Abstract 980P
Background
Eribulin is a halichondrin-class microtubule dynamics inhibitor with cytotoxic and vascular remodeling effects leading to tumor immune modulation. E7389-LF is a liposomal formulation of eribulin designed to enhance antitumor activity and improve pharmacokinetic (PK) profiles. The combination of E7389-LF + Nivo is expected to show antitumor activity by cytotoxic and antitumor immune effects.
Methods
The primary objective of this phase 1b study (Study 120) was to determine the recommended phase 2 dose (RP2D). Nivo was administered IV at 360 mg Q3W (day 1 of a 21-day cycle) and 240 mg Q2W (days 1 and 15 of a 28-day cycle) in combination with E7389-LF (1.7–2.1 mg/m2 Q3W and 1.1–1.4 mg/m2 Q2W, respectively; Table) to pts with advanced solid tumors for which no alternative standard or effective therapy existed.
Results
Of the 25 enrolled pts, 16 were male, median age was 55 years (range 34–79), and 21 had ECOG PS 0. A dose-limiting toxicity (DLT) was observed in 3 pts (Table), and all DLTs were resolved. Based on neutrophil counts, Q3W dosing was preferred. Safety profiles in all cohorts were determined to be tolerable. The most common grade ≥ 3 treatment-related adverse events were neutropenia (52%), leukopenia (36%), and lymphopenia (16%). A partial response was observed in 4 pts (16%; Table). There were no substantial changes in the PK profiles of E7389-LF and Nivo compared to those of each monotherapy. In all cohorts, plasma-vasculature-related markers and interferon-related markers tended to increase from baseline during cycle 1. Of the 9 pts evaluable for pre/post biopsy and who had an immune-desert or immune-excluded phenotype at baseline, 4 had an immune-inflamed phenotype at C2D1.
Conclusions
E7389-LF + Nivo was tolerable in pts with advanced solid tumors, with antitumor effects and positive effects on vascularity and antitumor immunity. Based on these results, the RP2D was determined to be E7389-LF 2.1 mg/m2 Q3W + Nivo 360 mg Q3W. Table: 980P
Dosing, DLTs, responses
| Schedule | E7389-LF dose | Nivo dose | n | DLTs Grade and type | Partial response by RECIST v1.1 n (tumor type) |
| Once every 2 weeks (Q2W) | 1.1 mg/m2 | 240 mg | 7 | Dose skip of E7389-LF on D15 due to absolute neutrophil count <1000/mm3 | 1 (intrahepatic cholangiocarcinoma) |
| 1.4 mg/m2 | 6 | Grade 3 febrile neutropenia | 0 | ||
| Once every 3 weeks (Q3W) | 1.7 mg/m2 | 360 mg | 6 | Grade 3 febrile neutropenia | 2 (thymic carcinoma) |
| 2.1 mg/m2 | 6 | None | 1 (small cell lung cancer) |
Clinical trial identification
NCT04078295.
Editorial acknowledgement
Medical writing support was provided by Heather A. Mitchell, PhD, of Oxford PharmaGenesis Inc., Newtown, PA, USA, and was funded by Eisai Inc., Woodcliff Lake, NJ, USA.
Legal entity responsible for the study
Eisai Co. Ltd., Tokyo, Japan
Funding
Study funding from Eisai Co. Ltd., Tokyo, Japan. Nivolumab provided by Ono Pharmaceutical Co. Ltd., Osaka, Japan.
Disclosure
N. Yamamoto: Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Advisory Board: Boehringer Ingelheim; Financial Interests, Personal, Advisory Board: Chugai; Financial Interests, Personal, Invited Speaker: Chugai; Financial Interests, Personal, Advisory Board: Cimic; Financial Interests, Personal, Invited Speaker: Daiichi-Sankyo; Financial Interests, Personal, Advisory Board: Eisai; Financial Interests, Personal, Invited Speaker: Eli Lilly; Financial Interests, Personal, Invited Speaker: ONO; Financial Interests, Personal, Advisory Board: Otsuka; Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Invited Speaker: Sysmex; Financial Interests, Personal, Advisory Board: Takeda; Financial Interests, Institutional, Principal Investigator: AbbVie; Financial Interests, Institutional, Principal Investigator: Astellas; Financial Interests, Institutional, Principal Investigator: Bayer; Financial Interests, Institutional, Principal Investigator: BMS; Financial Interests, Institutional, Principal Investigator: Boehringer Ingelheim; Financial Interests, Institutional, Principal Investigator: Chiome Bioscience; Financial Interests, Institutional, Principal Investigator: Chugai; Financial Interests, Institutional, Principal Investigator: Daiichi-Sankyo; Financial Interests, Institutional, Principal Investigator: Eisai; Financial Interests, Institutional, Principal Investigator: Eli Lilly; Financial Interests, Institutional, Principal Investigator: GSK; Financial Interests, Institutional, Principal Investigator: Janssen Pharma; Financial Interests, Institutional, Principal Investigator: Kyowa-Hakko Kirin; Financial Interests, Institutional, Principal Investigator: Merck; Financial Interests, Institutional, Principal Investigator: MSD; Financial Interests, Institutional, Principal Investigator: Novartis; Financial Interests, Institutional, Principal Investigator: ONO; Financial Interests, Institutional, Principal Investigator: Otsuka; Financial Interests, Institutional, Principal Investigator: Pfizer; Financial Interests, Institutional, Principal Investigator: Sumitomo Dainippon; Financial Interests, Institutional, Principal Investigator: Taiho; Financial Interests, Institutional, Principal Investigator: Takeda. T. Shimizu: Financial Interests, Personal, Speaker’s Bureau: AbbVie; Financial Interests, Personal, Speaker’s Bureau: Daiichi-Sankyo; Financial Interests, Personal, Speaker’s Bureau: Eisai; Financial Interests, Personal, Speaker’s Bureau: Takeda Oncology; Financial Interests, Personal, Speaker’s Bureau: MSD; Financial Interests, Personal, Advisory Board: Daiichi-Sankyo; Financial Interests, Personal, Advisory Board: AbbVie; Financial Interests, Personal, Advisory Board: Takeda Oncology; Financial Interests, Institutional, Research Grant: Novartis; Financial Interests, Institutional, Research Grant: AbbVie; Financial Interests, Institutional, Research Grant: Daiichi-Sankyo; Financial Interests, Institutional, Research Grant: Takeda Oncology; Financial Interests, Institutional, Research Grant: Eli Lilly; Financial Interests, Institutional, Research Grant: LOXO Oncology; Financial Interests, Institutional, Research Grant: Bristol-Myers Squibb; Financial Interests, Institutional, Research Grant: Eisai; Financial Interests, Institutional, Research Grant: Incyte; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Research Grant: Pfizer; Financial Interests, Institutional, Research Grant: Chordia Therapeutics; Financial Interests, Institutional, Research Grant: Symbio Pharmaceuticals; Financial Interests, Institutional, Research Grant: 3D-Medicine; Financial Interests, Institutional, Research Grant: Five Prime; Financial Interests, Institutional, Research Grant: PharmaMar; Financial Interests, Institutional, Research Grant: Astellas; Financial Interests, Institutional, Principal Investigator: Novartis; Financial Interests, Institutional, Principal Investigator: AbbVie; Financial Interests, Institutional, Principal Investigator: Daiichi-Sankyo; Financial Interests, Institutional, Principal Investigator: Takeda Oncology; Financial Interests, Institutional, Principal Investigator: Eli Lilly; Financial Interests, Institutional, Principal Investigator: LOXO Oncology; Financial Interests, Institutional, Principal Investigator: Bristol-Myers Squibb; Financial Interests, Institutional, Principal Investigator: Eisai; Financial Interests, Institutional, Principal Investigator: Incyte; Financial Interests, Institutional, Principal Investigator: AstraZeneca; Financial Interests, Institutional, Principal Investigator: Pfizer; Financial Interests, Institutional, Principal Investigator: Chordia Therapeutics; Financial Interests, Institutional, Principal Investigator: Symbio Pharmaceuticals; Financial Interests, Institutional, Principal Investigator: 3D-Medicine; Financial Interests, Institutional, Principal Investigator: Five Prime; Financial Interests, Institutional, Principal Investigator: PharmaMar; Financial Interests, Institutional, Principal Investigator: Astellas. Y. Nakamura: Financial Interests, Institutional, Research Grant: Genomedia; Financial Interests, Institutional, Research Grant: Guardant Health; Financial Interests, Institutional, Research Grant: Chugai Pharma; Financial Interests, Institutional, Research Grant: Taiho Pharma; Financial Interests, Institutional, Research Grant: Daiichi-Sankyo Pharma. M. Nishino: Financial Interests, Personal, Speaker’s Bureau: AstraZeneca; Financial Interests, Personal, Speaker’s Bureau: Bristol-Myers Squibb; Financial Interests, Personal, Speaker’s Bureau: Boehringer Ingelheim Japan; Financial Interests, Personal, Speaker’s Bureau: Chugai; Financial Interests, Personal, Speaker’s Bureau: Eli Lilly Japan; Financial Interests, Personal, Speaker’s Bureau: MSD; Financial Interests, Personal, Speaker’s Bureau: ONO Pharmaceutical; Financial Interests, Personal, Speaker’s Bureau: Pfizer Japan; Financial Interests, Personal, Speaker’s Bureau: Taiho. T. Koyama: Financial Interests, Personal, Speaker’s Bureau: Sysmex; Financial Interests, Personal, Speaker’s Bureau: Chugai; Financial Interests, Personal, Principal Investigator: PACT. S. Iwasa: Financial Interests, Personal, Speaker’s Bureau: ONO; Financial Interests, Personal, Speaker’s Bureau: BMS; Financial Interests, Institutional, Research Grant: Eisai; Financial Interests, Institutional, Research Grant: ONO; Financial Interests, Institutional, Research Grant: BMS. K. Sudo: Financial Interests, Personal, Invited Speaker: Eisai Co. Ltd.; Financial Interests, Personal, Sponsor/Funding: Eisai Co. Ltd. K. Yonemori: Financial Interests, Personal, Invited Speaker: Eisai; Financial Interests, Personal, Advisory Board: Eisai. S. Shiono: Financial Interests, Personal, Full or part-time Employment: Ono Pharmaceutical Co. Ltd. T. Suzuki: Financial Interests, Personal, Full or part-time Employment: Eisai Co. Ltd. T. Takase: Financial Interests, Personal, Full or part-time Employment: Eisai Co. Ltd. S. Takashima: Financial Interests, Personal, Full or part-time Employment: Eisai. K. Yamaguchi: Financial Interests, Personal, Full or part-time Employment: Eisai Co. Ltd. T. Semba: Financial Interests, Personal, Full or part-time Employment: Eisai Co. Ltd. K. Shitara: Financial Interests, Personal, Invited Speaker: AbbVie; Financial Interests, Personal, Advisory Board: AbbVie; Financial Interests, Personal, Advisory Board: Amgen; Financial Interests, Personal, Advisory Board: Astellas; Financial Interests, Personal, Advisory Board: Boehringer Ingelheim; Financial Interests, Personal, Advisory Board: Bristol-Myers Squibb; Financial Interests, Personal, Advisory Board: Daiichi Sankyo; Financial Interests, Personal, Advisory Board: GlaxoSmithKline; Financial Interests, Personal, Advisory Board: Lilly; Financial Interests, Personal, Advisory Board: MSD; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board: ONO Pharmaceutical; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Advisory Board: Taiho Pharmaceutical; Financial Interests, Personal, Advisory Board: Takeda; Financial Interests, Personal, Invited Speaker: Yakult Honsha; Financial Interests, Institutional, Research Grant: Astellas; Financial Interests, Institutional, Research Grant: Chugai Pharmaceutical; Financial Interests, Institutional, Research Grant: Daiichi Sankyo; Financial Interests, Institutional, Research Grant: Eisai; Financial Interests, Institutional, Research Grant: Lilly; Financial Interests, Institutional, Research Grant: Medi Science; Financial Interests, Institutional, Research Grant: MSD; Financial Interests, Institutional, Research Grant: Ono Pharmaceutical; Financial Interests, Institutional, Research Grant: Sumitomo Dainippon; Financial Interests, Institutional, Research Grant: Taiho Pharmaceutical. All other authors have declared no conflicts of interest.