Characterization of Ocular Adverse Events in Patients Receiving Belantamab Mafadotin for ≥12 Months: Post-Hoc Analysis of DREAMM-2 Study in Relapsed/Refractory Multiple Myeloma

S. LONIAL1; A.K. NOOKA1; P. THULASI2; A.Z. BADROS3; B.H. JENG3; N.S. CALLANDER4; D. SBOROV5; B.E. ZAUGG6; R. POPAT7; S. DEGLI ESPOSTI8; J. BARON9; A. DOHERTY9; E. LEWIS10; J. OPALINSKA9; P. PAKA9; T. PIONTEK9; I. GUPTA9; A.V. FAROOQ11; A. JAKUBOWIAK11 | 1Emory University, Winship Cancer Institute, Atlanta, GA, USA; 2Emory Eye Center, Emory University, Atlanta, GA, USA; 3University of Maryland School of Medicine, Baltimore, MD, USA; 4University of Wisconsin, Carbone Cancer Center, Madison, WI, USA; 5Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA; 6Moran Eye Center, University of Utah, Salt Lake City, UT, USA; 7University College London Hospitals, NHS Foundation Trust, London, UK; 8NIHR Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, London, UK; 9GlaxoSmithKline, Collegeville, PA, USA; 10GlaxoSmithKline, Research Triangle Park, NC, USA; 11University of Chicago Medical Center, Chicago, IL, USA

Dose delays and reductions related to ocular adverse events INTRODUCTION RESULTS All 14 patients required ≥2 dose delays, with dose reduction (to 1.92 mg/kg) in CONCLUSIONS Belantamab mafodotin (belamaf; GSK2857916) is a first-in-class, monomethyl auristatin F (MMAF)-containing 12 patients (86%). Demographics, efficacy, and overall safety information for patients treated with belamaf In this subset of 14 patients from the DREAMM-2 study, the median duration of response was antibody–drug conjugate (ADC) that binds to B-cell maturation antigen (BCMA) and eliminates multiple myeloma cells by for ≥12 months ● Patients experienced a mean of 3.6 dose delays over the ≥12 months of treatment a multimodal mechanism of action.1 (median: 3.5, range: 2–6). 12.5 months. A total of 97 patients were randomized to the belamaf 2.5 mg/kg cohort; 14 patients (15%) Over the course of belamaf treatment, patients and clinicians should expect dose delays Belamaf is approved for the treatment of adult patients with heavily pretreated relapsed or refractory multiple myeloma received ≥12 months of treatment with 2.5 mg/kg Q3W belamaf at the data cut-off ● Ten patients (71%) required dose delays of >63 days. 2,3 related to ocular events. (RRMM). (patient demographics in Table 1). There was a trend towards a decrease in duration of delays over the course of the treatment (Figure Durable responses observed with single-agent belamaf were sustained at the 13-month analysis of the ● The mean (SD) time on belamaf treatment was 62.2 (6.3) weeks; the median was 61.5 (54.4– 3A) with a median duration of 42 days (range: 4–212). All patients had at least 2 dose holds, and 10 patients had dose holds longer than 63 days. DREAMM-2 study (NCT03525678).4 75.4) weeks. ● Earlier dose delays tended to be longer than later delays (Figure 3A). Dose modifications were effective in managing ocular symptoms and decreasing findings at eye ● In patients receiving 2.5 mg/kg belamaf, the estimates for median duration of response and overall survival were ● Most patients (8/14; 57%) were in the 65 to <75 years age group. ● The median latency until first delay was 66.5 days (range: 22–213; Figure 3B); patients examinations, therefore allowing patients to stay on therapy and gain the clinical benefit of 11 months and 13.7 months, respectively.4 ● The median duration of response was 12.5 months. experienced shorter duration between delays over the course of therapy. continuing treatment with belamaf. Corneal events are a known side-effect of MMAF-containing ADCs.5 ● 29% of the patients had completed 7 prior lines of therapy (Table 2). Figure 3: (A) Median duration of dose delays and (B) median duration between dose delays The safety profile of belamaf will be further characterized in ongoing analyses and studies. ● In DREAMM-2, corneal events including keratopathy (superficial punctate keratopathy and/or microcyst-like ● The most common non-ocular adverse events were nausea (50%, n=7), diarrhea (43%, n=6), A Duration of dose delay B Duration between delays epithelial changes [MECs], an eye examination finding with/without symptoms), change in best-corrected visual 66.5 62.5 (22-213) arthralgia (36%, n=5), constipation (26%, n=5), infusion-related reaction (36%, n=5) and 70 (18-107) 70 acuity (BCVA), or symptoms (blurred vision and dry eye) were common adverse events (AEs) reported 52.5* 60 6,7 pyrexia (36%, n=5). 60 (6-212) 44.0 45.0 43.0 42.0 during treatment. 42.0 (23-87) (23-88) (23-65) 50 (7-81) 50 (4-87) 33.0 31.0 40 40 (23-43) ● Belamaf-related corneal events were adequately managed with dose modifications (delays or reductions) or (22-40) 23 30 20.5 30 (23-65) 7 (4-28) treatment discontinuation in DREAMM-2; no complete loss of vision has been reported. 20 20 Table 1: Demographics and baseline characteristics (days) Duration DISCLOSURES ̶ Durable responses to belamaf have been observed with dose modifications. 6 (days) Duration 10 10 SL received research funding from Celgene and Takeda, and personal fees from Amgen, Bristol Myers Squibb, Celgene, Belamaf 2.5 mg/kg 0 0 GlaxoSmithKline, Janssen, Merck, Novartis, and Takeda. PT has no disclosures beyond employment. AKN has received 7 Longer-term management of AEs such as ocular events needs to be characterized more fully to optimize clinical care. (n=14) 1 2 3 4 5 6 0 to 1 1 to 2 2 to 3 3 to 4 4 to 5 5 to 6 consulting fees from Amgen, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Janssen Oncology, Karyopharm Therapeutics, n = 14 14 9 7 4 2 n = 14 14 9 7 4 2 Age, years, mean (SD; range) 65.1 (9.2; 47─81) Oncopeptides, Spectrum Pharmaceuticals, and Takeda; research funding from Amgen, Janssen Oncology, and Takeda; and *Median (range) personal fees from GlaxoSmithKline. AZB has received consulting fees from Amgen. BHJ has received consulting fees from Sex, female, n (%) 6 (43) GlaxoSmithKline, Kedrion, Sanofi, Santen, and Merck and holds stocks/shares in EyeGate. NSC has nothing to disclose. DS ISS stage at screening, n (%) Profile plots of individual patients: corneal events (KVA graded), dose modifications has received consulting fees from Amgen, GlaxoSmithKline, Janssen, Legend Biotech, Sanofi, and SkylineDx; and honoraria 6 (43) I (delays and reductions), and duration of response and personal fees from Janssen. BEZ has received consulting fees from GlaxoSmithKline. RP has received consulting fees 4 (29) II from AbbVie, Celgene, GlaxoSmithKline, and Takeda; research funding from Takeda; honoraria from Celgene, 4 (29) Dose delays or reductions permitted recovery from ocular events, allowing treatment to be resumed III GlaxoSmithKline, Janssen, and Takeda; and travel expenses from GlaxoSmithKline, Janssen, and Takeda. SDE has received multiple times in all 14 patients (Figure 4). consulting fees and honoraria from GlaxoSmithKline. AD, JB, TP, EL, JO, PP, and IG are paid employees of GlaxoSmithKline; OBJECTIVE Race, n (%) JB, TP, and JO hold stocks/shares in GlaxoSmithKline; and IG holds stocks/share in GlaxoSmithKline and Novartis. AF has Black or African American 3 (21) Figure 4: Profile plots of patients with corneal events graded on the KVA scale* received consulting fees from GlaxoSmithKline, Five Prime Therapeutics, and Secure Transfusion Services. AJ has received To characterize the ocular safety profile of belamaf in patients treated for ≥12 months, in a post-hoc analysis of the White 10 (71) consulting fees and honoraria from AbbVie, Adaptive, Amgen, Bristol-Myers Squibb, Celgene, Janssen, Juno, and 2.5 mg/kg arm of the DREAMM-2 study at 13-month follow-up. Asian 1 (7) Karyopharm. Extramedullary disease, n (%) 1 (7) High-risk cytogenetic features*, n (%) 6 (43) Prior lines of therapy, median (range) 5 (3─8) *Any of the following cytogenetics: t(4:14), t(14;16), del17p13. METHODS SD, standard deviation. ACKNOWLEDGEMENTS This study was funded by GlaxoSmithKline (Study 205678, NCT03525678). Drug linker technology licensed from DREAMM 2 is an ongoing, open label, two-arm, randomized, multicenter study of single-agent belamaf 2.5 or 3.4 mg/kg, Seagen Inc.; monoclonal antibody produced using POTELLIGENT Technology licensed from BioWa. intravenously every 3 weeks (until disease progression or unacceptable toxicity) in patients with RRMM who are The authors acknowledge Alessandra Tosolini, BS for her contributions in overseeing the study, and her involvement in the refractory to an immunomodulatory drug and proteasome inhibitor, and were refractory or intolerant (or both) to an Table 2: Prior lines of therapy completed at screening review and interpretation of data presented in this poster. 6 anti-CD38 monoclonal antibody (Figure 1). Editorial assistance was provided by Jiah Pearson-Leary, PhD, of Fishawack Indicia Ltd, part of Fishawack Health, Belamaf 2.5 mg/kg ● The data presented in this poster are based on a snapshot of existing information at the time of the cutoff. Patients and funded by GlaxoSmithKline. Prior line n (%) from DREAMM-2 who received belamaf 3.4 mg/kg are not included. < 3 lines 0 Figure 1. DREAMM-2 study design with focus on ocular toxicity monitoring4,6 3 lines 3 (21) 4 lines 2 (14) Treatment until disease 5 lines 3 (21) progression or Primary outcome Key secondary outcomes REFERENCES unacceptable toxicity 6 lines 0 1. Tai YT, Mayes PA, Acharya C, Zhong MY, Cea M, Cagnetta A, et al. Novel anti-B-cell maturation antigen antibody-drug 7 lines 4 (29) conjugate (GSK2857916) selectively induces killing of multiple myeloma. Blood. 2014;123(20):3128–38. Belamaf 2.5 mg/kg 8 lines 2 (14) ● DoR (time from ≥PR until 2. BLENREP US Label. [Cited 2021 May 13]. Available from: IV, Q3W https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/761158s000lbl.pdf (n=97) disease progression 9 lines 0 or death due to PD) ORR: 3. BLENREP EU Label [Cited 2021 May 13]. Available from: https://www.ema.europa.eu/en/documents/product- ● Other efficacy: CBR, PFS, % of patients with ≥PR information/blenrep-epar-product-information_en.pdf (IMWG 2016 criteria)8 OS, TTBR, TTP, TTR Belamaf 3.4 mg/kg Screening ● Safety, including 4. Lonial S, Lee HC, Badros A, Trudel S, Nooka A, Chari A, et al. DREAMM-2: single-agent belantamab mafodotin Patients: Randomization IV, Q3W ≥3L RRMM keratopathy (MECs), BCVA 1:1* (n=99) Ocular events (belamaf) in patients with relapsed/refractory multiple myeloma (RRMM) – 1-year outcomes by prior therapies. All 14 patients experienced keratopathy and 13 patients had ocular symptoms, which are Presented at 62nd American Society of Hematology Annual Meeting and Exposition, 2020. Ocular toxicity monitoring in the DREAMM-2 study† Ocular examinations in the DREAMM-2 study summarized in Table 3. 5. Eaton JS, Miller PE, Mannis MJ, Murphy CJ. Ocular adverse events associated with antibody-drug conjugates in human clinical trials. J Ocul Pharmacol Ther. 2015;31(10):589–604. Keratopathy and blurred vision led to the most dose modifications (Table 3). Patients had regular ocular examinations (at baseline, prior to each treatment cycle, or Q3W) 6. Lonial S, Lee HC, Badros A, Trudel S, Nooka AK, Chari A, et al. Belantamab mafodotin for relapsed or refractory by an eye care professional multiple myeloma (DREAMM-2): a two-arm, randomised, open-label, phase 2 study. Lancet Oncol. 2020;21(2): 207–21. To fully characterize corneal events, a protocol-specified KVA scale was used, which focused on Table 3: Drug-related ocular events, and ocular events leading to dose modifications corneal exam findings (slit lamp examination identifying changes in the corneal epithelium, 7. Farooq AV, Degli Esposti S, Popat R, Thulasi P, Lonial S, Nooka AK, et al. Corneal epithelial findings in patients with termed superficial punctate keratopathy [MECs; also reported as keratopathy AEs, Patients with drug- Patients with ocular Patients with ocular multiple myeloma treated with antibody-drug conjugate belantamab mafodotin in the pivotal, randomized, with or without symptoms]) as well as changes in BCVA (measured by the Snellen Test) related ocular adverse events leading adverse events leading DREAMM-2 study. Ophthalmol Ther. 2020;9(4):889–911. Keratopathy (MECs) Graded on BCVA‡ Patient-reported ocular symptoms (eg, blurred vision and dry eye) and keratopathy were reported as Slit-lamp exam KVA scale adverse events to dose reduction to dose delays 8. Kumar S, Paiva B, Anderson KC, Durie B, Landgren O, Moreau P, et al. International Myeloma Working Group AEs and assessed by CTCAE criteria (v4.03)9 n (%) n (%) n (%) consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol. Keratopathy 14 (100) 10 (71) 13 (93) 2016;17(8):e328-e346 *Patients stratified based on number of previous lines of therapy (≤4 vs >4) and presence or absence of HR cytogenetic features; †Please check your local belamaf prescribing information for guidance on ocular toxicity monitoring. ‡BCVA was assessed by manifest refraction using the Snellen eye chart. Vision blurred 8 (57) 1 (7) 3 (21) 9. National Cancer Institute. [Updated 2010; Cited 2021 May 13]. Available from: https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf AE, adverse event; BCVA, best-corrected visual acuity; CBR, clinical benefit rate; CTCAE, Common Terminology Criteria for Adverse Events; HR, high-risk; IMWG, International Dry eye 5 (36) 0 1 (7) myeloma working group; KVA, keratopathy and visual acuity; MECs, microcyst-like epithelial changes; ORR, overall response rate; OS, overall survival; PD, progressive disease; *The data in Figure 4 represent a snapshot of each patient’s journey. In a number of cases treatment has continued well after the 504 days PFS, progression-free survival; PR, partial response; Q3W, every 3 weeks; RRMM, relapsed/refractory multiple myeloma; TTBR, time to best response; TTP, time to progression; TTR, Photophobia 3 (21) 0 0 presented in Figure 4. Some of these patients remain on belamaf treatment >900 days. All relevant information for the complete journey cannot time to response. be captured by snapshots when treatment extends well beyond the cutoff. Visual acuity reduced 3 (21) 0 0 KVA grade at each dose delay is displayed. Duration on treatment is only displayed for non-responders in order to help distinguish between patients in the figure. Time on study drug does not exclude dose delays. As outlined in the SmPC and US PI, dose modifications (dose reductions or delays) determined by ocular events were Ocular discomfort 2 (14) 0 1 (7) AE, adverse event; CR, complete response; KVA, keratopathy and visual acuity; MR, minimal response; NE, not evaluable; based on the severity of eye exam findings and BCVA changes from baseline using the keratopathy and visual acuity Visual impairment 2 (14) 0 0 PD, progressive disease; sCR, stringent complete response; SD, stable disease; VGPR, very good partial response. 2,3 (KVA) scale. Glaucoma 1 (7) 0 1 (7) CONTACT INFORMATION Clinical benefit in patients with long dose delays (>63 days) Sagar Lonial, [email protected] ● Keratopathy (including superficial punctate keratopathy and/or microcyst-like epithelial changes) was graded from Retinal hemorrhage 1 (7) 0 1 (7) Dose delays or reductions permitted recovery of ocular events, allowing treatment to be resumed 0 (none), 1 (mild superficial keratopathy), 2 (e.g., moderate superficial keratopathy), 3 (e.g., severe superficial Ulcerative keratitis 1 (7) 0 1 (7) multiple times in all 14 patients ( ). keratopathy) Figure 4 Vitreous detachment 1 (7) 0 0 to 4 (corneal epithelial defect). ● 12 patients had a clinical response (partial response or better) and 11 patients had a clinical Copies of this poster obtained through Quick Response (QR) Code are for response for ≥6 months. personal use only and may not be reproduced without permission from GSK. ● Recovery was defined as Grade 1 exam findings/no exam findings, and ≤1-line decline in BCVA vs baseline. The QR code will be activated August 15. Please re-visit this presentation on 9 ● Of the 10 patients with dose delays >63 days, 5 patients had a response of VGPR or CR (Figure 4). ● Patient-reported ocular symptoms were graded per Common Terminology for Adverse Events (CTCAE) version 4.03. August 15 to retrieve a downloadable version via this QR code.