Bispecific antibodies are showing promise in patients with hematologic malignancies, notably relapsed or refractory multiple myeloma. Results from studies of 3 bispecific antibodies were presented at ASH 2020, showing deep and durable responses.
Cevostamab is a bispecific T-cell engaging antibody, which targets the tumor-associated antigen Fc receptor homolog 5 (FcRH5; a type of membrane protein expressed on B-cells and plasma cells), as well as the CD3 antigen found on T-lymphocytes. Cevostamab is being studied in an ongoing dose-escalation phase 1 multicenter clinical trial as monotherapy in 51 patients with heavily pretreated relapsed or refractory multiple myeloma who have received intravenous (IV) infusion every 3 weeks.
Among the 34 patients who received target doses of cevostamab ≥20 mg, 18 patients had a response to therapy, for a 53% overall response rate (ORR), reported Adam D. Cohen, MD, Director, Myeloma Immunotherapy, University of Pennsylvania, Abramson Cancer Center, Philadelphia.
Of the 34 patients, 32% had a very good partial response or better at the 20-mg target dose and 18% had a complete response.
The ORR was 61% in the 18 patients who received the highest dose levels (90 mg or 132 mg). The response rates included 28% very good partial response or better and 11% complete responses. At the 132-mg dose level, responses were ongoing in 5 of 7 patients at data cutoff.
A total of 24 patients in the study had penta-refractory disease, and the ORR in this subset was 41%. In all, of 8 patients who received previous B-cell maturation antigen (BCMA)-targeted therapy, 5 (63%) had a response to therapy.
The most common nonhematologic adverse event was cytokine release syndrome (CRS), which was reported in 76% of the patients, including 34% grade 1 and 40% grade 2.
“These data establish FcRH5 as a novel target in multiple myeloma and demonstrate the activity of cevostamab monotherapy in this difficult-to-treat, relapsed/refractory patient population,” said Dr Cohen.
A first-in-human study of talquetamab, a first-in-class bispecific antibody that binds to the orphan receptor GPRC5D and to CD3 on T-cells, showed a 66% ORR among patients with relapsed or refractory multiple myeloma who received the most active doses of this drug, said Ajai Chari, MD, Director of Clinical Research, Multiple Myeloma Program, Mount Sinai Medical Center, New York, NY.
At the subcutaneous recommended phase 2 dose of 405 µg/kg, 9 of 13 patients had a response to therapy, for an ORR of 69%, and 39% of patients had a very good partial response or better. In addition, 6 of 9 (67%) patients with triple-refractory disease had a response, and the 2 patients with penta-refractory disease also had responses. “Subcutaneous dosing is more convenient and may offer an opportunity for less frequent dosing,” he said.
The 19 patients who received the recommended phase 2 dose had received a median of 4.5 previous lines of therapy, 68% had triple-class refractory disease, and 21% had penta-drug refractory disease.
This phase 1 study enrolled 157 patients with relapsed or refractory multiple myeloma who had received a median of 6 previous lines of therapy. A total of 102 patients received talquetamab intravenously (0.5-180 µg/kg) and 55 patients received talquetamab subcutaneously (5-800 µg/kg). Overall, 95% had disease refractory to an anti-CD38 agent, 87% had disease refractory to their last line of therapy, 82% had triple-class refractory disease, and 33% had penta-refractory disease. A total of 16% of patients received previous anti-BCMA therapy.
Responses were seen in patients who received talquetamab across the different dosing groups; the median time to first confirmed response across all the doses was 1 month.
At the most active IV doses of 20 µg/kg to 180 µg/kg and the most active subcutaneous doses of 135 µg/kg to 800 µg/kg, talquetamab induced an ORR of 66%, with 33 of 50 patients having a response to treatment; the very good partial response or better rate was 42%. The ORR was 67% in the cohorts who received IV talquetamab and 66% in the cohorts who received subcutaneous talquetamab.
Responses to talquetamab were durable and deepened over time. Data for the IV cohorts are more mature than those for the subcutaneous cohorts. Of the 8 responders to IV dosing with a duration of more than 12 months, all have ongoing responses with 7 complete responses or better and 3 with a duration of response >2 years, “indicating the favorable durability of efficacy with this novel agent,” said Dr Chari.
None of the 17 responders at the recommended phase 2 dose have had disease progression at a median follow-up of 3.7 months.
There were 3 dose-limiting toxicities across all doses, but none at the recommended phase 2 dose. The rate of infection overall was 38% and 16% at the recommended phase 2 dose. There were no grade 5 adverse events. CRS occurred in 48% of the IV recipients and 64% of those dosed subcutaneously.
REGN5458 Bispecific Antibody
REGN5458 is a bispecific antibody that binds to BCMA and to CD3 and is being studied in a phase 1 clinical trial of 49 patients with relapsed or refractory multiple myeloma. The updated results of this study were reported by Deepu Madduri, MD, Director of Clinical Operations, Center of Excellence for Multiple Myeloma, Tisch Cancer Institute and the Icahn School of Medicine at Mount Sinai, New York, NY.
The ORR was 62.5% in the 8 patients who received the highest dose of REGN5458 (96 mg), all 5 being very good partial responses, with a median follow-up of 2 months.
Among all 19 patients who responded to any dose level of REGN5458, 18 (95%) patients had a very good partial response or better, including 42% complete responses or stringent complete response. Among responding patients who had ≥6 months of follow-up, 83% had ongoing responses for up to 13 months at the time of the analysis. In addition, 37% of responders had a response lasting ≥8 months.
Overall, patients in the study had a median of 5 previous lines of therapy; all patients had triple-refractory disease and 57% of patients had penta-refractory disease. In addition, all patients had disease refractory to anti-CD38 therapy.
Grade ≥3 adverse events occurred in 69% of the patients, including anemia (22%), neutropenia (14%), and lymphopenia (12%).
CRS occurred in 39% of patients, and dose-limiting toxicities were reported in 2 patients.