---1 (0.4)CHF---1 (0.4)---0CHF, congestive heart failure; EF, ejection fraction; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PLD, pegylated liposomal doxorubicin; PPE, palmar-plantar erythrodysaesthesia; T, trabectedin; TEAE, treatment-emergent adverse event. Conclusions This pre-stratified exploratory analysis suggests that prior treatment with PLD in ROC does not increase the incidence of Grade 3/4 TEAEs or negatively influence ORR, PFS, and OS in patients receiving T+PLD or PLD alone. Clinical trial identification NCT01846611. Editorial acknowledgement Lakshmi Kasthurirangan, PhD (SIRO Clinpharm Pvt. Ltd.) provided medical writing assistance and Namit Ghildyal, PhD (Janssen Research & Development, LLC) provided editorial support. Legal entity responsible for the study The authors. Funding Janssen Research & Development, LLC, USA. Disclosure B.J. Monk: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Johnson & Johnson; Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony: Clovis; Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche/Genentech; Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony: Tesaro; Honoraria (institution), Advisory / Consultancy: AbbVie; Honoraria (institution), Advisory / Consultancy: Advaxis; Honoraria (institution), Advisory / Consultancy: Amgen; Honoraria (institution), Advisory / Consultancy: Biodesix; Honoraria (institution), Advisory / Consultancy: Genmab; Honoraria (institution), Advisory / Consultancy: Gradalis; Honoraria (institution), Advisory / Consultancy: Immunogen; Honoraria (institution), Advisory / Consultancy: Immunomedics; Honoraria (institution), Advisory / Consultancy: Incyte; Honoraria (institution), Advisory / Consultancy: Mateon (formally Oxigene); Honoraria (institution), Advisory / Consultancy: Merck; Honoraria (institution), Advisory / Consultancy: Myriad; Honoraria (institution), Advisory / Consultancy: Perthera; Honoraria (institution), Advisory / Consultancy: Pfizer; Honoraria (institution), Advisory / Consultancy: Precision Oncology, Puma, Samumed, Takeda, VBL. T.J. Herzog: Advisory / Consultancy: Morphotek, Merck, AstraZeneca, Genentech, and Johnson and Johnson. S. Triantos: Shareholder / Stockholder / Stock options, Full / Part-time employment: Janssen Research & Development. S. Maul: Shareholder / Stockholder / Stock options, Full / Part-time employment: Janssen Research & Development. G. Wang: Shareholder / Stockholder / Stock options, Full / Part-time employment: Janssen Research & Development. M.J. Pontes Valero: Full / Part-time employment: PharmaMar SA. T. McGowan: Shareholder / Stockholder / Stock options, Full / Part-time employment: Janssen Scientific Affairs. W.S. Shalaby: Shareholder / Stockholder / Stock options, Full / Part-time employment: Janssen Scientific Affairs. R.L. Coleman: Honoraria (institution), Research grant / Funding (institution), Served on a DSMB for trabectedin on an unrelated trial: Honoraria and research funding from Johnson & Johnson.