A Phase 1 First-in-Human Study of Abbv-383, a BCMA × CD3 Bispecific T-Cell-Redirecting Antibody, As Monotherapy in Patients with Relapsed/Refractory Multiple Myeloma

Background

Relapsed/refractory multiple myeloma (RRMM) has a poor prognosis, especially when refractory to ≥3 drug classes. Immunotherapies targeting B-cell maturation antigen (BCMA), a plasma cell-specific biomarker, have shown promise in treating RRMM. ABBV-383 (formerly TNB-383B) is a BCMA × CD3 bispecific T-cell-redirecting antibody with 2 BCMA-binding domains and a low-affinity CD3-binding domain to potentially mitigate the incidence of cytokine release syndrome (CRS) and eliminate the need for step-up dosing. ABBV-383 monotherapy has shown promising activity in patients (pts) with RRMM at ≥40mg with an overall response rate (ORR) of 79% in an ongoing phase 1 study (Kumar S, et al. Blood 2021;138[suppl 1]:900). Two doses of ABBV-383 (40mg and 60mg) are being explored as potential recommended phase 2 dose (RP2D) on the basis of aggregate dose-escalation (ESC) data. We report results from 40mg ESC and 60mg ESC and expansion (ESC+EXP) cohorts of this study. A 40mg EXP cohort is enrolling (planned accrual n=48 pts).

Methods

This is a phase 1, open-label ESC and EXP study (NCT03933735) in pts aged ≥18 years with RRMM. Key eligibility criteria were ≥3 prior treatments (Tx) including ≥1 proteasome inhibitor, immunomodulatory drug, and anti-CD38 monoclonal antibody, Eastern Cooperative Oncology Group performance status ≤2, and adequate hepatic, bone marrow, and renal function. Prior BCMA-targeted therapy is prohibited.

The primary objectives were to determine safety/tolerability, pharmacokinetics/pharmacodynamics, and maximum tolerated dose or RP2D on the basis of dose-limiting toxicity (DLT). The secondary objective was to evaluate clinical activity. The study used a 3+3 design for ESC. ABBV-383 was administered intravenously once every 3 weeks (Q3W) until progressive disease (PD), unacceptable toxicity, or other study discontinuation criteria were met.

DLT and adverse events (AEs) were assessed per National Cancer Institute Common Terminology Criteria for Adverse Events v5.0. Tumor response including ORR, duration of response (DOR), and progression-free survival (PFS) was assessed per International Myeloma Working Group 2016 criteria in the efficacy-evaluable population (all pts receiving at least 1 ABBV-383 dose and 1 postdose evaluation).

Results

As of 8 Jan 2022, 124 pts were treated: 73 pts in ESC (0.25-120 mg; 40mg, n=6; 60mg, n=9) and 51 pts in EXP at 60 mg. Pts in 40mg ESC (n=6) and 60mg ESC+EXP cohorts (n=60) had a median age of 64 (range 56-76) and 68 years (range 35-92), received 4 (range 3-10) and 5 (range 3-12) prior lines of therapy, and 67% and 83% of pts were triple refractory, respectively. Pt demographics and baseline characteristics are shown in Table 1. Median follow-up was 17.4 and 8.4 months in 40mg ESC and 60mg ESC+EXP cohorts, with 50% and 45% continuing Tx, respectively. All 3 pts in 40mg ESC cohort and 23 of 33 pts in 60mg ESC+EXP cohort discontinued Tx due to PD.

Tx-emergent AEs (TEAE) were reported in 100% (50% grade [G]≥3) of pts in 40mg ESC cohort (n=6) and 98% (78% G≥3) of pts in 60mg ESC+EXP cohort (n=60), with 0 and 1 DLT-associated TEAE, and AE-led study drug discontinuation in 0% and 5% pts, respectively. CRS occurred in 83% (0% G≥3) of pts receiving 40mg in ESC and 72% (2% G≥3) of pts receiving 60mg in ESC+EXP. Infections occurred in 50% (17% G≥3) of 40mg ESC cohort and 43% (22% G≥3) of 60mg ESC+EXP cohort. In 40mg ESC and 60mg ESC+EXP cohorts, the incidence of neutropenia was 67% (67% G≥3) and 40% (35% G≥3), anemia was 33% (17% G≥3) and 32% (12% G≥3), and thrombocytopenia was 33% (0% G≥3) and 25% (12% G≥3), respectively.

Clinical response for all pts (N=122), 40mg ESC (n=6), and 60mg ESC+EXP cohorts (n=58) is shown in Figure 1. In the triple-refractory subpopulation of 40mg ESC cohort (n=4), ORR was 75% with rates of complete response + stringent complete response (≥CR) and very good partial response or better (≥VGPR) of 50% and 75%, respectively. An ORR of 54%, ≥CR of 29%, and ≥VGPR of 40% was observed in the triple-refractory subpopulation of 60mg ESC+EXP cohort (n=48). Median DOR and PFS, analyzed by Kaplan-Meier method, were not reached (NR) in any cohort.

Conclusions

ABBV-383 monotherapy at 40mg and 60mg Q3W doses is well tolerated in pts with RRMM. Durable responses were observed at both doses, including in pts with triple-refractory RRMM. Median DOR and PFS were NR. Enrollment in 40mg EXP cohort is ongoing (n=42 currently enrolled). Updated data from these pts will be presented.

Voorhees:Karyopharm Therapeutics: Consultancy; Oncopeptides: Consultancy; Pfizer: Consultancy; Sanofi: Consultancy; AbbVie: Consultancy; Janssen: Consultancy; GSK: Consultancy; Bristol Myers Squibb: Consultancy, Other: Data Safety and Monitoring. D'Souza:Takeda, Sanofi, TeneoBio, Prothena, Caelum Biosciences, Janssen Oncology, Regeneron, Abbvie: Research Funding; Pfizer, Janssen Oncology, Bristol-Myers Squibb/Celgene, Prothena: Consultancy, Membership on an entity's Board of Directors or advisory committees. Weisel:Janssen: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Stemline: Honoraria; BeiGene: Consultancy, Honoraria; Novartis: Honoraria; BMS/Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; AstraZeneca: Honoraria; Adaptive Biotech: Consultancy, Honoraria; Oncopeptides: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria. Hurd:Johnson & Johnson, BMS/Celgene, Merck, Pfizer: Current equity holder in publicly-traded company. Teipel:Janssen; Travel Expenses: Janssen, Amgen: Research Funding; Amgen, BMS/Celgene, Janssen, GSK, Karyopharm, Oncopeptides, Pfizer, Sanofi, Takeda: Honoraria. Chung:Janssen: Research Funding; Cellectis: Research Funding; BMS/Celgene: Research Funding; AbbVie: Research Funding; Merck: Research Funding; Caelum: Research Funding; Sanofi: Honoraria. Rodriguez:Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Karyopharm Therapeutics: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Tuchman:Shattuck Labs: Honoraria; Prothena: Honoraria; Janssen: Honoraria. Korde:Amgen, Janssen: Research Funding; Clinical Care Options, OncLive, Intellisphere: Consultancy. Safah:Incyte: Speakers Bureau; Janssen: Speakers Bureau; Blueprint: Speakers Bureau; Astellas: Speakers Bureau. Bueno:Abbvie: Current Employment, Current equity holder in publicly-traded company. Pumford:AbbVie Inc.: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company. Rosenberg:AbbVie: Current Employment, Current equity holder in private company. Pothacamury:AbbVie: Current Employment, Current holder of stock options in a privately-held company. Ross:AbbVie: Current Employment, Current equity holder in publicly-traded company. Polepally:AbbVie: Current Employment, Current equity holder in publicly-traded company. Lee:AbbVie: Current Employment, Current equity holder in private company. Jin:AbbVie: Current Employment, Current equity holder in publicly-traded company. Talati:AbbVie: Current equity holder in private company. Vij:BMS, Takeda, Sanofi: Research Funding; Takeda, Bristol Myers Squibb, Sanofi, GlaxoSmithKline, Janssen, Oncopeptides, Harpoon, Adaptive, Legend, BeiGene, CareDx: Honoraria; BMS, Sanofi, Takeda, Janssen, GSK, Oncopeptides, Pfizer, Legend, Adaptive: Consultancy. Kumar:AbbVie,: 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; Takeda,: 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; KITE,: Research Funding; MedImmune/Astra Zeneca,: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck,: Research Funding; Novartis,: Research Funding; Roche: Research Funding; Sanofi: Research Funding; Oncopeptides: Other: Independent review committee.