Linker Technology Research Articles

DREAMM-9: Phase III study of belantamab mafodotin plus VRd versus VRd alone in transplant-ineligible newly diagnosed multiple myeloma (TI NDMM).

TPS8556 Background: Bortezomib, lenalidomide, and dexamethasone (VRd) is the standard of care for transplant-eligible and TI NDMM, but relapse is usually inevitable. The median progression-free survival (PFS) is ~3 years for patients with TI NDMM, and with each relapse, the duration of response (DoR) diminishes, highlighting the need for novel, effective, targeted agents. Single-agent belantamab mafodotin is a first-in-class B-cell maturation antigen–binding, humanized, afucosylated, monoclonal immunoconjugate, showing deep and durable responses in heavily pretreated patients with relapsed/refractory multiple myeloma ( Lancet Oncol2020). Preclinical work suggests belantamab mafodotin plus bortezomib or lenalidomide enhances anti-myeloma activity. Therefore, studying clinical activity of belantamab mafodotin in combination with these agents is warranted. Methods: DREAMM-9 (NCT04091126) is a two-part, open-label study to determine efficacy and safety of single-agent belantamab mafodotin with VRd vs. VRd alone in patients with TI NDMM. Patients aged ≥18 years with ECOG status 0–2 and adequate organ system functions will be eligible. Part 1 (dose selection) will evaluate safety/tolerability of belantamab mafodotin with VRd administered by single (Day 1) or split dosing (Days 1 and 8) in ≤5 cohorts (n = 12/cohort): 1.9 mg/kg, 2.5 mg/kg split and single, and 3.4 mg/kg split and single. Six more patients may be added to cohort(s) most likely to be selected as recommended Phase III dose (RP3D). Dose-limiting toxicities and adverse events (AEs) will be assessed, and belantamab mafodotin RP3D determined through modified toxicity probability interval criteria. Part 2 (randomized Phase III) will determine efficacy and safety of belantamab mafodotin at RP3D with VRd vs. VRd alone (n = 750) in two arms randomized 1:1. Dual primary endpoints will be rate of minimal residual disease (MRD) negativity and PFS. Secondary endpoints will be response rates (overall response, complete response, very good partial response or better, sustained MRD negativity), DoR, time to progression, and overall survival. Safety assessment will include AEs, serious AEs and ocular findings. In both parts, belantamab mafodotin will be given with VRd for eight induction cycles and then with Rd for maintenance until disease progression or unacceptable toxicity. Funding: GlaxoSmithKline (209664). Drug linker technology licensed from Seattle Genetics; monoclonal antibody produced using POTELLIGENT Technology licensed from BioWa. Clinical trial information: NCT04091126 .

DREAMM-2: Assessing efficacy via indirect comparison of single-agent belantamab mafodotin versus selinexor plus dexamethasone combination in anti-CD38 exposed relapsed/refractory multiple myeloma (RRMM).

e20527 Background: Single-agent belantamab mafodotin (GSK2857916) is a first-in-class immunoconjugate targeting B-cell maturation antigen that demonstrated deep and durable responses in heavily pretreated patients with RRMM in the pivotal DREAMM-2 study (NCT03525678; Lancet Oncol 2020). Methods: DREAMM-2 included patients with late-line RRMM treated with ≥3 prior lines of therapy, refractory to an immunomodulatory agent and a proteasome inhibitor, with prior exposure to an anti-CD38 antibody. Evidence from Phase II/III trials in a similar patient population was systematically identified following PRISMA guidelines. Based on the specificity of the DREAMM-2 population, selinexor plus low-dose dexamethasone (sel+dex) was identified as the only feasible comparator (STORM Part 2, NCT02336815). Matching-adjusted indirect comparisons (MAIC) were used to investigate the efficacy of single-agent belantamab mafodotin vs. sel+dex. Populations were matched for all clinically validated effect modifiers and prognostic factors with available data. MAIC were performed for overall response rate (ORR), time to response (TTR), duration of response (DoR), progression-free survival (PFS), and overall survival (OS), as per NICE guidelines. Results: Single-agent belantamab mafodotin was more efficacious than sel+dex in terms of OS and DoR (Table). Results for ORR, TTR, and PFS showed no statistical difference between the two regimens. Conclusions: MAIC of single-agent belantamab mafodotin vs. sel+dex in this patient population with RRMM showed significantly improved efficacy on OS and DoR for belantamab mafodotin. Further validation is required owing to limited data availability. Additional safety analyses will further inform comparisons of the two. Clinical trial information: NCT03525678; NCT02336815. Funding: GlaxoSmithKline (207145). Drug linker technology licensed from Seattle Genetics; monoclonal antibody produced using POTELLIGENT Technology licensed from BioWa. [Table: see text]

DREAMM-2: Single-agent belantamab mafodotin (GSK2857916) in patients with relapsed/refractory multiple myeloma (RRMM) and renal impairment.

8519 Background: Renal impairment, a frequent complication and poor prognostic factor in RRMM, often leads to poor tolerability of standard regimens. We report outcomes in patients with renal impairment receiving single-agent belantamab mafodotin (2.5 or 3.4 mg/kg; B-cell maturation antigen targeting immunoconjugate not renally metabolized) from the DREAMM-2 post-hoc analysis (NCT03525678). Methods: Eligible patients with RRMM had no active renal conditions and adequate renal function (based on albumin/creatinine ratio [<500 mg/g] and eGFR [mL/min/1.73 m2]: normal [≥90], mild impairment [mild, ≥60≤90], moderate impairment [mod, ≥30≤60]). Results: Overall response rates (95% CI) in patients with mild/mod impairment (2.5 mg/kg: 32% [21.4–44.0]; 3.4 mg/kg: 36% [25.6–48.5]) were similar to those in the overall population ( Lancet Oncol.2020). The median duration of response (DoR) was not reached (NR) in 2.5 mg/kg mild/mod subgroup (95% CI estimate: 4.2 months–NR); median DoR was 7.5 months (4.9–NR) in 3.4 mg/kg mild/mod subgroup. Rates of keratopathy and albuminuria were similar regardless of renal function; rates of anemia, pyrexia, and thrombocytopenia were more frequent in patients with impaired renal function (Table). eGFR did not change or changed to normal in most patients. Conclusions: Following treatment with single-agent belantamab mafodotin, patients with mild/mod renal impairment achieved a similar efficacy and safety profile as patients with normal renal function. Funding: GlaxoSmithKline (205678). Drug linker technology licensed from Seattle Genetics; monoclonal antibody produced using POTELLIGENT Technology licensed from BioWa. Clinical trial information: NCT03525678 . [Table: see text]

DREAMM-1 Patient perspectives from the first-in-human study of single-agent belantamab mafodotin for relapsed and refractory multiple myeloma (RRMM).

e20531 Background: Patient-reported outcomes in RRMM remain poor, particularly for those refractory to immunomodulatory agents, proteasome inhibitors, and anti-CD38 antibodies, and there is an increased risk of cumulative toxicities in these patients. Single-agent belantamab mafodotin (GSK2857916), a first-in-class, B-cell maturation antigen–binding immunoconjugate, has demonstrated deep and durable responses with a manageable safety profile in heavily pretreated patients with RRMM (DREAMM-1, NCT02064387). Here, we present patient-reported clinical benefit/tolerability of belantamab mafodotin evaluated by trial-embedded end-of-treatment (EOT) and follow-up interviews. Methods: DREAMM-1 study design and results have been reported ( Blood Cancer J 2019). Patients in the Part 2 expansion phase were administered single-agent belantamab mafodotin 3.4 mg/kg IV once every 3 weeks for 16 cycles and invited to participate in interviews at EOT and 6-month follow-up. Patients discussed symptoms, treatment-related adverse events (AEs), treatment burden, and overall treatment satisfaction, rated 0–10 (0 = not severe to 10 = most severe/0 = not at all satisfied to 10 = extremely satisfied). Results: A total of 17/35 patients (9 female [53%]) were interviewed; 4/17 patients completed both interviews. Most patients (94%; 16/17) achieved a partial response or better. At EOT, patients reported an improvement from the worst point in symptoms of bone pain (mean change in score from 6.4 to 4.0) and fatigue (8.0 to 5.5). The most commonly reported treatment-related AE was blurred vision (76%; 13/17). Among those reporting this AE, 62% (8/13) reported resolution or steady improvement in vision after EOT; with a reduction in severity rating from 7.3 at worst to 5.3 at EOT for this event. Most patients (93%; 13/14) never considered stopping treatment owing to AEs, including ocular events. Overall treatment satisfaction was high (mean score 7.9; median 9.0). Conclusions: Despite small sample sizes, trial-embedded interviews provide valuable insight into patient experience with belantamab mafodotin. Patients treated with single-agent belantamab mafodotin reported high treatment satisfaction and improvements in symptoms. Visual symptoms were frequent but manageable, and improved or resolved after treatment. Funding: GlaxoSmithKline (117159). Drug linker technology licensed from Seattle Genetics; monoclonal antibody produced using POTELLIGENT Technology licensed from BioWa. Clinical trial information: NCT02064387.

DREAMM-5 platform trial: Belantamab mafodotin in combination with novel agents in patients with relapsed/refractory multiple myeloma (RRMM).

TPS8552 Background: Single-agent belantamab mafodotin (GSK2857916), a B-cell maturation antigen targeting immunoconjugate, induced deep and durable responses in patients with RRMM, with a manageable safety profile (DREAMM-2, NCT03525678, Lancet Oncol.2020). A platform trial design allows efficient evaluation of belantamab mafodotin in combination with other anti-myeloma agents, such as a humanized wild-type IgG1 anti-OX40 agonist, an IgG4 inducible T-cell costimulatory (ICOS) agonist, and a gamma-secretase inhibitor. The unique, multimodal mechanisms of action (MoAs) of belantamab mafodotin, in combination with MoAs of these agents, has the potential to achieve synergistic effects in MM, to further enhance anti-myeloma activity without compromising safety. Methods: DREAMM-5 (NCT04162210) utilizes a master protocol with separate sub-studies comprised of sequential dose exploration (DE) and cohort expansion (CE) phases, to identify promising, effective belantamab mafodotin combinations when compared with a shared belantamab mafodotin monotherapy control arm (CE phase only). DE phases consist of multiple dosing cohorts with belantamab mafodotin combinations where patients are assigned to treatment slots by predetermined algorithmic approach (modified toxicity probability interval; N≤10 per cohort). Recommended phase 2 doses (RP2D) will be based on dose-limiting toxicities, safety, and pharmacokinetics. Interim analyses, based on overall response rate (ORR), determine if a RP2D is moved forward to a CE phase (N≥35 per cohort). Patients in the CE (stratified by number of prior therapies) will be randomized equally to open sub-studies. Eligible patients will have received ≥3 prior therapy lines which must include ≥1 immunomodulatory agent, proteasome inhibitor, and anti-CD38 antibody. The primary objectives are to identify RP2D for each combination (DE phase) and ORR (≥partial response, CE phase). Sub-studies 1 (combination with GSK3174998, OX40 agonist antibody) and 2 (combination with GSK3359609, ICOS agonist antibody) are currently enrolling. Sub-study 3 (combination with nirogacestat [PF-03084014; SpringWorks Therapeutics]) is projected to begin enrollment in the first half of 2020. Additional sub-studies will be explored based on scientific rationale and/or preclinical combination study results. Funding: GlaxoSmithKline (207495). Drug linker technology licensed from Seattle Genetics; monoclonal antibody produced using POTELLIGENT Technology licensed from BioWa. Clinical trial information: NCT04162210 .

DREAMM-2: Single-agent belantamab mafodotin (GSK2857916) in patients with relapsed/refractory multiple myeloma (RRMM) and high-risk (HR) cytogenetics.

8541 Background: Patients with RRMM and HR cytogenetics have a poor prognosis and need effective therapies. In DREAMM-2 (NCT03525678), single-agent belantamab mafodotin (an immunoconjugate targeting B-cell maturation antigen) demonstrated clinically meaningful activity and a manageable safety profile in patients with heavily pretreated RRMM ( Lancet Oncol.2020). We present outcomes in patients with HR-cytogenetics (9-month follow-up). Methods: Patients with RRMM received single-agent belantamab mafodotin (2.5 or 3.4 mg/kg). For this post hoc analysis, HR-cytogenetics included t(4;14), t(14;16), 17p13del, or 1q21+ (tested locally). Results: The median number of cycles was 3 (2.5: range: 1–15) and 4 (3.4: range: 1–14). Overall response rate (ORR; ≥partial response [PR] per independent review committee) was 27% in the 2.5 mg/kg group (22% with ≥very good partial response [VGPR]) and 40% in the 3.4 mg/kg group (27% with ≥VGPR). The median duration of response (DoR) was not reached in the 2.5 mg/kg group and was 6.2 months in the 3.4 mg/kg group. The most common adverse events ( > 30% in either group) were consistent with the overall population ( Lancet Oncol.2020): keratopathy (2.5: 59%;3.4: 79%), thrombocytopenia (2.5: 44%; 3.4: 65%), nausea (2.5: 27%; 3.4: 33%), anemia (2.5: 24%; 3.4: 42%), and blurred vision (2.5: 20%; 3.4: 42%). Conclusions: Patients with HR-cytogenetics maintain deep and durable clinical responses with single-agent belantamab mafodotin, comparable to that reported in the overall population. The safety profile remained consistent with previous reports. Funding: GlaxoSmithKline (205678). Drug linker technology licensed from Seattle Genetics; monoclonal antibody produced using POTELLIGENT Technology licensed from BioWa. Clinical trial information: NCT03525678 . [Table: see text]

Pivotal DREAMM-2 study: Single-agent belantamab mafodotin (GSK2857916) in patients with relapsed/refractory multiple myeloma (RRMM) refractory to proteasome inhibitors (PIs), immunomodulatory agents, and refractory and/or intolerant to anti-CD38 monoclonal antibodies (mAbs).

8536 Background: Single-agent belantamab mafodotin (B-cell maturation antigen targeting immunoconjugate) showed clinically meaningful activity and manageable safety in patients with heavily pre-treated RRMM (DREAMM-2, NCT03525678, Lancet Oncol.2020). We report updated results (median follow-up 9 months). Methods: DREAMM-2 is an ongoing single-agent belantamab mafodotin (2.5 or 3.4 mg/kg) study in patients with RRMM after ≥3 prior therapy lines and refractory to an immunomodulatory agent, a PI, and refractory and/or intolerant to an anti-CD38 mAb. Primary endpoint: overall response rate (ORR; ≥partial response per independent review committee). Results: ORR was 31% in the 2.5 mg/kg (19% with ≥very good partial responses [VGPR]) and 35% (24% with ≥VGPR) in the 3.4 mg/kg groups (Table). Duration of response (DoR) was not reached (NR) in the 2.5 mg/kg and 6.2 months in the 3.4 mg/kg groups; 1-year overall survival (OS) estimate was 53%. Common Grade 3/4 AEs ( > 10% in either group) were keratopathy (2.5: 29%; 3.5: 24%), thrombocytopenia (2.5: 21%; 3.4: 32%), anemia (2.5: 20%; 3.4: 27%), pneumonia (2.5: 6%; 3.4: 13%), and neutropenia (2.5: 11%; 3.4: 16%). AEs were managed with dose delays (2.5: 54%; 3.4: 62%) and reductions (2.5: 34%; 3.4: 43%); discontinuations due to AEs were uncommon (2.5: 9%; 3.4: 12%). Conclusions: Single-agent belantamab mafodotin was well-tolerated, and clinically meaningful responses were sustained despite dose modifications with longer follow-up. Funding: GlaxoSmithKline (205678). Drug linker technology licensed from Seattle Genetics; monoclonal antibody produced using POTELLIGENT Technology licensed from BioWa. Clinical trial information: NCT03525678 . [Table: see text]

DREAMM-6: Safety and tolerability of belantamab mafodotin in combination with bortezomib/dexamethasone in relapsed/refractory multiple myeloma (RRMM).

8502 Background: Belantamab mafodotin, a B-cell maturation antigen targeting immunoconjugate, demonstrated clinically meaningful, single-agent activity in patients with heavily pre-treated RRMM refractory to an immunomodulatory agent, a proteasome inhibitor, and refractory and/or intolerant to an anti-CD38 monoclonal antibody (DREAMM-2, NCT03525678, Lancet Oncol.2020). The multimodal mechanism of action and manageable safety profile make belantamab mafodotin a promising candidate for use in different RRMM combination regimens. Methods: DREAMM-6 (NCT03544281) is an ongoing, two-part, two-arm, study evaluating the safety, tolerability, and clinical activity of belantamab mafodotin in combination with bortezomib/dexamethasone (BorDex) and lenalidomide/dexamethasone in patients previously treated with ≥1 prior therapy line. Here, we present data for belantamab mafodotin in combination with BorDex. Part 1 (dose escalation) and Part 2 (dose expansion) evaluated belantamab mafodotin (2.5 and 3.4 mg/kg) administered as SINGLE (Day 1) or SPLIT dose (divided equally on Days 1 and 8) in combination with BorDex. Results: As of February 6, 2020, 52 patients were enrolled: 6 patients were enrolled at 2.5 mg/kg single dose and 7 at 3.4 mg/kg single dosing in Part 1, and 45 patients in Part 2. No dose-limiting toxicities were observed. Corneal events (including keratopathy, blurred vision, and dry eye) and thrombocytopenia were the most frequently reported AEs and were clinically manageable. Conclusions: In DREAMM-6, preliminary data demonstrate that the combination of belantamab mafodotin and BorDex has an acceptable safety profile, with no new safety signals identified. Funding: GlaxoSmithKline (207497). Drug linker technology licensed from Seattle Genetics; monoclonal antibody produced using POTELLIGENT Technology licensed from BioWa. Clinical trial information: NCT03544281 .

The Resurgence of Antibody Drug Conjugates in Cancer Therapeutics: Novel Targets and Payloads.

Antibody drug conjugates (ADCs) are an emerging class of therapeutics that consist of a cytotoxic agent linked covalently to an antibody, which is directed toward a specific cell surface target expressed by tumor cells and/or the microenvironment. ADCs leverage the specificity of the antibody such that it functions as a carrier to deliver the cytotoxic payload into the tumor. Four parameters are considered critical for this class of complex engineered therapeutics: target selection, antibody, cytotoxic payload, as well as conjugation and linker technology. The development of this class of drugs has proven more complex than expected. Several challenges have arisen, including a lack of true tumor antigen specificity, early release of the cytotoxic payload into the bloodstream due to linker instability, and low potency of the payload, resulting in either greater toxicity or lack of improved efficacy compared with unconjugated cytotoxics. The approval of trastuzumab emtansine in 2013 for HER2-positive breast cancer served as a proof of concept that ADCs have therapeutic application in solid tumors. Two novel ADCs have recently been approved: trastuzumab deruxtecan for HER2-positive breast cancer and enfortumab vedotin for locally advanced or metastatic urothelial cancer. Trastuzumab deruxtecan is distinguished by a unique biochemical structure with a novel cytotoxic payload, deruxtecan-a highly potent, topoisomerase I inhibitor. Enfortumab vedotin is directed toward nectin-4 and represents an example of successful and strategic target selection. This review focuses on the concepts underlying the choice of suitable targets and novel payloads, discusses specific examples of ADCs in preclinical and clinical development, and provides future directions related to this unique class of therapeutics.

Dreamm-5: Platform Trial Evaluating Belantamab Mafodotin (a BCMA-directed Immuno-conjugate) in Combination with Novel Agents in Relapsed or Refractory Multiple Myeloma (RRMM)

Background: Patients with RRMM who have relapsed through multiple prior lines of therapy need novel, effective, targeted agents. B-cell maturation antigen (BCMA) is a cell-surface receptor required for plasma cell survival that is ubiquitously expressed on MM cells, but virtually absent on naïve and memory B cells. Belantamab mafodotin (GSK2857916) is a BCMA-directed immuno-conjugate with an afucosylated, humanized anti-BCMA monoclonal antibody (mAb) conjugated by a protease-resistant cysteine linker to a microtubule disrupting agent, monomethyl auristatin F (MMAF). Belantamab mafodotin specifically binds to BCMA, eliminating MM cells by a multimodal mechanism including delivering MMAF to BCMA-expressing malignant cells, enhancing antibody-dependent cellular cytotoxicity, and leveraging immunogenic cell death. In an open-label, phase 1 study (DREAMM-1), belantamab mafodotin monotherapy had a manageable safety profile and demonstrated rapid, deep and durable clinical response (60% overall response rate, 14.3 months duration of response) with significant progression free-survival (PFS; 12 months) in patients with heavily pretreated MM. Belantamab mafodotin is being evaluated in clinical trials in various lines of MM therapy, either as monotherapy or in combination. The DREAMM-5 platform trial is a phase 1/2 study that incorporates an efficient design with 1 master protocol, wherein multiple belantamab mafodotin-containing combinations will be evaluated in separate substudies to identify effective doublet combinations versus a shared belantamab mafodotin monotherapy control arm. Initial substudies will include combinations with the T-cell activating checkpoint mAbs GSK3359609 (an IgG4 inducible T-cell costimulatory [ICOS] agonist antibody that is Fc optimized to selectively enhance T-cell function to enable antitumor responses), GSK3174998 (a humanized wild-type IgG1 anti-OX40 agonistic mAb), and a gamma-secretase inhibitor, Nirogacestat (PF-03084014, SpringWorks Therapeutics). Furthermore, as treatment paradigms evolve, including potential genomic subsets of patients with RRMM and actionable mutations, other control arms may be introduced. The combination agent for evaluation in each substudy will be selected based on scientific rationale and/or results of preclinical experiments with the selected agent in combination with belantamab mafodotin. Methods: Patients with RRMM will be eligible if they have received ≥3 prior lines of therapy (consisting of an immunomodulatory drug, proteasome inhibitor, and an anti-CD38 mAb), have measurable disease (as measured by M-protein and free light chain), and acceptable hematologic and vital organ functions. Participants previously treated with an anti-BCMA targeted therapy are eligible except for prior belantamab mafodotin treatment and chimeric antigen receptor (CAR) T-cell therapy within 3 months of screening. Each substudy will have 2 sequential phases to evaluate safety and efficacy (Figure). The dose exploration (DE) phase will evaluate the safety and tolerability of belantamab mafodotin administered in combination with a partner agent. Each DE phase will consist of multiple dosing cohorts (N≤10 per cohort), 1 cohort per doublet combination. The primary objective is to identify a recommended phase 2 dose for each doublet combination based on safety and preliminary efficacy. Once a substudy is selected for the cohort expansion (CE) phase (N=35 per substudy), the objective is to compare the response rate between the doublet combination and the shared belantamab mafodotin monotherapy control arm. Secondary objectives in CE are to assess AEs, durability of response, PFS, and overall survival. Exploratory objectives include assessment of PK for belantamab mafodotin with each partner agent, bone marrow minimal residual disease status, and plasma soluble BCMA levels as candidate prognostic and predictive biomarkers. DREAMM-5 is designed to efficiently identify novel, highly effective belantamab mafodotin-containing doublet combinations for evaluation in pivotal trials against current standard-of-care MM agents. Acknowledgments: Editorial assistance provided by Sarah Hauze, PhD, at Fishawack Indicia Ltd and funded by GSK. Study funded by GSK (208887); drug linker technology licensed from Seattle Genetics; monoclonal antibody produced using POTELLIGENT Technology licensed from BioWa. Figure Disclosures Richardson: Oncopeptides: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Biswas:GSK: Employment, Equity Ownership. Holkova:GlaxoSmithKline: Employment, Equity Ownership. Jackson:GlaxoSmithKline: Employment, Equity Ownership. Netherway:GlaxoSmithKline: Employment, Equity Ownership. Bao:GSK: Employment, Equity Ownership. Ferron-Brady:GlaxoSmithKline: Employment, Equity Ownership. Yeakey:GlaxoSmithKline: Employment, Equity Ownership. Shelton:GlaxoSmithKline: Employment, Equity Ownership. Montes De Oca:GlaxoSmithKline: Employment. Ahlers:GlaxoSmithKline: Employment, Equity Ownership. Franco:GlaxoSmithKline: Employment, Equity Ownership. Ballas:GlaxoSmithKline: Employment, Equity Ownership; Bristol-Myers Squibb: Equity Ownership; AstraZeneca: Patents & Royalties: Uncompensated copyrights. Paul:GlaxoSmithKline: Employment, Equity Ownership. Luptakova:GlaxoSmithKline: Employment, Equity Ownership. Gupta:GlaxoSmithKline: Employment, Equity Ownership. Opalinska:GSK: Employment, Equity Ownership.

Dreamm-3: A Phase 3, Open-Label, Randomized Study to Evaluate the Efficacy and Safety of Belantamab Mafodotin (GSK2857916) Monotherapy Compared with Pomalidomide Plus Low-Dose Dexamethasone (Pom/Dex) in Participants with Relapsed/Refractory Multiple Myeloma (RRMM)

Background: Belantamab mafodotin is a humanized, afucosylated, anti-B-cell maturation antigen (BCMA) monoclonal antibody conjugated to monomethyl auristatin F via a maleimidocaproyl linker (mcMMAF). Upon binding to BCMA on the surface of plasma cells, it is rapidly internalized and the cytotoxic moiety (cys-mcMMAF) is released, antibody-dependent cellular cytotoxicity is enhanced, and immunogenic cell death occurs. In vitro and in vivo cytotoxic activity against both myeloma cell lines and primary patient cells has been demonstrated in preclinical studies. In the first-in-human phase 1 study (DREAMM-1/BMA117159, NCT02064387), belantamab mafodotin had a manageable safety profile and demonstrated a rapid, deep, and durable clinical response as a monotherapy in patients with relapsed/refractory multiple myeloma (RRMM). In a cohort of 35 heavily pretreated patients with RRMM (57% with ≥5 lines of prior therapy) who received belantamab mafodotin 3.4 mg/kg by intravenous (IV) infusion every 3 weeks (Q3W) overall response rate (ORR) of 60% (95% confidence interval [CI]: 42.1, 76.1) was demonstrated. The median progression-free survival (PFS) was 12.0 months (95% CI: 3.1, not estimable [NE]) and the median duration of response (DoR) was 14.3 months (95% CI: 10.6, NE). Belantamab mafodotin monotherapy in patients with RRMM is being further evaluated against the standard-of-care pomalidomide/dexamethasone (Pom/Dex) regimen in the DREAMM-3 study. Methods: The phase 3, multicenter, randomized, open-label DREAMM-3 study will evaluate the efficacy and safety of belantamab mafodotin monotherapy compared with Pom/Dex, an established standard-of-care regimen in RRMM. In this global study, patients treated with ≥2 prior lines of therapy, including ≥2 consecutive cycles of both lenalidomide and a proteasome inhibitor, and refractory to the last line of treatment, will be eligible for inclusion. Participants with prior allogeneic transplant will be excluded, as will those with prior exposure to BCMA-targeted therapies and Pom. Approximately 320 participants will be randomized (2:1) to receive either belantamab mafodotin or Pom/Dex and will be stratified by age, exposure to anti-CD38 therapy, and number of prior lines of treatment. Belantamab mafodotin will be administered IV Q3W, at the dose confirmed in the ongoing DREAMM-2 study (NCT03525678). Pom will be administered orally at 4 mg on Days 1-21 of each 28-day cycle, with Dex 40 or 20 mg (depending on age) on Days 1, 8, 15, and 22. Treatment in both arms will continue until progressive disease, unacceptable toxicity, or death. The primary endpoint is PFS, and overall survival is a key secondary endpoint. Additional secondary endpoints include ORR, time to response, minimal residual disease negativity rate (10-5 threshold assessed by next-generation sequencing), DoR, safety, and health-related quality of life. Bone marrow and blood samples will be collected for biomarker research. The study is planned to start in late 2019. Acknowledgments: Editorial assistance was provided by Sarah Hauze, PhD, at Fishawack Indicia Ltd, UK, and funded by GlaxoSmithKline. Study is funded by GlaxoSmithKline (ID: 207495); drug linker technology is licensed from Seattle Genetics; monoclonal antibody is produced using POTELLIGENT Technology licensed from BioWa. Disclosures Weisel: Sanofi: Consultancy, Honoraria, Research Funding; Adaptive Biotech: Consultancy, Honoraria; GSK: Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Juno: Consultancy; Bristol-Myers Squibb: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Hopkins:GSK: Employment, Equity Ownership. Fecteau:GSK: Employment, Equity Ownership. Bao:GSK: Employment, Equity Ownership. Quigley:GSK: Employment, Equity Ownership. Jewell:GSK: Employment, Equity Ownership. Nichols:GSK: Employment, Equity Ownership. Opalinska:GSK: Employment, Equity Ownership.

1105TiP - DREAMM 4: A phase I/II single-arm open-label study to explore safety and clinical activity of belantamab mafodotin (GSK2857916) administered in combination with pembrolizumab in patients with relapsed/refractory multiple myeloma (RRMM)

BackgroundIn BMA117159, GSK2857916, a humanised (IgG1), afucosylated, anti-BCMA monoclonal antibody conjugated to monomethyl auristatin-F, has shown clinical activity (overall response rate [ORR]=60%; mPFS 12 months [95% CI, 3.1–NE]) as monotherapy in heavily pre-treated patients with MM. Pre-clinical data indicate that GSK’916 induces immunogenic cell death that activates dendritic cells and an antigen-specific T-cell response. PD-L1 overexpression may be a mechanism of immune evasion in MM. Pembrolizumab, a selective, humanised IgG4 anti-PD-1 monoclonal antibody that blocks the interaction of PD-1 with PD-L1 and PD-L2, may synergise with immunomodulatory drugs to enhance tumor suppression. T-cell-dependent antitumor response induced by GSK’916 may be augmented by combining with pembrolizumab. Trial designDREAMM 4 is a Phase I/II, single-arm, open-label, two-part study to evaluate safety and determine the recommended Phase 2 dose (RP2D) and clinical activity of GSK’916 in combination with pembrolizumab in patients with RRMM previously treated with ≥3 prior lines. Part 1 (dose escalation) will evaluate two doses of GSK’916 with a fixed dose of pembrolizumab in up to 12 participants. Modified Toxicity Probability Interval design will guide GSK’916 dose escalation. Primary objectives of Part 1 are to define safety and tolerability and define the RP2D dose of GSK’916 combined with pembrolizumab. Part 2 (dose expansion) will evaluate clinical activity of the RP2D, confirm safety, and collect pharmacokinetic information for GSK’916 in up to 28 participants. Dose expansion may stop early for futility at interim analysis. An additional stopping rule may stop enrolment early if the observed rate of treatment-related ≥Grade 4 AEs equals or exceeds the specified rate (12%). Part 2 objectives are to assess the ORR and confirm the safety profile of GSK’916 and pembrolizumab. Patients will continue combination treatment for 35 cycles or until progression, intolerance, consent withdrawal or death. Enrolment began in March 2019 and is ongoing. Clinical trial identificationNCT03848845 (Rel. 19Feb2019). Editorial acknowledgementClare Slater, PhD, of Fishawack Indicia Ltd, UK, funded by GlaxoSmithKline (GSK). Legal entity responsible for the studyGlaxoSmithKline. FundingGlaxoSmithKline and is in collaboration with Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA; drug linker technology licensed from Seattle Genetics; monoclonal antibody produced using POTELLIGENT Technology licensed from BioWa. DisclosureS. Trudel: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: GlaxoSmithKline. A. Nooka: Honoraria (self), Advisory / Consultancy: Emory University Winship Cancer Institute; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): Takeda; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): BMS; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): Janssen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Celgene; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): GlaxoSmithKline; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Amgen; Honoraria (self), Advisory / Consultancy: Adaptive; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Spectrum; Research grant / Funding (institution): Aduro; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): KITE pharmaceuticals. D. Fecteau: Shareholder / Stockholder / Stock options, Full / Part-time employment: GlaxoSmithKline. M. Talekar: Shareholder / Stockholder / Stock options, Full / Part-time employment: GlaxoSmithKline. R.C. Jewell: Shareholder / Stockholder / Stock options, Full / Part-time employment: GlaxoSmithKline. D. Williams: Full / Part-time employment: GlaxoSmithKline. J. Evans: Shareholder / Stockholder / Stock options, Full / Part-time employment: GlaxoSmithKline. J. Opalinska: Shareholder / Stockholder / Stock options, Full / Part-time employment: GlaxoSmithKline.

Activity-Based Optical Sensing Enabled by Self-Immolative Scaffolds: Monitoring of Release Events by Fluorescence or Chemiluminescence Output.

Functional molecular scaffolds comprised of self-immolative adaptors are being used in widespread applications in the fields of enzyme activity analyses, signal amplification, and bioimaging. Optically detected chemical probes are very promising compounds for sensing and diagnosis, since they present several attractive features such as high specificity, low detection limits, fast response times, and technical simplicity. During the last two decades, we have developed several distinct molecular scaffolds that harness the self-immolative disassembly feature of these adaptors to amplify chromogenic output for diagnosis and drug delivery applications. In order to study the molecular behavior of the various amplification systems, an optical output, used to monitor the progress of the disassembly pattern, was required. Therefore, over the course of our research, diverse molecular scaffolds that produce an optical signal in response to a disassembly step, were evaluated. These optically active scaffolds have been incorporated into self-immolative dendrimers and self-immolative polymers to implement unique disassembly properties that result with linear and exponential signal amplification capabilities. In addition, some scaffolds, aimed for linker technology, were used in delivery systems to monitor release of drug molecules. The optical signal used to monitor the release event could be produced by analysis of reporter molecules with chromogenic or fluorogenic properties. Recently, we have also developed molecular scaffolds modified to produce a chemiluminescent signal to monitor the self-immolative disassembly step. The main advantage of these scaffolds over others is the use of chemiluminescence as an output signal. It is well-known that chemiluminescence is considered as one the most sensitive diagnostic methods due to its high signal-to-noise ratio. The unique structures of the self-immolative chemiluminescence scaffolds have been used in the design of three different distinctive concepts: self-immolative chemiluminescence polymers, auto-inductive amplification systems with chemiluminescence signal and monitoring of drug release by a chemiluminescence output. Furthermore, we reported the design and synthesis of the first theranostic prodrug for the monitoring of drug release achieved by a chemiluminescence mode of action. Quinone-methide elimination has proven to serve as a valuable functional tool for composing molecular scaffolds with self-immolative capabilities. Such scaffolds function as molecular adaptors that can almost simultaneously release a target molecule with an accompanied emission of a light signal that is used to monitor the release event. We anticipate that these self-immolative scaffolds will continue to find utility as functional linkers in various chemical and biological research areas such as drug delivery, theranostic applications, and as molecular sensors with signal amplification.

First platinum(II)-based metal-organic linker technology (Lx®) for a plug-and-play development of antibody-drug conjugates (ADCs)

ABSTRACTIntroduction: Compared to the antibody and drug components of an ADC, the linker part has been somewhat neglected. However, its importance for the reduction of failures in ADC approvals is increasingly recognized. Next of being a stable glue between drug and antibody, an ideal linker should improve the manufacturability and widen the therapeutic window of ADCs.Areas covered: The biopharmaceutical company LinXis started an ADC development program in which platinum(II) is the key element of the first metal-organic linker. The cationic complex [ethylenediamineplatinum(II)]2+, herein called ‘Lx®’, is used successfully for conjugation of drugs to antibodies.Expert opinion: Based on lessons learned from ADC development, Lx linker technology fulfills most of the desirable linker characteristics. Lx allows large-scale cost-effective manufacturing of ADCs via a straightforward two-step ‘plug-and-play’ process. First clinical candidate trastuzumab-Lx-auristatin F shows favorable preclinical safety as well as outstanding in vivo tumor targeting performance and therapeutic efficacy.

Abstract LB-106: Overcoming limitations of current Antibody-Drug Conjugates (ADCs) by a novel linker technology

Abstract We introduce a novel and versatile ADC-linker technology that is based on site-specific enzymatic payload conjugation to ‘off-the-shelf’ antibodies, i.e., without the need to reduce or engineer the antibody. The functionalization takes place site-specifically and stoichiometrically (drug-to-antibody ratio, DAR = 2.0) at the Fc-part of antibodies. The resulting ADCs show favorable biophysical properties such as high solubility and stability using different payloads. Additionally, initial ELISA findings show that our modification does not interfere with Fc-gamma receptor and FcRn binding. Importantly, our ADCs showed superior efficacy in different tumor animal models as compared to control Thiomab™ ADCs. Using native trastuzumab (non-engineered) as the targeting antibody and amanitin as payload, we generated within 36 hours highly homogeneous and pure ADCs with a well-defined DAR of 2.0 as confirmed by LC-MS. In in-vitro assays our ADCs demonstrated potent cytotoxicity in all tested cell-lines (SKBR-3, BT-474, JIMT-1, and NCI-N87) as compared to the control Thiomab™ ADCs, most strikingly for the JIMT-1 cell-line: EC50 of 0.15nM vs 2.5nM. In the mouse JIMT-1 tumor model, our anti-HER2 ADC was highly potent and resulted in complete tumor remission in all mice (10/10 mice) at a single dose of 2mg/kg. In contrast, the control Thiomab™-functionalized ADC showed tumor regrowth in 4 out of 10 animals, starting on day 50. The same high potency was observed for the NCI-N87 xenograft model at a dose of 3mg/kg in which tumor growth inhibition was significantly delayed versus the reference ADC (8/10 vs 4/10 animals alive on day 110). These encouraging results obtained so far indicate that our linker technology a) allows for fast (< 36 hours) and straightforward manufacturing of ADCs using different payloads without protein engineering efforts, b) results in ADCs with favorable biophysical properties and a clear defined drug-to-antibody ratio, and c) enables the generation of highly potent and stable, thus safer, next-generation ADCs. Citation Format: Philipp Rene Spycher, Julia Carina Frei, Jöri Elias Wehrmüller, Isabella Attinger-toller, Dragan Grabulovski, Torsten Hechler, Michael Kulke, Andreas Pahl, Martin Behe, Roger Schibli. Overcoming limitations of current Antibody-Drug Conjugates (ADCs) by a novel linker technology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-106.

Abstract 2167: Antibody glycoengineering for drug delivery applications

Abstract Antibody-drug conjugates (ADC) hold considerable promise as anticancer agents. A critical determinant of the effectiveness of ADCs is the chemistry that is used to conjugate the payload. Currently used approaches include primarily conjugation to either side-chain amine or carboxylic acid groups or conjugation to thiols. Because these reactions are not site specific and not easily controlled, these chemistries can result in reduced affinity for the target antigen. Further, these conjugation reactions lack selectivity and can result in heterogeneous mixtures of products that differ in the sites and stoichiometry of modification. We investigated a glycoengineering strategy that enables the introduction of artificial azide groups in the antibody without affecting their antigen affinity. This is based on the observation that glycosyltransferases can incorporate non-natural sugars (e.g., azido mannose) at different sites on an IgG molecule. The azide groups in these artificial sugars are then available to react with alkynes through copper-catalyzed ‘click’ chemistry or with strained alkynes such as dibenzyl cyclooctyne (DBCO) allowing for biorthogonal, copper-free ‘click’ chemistry. Because the sugars are added reproducibly and at a site that does not affect antigen binding, the glycoengineering technology would overcome problems associated with traditional conjugation strategies. Using this approach, azide groups were introduced in anti-CD133 and anti-perlecan antibodies. Further, the azide groups were available to react with various DBCO conjugates including fluorophores, drug molecules and nanoparticles. Importantly, the addition of artificial sugar and subsequent azide-alkyne reaction did not affect the affinity of the antibody for the target antigen. Conjugation of a cytotoxin to the antibody resulted in enhanced cell kill in vitro and efficacy in vivo. We plan on further improving the effectiveness of this approach by investigating cleavable linker technology in combination with the glycoengineering strategy. We expect that this strategy will prove to be a unique platform technology that will have a significant impact on antibody-based therapeutics. Citation Format: Drishti Navin Sehgal, Stephen Kalscheuer, Jayanth Panyam. Antibody glycoengineering for drug delivery applications [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2167.

Abstract 211: A new class of sequence-selective DNA cross-linking ADC payloads with increased in vivotolerability

Abstract Although five Antibody-Drug Conjugates (ADCs) have been approved and over eighty others are in development, the majority contain payloads belonging to two classes: tubulin inhibitors and DNA interactive agents. Most DNA cross-linking payloads (e.g., the PBD dimers) have potent cytotoxicity but ADCs containing them have high hydrophobicity and a narrow therapeutic window. Thus, there is interest in developing novel payloads which benefit from a potency similar to the PBD dimers but that possess lower hydrophobicity and produce ADCs with a wider Therapeutic Index (TI). The pyridinobenzodiazepines (PDDs) are a new class of guanine-alkylating payloads, and these have been coupled to an adenine-alkylating CXI/duocarmycin pharmacophore to generate molecules that can form G-A DNA cross-links. The lead PDD-CXI payload (FGX-8-46) has a sequence-selectivity profile that differs from other DNA cross-linking agents in that it spans seven to eight base-pairs compared to six to seven for a typical PBD dimer. DNA cleavage experiments have indicated that it cleaves at discrete Adenine-containing sequences of the type 5’-XGXWWWW-3’ (X is any base; W is A/T, and the underlined bases show the cleavage points), and Transcription Factor (TF) Array studies show that it is a potent TF inhibitor, down-regulating several key oncogenic TFs (e.g., NF-κB). In in vitro cell line studies, the G-A cross-linkers have low pM cytotoxicity comparable to the PBD dimers in a wide and diverse range of cell lines, including those from both solid and haematological cancers (e.g., IC50 of ~2 pM in SW-48). This payload class is also compatible with a wide variety of linker technologies, and attachment can be made through either the PDD or CXI units. Importantly, these payloads are significantly less hydrophobic than other equivalent payload classes. ADCs have been generated by conjugating these new payloads to the EGFR-targeting antibody Cetuximab with DARs of between 1.8 and 2.2. The ADCs exhibit potent cytotoxicity in vitro, significant in vivo efficacy and substantially increased tolerability compared to other DNA cross-linking payloads (e.g., the PBD dimer Tesirine). While the G-A cross-linkers retain the cytotoxic potency of the PBD dimers, the “softer” cross-link formed compared to the G-G cross-linking PBD dimers may contribute to the enhanced tolerability profile of this molecular class. The favourable hydrophobicity profile of the PDD-CXI payloads and their ease of conjugation to antibodies, along with their significant in vitro cytotoxicity, in vivo efficacy and tolerability of ADCs produced from them, suggest that they represent a promising new class of ADC payloads. Citation Format: George Procopiou, Jennifer Auer, Daniella di Mascio, Keith R. Fox, Paolo Andriollo, Ilona Pysz, Francesco Cascio, Nicolas Veillard, K. Miraz Rahman, Paul J. Jackson, David E. Thurston. A new class of sequence-selective DNA cross-linking ADC payloads with increased in vivotolerability [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 211.

Phase I/II, open-label, 2-arm study to evaluate safety, tolerability, and clinical activity of GSK2857916 in combination with 2 standard-of-care (SoC) regimens in relapsed/refractory multiple myeloma: (DREAMM 6).

TPS8053 Background: B-cell maturation antigen (BCMA) is a validated therapeutic target in Multiple Myeloma (MM). GSK2857916 is a humanized (IgG1) anti-BCMA monoclonal antibody conjugated to monomethyl auristatin-F via protease resistant maleimidocaproyl linker and produced in afucosylated form to enhance antibody-dependent cellular cytotoxicity. In FTIH study BMA117159, GSK2857916 was well tolerated and showed unprecedented clinical activity [ORR=60%; mPFS 7.9 months (95% CI, 3.1–not estimable)] as monotherapy in heavily pretreated MM patients. GSK2857916 in combination with SoC regimens, could potentially further improve outcomes for patients with relapsed/refractory (RR) MM. Methods: DREAMM 6 is a 2-part study: Part 1 (dose escalation) is evaluating safety and tolerability of 2 doses (2.5 mg/kg and 3.4 mg/kg) of GSK2857916, in combination with SoC regimens in two independent arms: Arm A with Lenalidomide/Dexamethasone, and Arm B with Bortezomib/Dexamethasone. Modified Toxicity Probability Interval design will guide dose escalation and RP2D of GSK2857916 in each arm for Part 2 (cohort expansion). Part 2 will confirm safety, evaluate clinical activity of GSK2857916 RP2D with either combination and collect pharmacokinetic information on GSK2857916, Lenalidomide and bortezomib. Up to 90 subjects previously treated with at least 1 prior line of therapy who have undergone autologous stem cell transplant or are transplant-ineligible will be enrolled; up to 24 in Part 1 and up to 66 in Part 2. Subjects in Arm A will continue combination treatment until progression, intolerance, consent withdrawal or death. Subjects in Arm B will receive up to 8 cycles of GSK2857916 in combination with Bor/Dex and then continue GSK2857916 monotherapy until progression, intolerance, consent withdrawal, or death. Enrolment on study started in October 2018 and is ongoing. Study funded by GlaxoSmithKline; drug linker technology licensed from Seattle Genetics; monoclonal antibody produced using POTELLIGENT Technology licensed from BioWa. ClinicalTrials.gov Identifier: NCT03544281.

Peptide Conjugates with Small Molecules Designed to Enhance Efficacy and Safety.

Peptides constitute molecular diversity with unique molecular mechanisms of action that are proven indispensable in the management of many human diseases, but of only a mere fraction relative to more traditional small molecule-based medicines. The integration of these two therapeutic modalities offers the potential to enhance and broaden pharmacology while minimizing dose-dependent toxicology. This review summarizes numerous advances in drug design, synthesis and development that provide direction for next-generation research endeavors in this field. Medicinal studies in this area have largely focused upon the application of peptides to selectively enhance small molecule cytotoxicity to more effectively treat multiple oncologic diseases. To a lesser and steadily emerging extent peptides are being therapeutically employed to complement and diversify the pharmacology of small molecule drugs in diseases other than just cancer. No matter the disease, the purpose of the molecular integration remains constant and it is to achieve superior therapeutic outcomes with diminished adverse effects. We review linker technology and conjugation chemistries that have enabled integrated and targeted pharmacology with controlled release. Finally, we offer our perspective on opportunities and obstacles in the field.

Cleavable linkers in antibody-drug conjugates.

Antibody-Drug Conjugates (ADCs) are now established as a major class of therapeutics for the clinical treatment of cancer. The properties of the linker between the antibody and the payload are proven to be critical to the success of an ADC. Although ADC linkers can be 'non-cleavable', the vast majority of ADCs in clinical development have specific release mechanisms to allow controlled linker cleavage at the target site and are thus termed 'cleavable'. In recent years, the development of new methods of drug release from ADCs has continued in parallel to the deepening understanding of the biological processes underlying the mechanisms of action of pre-existing technologies. This review summarises the advances in the field of cleavable linker technologies for ADCs.