Freise, Kevin J.

PURPOSE ABBV-383, a B-cell maturation antigen × CD3 T-cell engaging bispecific antibody, has demonstrated promising results in an ongoing first-in-human phase I study (ClinicalTrials.gov identifier: NCT03933735 ) in patients with relapsed/refractory multiple myeloma (RRMM). Herein, we report safety and efficacy outcomes of this phase I dose escalation/expansion study. METHODS Patients with RRMM (≥ three prior lines including a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 monoclonal antibody) were eligible. ABBV-383 was administered intravenously over 1-2 hours once every 3 weeks, without any step dosing. A 3 + 3 design with backfilling for dose escalation was used (intrapatient escalation to highest safe dose permitted) followed by initiation of dose expansion. RESULTS As of January 8, 2022, 124 patients (dose escalation [0.025-120 mg], n = 73; dose expansion [60 mg], n = 51) have received ABBV-383; median age was 68 years (range, 35-92 years). The most common hematologic treatment-emergent adverse events (TEAEs) were neutropenia (all grades: 37%) and anemia (29%). The most common nonhematologic TEAEs were cytokine release syndrome (57%) and fatigue (30%). Seven deaths from TEAEs were reported with all considered unrelated to study drug by the investigator. For all efficacy-evaluable patients (n = 122; all doses), the objective response rate (ORR) was 57% and very good partial response (VGPR) or better (≥ VGPR) rate was 43%. In the 60 mg dose expansion cohort (n = 49), the ORR and ≥ VGPR rates were 59% and 39%, respectively; and in the ≥ 40 mg dose escalation plus dose expansion cohorts (n = 79) were 68% and 54%, respectively. CONCLUSION ABBV-383 in patients with RRMM was well tolerated with an ORR of 68% at doses ≥ 40 mg. This novel therapy's promising preliminary antitumor activity in heavily pretreated patients warrants further clinical evaluation.

Abstract Background Prognosis is poor for patients (pts) with relapsed/refractory multiple myeloma (RRMM; median overall survival: <1 year), indicating a clear need to identify agents with novel mechanisms of action. B-cell maturation antigen (BCMA) has recently emerged as a novel treatment target for MM due to its highly selective expression in plasma cells. TNB-383B, a BCMA x CD3 T-cell engaging bispecific antibody, was designed to overcome the toxicity limitations of existing BCMA therapies and has demonstrated promising results in an ongoing first-in-human phase 1 study in pts with RRMM (Rodriguez C, et al. Blood 2020;136[suppl 1]:43-44). Herein, we report the updated efficacy and safety outcomes of this phase 1 study. Methods This multicenter, phase 1, open-label, dose-escalation/expansion study (NCT03933735) enrolled pts with RRMM (≥3 prior lines of therapy that included a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 monoclonal antibody), estimated glomerular filtration rate ≥30 mL/min as calculated by the Modification of Diet in Renal Disease formula, and ECOG performance status ≤2. Prior BCMA-targeted therapy is prohibited. Primary objectives include safety/tolerability, pharmacokinetics (PK), and determination of recommended phase 2 dose (RP2D); secondary objectives include assessment of clinical activity (per IMWG criteria 2016). TNB-383B is administered intravenously over 1-2 hours every 3 weeks (Q3W) with the first dose administered inpatient. The study uses a 3+3 design with backfilling for dose and permits intrapatient dose escalation to highest safe dose. Dose expansion was initiated on selection of RP2D. Pts are treated until progression, unacceptable toxicity, or other discontinuation criteria are met. The efficacy-evaluable population includes all pts who received at least 1 dose of TNB-383B and have at least 1 postdose assessment. The safety population includes all pts who received at least 1 dose of study drug; adverse events (AEs) are graded according to NCI CTCAE v5.0. Results As of 10 May 2021, 103 pts (dose escalation, n=73; dose expansion, n=30) have been treated with TNB-383B (0.025-120 mg). The RP2D of 60 mg Q3W was selected on the basis of tolerability, safety, PK, and clinical activity. Pt demographics and baseline characteristics are summarized in Table 1. Three dose-limiting toxicities were reported in dose escalation (platelet count decreased: grade [Gr] 4, 60 mg; cytokine release syndrome [CRS]: Gr 3, 90 mg and 120 mg); none were reported as serious. Treatment-related AEs (TRAEs) were reported in 79 (77%) pts, with Gr ≥3 and serious AEs occurring in 33 (32%) and 23 (22%) pts, respectively. The most common TRAEs (Table 2) include CRS (n=54, 52%), neutropenia (n=18, 17%), and fatigue (n=14, 14%). At the RP2D (n=39), the Gr ≥3 CRS rate was 3% (n=1). Onset of CRS typically occurred on the same or next day following the first dose and all pts recovered using tocilizumab or standard supportive care measures. Treatment-emergent AEs (TEAEs) of infusion-related reactions were reported in 8 (8%) pts and infections occurred in 29 (28%) pts; pneumonia (n=5, 5%) and upper respiratory tract infection (n=4, 4%) were the most common. Five deaths from TEAEs were reported; all were unrelated to study drug. Forty-two (40%) pts discontinued treatment due to disease progression. In the dose-escalation cohorts of ≥40 mg Q3W (n=24), the objective response rate (ORR) was 79% (19/24), with a very good partial response or better (≥VGPR) rate of 63% (15/24), and a complete response (CR) rate of 29% (7/24) at the data cutoff date; these pts have the longest follow-up (ie, mature data) with median time on study of 6.1 months (Figure 1). At doses ≥40 mg in the combined dose-escalation and -expansion cohorts (n=44), the observed ORR, ≥VGPR, and CR rates were 64% (28/44), 43% (19/44), and 16% (7/44), respectively; these pts have shorter follow-up (ie, immature data) with median time on study of 3.1 months. Twenty-nine (66%) of the 44 pts administered ≥40 mg were triple-class refractory and reported an ORR of 55% (16/29). Conclusions TNB-383B in pts with RRMM is well tolerated with an ORR of 79% observed at doses ≥40 mg in the dose-escalation cohorts. Despite having a shorter follow-up period, this trend was also observed at doses ≥40 mg in the combined dose-escalation/expansion cohorts (ORR: 64%). Enrollment into the dose-expansion arm is ongoing; updated data will be presented at the meeting. Figure 1 Figure 1. Disclosures Kumar: Novartis: Research Funding; Carsgen: Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Roche-Genentech: Consultancy, Research Funding; Bluebird Bio: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding; Beigene: Consultancy; Oncopeptides: Consultancy; Antengene: Consultancy, Honoraria; Tenebio: Research Funding; BMS: Consultancy, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding. D'Souza: Imbrium, Pfizer, BMS: Membership on an entity's Board of Directors or advisory committees; Sanofi, Takeda, Teneobio, CAELUM, Prothena: Research Funding; Janssen, Prothena: Consultancy. Shah: Oncopeptides: Consultancy; Nektar: Research Funding; Poseida: Research Funding; Janssen: Research Funding; Indapta Therapeutics: Consultancy; GSK: Consultancy; CareDx: Consultancy; BMS/Celgene: Research Funding; Bluebird Bio: Research Funding; CSL Behring: Consultancy; Teneobio: Research Funding; Kite: Consultancy; Sutro Biopharma: Research Funding; Karyopharm: Consultancy; Amgen: Consultancy; Precision Biosciences: Research Funding; Sanofi: Consultancy. Rodriguez: Takeda: Consultancy, Speakers Bureau; Karyopharm: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Oncopeptides: Consultancy, Honoraria; Amgen: Consultancy, Speakers Bureau. Voorhees: AbbVie Inc, Bristol-Myers Squibb Company; Consulting Agreement: GlaxoSmithKline, Novartis, Oncopeptides: Other: Advisory Committee; Bristol-Myers Squibb Company.: Other: Data Safety & Monitoring. Bueno: AbbVie: Current Employment, Current equity holder in publicly-traded company. Buelow: Teneobio, Inc.: Current Employment, Current holder of stock options in a privately-held company. Freise: Abbvie, Inc.: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company. Yue: Abbvie, Inc.: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company. Pothacamury: AbbVie: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company. Polepally: Abbvie, Inc.: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company. Vij: BMS: Research Funding; Takeda: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; BMS: Honoraria; GSK: Honoraria; Oncopeptides: Honoraria; Karyopharm: Honoraria; CareDx: Honoraria; Legend: Honoraria; Biegene: Honoraria; Adaptive: Honoraria; Harpoon: Honoraria.

Abstract Introduction: Venetoclax (Ven), an oral agent that targets the antiapoptotic protein, BCL-2, has demonstrated efficacy, as monotherapy and combined with proteasome inhibitor (PI) bortezomib, in relapsed/refractory (R/R) multiple myeloma (MM). We report preliminary safety and efficacy data for Ven combined with the second generation PI carfilzomib (K) and dexamethasone (VenKd) in R/R MM. Methods: In this ongoing phase 2, dose escalation study (NCT02899052), patients with R/R MM and no prior K exposure received VenKd on 28-d cycles in 4 dose finding and one expansion cohorts: Ven 400 mg/day + K 27 mg/m2 Day 1, 2, 8, 9, 15, 16 + dex 40 mg Day 1, 8, 15, 22 (Cohort 1), same regimen but with Ven 800 mg/day (Cohort 2), Ven 800 mg/day + K 70 mg/m2 Day 1, 8, 15 + dex 40 mg Day 1, 8, 15, 22 (Cohort 3/expansion cohort), or Ven 800 mg + K 56 mg/m2 Day 1, 2, 8, 9, 15, 16 + dex 40 mg Day 1, 2, 8, 9, 15, 16, 22, 23 (Cohort 4). Treatment continued until progressive disease (PD) or unacceptable toxicity. Results: As of June 11, 2018, 42 patients were enrolled. The median age was 66.5 years (min, max: 37, 79), 63% had ISS II/III disease, and 8 patients (19%) had t(11;14). Patients received a median of 2 prior therapies (range: 1 - 3), 93% had received prior PI (50% refractory), 62% were refractory to immunomodulatory therapies, and 33% double refractory. At the data cut off, 29 patients were still active and had completed ≥2 cycles and 13 patients discontinued with the primary reason being disease progression (n=4), death (n=3), physician decision (n=2), withdrawal of consent (n=2), lack of efficacy (n=1), and AE (n=1). All patients experienced at least one AE, and grade 3/4 AEs experienced by >10% of subjects included: decreased lymphocyte count (26%), decreased neutrophil count (14%), and hypertension (12%). Thirteen subjects experienced at least one serious AE. Maximum tolerated dose was not reached and Ven 800 mg/day + K 70 mg/m2 was selected for expansion. Ven mean (% coefficient of variation) maximum plasma concentration (Cmax) and area under the plasma concentration-time curve over 24 hours (AUC24) on Cycle 1 Day 15 were 2.7 (57) mg/mL and 33.1 (54) mg×h/mL, respectively, at 400 mg venetoclax (n=4); and were 2.42 (53) mg/mL and 38.7 (51) mg×h/mL, respectively, at 800 mg venetoclax (n=13) in the dose escalation cohorts. The overall response rate (ORR) was 78% and the very good partial response (VGPR) or better rate was 56% (Table). Median time from first dose to the data cut or discontinuation was 5.7 months (range: 0.9 - 16.3) and the median time to first response was 1.9 months (95% CI: 0.9, 9.2). ORRs for subgroups of interest are reported in the Table. Conclusions: The combination of VenKd appears tolerable with no new safety signals or changes in Ven pharmacokinetics. VenKd shows promising preliminary efficacy in R/R MM patient subgroups. Response rates were comparable in all high risk subgroups and overall population. However, the subset of patients with t(11;14) had the highest response. Overall, these results demonstrate that VenKd is a safe and efficacious regimen in R/R MM and support the continued study of VenKd. Disclosures Costa: Abbvie: Research Funding; BMS: Research Funding; Karyopharm: Research Funding; Amgen: Honoraria, Research Funding; Sanofi: Honoraria; Celgene: Honoraria, Research Funding; Janssen: Research Funding. Stadtmauer:Celgene: Consultancy; AbbVie, Inc: Research Funding; Janssen: Consultancy; Takeda: Consultancy; Amgen: Consultancy. Morgan:Bristol-Myers Squibb: Consultancy, Honoraria; Janssen: Research Funding; Takeda: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding. Kovacsovics:Amgen: Honoraria, Research Funding; Abbvie: Research Funding. Jakubowiak:Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; SkylineDx: Consultancy, Honoraria; Adaptive Biotechnologies: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Kaufman:Roche: Consultancy; BMS: Consultancy; Karyopharm: Other: data monitoring committee; Janssen: Consultancy; Abbvie: Consultancy. Mobasher:Genentech Inc: Employment; F. Hoffmann-La Roche Ltd: Other: Ownership interests non-PLC. Freise:AbbVie, Inc: Employment, Equity Ownership. Ross:AbbVie, Inc: Employment, Equity Ownership. Pesko:AbbVie, Inc: Employment, Equity Ownership. Munasinghe:AbbVie, Inc: Employment, Equity Ownership. Gudipati:AbbVie, Inc: Employment, Equity Ownership. Mudd:AbbVie, Inc: Employment, Equity Ownership. Bueno:AbbVie, Inc: Employment, Equity Ownership. Kumar:Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Background:Venetoclax (Ven) is a highly selective, potent, oral BCL‐2 inhibitor that induces apoptosis in malignant cells dependent on BCL‐2 for survival. Proteasome inhibitors (PIs) and dexamethasone (d) were shown to increase BCL‐2 dependence in multiple myeloma (MM) cells, and preclinical studies showed enhanced inhibition of MM tumor growth with Ven+PI compared to either alone. Moreover, d has been shown to indirectly promote BCL‐2 dependency in MM cells. Clinical trials have since demonstrated efficacy of Ven in combination with the PI bortezomib in patients (pts) with relapsed/refractory MM (RRMM).Aims:We report interim data for Ven combined with second‐generation PI carfilzomib (K) and d in pts with RRMM.Methods:In this ongoing Phase 2 study (NCT02899052), pts with RRMM (1–3 prior lines of therapy) and no prior K exposure received VenKd on 28‐day cycles in 4 dose‐finding and 1 expansion cohort: Ven 400 mg/day + K 27 mg/m2 Day 1, 2, 8, 9, 15, 16 + d 40 mg Day 1, 8, 15, 22 (Cohort 1); same regimen but with Ven 800 mg/day (Cohort 2); Ven 800 mg/day + K 70 mg/m2 Day 1, 8, 15 + d 40 mg Day 1, 8, 15, 22 (Cohort 3/expansion cohort); or Ven 800 mg + K 56 mg/m2 Day 1, 2, 8, 9, 15, 16 + d 40 mg Day 1, 2, 8, 9, 15, 16, 22, 23 (Cohort 4). Treatment continued until progressive disease or unacceptable toxicity.Results:As of the clinical data cut‐off of 1 Feb 2019, 43 pts were enrolled. Median age was 67 (range, 37–79), 26 (62%) pts had ISS II/III disease, and 8 (19%) were t (11;14)+. Median number of prior lines of therapy was 2 (range, 1–3). Forty (93%) pts received prior PI (49% refractory), 33 (77%) received prior immunomodulatory drug (IMiD, 61% refractory), and 33 (77%) received prior PI+IMiD (33% double refractory).All pts had at least 1 adverse event (AE). The most common AEs of any grade were diarrhea (65%), nausea (49%), fatigue (47%), cough (35%), insomnia, dyspnea, vomiting, upper respiratory infection (33% each), lymphopenia (28%), thrombocytopenia, and dyspepsia (26% each). Thirty‐six (84%) pts had a Grade 3/4 AE, the most common being lymphopenia (23%), pneumonia, hypertension (16% each), and hypophosphatemia (12%).The overall response rate (ORR) was 79%, complete response or better (≥CR) rate was 40%, and very good partial response or better (≥VGPR) rate was 64% for all pts (Table). Median follow‐up for 42 pts was 10.4 months (95% CI = 8.0–13.8); 15 pts had progression‐free survival (PFS) events, with median PFS yet to be achieved. Baseline bone marrow core biopsy samples from 25 pts were evaluated for BCL‐2 expression by immunohistochemistry, with high expression (≥50% of tumor cells with moderate or higher cytoplasmic staining) seen in 23 (92%) samples. Pts with high BCL‐2 expression had response rates similar to the overall study population. Other correlative biomarker analyses are ongoing.Summary/Conclusion:The combination of VenKd was found to be tolerable with no new safety signals. VenKd demonstrates promising efficacy in pts with RRMM. The study remains ongoing with an additional 60 pts with RRMM enrolling to assess efficacy and safety in a larger group of pts with similar eligibility (Cohort 6) and t (11;14)+ pts (Cohort 7).image

Key Points In relapsed/refractory MM, venetoclax plus bortezomib and dexamethasone appears to be safe and efficacious. This is a novel therapeutic approach for MM.