Background: Belantamab mafodotin (GSK2857916) is a first-in-class B-cell maturation antigen (BCMA)-targeting immunoconjugate with a humanized afucosylated anti-BCMA mAb conjugated to a cytotoxic payload mafodotin (MMAF) by a protease-resistant maleimidocaproyl linker (mc). This antibody-drug conjugate (ADC) binds to BCMA and eliminates MM cells by a multimodal mechanism. It delivers MMAF to MM cells which inhibits microtubule polymerization, resulting in apoptosis, enhances antibody-dependent cellular cytotoxicity and phagocytosis, and induces immunogenic cell death. This analysis assessed PopPK of ADC and cys-mcMMAF and E-R relationships for key endpoints to contribute to monotherapy dose selection. Methods: Heavily pretreated RRMM patients were administered intravenous (IV) doses ranging from 0.03 to 4.6 mg/kg Q3W in DREAMM-1 (n=73) and doses of 2.5 or 3.4 mg/kg Q3W in the pivotal phase 2 study (DREAMM-2; n=218). PopPK models of ADC and cys-mcMMAF were developed and used to predict individual Cycle 1 exposure measures. Exposure-efficacy analyses evaluated the probability of response (PoR), duration of progression-free survival (PFS), and time to response or best response (TTR, TTBR). Exposure-safety analyses evaluated the probability of grade ≥2 or ≥3 ocular exam finding (OEF), grade ≥3 thrombocytopenia (TCP) or neutropenia (NTP), and infusion-related reactions (IRR). Generalized linear models were used to assess event probabilities, while Cox proportional hazard models were used to assess time to event endpoints. Results: The PK data were described well by two-compartment models with linear elimination. The ADC model included time-varying clearance influenced by disease-related factors and body weight. The cys-mcMMAF model included decreasing MMAF:mAb ratio after each dose. In DREAMM-2, PoR and PFS were not related to drug exposure when accounting for the inverse relationship to baseline disease factors. TTR but not TTBR was inversely related to ADC trough concentration (Ctau). Safety endpoints were strongly associated with exposure. Higher ADC Ctau was associated with probability of developing OEF and inversely correlated to time to onset of OEF. Baseline disease factors were inversely associated with probability of OEF. Higher cys-mcMMAF maximum concentration and lower baseline platelet count were associated with increased probability of TCP. No factors were found for probability of NTP or IRR. Conclusion: Integrated E-R analyses suggested that, after accounting for patient and disease factors, increased probability of OEF and TCP with higher exposure or dose was not associated with a commensurate improvement in efficacy in DREAMM-2, supporting a monotherapy dose of 2.5 mg/kg IV Q3W of belantamab mafodotin in RRMM patients. Support: Funded by GSK. Drug linker technology was licensed from Seattle Genetics (Bothell, WA, USA) and the monoclonal antibody was produced with POTELLIGENT Technology licensed from BioWa (Princeton, NJ, USA).
Citation Format: Geraldine Ferron-Brady, Chetan Rathi, Jon Collins, Herbert Struemper, Joanna Opalinska, Roxanne C Jewell. Therapeutic dose selection for belantamab mafodotin, a BCMA-targeting agent, in patients with relapsed/refractory multiple myeloma (RRMM): Application of population pharmacokinetics (PopPK) and exposure-response (E-R) analyses [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT196.