Combinations of belantamab mafodotin with lenalidomide, pomalidomide, bortezomib and/or dexamethasone synergize in vitro and potentiate in vivo anti-tumor activity in multiple myeloma Poster No. 6711

Rocio Montes De Oca1*, Ira Gupta1, Chris Shelton1 1GlaxoSmithKline, 1250 South Collegeville Ave, Collegeville, PA, 19426

Background Figure 3. Single-agent activity of bortezomib, lenalidomide, pomalidomide, and Figure 5. Activity of belantamab mafodotin in combination with bortezomib, ● In vitro combination synergy was analyzed based on the Bliss independence dexamethasone in two MM cell lines lenalidomide, pomalidomide and dexamethasone in two MM cell lines (cont.) principle, which is appropriate when two drugs are mutually nonexclusive and/or ● Multiple myeloma (MM) is a hematological malignancy that affects plasma cells and have different mechanisms of action.5 leads to devastating clinical features. Typically, front line and relapsed/refractory OPM-2 OPM-2 120 120 MM (RRMM) treatments comprise standard of care (SOC) combinations that include Bor Len ● The Bliss model showed potential synergy in both cell lines with all agents to 100 Dex 100 Pom 80 proteasome inhibitors (e.g., bortezomib [Bor]), immunostimulatory drugs (e.g., 80 ● Dose response varying degrees, particularly when the combinations employed lower doses of 60 lenalidomide [Len] or pomalidomide [Pom]) and/or a steroid (e.g., dexamethasone 60 40 OPM-2 OPM-2 curves and Bliss 3D each drug than those used when delivered as single agents. [Dex]). While these therapies have significantly improved patient outcomes, the 20 40 916+Bor 916+Len response surface Survival (%) 1 T0 Survival (%) T0 ● Belantamab mafodotin had significant tumor growth inhibition efficacy and disease remains incurable and novel targeted therapies are urgently needed. 0 20 plots show synergy -20 0 between belantamab provided a survival advantage when administered as monotherapy in the OPM-2 ● Belantamab mafodotin (belamaf; GSK2857916) is a promising candidate for the 0.0001 0.001 0.01 0.1 1 10 0.0001 0.001 0.01 0.1 1 10 100 mafodotin and SOC and MOLP-8 (not shown) MM xenograft models. treatment of MM. In the primary analysis of the pivotal, Phase II study DREAMM-2 Concentration (µM) Concentration (µM) agents in OPM-2 cells. (NCT03525678), single-agent belamaf demonstrated an acceptable safety profile MOLP-8 MOLP-8 ● Belantamab mafodotin combinations with immunomodulatory drugs (IMiDs) and rapid, deep and durable clinical responses (at a follow-up of 13 months, overall 120 120 (e.g., Len or Pom) or Bor provided additional benefit compared with each single survival was 14.9 and 14.0 months and duration of response was 11 and 6.2 Bor Len ● Similar in vitro 100 Dex 100 Pom combinatorial activity agent by significantly increasing tumor growth inhibition and survival in the OPM-2 months in the 2.5 mg/kg and 3.4 mg/kg cohorts, respectively) in patients with heavily 80 80 was obtained in the 2,3 60 OPM-2 OPM-2 model. Similar results were obtained with the MOLP-8 model, but to a lesser extent. pretreated MM. 60 MOLP-8 cells (not 40 916+Dex 916+Pom Figure 1. Mechanisms of action of 40 shown), but to a ● Combining belantamab mafodotin with Dex in double or triple combinations did

● Belantamab mafodotin targets the Survival (%) 20 T0 Survival (%) 20 T0 lesser extent. B-cell maturation antigen (BCMA) belantamab mafodotin 0 not provide significant added benefit compared to single agents or double 0 protein, highly expressed in MM 0.0001 0.001 0.01 0.1 1 10 0.0001 0.001 0.01 0.1 1 10 100 combinations, respectively. Belantamab µ mafodotin ADC Concentration ( M) Concentration (µM) and other B cell malignancies. Synergy score (Bliss) 3D response surface plots. ADCC/ADCP Belantamab mafodotin is an BCMA Fc immunoconjugate that consists of receptor ● Treatment of OPM-2 cells with Bor, Dex, Len, or Pom led to direct cell kill. Conclusions Lysosome BCMA Figure 6. In vivo combination of belantamab mafodotin with lenalidomide, a humanized afucosylated anti- Effector ● Direct cell kill of MOLP-8 cells was only observed with Bor treatment. cell bortezomib and/or dexamethasone in the OPM-2 xenograft model BCMA monoclonal antibody BCMA ● IC (µM) and maximum growth inhibition (%) values are shown in . ● In vitro, belantamab mafodotin as a single agent demonstrated direct cell kill (GSK2857914) conjugated to the BCMA 50 Table 1 Saline activity in OPM-2 and MOLP-8 cells after 72 hours of exposure. Treatment of microtubule inhibitor monomethyl Vehicles + IgG-MMAF Table 1. IC50 and maximum growth inhibition OPM-2 cells with Bor, Dex, Len or Pom also led to direct cell kill. However, direct auristatin-F (MMAF) that enables Malignant plasma 916 MOLP-8 OPM-2 cell kill of MOLP-8 cells was only observed with Bor treatment. Combining anti-tumor activity by: 1) direct cell cell Compound Len + IgG-MMAF kill (ADC), 2) antibody-dependent IC50 (µM) Max inh.(%) IC50 (µM) Max inh.(%) belantamab mafodotin with each SOC agent led to synergistic activity in both cellular cytotoxicity or cellular GSK2857916 1.77 81.3% 0.5 99.1% Len + 916 cell lines. NA 0.7 NA NA phagocytosis (ADCC/ADCP), and GSK2857914 Bor + IgG-MMAF ICD 3) immunogenic cell death (ICD; Bor 0.002 100.6% 0.001 100.1% ● In vivo, belantamab mafodotin induced tumor growth inhibition and provided 4 Bor + 916 Figure 1). Dex NA 7.1% 0.031 65.9% survival advantage when administered as monotherapy to immune-compromised Dex + IgG-MMAF mice bearing OPM-2 and MOLP-8 xenografts. Combinations with Len, Pom, or ● To determine potential combinatorial activity, we conducted in vitro and in vivo Len NA -8.1% NA 44.4% Bor enhanced this anti-tumor activity and provided additional survival benefit studies of belantamab mafodotin in double and/or triple combinations with MM SOC Pom NA -6.9% 1.110 57.8% Dex + 916 compared to each single agent. agents (Bor, Dex, Len, or Pom) in two MM models: OPM-2 and MOLP-8. Bort + Dex + IgG-MMAF Figure 4. Activity of belantamab mafodotin in combination with bortezomib, Bort + Dex + 916 ● The observed synergy in in vitro cell cultures and in vivo xenograft models lenalidomide, pomalidomide, and dexamethasone in two MM cell lines Methods Dosing started at Day 12 after cell inoculation. provided preclinical evidence for combining belantamab mafodotin with IMiDs or Concentrations GSK2857916 Bor Dex Len Pom 916 or IgG-MMAF (isotype control) were Bor in MM. Selected combinations are currently under clinical evaluation in ● We evaluated direct cell kill activity of GSK2857916, GSK2857914 (naked antibody tested (μg/mL) (μM) (μM) (μM) (μM) dosed BIW x 2 wk at 2 mg/kg. Len was dosed RRMM in the DREAMM-6 trial. QDx4 x 2 wk at 10 mg/kg. Bor was dosed BIW without MMAF toxin) and SOC agents (Len, Pom, Bor, Dex) in two human MM cell lines. 50, 12.5, 3.125, 0.01, 0.0033, 10, 3.333, 1.111, 30, 10, 3.333, 30, 10, 3.333, x 2 wk at 1 mg/kg. Dex was dosed QD x 2 wk MOLP-8 0.7813, 0.1953, 0.0011, 0.00037, ● Additionally, we evaluated tumor growth inhibition and effects on survival of 0.3704, 0.1235 1.111, 0.3704 1.111, 0.3704 0.0488, 0.0122 0.00012 BIW, twice per week; QD, once per day; IgG, immunoglobulin G. at 3 mg/kg. GSK2857916 and SOC as single agents and/or in combination in murine 50, 12.5, 3.125, 0.01, 0.0033, subcutaneous xenograft models using the same two MM cell lines. 0.3, 0.1, 0.033, 10, 2, 0.4, 0.08, 10, 2, 0.4, 0.08, OPM-2 0.7813, 0.1953, 0.0011, 0.00037, 0.011, 0.0037 0.016 0.016 0.0488, 0.0122 0.00012 Figure 7. In vivo combination of belatamab mafodotin with pomalidomide and/or dexamethasone in the OPM-2 xenograft model Results OPM-2 OPM-2 916+Bor 916+Len Vehicle + IgG-MMAF References 120 120 916 + Bor (µM) 0.01 916 + Len (µM) 10 Figure 2. Single-agent activity of belantamab mafodotin (GSK2857916) versus 100 916 + Bor (µM) 0.0033 100 916 + Len (µM) 2 916 µ unconjugated antibody (GSK2857914) in two MM cell lines 80 916 + Bor ( M) 0.0011 80 916 + Len (µM) 0.4 1. Goldschmidt, et al. Annals of Hematology (2019) 98:1–18. 916 + Bor (µM) 0.00037 916 + Len (µM) 0.08 60 60 2. Lonial S, et al. Lancet Oncology (2020) 21(2):207–21. 916 + Bor (µM) 0.00012 916 + Len (µM) 0.016 Pom + IgG-MMAF MOLP-8 3. Lonial S, et al. ASCO (2020) Poster 436. OPM-2 40 916 40 916 % Survival % % Survival % 120 120 4. Tai, Y.T. & Anderson, K.C. Immunotherapy (2015) 11:1187-99. 20 20 Pom + 916 100 100 5. Bliss, C.I. Annals of Applied Biology (1939) 26:585–615. 0 0 80 80 GSK2857914 GSK2857914 0.001 0.01 0.1 1 10 100 0.001 0.01 0.1 1 10 100 Dex + IgG-MMAF 60 60 µg/mL µg/mL GSK2857916 GSK2857916 40 40 OPM-2 OPM-2 Disclosures and acknowledgments % Survival % % Survival % Cisplatin Dex + Pom + IgG-MMAF 20 Cisplatin 20 916+Dex 916+Pom 0 0 120 120 -20 -20 916 + Dex (µM) 0.3 916 + Pom (µM) 10 Dex + Pom + 916 ● All authors are employees of GlaxoSmithKline (GSK) and hold stocks/shares. 0.001 0.01 0.1 1 10 100 0.001 0.01 0.1 1 10 100 100 916 + Dex (µM) 0.1 100 916 + Pom (µM) 2 µ µ Concentration(Concentration (µg/mL)µg/mL) ConcentrationConcentration (µg/mL)(µg/mL) 80 916 + Dex ( M) 0.033 80 916 + Pom ( M) 0.4 ● This study was funded by GSK; drug linker technology licensed from Seattle Genetics; monoclonal 916 + Dex (µM) 0.011 916 + Pom (µM) 0.08 Dosing started at Day 17 after cell inoculation. 60 60 antibody produced using POTELLIGENT Technology licensed from BioWa. All studies were 916 + Dex (µM) 0.004 916 + Pom (µM) 0.016 916 or IgG-MMAF (isotype control) were 40 916 40 916 % Survival % ● GSK2857916 has direct cell kill activity in OPM-2 and MOLP-8 MM cell lines Survival % conducted in accordance with the GSK Policy on the Care, Welfare and Treatment of Laboratory dosed BIW x 2 wk at 2 mg/kg. Pom was compared with the naked antibody GSK2857914. The half maximal inhibitory 20 20 dosed QD x 2 wk at 2.5 mg/kg. Dex was Animals and were reviewed by the Institutional Animal Care and Use Committee either at GSK or by 0 0 the ethical review process at the institution where the work was performed. concentration (IC50) values were 0.5 and 1.77 µg/mL, respectively, for each cell line 0.001 0.01 0.1 1 10 100 0.001 0.01 0.1 1 10 100 dosed QD x 2 wk at 3 mg/kg. after a 72 h exposure to GSK2857916. Cisplatin was used as a positive control. µg/mL µg/mL ● Editorial assistance was provided by Gillian Wallace, MSc, at Fishawack Indicia Ltd, and funded by GSK.

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