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New Targets Explored for Bispecific T-Cell–Engaging Antibodies in Myeloma


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B-cell maturation antigen (BCMA) is the most frequent target of immunotherapies in relapsed or refractory multiple myeloma, but bispecific T-cell–engaging (BiTE) antibodies with novel targets are also achieving promising results. Studies presented at the 2020 American Society of Hematology (ASH) Annual Meeting & Exposition showed an early benefit from two such antibodies—talquetamab and cevostamab—indicating a potential widening of the therapeutic landscape.1,2

Talquetamab is a first-in-class, off-the-shelf bispecific T-cell–engaging antibody targeting the G protein–coupled receptor family C group 5 member D (GPRC5D). Responses in heavily pretreated patients were encouraging in the first clinical study of the drug. Its potential value in the clinical setting is enhanced by its subcutaneous (SC) dosing, according to Ajai Chari, MD, Professor of Medicine at Mount Sinai Medical Center, New York.

Ajai Chari, MD

Ajai Chari, MD

GPRC5D is an orphan receptor whose transcript is highly expressed in myeloma cells but is limited in other cells of the body, “making it an attractive therapeutic target,” he said. ­Talquetamab binds to GPRC5D in addition to CD3, redirecting T cells to GPRC5D-expressing myeloma cells to mediate cell killing.

Phase I Study of Talquetamab

In the ongoing phase I dose-escalation study, patients received escalating doses of intravenous (IV) or SC talquetamab weekly or every 2 weeks in a step-up dosing scheme. Dr. Chari reported the outcomes for 157 patients, of whom 102 received the IV form of the drug and 55, the SC form. The investigators determined the recommended phase II dose to be 405 μg/kg.

The median age of study patients was 61 years. The median number of prior therapies was 4.5, and 95% of patients were triple-class–exposed, 68% were triple-refractory, 21% were penta-refractory, and 80% were refractory to their last line of treatment.

At the recommended phase II dose of 405 μg/kg SC, the overall response rate was 69%, with 39% achieving a very good partial response or better. The median time to first response was 1 month.

“Of note, responses were observed in six of nine triple-refractory patients and two of two pentarefractory patients, indicating the efficacy of this novel agent in heavily pretreated patients,” Dr. Chari said.

At the most active doses (20–180 μg/kg IV and 135–800 μg/kg SC), 66% of patients responded, and 42% had at least a very good partial response. These response rates were comparable between the IV and SC groups.

“Responses were durable and continued to deepen over time,” noted Dr. Chari. Responses are ongoing in the vast majority of responding patients in both the IV (at 7.4 months’ follow-up) and SC (at 3.7 months’ follow-up) groups. For three patients, the duration of response exceeded 2 years, “indicating favorable durability of efficacy with this novel agent,” he added.

Pharmacokinetics/Pharmacodynamics and Safety

At the recommended dose, target exposures were reached, and the pharmacodynamic data demonstrated consistent T-cell activation, cytokine production, and redistribution. The pharmacokinetic, pharmacodynamic, and safety data support a recommended phase II dose of 405 μg/kg SC.

Two dose-limiting toxicities were observed: one clinically ­asymptomatic grade 4 increased lipase level in the IV group and two cases of grade 3 maculopapular rash at the highest SC dose. At the recommended phase II dose, there were no dose-limiting toxicities, and dose reductions were less frequent and occurred later as compared with higher doses. There were no grade 5 toxicities at any dose level.

Infections were seen in 38% of patients (mostly respiratory), including 16% at the recommended dose, and grade ≥ 3 infections, in 8%. In comparison to other studies of relapsed or refractory multiple myeloma, Dr. Chari considered these rates “encouraging.” Injection-site reactions, in 18%, were all mild. Easily managed skin-related adverse events were seen in 45% and nail disorders, in 17%.

At the recommended dose of 405 μg/kg SC, hematologic adverse events grade ≥ 3 included neutropenia (42%), lymphopenia (16%), leukopenia (16%), and thrombocytopenia (5%).

Neurotoxicity was observed in nine patients, with the incidence similar in the IV and SC cohorts, although none was greater than grade 3 in the SC cohort. One case of grade 2 encephalopathy occurred at the recommended dose, but it resolved. Also, at the recommended dose, 68% of patients developed cytokine-release syndrome, but this was generally low grade.

Talquetamab is being studied in combination with anti-CD38 antibodies and T-cell–redirected therapies. One study will evaluate a regimen of talquetamab, the anti-BCMA bispecific T-cell–engaging molecule teclistamab, daratumumab, and dexamethasone. Updated data for teclistamab, also presented at the 2020 ASH meeting, showed a 69% response rate, including a complete response or better in 26%.3

Cevostamab: Bispecific T-Cell–Engaging Antibody Targeting FcRH5

Monotherapy with the bispecific T-cell–engaging antibody cevostamab (BFCR4350A) led to promising activity in heavily pretreated patients, with deep and durable responses observed in patients with high-risk cytogenetics; triple-class–refractory disease; and/or prior exposure to anti-CD38 monoclonal antibodies, chimeric antigen receptor (CAR) T-cell therapy, or antibody-drug conjugates, according to Adam D. Cohen, MD, Associate Professor of Medicine, Abramson Cancer Center at the University of Pennsylvania, Philadelphia.2

Adam D. Cohen, MD

Adam D. Cohen, MD

“Data from this phase I study establish FcRH5 as a novel target in multiple myeloma and demonstrate the activity of cevostamab monotherapy in late relapsed or refractory disease,” Dr. Cohen said.

Fc receptor homolog 5 (FcRH5) is a type I membrane protein that is expressed on B cells, plasma cells, and nearly 100% of myeloma cells. Cevostamab targets the most membrane-proximal domain of FcRH5 on myeloma cells and CD3 on T cells. Dual binding facilitates efficient immunologic synapse formation, resulting in T-cell activation and potent killing of myeloma cells, according to Dr. Cohen.

Dose-Escalation Data on Cevostamab

Dr. Cohen presented the dose-escalation data from the single step-up dosing cohort of the ongoing multicenter phase I GO39775 trial of cevostamab monotherapy. Patients were allowed to have prior exposure to CAR T cells, bispecific T-cell–engaging antibodies, and antibody-drug conjugates (including those targeting BCMA).

Patients received cevostamab by IV infusion every 3 weeks by a step-up dosing schema. The step dose (0.05–3.6 mg) was given on cycle 1 day 1, and the target dose (0.15–160 mg) was given on cycle 1 day 8 and day 1 of each subsequent cycle. Patients were hospitalized for cycle 1 infusions alone. “The step-up dosing was used to mitigate the risk of high-grade cytokine-release syndrome,” he explained.

Dr. Cohen reported on 53 patients (51 evaluable) with a median of 6 prior lines of therapy. Almost 90% had high-risk cytogenetics, more than 70% were triple-class–refractory, 45% were penta-refractory, and 21% had received prior anti-BCMA therapy with CAR T-cell or antibody-drug conjugates. Almost all were refractory to their last treatment.

Responses by Dose

In the 34 patients receiving at least 3.6/20 mg, 53% responded, including 41% of the penta-refractory patients and 63% of patients who had prior anti-BCMA treatment. Complete responses or better were achieved by 18% and at least a very good partial response, in 32%, Dr. Cohen reported.

The response rate was higher, 61%, in patients treated at the highest doses, 3.6/90 mg to 3.6/132 mg, with a complete response or better achieved by 17% and at least a very good partial response, by 28%. In seven evaluable patients achieving at least a very good partial response, six became negative for minimal residual disease (also known as measurable residual disease).

“To date, responses were seen irrespective of the target expression level of FcRH5,” Dr. Cohen said, further emphasizing the durability of response. “A number of patients have durable responses ongoing beyond 6 months and several beyond 1 year. Four patients have continued to respond after discontinuing treatment. Median follow-up in responders is 10.3 months (shorter at the highest dose level). With a dose of 132 mg, five of seven patients responded, and all were ongoing at data cutoff.”

Safety Profile

Toxicity was reportedly manageable, with cycle 1 single step-up dosing effectively mitigating the risk for severe cytokine-release syndrome and allowing escalation to clinically active doses, Dr. Cohen said.

The most common nonhematologic treatment-related adverse event was cytokine-release syndrome, which developed in 76% of patients but was grade ≥ 3 in one patient (due to grade 4 transaminase level elevation). Cytokine-release syndrome was most common during cycle 1 and was uncommon or absent during subsequent cycles. Neurologic events were observed in 28%, but none were grade ≥ 3.

Hematologic adverse events grade ≥ 3 (eg, thrombocytopenia, anemia, neutropenia, decreased lymphocyte count) were seen in 15% to 25% of patients. In 9% of patients, adverse events led to treatment withdrawal (two were related to treatment). There were no treatment-related grade 5 events.

The pharmacokinetics of cevostamab were linear across the active dose levels tested, and the estimated half-life was supportive of the every-3-week dosing regimen, added Dr. Cohen. 

DISCLOSURE: Dr. Chari has received honoraria from Array BioPharma, The Binding Site, Adaptive Biotechnology, and Novartis and has served as a consultant for Janssen, Secura Bio, GlaxoSmithKline, Antengene, Takeda, Oncopeptides, Seattle Genetics, Sanofi Genzyme, Karyopharm, Bristol Myers Squibb, Amgen, and Celgene. Dr. Cohen has served in a consulting or advisory role for Bristol Meyers Squibb, Celgene, GlaxoSmithKline, Janssen Oncology, Oncopeptides, Seattle Genetics, Genentech/Roche, AstraZeneca, and Takeda; has received research funding from Novartis; and holds patents related to CAR T cells and biomarkers of cytokine-release syndrome.

REFERENCES

1. Chari A, Berdeja JG, Oriol A, et al: A phase 1, first-in-human study of talquetamad, a G protein-coupled receptor family C group 5 member D (GPRC5D) x CD3 bispecific antibody, in patients with relapsed and/or refractory multiple myeloma. 2020 ASH Annual Meeting & Exposition. Abstract 290. Presented December 5, 2020.

2. Cohen AD, Harrison SJ, Krishnan A, et al: Initial clinical activity and safety of BFCR4350A, a FcRH5/CD3 T-cell-engaging bispecific antibody, in relapsed/refractory multiple myeloma. 2020 ASH Annual Meeting & Exposition. Abstract 292. Presented December 5, 2020.

3. Garfall AL, Usmani SZ, Mateos MV, et al: Updated phase I results of teclistamab, a B-cell maturation antigen x CD3 bispecific antibody, in relapsed/or refractory multiple myeloma. 2020 ASH Annual Meeting & Exposition. Abstract 180. Presented December 5, 2020.

 


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