Exposure-Response (E-R) for Ocular Safety Endpoints for Belantamab Mafodotin (Belamaf), a B-Cell Maturation Antigen (BCMA)-Targeting Agent, in Patients with Relapsed/Refractory Multiple Myeloma (RRMM) in the DREAMM-2 Study
Authors: Ferron-Brady Geraldine , Rathi Chetan , Collins Jon , Struemper Herbert , Opalinska Joanna , Jewell Roxanne C 
Published: November 2020

Introduction: Belamaf (GSK2857916) is a first-in-class BCMA-targeting antibody-drug conjugate (ADC) with a humanized afucosylated anti-BCMA mAb conjugated to a cytotoxic payload mafodotin (MMAF) by a protease-resistant maleimidocaproyl linker (mc). This 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 release of markers characteristic of immunogenic cell death. This analysis assessed the E-R relationships for ocular safety endpoints in the DREAMM-2 study (NCT03525678; Lonial et al. Lancet Oncol 2020).
Methods: Heavily pretreated patients with RRMM were administered belamaf 2.5 or 3.4 mg/kg intravenously every 3 weeks in the pivotal Phase II study, DREAMM-2 (N=218; Lonial et al., Lancet Oncol 2020). Population pharmacokinetic (PK) models of belamaf and cys-mcMMAF were developed and used to predict individual Cycle 1 exposure measures (Ferron-Brady et al., AACR 2020; presentation CT196). Exposure-safety analyses evaluated the probability of Grade ≥2 or ≥3 corneal adverse event (CAE; based on ocular examination and graded using a study-specific keratopathy and visual acuity [KVA] scale), or ocular events including Grade ≥1 or ≥2 blurred vision or dry eye (graded with Common Terminology Criteria for Adverse Events [CTCAE] v4.03), definite worsening in best corrected visual acuity (BCVA) in the better-seeing eye, and unilateral or bilateral worsening in BCVA to 20/50 or worse (BCVA measured with Snellen scale). The time to first occurrence of these events was also evaluated. Generalized linear models were used to assess event probabilities, while Cox proportional hazard models were used to assess time to event endpoints. Baseline patient characteristics, including serum levels of free soluble BCMA (sBMCA), a marker of disease burden, and history of eye conditions (Popat et al., ASH 2020; presentation TBD), were also evaluated for association with these endpoints.
Results: Higher belamaf Ctau (the predicted concentration on Day 21 at the end of the first cycle) was associated with greater probability of developing Grade ≥2 or ≥3 CAE as well as an earlier onset of these events. History of dry eye was associated with an increased probability of Grade ≥2 CAE; lower baseline sBCMA level was associated with higher probability of Grade ≥2 or ≥3 CAE. Higher belamaf Ctau was not found to be associated with probability of occurrence or timing of first occurrence of blurred vision, dry eye (Ferron-Brady et al. AACR 2020; presentation CT196), definite worsening in BCVA, and unilateral or bilateral worsening in BCVA to 20/50 or worse.Lower baseline sBCMA level was associated with higher probability of occurrence for most of these endpoints, with some showing an earlier occurrence. History of dry eye was associated with higher probability of any grade of blurred vision, while presence of keratopathy at baseline increased the probability of a Grade ≥2 blurred vision with an earlier occurrence of any grade and Grade ≥2 blurred vision.
Conclusions: After accounting for patient and disease factors, higher belamaf exposure (Ctau) was associated with an increased probability of corneal AEs (KVA scale) but not with other ocular events (e.g., blurred vision, dry eye, or worsening in visual acuity) in integrated E-R safety analyses of DREAMM-2.
Funding: GSK (Study 205678); drug linker technology licensed from Seattle Genetics; mAb produced using POTELLIGENT Technology licensed from BioWa.

Disclosures
Ferron-Brady: GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Rathi:GSK: Current Employment, Current equity holder in publicly-traded company. Collins:GSK: Current Employment, Current equity holder in publicly-traded company. Struemper:GSK: Current Employment, Current equity holder in publicly-traded company. Opalinska:GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Jewell:GSK: Current Employment, Current equity holder in publicly-traded company; Novartis: Current equity holder in publicly-traded company.