Abstract 592P
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 serous ovarian cancer. An ER analysis was conducted across 3 studies to understand the impact of MIRV, DM4, and S-methyl-DM4 (SmDM4) metabolite exposure on efficacy and safety in pts with FRα-positive tumors.
Methods
A validated population pharmacokinetic model was used to derive the exposure metrics including area under the concentration-time curve (AUC) and trough concentration for eligible pts in 3 studies, 2 studies (n=445) with extensive sampling and a 3rd study (n=97) with sparse sampling. The objective response rate (ORR) and progression free survival (PFS) were analyzed as well as adverse events (AE) of grade 2 or higher. Logistic regression and Cox proportional hazard approach were used, and covariate search was performed.
Results
The AUC and trough concentration of MIRV were found to correlate with efficacy. Higher exposure to MIRV resulted in higher probability of therapeutic response in both study pools in terms of ORR (p<0.01) and PFS (p<0.03). In the safety analysis, MIRV AUC was the exposure parameter that correlated best with ocular AEs. The incident rate of grade 2+ ocular AEs increased with increasing MIRV exposure (p<0.01 for the pooled analysis). The overall ER relationship for peripheral neuropathy was flat. MIRV exposure did not have a significant impact on pneumonitis. The exposures of the payload, DM4, or the metabolite, SmDM4, were not found to associate with either efficacy or safety. Covariates, including patient demographics and clinical laboratory test results, identified in this model had limited impact of efficacy and safety, and are likely not of clinical significance.
Conclusions
ER analysis demonstrated that both efficacy and probability of ocular toxicity correlate with exposure of MIRV. The analyses support the final recommended dose of 6 mg/kg based on adjusted ideal body weight every 3 weeks with balanced efficacy and safety.
Clinical trial identification
NCT01609556, NCT02631876, NCT04296890.
Editorial acknowledgement
Legal entity responsible for the study
ImmunoGen.
Funding
ImmunoGen.
Disclosure
U.A. Matulonis: Financial Interests, Institutional, Other, Investigator: ImmunoGen. 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. D. O'Malley: Financial Interests, Institutional, Other, Investigator: Immunogen.