The RedirecTT-1 trial (NCT04586426) enrolled patients who had received an average of four previous lines of therapy. Among those who received the recommended Phase 2 regimen (RP2R), 76.5 percent of patients were resistant to treatment involving an immunomodulatory drug (IMiD), proteasome inhibitor (PI), and anti-CD38 antibody. Furthermore, 58.8 percent of patients had been exposed to a combination of two IMiDs, two PIs, and an anti-CD38 antibody, while 32.4 percent of patients had extramedullary disease (EMD) characterized by soft tissue plasmacytomas.
The primary objective of the study was to determine the recommended Phase II regimen(s) (RP2R[s]) and treatment schedule for the investigational therapy. Additionally, the study aimed to assess the safety profile of the RP2R(s) for the treatment. The RP2R(s) will outline the specific doses and schedules of talquetamab and TECVAYLI (teclistamab) in the combination treatment, which will be further explored in the Phase II stage of the research.
Results presented at ASCO 2023 demonstrated significant response rates across various dosage levels. The study included 82 patients from different cohorts, with 27 patients receiving the recommended Phase 2 regimen (RP2R). The ORR for all patients was 86.6% (71 out of 82). Among those who received the RP2R, the ORR was even higher at 96.3% (26 out of 27). The duration of response was not determined yet for both the overall study population and the RP2R cohort.
In the RP2R group, patients with extramedullary disease (EMD) achieved an ORR of 85.7% (6 out of 7), and the duration of response has not been reached at a median follow-up of 7.2 months.
The median duration of observation for all patients in the study was 13.4 months, and the median progression-free survival (PFS) was 20.9 months. Among patients who received the recommended Phase 2 regimen (RP2R), the median follow-up period was 8.1 months, and the median PFS was not estimable (NE). At the time of data cutoff, 61% (57 out of 93) of all patients were still undergoing treatment with either TECVAYLI or talquetamab.
The safety profile of the combination was consistent with that observed with each drug as a monotherapy. The most common hematologic adverse events (AEs), observed in 20 percent of patients or more, were neutropenia (all dose levels: 65.6%, 61.3% Grade 3/4; RP2R dosing cohort: 55.9%, 44.1% Grade 3/4), anemia (all dose levels: 50.5%, 34.4% Grade 3/4; RP2R dosing cohort: 32.4%, 23.5% Grade 3/4), and thrombocytopenia (all dose levels: 43.0%, 29.0% Grade 3/4; RP2R dosing cohort: 32.4%, 23.5% Grade 3/4).
During the study, 94.1% (32 out of 34) of patients in the recommended Phase II regimen (RP2R) group and 96.8% (90 out of 93) of the entire study population experienced one or more treatment-emergent adverse events (TEAEs). The occurrence of Grade 3/4 non-hematologic AEs was generally low in both the overall study population and the RP2R cohort, except for cytokine release syndrome (CRS) of any grade, which was observed in 76.3% and 73.5% of patients, respectively. However, all CRS events were resolved by the data cutoff point. The incidence and severity of CRS were consistent with the side effects observed in TECVAYLI and talquetamab monotherapy treatments.
KOL insights
“By combining teclistamab and talquetamab, two bispecific antibodies that have demonstrated high efficacy responses in targeting distinct antigens, we evaluated the potential of this unique combination regimen for patients who were resistant or refractory to multiple lines of therapy. The high overall response rates characterized in this study are encouraging and support the continued evaluation of this regimen as a combination therapy.” – Expert Opinion.
Conclusion
TECVYALI and talquetamab represent the first combination of off-the-shelf bispecific antibodies targeting both BCMA and GPRC5D in hematological malignancies. For the treatment of multiple myeloma monoclonal antibodies have been approved since 2015, and the first bispecific antibody was approved last year. In October 2022, TECVYALI (BCMA X CD3), received accelerated approval from the US Food and Drug Administration (FDA) to treat myeloma that persisted after four or more lines of prior therapy. The oncology community is particularly enthusiastic about the bispecific antibody talquetamab due to its distinct target. Talquetamab and TECVYALI both bind to CD3, however TECVYALI targets BCMA whereas talquetamab's secondary target is GPRC5D. GPRC5D is a crucial target since it is largely overexpressed on malignant plasma cells compared to normal cells and is often not expressed in the majority of human tissues, with the exception of tissue that is strongly keratinized, including skin and nails. This is significant since the hematopoietic stem cell progenitors do not express it. This expression pattern implies a good balance between safety and efficacy.
These findings provide support for conducting larger studies using the same combination therapy. The safety profile observed in the study was similar to that of the individual monotherapies, with no new or additional toxicity observed. Furthermore, based on the promising results, an expansion cohort within the RedirecTT-1 study focusing on patients with the extramedullary disease (EMD) is being initiated.
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