Talquetamab Elicits Encouraging Responses in Heavily Pretreated Patients With Multiple Myeloma

Ajai Chari, MD

Encouraging response rates were observed in patients with relapsed or refractory multiple myeloma who were treated with off-the-shelf DuoBody® IgG4 PAA binding antibody talquetamab. In addition, the agent showed a tolerable safety profile, according to early data from a phase 1 clinical trial (NCT03399799).

Results presented during the 2020 American Society of Hematology (ASH) Annual Meeting showed that, at a median follow-up of 3.7 months, the agent elicited an overall response rate (ORR) of 69% (n = 9) in 13 patients who had received the recommended phase 2 dose (RP2D) of 405 µg/kg delivered subcutaneously. Moreover, the median time to the first confirmed response was relatively short, at 1 month (range, 1-2).

Notably, 67% (n = 6) of 9 patients with triple-class refractory disease responded to the treatment; 100% (n = 2/2) of patients with penta-refractory myeloma also experienced responses to the antibody.

At the most active intravenous (IV) doses of 20 µg/kg to 180 µg/kg and the most active subcutaneous (SC) doses of 135 µg/kg to 800 µg/kg, the agent induced an ORR of 66%, with 33 of 50 patients responding to treatment. Here, the very good partial response or better rate was 42%. The ORR in the IV cohorts was 67%; in the SC cohorts, the ORR was 66%.

“Talquetamab is a first-in-class therapy targeting GPRC5D that has shown encouraging efficacy in heavily pretreated patients with relapsed/refractory multiple myeloma,” Ajai Chari, MD, professor of medicine, hematology, and oncology at the Mount Sinai Hospital, said in a virtual presentation of the data.

Talquetamab redirects T cells to myeloma cells that express GPRC5D. When the drug binds both the myeloma cells and the T cell, perforin and granzymes are released, resulting in cell killing. Previously, the agent was found to showcase antitumor activity in both primary myeloma cells and xenograft myeloma models. The pharmacokinetic profile of the agent suggests that it may allow for less frequent, SC administration.

In the first-in-human phase 1 trial, investigators have set out to examine talquetamab in patients with relapsed/refractory multiple myeloma. The primary objective of the first portion of the trial was to identify the RP2D. The primary focus of part 2 was safety and tolerability at RP2D. Other objectives included antitumor activity, pharmacokinetics (PK), and pharmacodynamics (PD).

To be eligible for enrollment, patients had to have myeloma that was relapsed/refractory or intolerant to available therapies. They had to have measurable disease, appropriate blood counts with a hemoglobin of 8 g/dL or greater, platelets of 50 x 109/L or greater, absolute neutrophil count of 1.0 x 109/L or greater. Previous treatment with BCMA-targeted therapies was permitted.

The dosing overview includes weekly or every 2 weeks with or without step-up dosing “to decrease the risk of cytokine release syndrome [CRS],” noted Chari. Pre-medications were required for step-up doses and the first full dose, but no steroids were required following the first full dose of talquetamab. The IV cohorts were comprised of a total of 102 patients, while 55 patients were enrolled to the SC cohorts.

In the IV cohorts, doses escalated from 0.5 to 3.38 µg/kg, to 3.38 µg/kg, to 5 µg/kg, to 7.5 µg/kg, to 11.25 µg/kg, to 20 µg/kg, to 60 µg/kg, up to 180 µg/kg. In the SC, doses escalated from 5 µg/kg, to 15 µg/kg, to 45 µg/kg, to 135 µg/kg, to 405 µg/kg—which became the RP2D— up to 800 µg/kg.

The median age of all patients (n = 157) included in the trial was 64 years; the median age of just those who received the RP2D (n = 19) was 61 years. Approximately one-quarter of patients were over the age of 70 years, noted Chari. In the RP2D arm, 58% (n = 11) were male, 19% (n = 3) had bone marrow more than 60% plasma cells, and 37% (n = 7) had extramedullary plasmacytomas of 1 or greater.

There was a median of 6 years since diagnosis and about 4.5 lines of previous therapy in this time period. Notably, 95% were triple-class exposed and 68% were penta-drug exposed. Sixteen percent received previous anti-BCMA therapy. Fifty-eight percent of patients had received carfilzomib (Kyprolis), 79% had received pomalidomide (Pomalyst), and 95% had an anti-CD38 antibody. Sixty-eight percent of patients were triple-class refractory and 21% were penta-drug refractory. Seventy-nine percent of patients were refractory to their last line of treatment.

Additional results from the trial presented during the meeting showed that responses elicited with talquetamab were durable and were noted to deepen over time. Data for the IV cohorts are mature and showed that only 1 of 6 responders at 60 µg/kg or greater have experienced disease progression at a median follow-up of 7.4 months. None of the 17 responders at RP2D have had disease progression at a median follow-up of 3.7 months.

Notably, the 8 responders 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 of more than 2 years. “This indicates the favorable durability of efficacy in the novel agent,” said Chari.

The PK data with talquetamab support the RP2D, added Chari. Exposure is dose proportional following the initial dose. Moreover, a SC dose of 405 µg/kg has lower peak/trough ratio than an IV dose of 60 µg/kg; the former also maintains exposure over the maximum EC90. Anti-drug antibodies were found to be generally low titer in 12% of patients who received IV doses vs 8% in those who received SC doses. Anti-drug antibodies did not appear to impact safety, PK, or efficacy.

PD data also supported the RP2D of SC 405 µg/kg. “We see IL2Rα induction at higher levels with SC doses in 135 µg/kg to 800 µg/kg relative to the lower doses,” said Chari. “When we look at

maximum PD-1 T-cell activation, again, the 405 µg/kg dose shows a relatively high percentage of responders with T-cell activation.”

With regard to safety, in the RP2D cohort, all-grade hematologic toxicities included neutropenia (47%; 42% grade 3), anemia (26%; 0%), lymphopenia (16%; 16%), leukopenia (21%; 16%), and thrombocytopenia (21%; 5%). When looking at non-hematologic toxicities, all-grade CRS was reported in 68% of patients in this cohort but none were grade 3 or higher, and 47% had dysgeusia.

Three dose-limiting toxicities (DLT) were observed across all doses, but none were reported with the RP2D. Dose reductions at the RP2D were also determined to be less frequent and to happen later on versus those who received the agent at the 800 µg/kg. Thirty-eight percent of patients had infections, 16% at the RP2D. Eight percent had grade 3 or higher infections across the doses examined with no grade 3 or higher effects at RP2D.

“Neurotoxicity was relatively infrequent, as well,” said Chari. “Only 1 patient on the RP2D had grade 2 encephalopathy at it resolved.”

With regard to cutaneous toxicities, 18% of patients experienced injection-site reactions; this occurred in 21% of those in the RP2D cohort. Forty-five percent of patients experienced skin-related toxicities; 58% of those in the RP2D cohort had this but most were grade 1 or 2 in severity. Nail disorders occurred in 17% of all patients and 21% of patients in the RP2D cohort. No grade 5 toxicities were reported across all doses evaluated.

Overall rates of CRS in the IV and SC groups were 48% and 64%, respectively. The median time to CRS onset was 1 days and 2 days, respectively, and the median duration of CRS was 2 days in both cohorts. In the RP2D, half of patients received tocilizumab (Actemra), while the use of other supportive care options was relatively infrequent.

“Talquetamab has a tolerable safety profile at the RP2D of SC 405 tocilizumab,” concluded Chari,” and high response rates were observed [at this dose].”

_Reference:

_{1. Chari A, Berdeja JG, Oriol A, et al. A phase 1, first-in-human study of talquetamab, 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 (RRMM). Presented at: 2020 ASH Virtual Meeting & Exposition; December 5-8, 2020; Virtual. https://bit.ly/37KSUZk.}