Anti-BCMA, CD3 Agent CC-93269 Shows Promise for Heavily Pretreated Myeloma

CC-93269 showed encouraging signs of dose-dependent efficacy with a safety profile that continues to be refined for patients with heavily pretreated relapsed/refractory multiple myeloma.

Luciano J. Costa, MD, PhD, Division of Hematology and Oncology, University of Alabama at Birmingham

Luciano J. Costa, MD, PhD, Division of Hematology and Oncology, University of Alabama at Birmingham

Luciano J. Costa, MD, PhD

CC-93269, a human IgG1-based T-cell engager that binds to BCMA and CD3 epsilon in a 2+1 format, showed encouraging signs of dose-dependent efficacy with a safety profile that continues to be refined for patients with heavily pretreated relapsed/refractory multiple myeloma, according to interim phase I data presented at the 2019 ASH Annual Meeting.

In the dose escalation trial, the 10 mg dose of CC-93269 induced an objective response rate (ORR) for 88.9% of patients, which included a complete remission (CR) or stringent CR (sCR) rate of 44.4%. Many of these responses tested negative for minimal residual disease (MRD). Cytokine release syndrome (CRS) occurred in 76.7% of patients, which was mostly grade 1 or 2 in severity, warranting further investigation. At this point, a recommended phase II dose has not yet been determined.

"The safety profile of CC-93269 supports further development, and enrollment is ongoing trying to define the recommended phase II dose and optimal schedule. Most of the grade 3 or higher adverse events were neutropenia, anemia, and infections," Luciano J. Costa, MD, PhD, Division of Hematology and Oncology, University of Alabama at Birmingham, said during a presentation of the results. "CC-93269 shows promising dose-dependent efficacy, including MRD-negative sCRs, with a convenient administration schedule in patients with heavily pretreated relapsed/refractory multiple myeloma."

The study included 30 patients with relapsed/refractory multiple myeloma who had received ≥3 prior therapies. The median age of patients was 64 years and the median time from diagnosis was 5.94 years. The most common ECOG performance score was 1 (73.3%) and patients were evenly distributed across ISS stages I, II, and III. A third of patients (30%) had high-risk cytogenetics. Two-thirds of patients were refractory to a proteasome inhibitor, IMiD, and an anti-CD38 antibody.

In the dose escalation phase of the study, doses ranged from 0.15 mg to 10 mg. Treatment with CC-93269 was given on days 1, 8, 15, and 22 in cycle 1 to 3 then on days 1 and 15 in cycle 4 to 6. For cycle 7 and up to 2 years, the treatment was administered on day 1 alone. In response to the rates of CRS observed, additional cohorts were added with intra-patient dose escalation. In one of these cohorts, patients started at 6 mg with the dose increasing to 10 mg (cohort 7). Additionally, patients were stratified between cohort 8 and cohort 9, based on whether they had low or high tumor burden, respectively. In these cohorts, the dose was started at 3 mg and escalated to 6 mg.

A response to CC-93269 was not observed for any patients receiving a dose of ≤3 mg (n = 7). In cohorts 8 and 9 and those receiving CC-93269 at 6 mg (n = 14), the ORR was 35.7%, which included an sCR/CR rate of 7.1% and a very good partial response (VGPR) rate of 7.1%. In the largest dose arms (cohort 7 and those receiving 10 mg), the ORR was 88.9%, which included an sCR/CR rate of 44.4% and a VGPR rate of 33.3%. There was a dose-dependent decrease seen in serum M protein, size of measurable disease, and serum free light chains in response to treatment with CC-93269.

The median time to first response was 4.1 weeks (range, 4.0-13.1). Eleven of the 13 observed responses remained ongoing at the assessment. Of these responses, 92.3% were negative for MRD (≤1/105) in the bone marrow.

Treatment-emergent adverse events (TEAE) were experienced by 96.7% of patients, of which 73.3% were grade ≥3 in severity. The most common grade ≥3 TEAEs were hematologic, including neutropenia (43.3%) and anemia (36.7%). Most of the non-hematologic TEAEs were grade 1 or 2 in severity. The most common TEAEs of all grades were CRS (76.7%), infections and infestations (56.7%), diarrhea (26.7%), and vomiting (26.7%). Grade ≥3 non-hematologic AEs included infections and infestations (30%), CRS (3.3%), and diarrhea (3.3%).

Almost all of the CRS events occurred after the first dose of CC-93269 and then tapered off with subsequent doses (23.3% after second dose and 7.4% after third dose). There was one grade 5 CRS event at the 10 mg dose. Tocilizumab was administered for 43.3% of patients and corticosteroids were administered for 73.3%. Dexamethasone prophylaxis is now being required for all patients receiving a dose ≥6 mg.

In pharmacodynamic findings, there was a dose-dependent change in immune cell redistribution and cytokine release. Pharmacokinetics showed target-mediated drug disposition and a dose proportional response. In these analyses, anti-drug antibodies were not observed.

The phase I study continues to enroll participants, with a total enrollment goal of 120. The estimated primary completion date is July 2021 (NCT03486067).

Costa LJ, Wong SW, Bermudez A, et al. First clinical study of the B-cell maturation antigen 2+1 T cell engager CC-93269 in patients with relapsed/refractory multiple myeloma: interim results of a phase 1 multicenter trial. Presented at: 2019 ASH Annual Meeting; December 7-10, 2019; Orlando, FL. Abstract 143.

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