New Targets Explored for Bispecific T-Cell–Engaging Antibodies in Myeloma
- 3 years ago
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.
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 consi
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.
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 consi