Dual Bispecific Combination Teclistamab/Talquetamab Displays High Activity in RRMM

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Based on findings from the phase 1b RedirecTT-1 study (NCT04586426), use of the investigational combination of the CD3 and B-cell maturation antigen (BCMA)-bispecific teclistamab-cqyv (Tecvayli) and the CD3 and GPRC5D-targeted bispecific talquetamab has promising activity with manageable toxicity in patients with relapsed or refractory multiple myeloma, a presentation given at the 2023 ASCO Annual Meeting shows.¹

In the study, the objective response rate (ORR) with the dual bispecific combination was 86.6% across all doses and 96.3% at the recommended phase 2 regimen (RP2R) dose level. The combined complete response (CR) or stringent CR (sCR) rate was 40.2% and 40.7% for those treated at all dose levels and the RP2R dose, respectively. The safety profile was consistent with the profiles of each agent as a monotherapy, said lead investigator Yael C. Cohen, MD.

Across all doses administered in the study, 88.2% of patients experienced a grade 3/4 treatment-emergent adverse event (TEAE) and 76.3% of patients experienced cytokine release syndrome (CRS).

"Teclistamab plus talquetamab is the first-ever reported dual bispecific combination in hematologic malignancies," said Cohen, a senior physician in the Department of Hematology at the Tel-Aviv Sourasky (Ichilov) Medical Center, and Sackler School of Medicine, Tel Aviv University. "These results support the initiation of larger studies with the combination of teclistamab and talquetamab."

The phase 1b study explored the combination of teclistamab and talquetamab across several predefined dose levels. The RP2R was identified as teclistamab at 3.0 mg/kg every 2 weeks and talquetamab at 0.8 mg/kg every 2 weeks. A step-up dosing strategy prior to the first cycle was utilized to minimize toxicity, Cohen noted. There were 93 patients included across all doses, with 34 specifically receiving the RP2R dose. All patients had measurable multiple myeloma and had received prior treatment with a proteasome inhibitor, immunomodulatory drug, and anti-CD38 antibody.

Across all dose levels, the median age was 65 years and 51.6% of patients were male. A majority of patients were white (79.6%), and 21.8% had 60% or more bone marrow plasma cells. Over a third of patients had extramedullary plasmacytomas (37.6%) and a third had high-risk cytogenetics (33.3%). The International Stating System stage was split between I (45.9%), II (29.4%), and III (24.7%). The median number of prior therapies was 4 (range, 1-11) and 65.6% of patients were penta-drug exposed, with a quarter being penta-drug refractory (25.8%). Nearly three-fourths of patients (79.6%) were triple-drug refractory and nearly all patients were refractory to their last line of therapy at study entry (89.2%).

The data cutoff for the phase 1b study was March 16, 2023, at which point 61% of patients remained on treatment. The median follow-up at all dose levels was 13.4 months and in the R2PR arm, it was 8.1 months. The median duration of response was not yet reached. Across all doses, the ORR consisted of an sCR for 18.3% of patients, CR for 22.0%, very good partial response (VGPR) for 36.6%, and partial response (PR) for 9.8%. In the RP2R group, the sCR, CR, VGPR, and PR rates were 18.5%, 22.2%, 48.1%, and 7.4%, respectively.

The median progression-free survival (PFS) was not yet reached in the RP2R arm compared with 20.9 months in the full population (95% CI, 13.0-not evaluable [NE]). The 9-month PFS rate was 70.1% (95% CI, 58.0%-79.4%) across all doses and 77.1% in the RP2R group (95% CI, 50.8%-90.5%).

In those specifically with extramedullary disease (EMD), the ORR with the RP2R dose was 85.7%, which consisted of a CR rate of 28.6%, VGPR of 42.9%, and a PR rate of 14.3%. Across all doses, the ORR in those with EMD was 71.4%, which included a sCR rate of 3.6%, CR of 17.9%, VGPR of 28.6%, and PR of 21.4%. The median duration of response across all doses was 12.9 months (95% CI, 4.17-NE). It was not yet reached in the RP2R group. Median PFS for those with EMD was 6.1 months (95% CI, 2.5-9.9) across all doses and 9.9 months in the RP2R arm (95% CI, 2.4-NE). "RedirecTT-1 expansion cohort in EMD is opening, based on these promising results," Cohen noted.

The most common grade 3/4 hematologic TEAEs across all dose levels and the RP2R dose level, respectively, were neutropenia (61.3% and 44.1%), anemia (34.4% and 23.5%), and thrombocytopenia (29.0% and 23.5%). Febrile neutropenia occurred in 12.9% of patients treated at all doses and for 8.8% of those receiving the RP2R dose. The most common non-hematologic grade 3/4 TEAEs across all doses and for the RP2R, respectively, were pneumonia (10.8% and 5.9%), COVID-19 (9.7% and 2.9%), and fatigue (7.5% and 5.9%).

Important all grade AEs in the full population and RP2R groups, respectively, were dysgeusia (61.3% and 47.1%), skin toxicity (53.8% and 52.9%), and nail disorders (46.2% and 41.2%). Immune effector cell-associated neurotoxicity syndrome (ICANS) was seen in 3 patients, with 1 patient in the non-RP2R group experiencing a grade 3 event. The remainder were grade 1.

Across all doses, CRS was primarily grade 1 in severity (47.3%), with 25.8% having grade 2 CRS and 3.2% experiencing grade 3 CRS. In the RP2R dose group, CRS was grade 1 (26.5%) and grade 2 (47.1%) in severity. Tocilizumab (Actemra) was administered for 26.9% of patients in the all-dose group and for 20.6% in the RP2R group. The median time to onset of CRS was 2 days across all dose levels. "The majority of CRS events occurred during step-up dosing or cycle 1," said Cohen.

Discontinuation due to drug-related TEAE was relatively low, at 6.5% across all doses and 5.9% in the RP2R arm. There were 6 deaths due to drug related TEAEs in the all-dose level group, and 1 in the R2PR group. The grade 5 events were all primarily opportunistic were infection-associated, Cohen noted, including 1 grade 5 case of septic shock.

Overall, infections of any grade occurred in 83.9% of patients in the full population and in 79.4% of those treated at the RP2R dose. Grade 3/4 infection rates in the full population and RP2R groups were 52.7% and 38.2%, respectively. Most patients (81.7%) were found to have post-baseline hypogammaglobulinemia, primarily grade 1/2 in severity. Intravenous immunoglobulin was administered to 37 patients, of which 15 were in the RP2R group.

"This is the first combination of 2 bispecifics in myeloma, showing promising efficacy compared with single bispecifics, without an apparent increase of toxicity," said ASCO discussant Andrzej J. Jakubowiak, MD, PhD, from the University of Chicago. "Regardless of what the next steps are, these results support strategies of combining immunotherapies, and I am looking forward to updated results from this study."

_REFERENCE:

_{Cohen YC, Morillo D, Gatt ME, et al. First results from the RedirecTT-1 study with teclistamab (tec) + talquetamab (tal) simultaneously targeting BCMA and GPRC5D in patients (pts) with relapsed/refractory multiple myeloma (RRMM). J Clin Oncol. 2023;41 (suppl 16):8002. doi:10.1200/JCO.2023.41.16_suppl.8002}