Abstract 605P
Background
MIRV is a first-in-class antibody-drug conjugate comprising an FRα-binding antibody, cleavable linker, and maytansinoid DM4 payload for patients (pts) with FRα-positive, high grade serious ovarian cancer (OC). Analysis was conducted across 3 studies to understand the impact of pt characteristics on the PK parameters of MIRV, DM4, and S-methyl-DM4 (SmDM4) metabolite in pts with FRα-positive tumors.
Methods
A base model was developed for MIRV followed by a stepwise covariate search. Structural components were added for DM4 and SmDM4 concentration data while fixing MIRV PK parameters. The final semi-mechanistic model accommodated saturable elimination of MIRV and the payload metabolite. Model construction was based on 2 studies (n=445) with extensive sampling and validated in a 3rd study (n=98) with sparse sampling. The evaluated doses ranged from 0.15 mg/kg to 7 mg/kg total body weight, including the final recommended dose of 6 mg/kg adjusted ideal body weight (AIBW) every 3 weeks, which was administered to 87.8% of total pts.
Results
The population PK model predicted a low clearance (CL), small volume of distribution (Vd), and long elimination half-life (t1/2) for MIRV. Statistically significant covariates include AIBW, serum albumin, and age. Tumor FRα expression was not a significant covariate. AIBW showed an impact on CL and Vd. Albumin showed significant effect on CL but not on Vd. Age did not impact CL and was found to be a minor covariate on Vd. For 6 mg/kg AIBW, the effects of these covariates on the exposures to MIRV do not require dose adjustment. With a terminal elimination t1/2 of 115 hrs (4.8 days), the steady state can be reached in ∼24 days. Mild or moderate renal impairment and mild hepatic impairment did not significantly alter PK. Coadministration with weak, moderate, and strong cytochrome P450 3A4 (CYP3A4) inhibitors did not have clinically meaningful effects on PK parameters for MIRV, DM4, or SmDM4; CYP3A4 inducers were not evaluated.
Conclusions
Population PK analysis supports 6 mg/kg AIBW dosing of MIRV, with exposure to MIRV, DM4, and SmDM4 maintained within the target range. Dosing adjustments would not be required for mild or moderate renal or mild hepatic impaired population.
Clinical trial identification
NCT01609556, NCT02631876, NCT04296890.
Editorial acknowledgement
Legal entity responsible for the study
ImmunoGen.
Funding
ImmunoGen.
Disclosure
K.N. Moore: Financial Interests, Personal, Advisory Board: AstraZeneca, Aravive, Alkemeres, Blueprint Pharma, Eisai, Emd Serono, GSK/Tesaro, Genentech/Roche, Hengrui, ImmunoGen, IMab, Mereo, Myriad, Caris, Mersana, Novartis, Novocure, OncXerna, OncoNova, Tarveda, VBL Therapeutics; Financial Interests, Personal, Full or part-time Employment: GOG Partners Associate Director; Financial Interests, Institutional, Full or Part-time Employment: NRG Ovarian Cancer Chair; Financial Interests, Personal, Royalties: UP to Date; Financial Interests, Institutional, Invited Speaker, international CO-PI, local site PI: AstraZeneca; Financial Interests, Institutional, Invited Speaker: Immunogen, GSK/Tesaro, Lilly, PTC Therapeutics, Daiichi Sankyo, Regeneron, Artios, Bolt, Verastem; Non-Financial Interests, Invited Speaker: GOG. D. Lorusso: Financial Interests, Personal, Advisory Board, Participation in Advisory Boards and Invited Speaker: GSK, Clovis Oncology, PharmaMar; Financial Interests, Personal, Advisory Board, Participation in Advisory Boards and Invited Speakers: AstraZeneca, MSD; Financial Interests, Personal, Other, Consultancy: PharmaMar, Amgen, AstraZeneca, Clovis Oncology, GSK, MSD, Immunogen, Genmab, Seagen; Financial Interests, Personal, Advisory Board, Participation in Advisory Boards: Merck Serono; Financial Interests, Personal, Advisory Board, Invited member of advisory board: Seagen, Immunogen, Genmab, Oncoinvest, Corcept, Sutro; Financial Interests, Institutional, Funding, Grant for founding accdemic trial: MSD, Clovis Oncology, PharmaMar; Financial Interests, Institutional, Funding, Grant for founding acamemic trial: GSK; Financial Interests, Institutional, Invited Speaker, ENGOT trial with institutional support for coordination: Clovis Oncology; Financial Interests, Institutional, Invited Speaker, ENGOT trial with insitutional support for coordination: Genmab, MSD; Financial Interests, Institutional, Funding, Clnical trial/contracted research: AstraZeneca, Clovis Oncology, GSK, MSD, Seagen; Financial Interests, Institutional, Funding, Clinical trials/contracted research: Genmab, Immunogen, Incyte, Novartis, Roche; Non-Financial Interests, Principal Investigator, PI of several trials, no compensation received: GSK; Non-Financial Interests, Principal Investigator, PI of several trials. No personal compensation received: AstraZeneca, Genmab; Non-Financial Interests, Principal Investigator, PI in several trials. No personal compensation received: MSD; Non-Financial Interests, Principal Investigator, PI of clinical trial. No personal compensation received: immunogen, clovis, Incyte; Non-Financial Interests, Principal Investigator, PI of clinical trial. No personal compensation receive: Roche; Non-Financial Interests, Member, Board of Directors: GCIG. A. Oaknin: Financial Interests, Personal, Advisory Board: AstraZeneca, Clovis Oncology, Deciphera Pharmaceuticals, Genmab, GSK, ImmunoGen, Mersana Therapeutics, PharmaMar, Roche, Tesaro, Merck Sharps & Dohme de España, SA, Agenus, Sutro, Corcept Therapeutics, EMD Serono, Novocure, prIME Oncology, Sattucklabs, Itheos, Eisai, F. Hoffmann-La Roche; Financial Interests, Personal, Other, Travel and accomodation: AstraZeneca, PharmaMar, Roche; Financial Interests, Institutional, Funding: Abbvie Deutschland, Advaxis Inc., Aeterna Zentaris, Amgen, Aprea Therapeutics AB, Clovis Oncology Inc, EISAI limited LTD, F. Hoffmann –La Roche LTD, Regeneron Pharmaceuticals, Immunogen Inc, Merck, Sharp & Dohme de España SA, Millennium Pharmaceuticals Inc, PharmaMar SA, Tesaro Inc., Bristol Myers Squibb; Non-Financial Interests, Leadership Role, Executive Board member as a Co-Chair: GEICO; Non-Financial Interests, Leadership Role, Phase II Committee and Cervix Cancer Committee Representative on behalf of GEICO: GCIG; Non-Financial Interests, Officer, Chair of Gynaecological Track ESMO 2019. Scientific Track Member Gynaecological Cancers ESMO 2018, ESMO 2020, ESMO 2022. Member of Gynaecological Cancers Faculty and Subject Editor Gyn ESMO Guidelines: ESMO; Non-Financial Interests, Member: ESMO, ASCO, GCIG, SEOM, GOG. S. Pignata: Financial Interests, Personal, Advisory Board: roche, az, msd, clovis, gsk, PharmaMar; Financial Interests, Institutional, Funding: roche, msd, pfizer, az. H. Denys: Financial Interests, Institutional, Other, Investigator: Immunogen. N. Colombo: Financial Interests, Personal, Advisory Board, Various: Roche, PharmaMar, AstraZeneca, MSD/Merck, Clovis Oncology, Tesaro, GSK, Pfizer, Takeda, BIOCAD, Immunogen, Mersana; Financial Interests, Personal, Invited Speaker, Congress, Symposia, Lectures: AstraZeneca, Tesaro; Financial Interests, Personal, Invited Speaker, Lectures: Novartis; Financial Interests, Personal, Advisory Board, Lectures: Eisai; Financial Interests, Personal, Advisory Board, Advisory role: Nuvation Bio, Pieris; Financial Interests, Personal, Advisory Board, Advisory Role: Onxerna; Financial Interests, Institutional, Research Grant: AstraZeneca, PharmaMar, Roche; Non-Financial Interests, Other, Sterring committee member Clinical Guidelines: ESMO; Non-Financial Interests, Leadership Role, Chair, Scientific Committee: ACTO( Alleanza contro il tumore ovarico). T. Van Gorp: Financial Interests, Institutional, Advisory Board, Apr-2021: MSD; Financial Interests, Institutional, Advisory Board, May-2021 until Dec-2021: GSK; Financial Interests, Institutional, Advisory Board, Feb-2021: OncXerna Therapeutics; Financial Interests, Institutional, Advisory Board, Jan-2021: Eisai, AstraZeneca; Financial Interests, Institutional, Research Grant, Oct-2020 until Oct-2021: Amgen; Financial Interests, Institutional, Research Grant, Oct-2020 onwards: Roche. J. Konner: Financial Interests, Personal, Advisory Board: AstraZeneca, clovis. M. Romeo Marin: Financial Interests, Personal, Expert Testimony, Educational purposes: MSD; Financial Interests, Personal, Advisory Board: GSK; Financial Interests, Institutional, Invited Speaker: Tesaro, MSD, Roche, IMNG. P. Harter: Financial Interests, Personal, Advisory Board, Value includes honoraria for lectures: AstraZeneca; Financial Interests, Personal, Advisory Board, includes honoraria for lectures: GSK, Roche, MSD; Financial Interests, Personal, Invited Speaker: Amgen, Stryker, Zailab; Financial Interests, Personal, Advisory Board: Clovis, ImmunoGen; Financial Interests, Personal, Other, IDMC member: Sotio; Financial Interests, Institutional, Invited Speaker: AstraZeneca, Roche, GSK, Genmab, Immunogen; Financial Interests, Institutional, Funding: Seagen, Clovis. C. Murphy: Financial Interests, Personal, Advisory Board: Daiichi Sanko; Financial Interests, Personal, Invited Speaker: Daiichi Sanko, Janssen. Y. Tu: Financial Interests, Personal, Full or part-time Employment: ImmunoGen. F. Zhu: Financial Interests, Institutional, Full or part-time Employment: Immunogen; Financial Interests, Institutional, Stocks/Shares: ImmunoGen. B. Esteves: Financial Interests, Institutional, Full or part-time Employment, Senior Director, Clinical Development: ImmunoGen; Financial Interests, Institutional, Stocks/Shares: ImmunoGen. M. Method: Financial Interests, Institutional, Full or part-time Employment, Executive Medical Director: Immunogen; Financial Interests, Personal, Stocks/Shares: Immunogen. M.J. Birrer: Financial Interests, Personal, Advisory Board: AstraZeneca, Mersana. R.L. Coleman: Financial Interests, Institutional, Other, Investigator: ImmunoGen. U.A. Matulonis: Financial Interests, Institutional, Other, Investigator: ImmunoGen. D. O'Malley: Financial Interests, Institutional, Other, Investigator: ImmunoGen.