Polepally, Akshanth

7541 Background: ABBV-383 is a fully human, B-cell maturation antigen (BCMA) × CD3 T-cell–engaging IgG4 bispecific with an effector-silenced Fc region, 2 high-affinity BCMA- and a low-affinity CD3-binding domains. ABBV-383 monotherapy has shown promising activity in patients (pts) with RRMM (Blood 2023;142[suppl 1]:3378). Here, exposure-response (ER) analyses of efficacy and safety endpoints supporting the optimal therapeutic ABBV-383 dose selection are reported in alignment with US FDA’s Project Optimus. Methods: Efficacy (n=218) and safety (n=220) data from the phase 1 study (NCT03933735) escalation cohorts of 0.025 - 120 mg Q3W and expansion cohorts of 20, 40, 60 mg Q3W and 60 mg Q4W including objective response rate (ORR), very good partial response or better (≥VGPR), stringent complete response (sCR)/CR, adverse events (≥G3 and serious), infections (≥G3, overall and serious), cytokine release syndrome (CRS; any-grade, G1, G2, and ≥G2) were modeled. Total(unbound + bound to soluble BCMA) and free (unbound + partially bound to soluble BCMA) Cycle 1 AUCinf, Cmax, and Ctrough and population pharmacokinetic model-derived up to the time of event Cavg and avgCtrough metrics were utilized in the ER analyses (logistic regression; R Version 4.2.2). Relevant pt-specific covariates were tested. Dexamethasone premedication (36 vs 10 mg) was included in CRS models. The ER relationships were utilized to predict the probabilities of efficacy and safety endpoints for relevant doses and thereby, support justification of the optimal therapeutic dose selection. Results: Based on overall assessment, ORR, ≥VGPR, sCR/CR and ≥G3 neutropenia strongly correlated with free Cavg; CRS endpoints (any-grade CRS and G1 only CRS) strongly correlated with Cycle 1 total Cmax (p <0.05). No other endpoints had ER relationships (p >0.05). Only MM type (IgG vs Others) was selected in ≥VGPR and sCR/CR models. ER relationships suggested high response rates of >63% ORR, >53% ≥VGPR, and ≥30% sCR/CR for 40, 60 mg Q3W and 60 mg Q4W. Predictions demonstrated that 20 mg Q3W (<39% ORR and ≥VGPR; <13% sCR/CR) and untested 40 mg Q4W (<60% ORR, <45% ≥VGPR and <23% sCR/CR) provide suboptimal efficacy. The 60 mg Q4W with 36 mg dexamethasone in Cycle1 (limited follow-up and data) was predicted to have ~30% sCR/CR and 31% ≥G3 neutropenia (≈ 40 mg Q3W) and substantially lower any-grade CRS events compared with 40 and 60 mg doses with 10 mg dexamethasone in Cycle 1. Conclusions: While ER analyses indicated promising efficacy and acceptable safety profiles for 40, 60 mg Q3W, and 60 mg Q4W, they support 60 mg Q4W as the optimal ABBV-383 therapeutic dose due to its predicted better therapeutic benefit/risk profile (high response rates, improved/equivalent ≥G3 neutropenia, and lower CRS events) and extended dosing interval. ABBV-383 at 60 mg Q4W will be investigated in the registrational phase 3 trial (NCT06158841) in RRMM.

7531 Background: MM eventually becomes refractory to current treatments, and new therapeutic options with convenient dosing and improved safety are needed to enhance patient (pt) adherence, access, and outcomes. ABBV-383 is a distinctive next-generation BCMA x CD3 bispecific antibody composed of 2 high-affinity BCMA-binding domains, a low-affinity CD3-binding domain designed to reduce cytokine release syndrome (CRS) risk, and a silenced Fc tail for an extended half-life allowing convenient dosing. ABBV-383 monotherapy has shown promising activity in the ongoing first-in-human phase 1 trial in RRMM (Vij et al. Blood 2023;142[suppl 1]:3378). Here, safety and efficacy results are reported that support the RP2D of 60mg Q4W as the optimal therapeutic ABBV-383 monotherapy dose. Methods: This phase 1 open-label, dose-escalation/expansion trial (NCT03933735) enrolled pts with RRMM who received ≥3 prior lines of therapy with exposure to PI, IMiD, and anti-CD38 mAb. ABBV-383 regimens explored in the expansion phase included 60mg Q4W and 40 or 60mg Q3W. A modified dexamethasone premedication schedule and shortened CRS monitoring period were implemented in the 60mg Q4W cohort for cycle 1. IV ABBV-383 was administered as a flat dose with no step-up schedule. Treatment was continued until disease progression/unacceptable toxicity. Primary objectives were to assess safety, tolerability, PK, PD, and determine the RP2D. Efficacy evaluation was a secondary objective. TEAEs were assessed per CTCAE v5.0 and tumor response per IMWG 2016 criteria. Results: As of May 2023, 220 pts received ABBV-383 (median age: 68 yr [35–92]; median prior therapy lines: 5 [3‒23]). Median FU was 4.1 mo (0.8–5.2) at 60mg Q4W (n=21), 12.2 mo (1.3–34.4) at 40mg Q3W (n=55), and 24.2 mo (0.6–33.4) at 60mg Q3W (n=61). At 60mg Q4W, with the modified premedication regimen, CRS was reported in 43% of pts (38% G1, 5% G2), and ICANS in 5% of pts (G2). In Q3W cohorts, CRS was reported in 71% (40mg; 45% G1, 25% G2) and 70% (60mg; 51% G1, 18% G2, 2% G3) of pts. The incidence of G3/4 neutropenia, anemia, and thrombocytopenia was 14/24/10% at 60mg Q4W, 31/31/16% at 40mg Q3W, and 34/13/13% at 60mg Q3W. G3/4 infections occurred in 10/24/34% of pts at 60mg Q4W, 40mg and 60mg Q3W, respectively. ORR and ≥VGPR were 65/50% at 60mg Q4W, 64/53% at 40mg Q3W, and 60/52% at 60mg Q3W. Corresponding exposure-response (ER) analyses and correlative analyses further supported RP2D determination (separate abstract submissions). Conclusions: The optimal therapeutic dose of 60mg Q4W ABBV-383 monotherapy was selected on the basis of safety, efficacy, and ER analyses. The extended interval of Q4W, with a shortened CRS monitoring period in cycle 1 and no step-up dosing, will improve convenience and reduce the treatment burden for pts. ABBV-383 at 60mg Q4W will be investigated in the registrational phase 3 trial (NCT06158841) in RRMM. Clinical trial information: NCT03933735 .