December 6, 2020 — The BCMA and CD3 bispecific T-cell redirecting antibody TNB-383B elicited significant responses when administered at a higher dose level and was well tolerated at all doses examined in heavily pretreated patients with relapsed/refractory multiple myeloma.
A novel BCMA and CD3 targeted bispecific T-cell engaging immunotherapy agent TNB-383B has demonstrated significant responses at higher dose levels and tolerability at all dose levels, including mild cases of cytokine release syndrome (CRS), according to initial results of a phase 1 trial (NCT03933735) presented during the 2020 American Society of Hematology (ASH) Annual Meeting.
“This off-the-shelf BCMA-targeted therapy has been given safely in the office setting following a short hospitalization for administration of the first dose,” Cesar Rodriguez, MD, said in his presentation of the findings. “With its safety profile, efficacy, and convenience of once-every-3-week dosing, this agent makes for a promising option for myeloma treatment.”
Patients with multiple myeloma who are refractory to available therapies typically have a median overall survival of under a year. BCMA approaches have become popular to try to fill this unmet need as the protein is widely expressed in multiple myeloma. However, these approaches have shown significant responses coupled with toxicity and other concerns.
“BCMA has become the most explored target for immunotherapy in myeloma, whether it is using CAR [chimeric antigen receptor] T constructs, antibody-drug conjugates, or bispecific T-cell engaging therapies. The promising data from studies…are shadowed by problems unique to each modality such as limited access, off-target toxicities, or the need for split dosing to reduce CRS,” said Rodriguez, a clinical associate professor of hematology and oncology at Wake Forest Baptist Comprehensive Cancer Center. “We aimed at developing a BCMA-directed immunotherapy that would overcome these obstacles and provide a safe and effective treatment approach for relapsed/refractory myeloma.”
TNB-383B is a fully human triple-chain antibody that targets BCMA and CD3. Rodriguez explained that the bispecific antibody was designed with a unique anti-CD3 moiety that would minimize cytokine release, 2 anti-BCMA domains to favor cell surface BCMA binding, and an IgG4 silenced backbone to reduce nonspecific T-cell activation and have a half-life of 2 to 3 weeks.
Preclinical models suggested that treatment with TNB-383B was associated with less toxicity without compromising on antitumor activity.
The ongoing phase 1 dose-escalation/expansion, open-label study is exploring the use of TNB-383B in patients with relapsed/refractory multiple myeloma who have received 3 prior lines of therapy including a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 monoclonal antibody. Patients were required to have a hemoglobin level ≥8 g/dL, absolute neutrophil count ≥1 × 109/L, and platelets ≥50 × 109/L. Unlike usual eligibility criteria, an estimated glomerular filtration rate of ≥30 mL/min and an ECOG performance status of up to 2 were allowed to more closely represent the patient population in the clinic, according to Rodriguez. Patients were not allowed to have received prior BCMA-targeted therapies.
Treatment with TNB-383B was administered intravenously at fixed dosing levels starting at 0.025 mg over 1 to 2 hours every 3 weeks. Intra-patient dose escalation was permitted on the study. The ASH presentation included patients who were treated at doses up to 60 mg.
Of the 58 enrolled patients, the median age was 66 years (range, 37-88) and 60% were male. More than half (57%) had an ECOG performance status of 1 and 16% had a score of 2. One-third of patients had International Staging System stage III disease. Patients had received a median of 6 prior lines of therapy (range, 3-15) with 64% triple-class refractory and 34% penta-refractory. Eighty-one percent had progressed on their last line of therapy.
“Of the patients enrolled to date, age, gender, and disease subtype fall in line with other myeloma studies,” Rodriguez noted. “I would like to mention that minorities are often not well represented in early-phase studies, so it is encouraging to see [that] Black patients made up [over] 20% enrollment in this study.”
As of data cutoff, 57% had discontinued due to progressive disease (91%), dose-limiting toxicity (3%), or due to coronavirus disease 2019 (COVID-19; 6%).
CRS was the most common adverse event (AE) reported on the study and was observed in 45% of patients at any grade, which increased to 80% in patients who received doses ≥40 mg, but cases were grade 1/2. The median onset to CRS was less than a day (range, 0-7) and the median duration was 1 day (range, 1-7). Five patients were treated with tocilizumab. Only 1 patient had a reoccurrence of CRS.
Other common AEs included fatigue (24%), headache (22%), infection (21%), nausea (21%), and anemia (21%). The most common grade ≥3 AEs were anemia (17%), neutropenia (16%), thrombocytopenia (14%), and infection (14%). Treatment-related AEs increased at higher doses ≥40 mg due to increased CRS, but there was no significant increase observed in the incidence of other AEs with higher doses of treatment.
Two dose-limiting toxicities were observed of grade 3 confusion at 20 mg and grade 4 thrombocytopenia at 60 mg. Both toxicities resolved without sequelae. Two deaths were reported on the study due to COVID-19, not due to treatment.
The objective response rate (ORR) at lower doses (0.025 to 1.8 mg; n = 15) was 20%, with a complete response (CR) rate or better of 6.7%. At doses from 5.4 to 30 mg (n = 28), the ORR was 43% with a CR or better rate of 17.9%. The ORR was 80% at higher dose levels (40 to 60 mg; n = 15) with a CR or better rate of 13.3%. Three of 4 patients evaluable for minimal residual disease were found to be negative.
Responses lasting up to 39 weeks were observed with 81% of responses ongoing. The median time to response was 3 weeks, or 1 cycle.
“It is interesting to see that in most cases, a significant response was seen with the first dose of TNB-383B,” Rodriguez said. “In addition, responses deepened over time as patients remained on therapy.”
TNB-383B had a half-life of 15 to 18 days at dose ≥20 mg, which supports the every-3-week dosing schedule.