ABBV-383 Shows Promising Efficacy, Safety in Pretreated Multiple Myeloma

The novel bispecific antibody ABBV-383 displayed preliminary safety and efficacy in patients with heavily pretreated relapsed or refractory multiple myeloma, based on updated results from a phase 1 trial (NCT03933735) presented at the 19th International Myeloma Society Meeting.¹

In 58 evaluable patients in the dose-expansion and dose-escalation cohorts of the trial who received ABBV-383 at a dose of 60 mg, the objective response rate was 60% and the median duration of response was not reached (NR; 95% CI, NR-NR). A very good partial response (VGPR) rate or better was reported for 43% of responders with a complete or stringent complete response (CR/sCR) reported among 29%, a VGPR reported among 14%, and a partial response (PR) reported among 17% of patients. The median time to first response was 0.8 months (range, 0.7-4.2) and the median time to first CR/sCR was 2.8 (range, 1.4-12.0). The 12-month estimated response rate was 76.8% (95% CI, 55.1%-89.0%).

Investigators reported safety outcomes for all patients treated in the escalation and expansion cohorts to receive ABBV-383 at 60 mg (n = 60). Cytokine release syndrome (CRS) of any grade was observed in 72% of patients, with 48% of events being grade 1, 22% grade 2, and 2% being grade 3 or higher. Serious CRS was documented in 16 patients. These events occurred following the first dose of the drug and the median time to onset and resolution was 1 day with supportive care measures. No patients experienced recurrence after cycle 1. Of note, per study protocol, the first dose of the agent is administered in the inpatient setting, which can allow for additional monitoring of CRS.

ABBV-383 is a novel investigational BCMA × CD3 T-cell–engaging bispecific monoclonal IgG4 antibody. The agent was designed to maximize off-target cell killing and minimize toxicity associated with other T-cell–engaging agents brought on by the overstimulation of T cells.^1,2

Peter Voorhees, MD, a hematologist/oncologist at the Atrium Health Levine Cancer Institute in Charlotte, North Carolina, noted 2 distinguishing features of ABBV-383 in a presentation of the data. “[ABBV-383] harbors 2 BCMA-binding domains to better engage its target and it also utilizes a lower affinity CD3-binding domain with the strategy [being to] try and mitigate the potential CRS [which] can occur with these therapeutics and potentially allow for full therapeutic dosing right from the beginning.”

Toxicity Profile of ABBV-383

A detailed portrait of CRS toxicity was presented for varying dose levels examined in the study. Premedications included intravenous dexamethasone 10 mg or equivalent in addition to diphenhydramine or equivalent, famotidine or equivalent, and acetaminophen or equivalent. These agents were administered 15 to 60 minutes prior to ABBV-383. Investigators noted that if CRS is not noted in a prior cycle, dexamethasone may be tapered.

Among the 15 patients who received ABBV-383 at 0.025 to 1.8 mg, 7% experienced grade 2 CRS. Among those who received doses ranging from 5.4 to 30 mg (n = 28), 18% had CRS grade 2 and 21% had CRS grade 1. Nine patients received doses ranging from 40 to 50 mg, with 22% having CRS grade 2 and 56% having CRS grade 1.

“As far as CRS is concerned, it’s a dose effect: the more you give, the higher the likelihood of CRS,” Voorhees said. Among the 9 patients who received the agent at 90 mg, 67% experienced CRS (grade 1, 22%; grade 2, 33%; grade 3, 11%). At the 120-mg dose (n = 3), 1 patient had grade 3 CRS and 2 others had grade 1 CRS.

In an expanded safety analysis, Voorhees presented data for the 60-mg cohort, as well as data for the entire treated population (n = 124). Serious AEs were reported in 58% of patients in the 60-mg cohort and 53% in the overall population. Three patients experienced immune effector cell–associated neurotoxicity syndrome, all of whom were treated with the 60-mg dose. Infection occurred in 43% of patients in the 60-mg cohort. Of the 41% of patients overall who experienced infections, 31% experienced serious events and 24% of events were grade 3 or higher and included pneumonia, sepsis, COVID-19, and urinary tract infections.

“Treatment is ongoing in 45% of patients, and the overwhelming majority of [individuals] who discontinued treatment did not discontinue because of AEs,” Voorhees noted, adding that 10 deaths were reported with the 60-mg dose. “Most of these occurred beyond 30 days with the last dose of drug [n = 10] and none were determined to be related to ABBV-383,” he said. These data were compared with the overall population in which 36% of patients were still receiving treatment and 33 patients across dose levels had died, 30 of whom died more than days from their last dose.

Among reported all-grade treatment-emergent AEs (TEAEs; ≥ 25%), the most common in the 60-mg and overall population were CRS (72% vs 57%, respectively), neutropenia (42% vs 37%), anemia (32% vs 29%), nausea (32% vs 29%), fatigue (27% vs 30%), diarrhea (28% vs 27%), and thrombocytopenia (25% vs 23%).

Hematologic grade 3 or higher events included neutropenia (37% vs 34%, respectively), anemia (12% vs 16%), thrombocytopenia (12% vs 12%), lymphopenia (17% vs 13%). Grade 3 or higher CRS, diarrhea, and hypogammaglobulinemia (the only instance) was reported in 1 patient each in the 60-mg cohort. Grade 3 or higher nonhematologic events reported in the overall population included CRS (n = 3), fatigue (n = 1), nausea (n = 2), diarrhea (n = 2), and headache (n = 2).

Discontinuation, dose-interruption, and dose-reduction rates because of TEAEs in the 60-mg cohort were 8%, 38%, and 7%, respectively; in the overall population, these rates were 10%, 37%, and 5%, respectively. The 3 dose-limiting toxicities observed in the entire population included grade 4 platelet count decrease at the 60-mg dose, and grade 3 CRS at the 90-mg and 120-mg dose levels. The 7 TEAE-reported deaths included 3 from COVID-19, 1 from sepsis, 1 from liver injury, 1 subdural hematoma, and 1 from myeloma.

Expanded Efficacy Data With ABBV-383

“Encouraging preliminary antitumor activity [observed] in heavily pretreated patients with relapsed refractory multiple myeloma supports further clinical evaluation,” Voorhees said following a discussion of response and progression-free survival (PFS) data.

At a median follow-up of 8.3 months in the 60-mg cohort, the median PFS was not reached (95% CI, 4.8-NR); the 6- and 12-month PFS rates were 60.9% (95% CI, 44.9%-73.6%) and 57.9% (95% CI, 41.6%-71.1%), respectively. In the overall population, with a median follow-up of 10.8 months, the median PFS was 10.4 months (95% CI, 5.0-19.2), with 6- and 12-month PFS rates of 57.5% (95% CI, 47.3%-66.4%) and 46.6% (95% CI, 35.9%-56.6%), respectively.

Additional response data were reported for the overall population (n = 122), the triple-class refractory population (n = 100), and a subgroup of triple-class refractory patients who received 60-mg dose (n = 48). The ORR for all patients was 57% comprising a 29% CR/sCR rate, a 14% VGPR rate, and a 14% VGPR rate. The median time to first response was 0.7 months (range, 0.3-7.6) and the median time to first CR/sCR was 3.5 months (range, 1.4-20.1). Further, among the 69 responders, the median DOR was not reached (95% CI, 12.9-NR), and the 6- and 12-month Kaplan-Meier estimates for response were 76.3% (95% CI, 63.2%-85.3%) and 67.2% (95% CI, 52.6%-78.2%), respectively.

For all triple-class refractory patients, the ORR was 51%, with a 29% CR/sCR rate, an 11% VGPR rate, and an 11% VGPR rate. Among those with triple-class refractory disease to receive ABBV-383 at 60 mg, the ORR was 54%, with a 29% CR/sCR rate, a 10% VGPR rate, and a 15% VGPR rate. Of the 11 patients who were evaluable for minimal residual disease (MRD) with a CR or sCR, 8 were MRD negative (≤ 10^-5).

Trial Design for Phase 1 Study of ABBV-383

Patients with relapsed or refractory multiple myeloma who previously received at least 3 prior lines of treatment, including a proteasome inhibitor, an immunomodulatory drug (IMiD), and an anti-CD38 monoclonal antibody were eligible for enrollment. No prior BCMA-targeted therapy was permitted. Patients must have had an ECOG performance status of 0 to 2 as well as a hemoglobin count of at least 8 g/dL, absolute neutrophil count of at least 1 × 10⁶/L, platelet count of 50 × 10⁹/L and an estimated glomerular filtration rate of at least 30 mL/min.

The first-in-human, dose-escalation strategy used a 3 + 3 design with backfilling, with cohort 1 receiving 0.025 mg of fixed-dose ABBV-383 up to 120 mg in cohort 14. The dose-expansion used 60 mg administered intravenously over 2 hours every 3 weeks until disease progression, with each additional dose administered over 1 hour. The primary end points were safety and tolerability, with a secondary end point of response by International Myeloma Working Group 2016 criteria.

At baseline, in the 60-mg cohort and the overall population, the median age was 68 years (range, 35-92) and most patients had an ECOG performance status of 1 (53% and 57%, respectively). The median number of prior lines of therapy was 5 (range, 3-15) and most patients were refractory to their last cancer therapy (85% and 87%, respectively); most patients had triple-class refractory disease (83% and 82%). More patients in the 60-mg cohort had penta-refractory disease (42%) vs the overall population (35%).

Enrollment in the 60-mg dose-expansion cohort has been completed; however, an additional dose-expansion cohort (40 mg) has been added to the protocol and is open for enrollment.

Next Steps for ABBV-383 in Multiple Myeloma

In a discussion of the abstract, Thomas G. Martin, MD, noted that bispecifics are primed to play a role in the community setting compared with CAR T-cell therapy. He noted that there are several areas where bispecifics can play a role in the myeloma space, but dosing is going to play a key role in the determination of which agents move forward.

“What we want is convenient dosing, every 3 to 4 weeks, which [ABBV-383] shows,” Martin, who is the clinical research director of hematologic malignancies at the University of California, San Francisco (USCF) Helen Diller Family Comprehensive Cancer Center, said. “[ABBV-383] had fixed dosing and was given at full dose for the first dose, so 1 hospitalization for 2 days. After that, it was all outpatient administration,” added Martin, who is also associate director of UCSF’s myeloma program, and director of the unrelated donor transplantation programs for adults at UCSF Medical Center.

Other factors to consider, safety and efficacy, Martin drew from a comparison of other agents, such as REG-5458 and elranatamab, noting that ORRs are similar across the agents in the 60% to 70% range, with CRS being the lowest with ABBV-383 and REG-5458.­

Martin concluded by adding that future development should include a focus on fixed-duration therapy, with MRD serving a prognostic role for treatment-discontinuation decisions.

_References

_{1. Voorhees P, Shah N, D’Souza A, et al. Updated Results of a Phase 1, First-in-Human Study of ABBV-383, a BCMA × CD3 Bispecific T-Cell Redirecting Antibody, in Patients with Relapsed/Refractory Multiple Myeloma. Presented at: 19th International Myeloma Society Annual Meeting. August 25-27, 2022; Los Angeles, CA. Abstract OAB-055}

_{2. Buelow B, Choudry P, Clarke S, et al. Pre-clinical development of TNB-383B, a fully human T-cell engaging bispecific antibody targeting BCMA for the treatment of multiple myeloma. J Clin Oncol. 2018;36(suppl 15):8034. doi:10.1200/JCO.2018.36.15_suppl.8034}