Janssen Presents First-Ever Results from Dual Bispecific Combination Study Showing 96 Percent Overall Response Rate in Patients with Relapsed or Refractory Multiple Myeloma

04 Jun 2023
pipelinereview.com
Clinical ResultASCOImmunotherapyDrug ApprovalOrphan Drug
CHICAGO, IL, USA I June 3, 2023 I The Janssen Pharmaceutical Companies of Johnson & Johnson announced today the first-ever results from the Phase 1b RedirecTT-1 study of TECVAYLI® (teclistamab-cqyv), a first-in-class BCMAxCD3 bispecific antibody, and talquetamab, a first-in-class GPRC5DxCD3 bispecific antibody, showing a high overall response rate (ORR) among patients with relapsed or refractory multiple myeloma (RRMM).1 These results underscore the potential combinability of these two novel bispecific therapies, which target distinct antigens on myeloma cells.1 The investigational combination immunotherapy regimen demonstrated an ORR of 86.6 percent (71/82) across all dose levels, and an ORR of 96.3 percent (26/27) among patients receiving the recommended Phase 2 regimen (RP2R).1 These data were presented during an oral session at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting (Abstract #8002).
"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," said Yael Cohen, M.D., Head of Myeloma UnitMyeloma Unit, Hematology Institute, Tel-Aviv Sourasky Medical Center, Israel, and principal study investigator.† "The high overall response rates characterized in this study are encouraging and support the continued evaluation of this regimen as a combination therapy."
The RedirecTT-1 study included patients who received a median of four prior lines of therapy (range, 1-11 for patients in all dose levels, n=93; range, 2-10 for patients in the RP2R dosing cohort, n=34).1 At the RP2R, 76.5 percent of patients were triple-class refractory to an immunomodulatory drug (IMiD), proteasome inhibitorproteasome inhibitor (PI) and anti-CD38 antibody; 58.8 percent of patients were penta-drug exposed to two IMiDs, two PIs and an anti-CD38 antibody; and 32.4 percent of patients had extramedullary disease (EMD), all soft tissue plasmacytomas.1
Results from the study showed that responses were high across all dose levels.1 Eighty-two patients across all study cohorts and 27 patients treated at the RP2R were evaluable for response.1 The ORR across all patients was 86.6 percent (71/82).1 Patients who received the RP2R achieved an ORR of 96.3 percent (26/27).1 The median duration of response was not reached in the overall study population or RP2R cohort.1 Patients with EMD who received the RP2R achieved an 85.7 percent (6/7) ORR, and median duration of response was not reached at a median follow-up of 7.2 months (range, 0.7-14.2).1 The median follow-up for all patients was 13.4 months (range, 0.3-25.6) with a median progression-free survival (PFS) of 20.9 months (95 percent Confidence Interval [CI]: 13.0-Not Estimable [NE]).1 The median follow-up for patients receiving the RP2R was 8.1 months (range, 0.7-15.0), and median PFS was NE for patients in the RP2R cohort (95 percent CI: 9.9-NE).1 At data cutoff, 61 percent (57/93) of all patients remained on either TECVAYLI® or talquetamab treatment.1
The safety profile of the combination was consistent with that observed with each drug as a monotherapy.1 The most common hematologic adverse events (AEs), observed in 20 percent of patients or more, were neutropenia (all dose levels: 65.6 percent, 61.3 percent Grade 3/4; RP2R dosing cohort: 55.9 percent, 44.1 percent Grade 3/4), anemia (all dose levels: 50.5 percent, 34.4 percent Grade 3/4; RP2R dosing cohort: 32.4 percent, 23.5 percent Grade 3/4), and thrombocytopenia (all dose levels: 43.0 percent, 29.0 percent Grade 3/4; RP2R dosing cohort: 32.4 percent, 23.5 percent Grade 3/4).1
In the study, 94.1 percent (32/34) of patients at the RP2R and 96.8 percent (90/93) of the overall study population had one or more treatment-emergent adverse events (TEAEs).1 Rates of Grade 3/4 nonhematologic AEs were low in both the full study population and the RP2R cohort, except for cytokine release syndrome (CRS) of any Grade, which occurred in 76.3 percent and 73.5 percent of patients, respectively.1 All CRS events were resolved at data cut-off. The incidence and severity of CRS were consistent with TECVAYLI® and talquetamab monotherapy treatment.1
"Multiple myeloma becomes progressively more difficult to treat as patients relapse or become refractory to treatment. The RedirecTT-1 data suggest the use of bispecific antibodies with high activity in myeloma, TECVAYLI and talquetamab, may have potential to yield high efficacy responses in this patient population," said Arnob Banerjee, M.D., Ph.D., Global Medical Head, Early Development Oncology, Janssen Research & Development, LLC. "The promising preliminary results observed with the combination, even in patients with extramedullary disease, are highly supportive of continued investigation and reinforce our commitment to evaluate and develop combination regimens built on our deep disease understanding and portfolio of therapeutics."
About the RedirecTT-1 Study2
The RedirecTT-1 (NCT04586426) study is an ongoing Phase 1b dose escalation study of the combination of the bispecific T-cell redirection antibodies talquetamab and TECVAYLI® in patients with relapsed or refractory multiple myeloma.
The primary objective is to identify the recommended Phase 2 regimen(s) (RP2R[s]) and schedule for the study treatment and to characterize the safety of the RP2R(s) for the study treatment. The RP2R(s) will describe the doses and schedules of talquetamab and TECVAYLI® in the treatment combination to be pursued in Phase 2.
About TECVAYLI®3
TECVAYLI® (teclistamab-cqyv) received approval from the U.S. Food and Drug Administration in October 2022 as an off-the-shelf (or ready to use) bispecific antibody that is administered as a subcutaneous treatment for adult patients with relapsed or refractory multiple myeloma who have received at least four prior lines of therapy, including a proteasome inhibitorproteasome inhibitor, an immunomodulatory agent and an anti-CD38 monoclonal antibody.3 TECVAYLI® is the only approved BCMA×CD3 bispecific antibody with a personalized, weight-based dosing schedule for the treatment of triple-class exposed RRMM.
In August 2022, TECVAYLI® received approval from the European Commission as an off-the-shelf bispecific antibody administered as a subcutaneous treatment for adult patients with relapsed or refractory multiple myeloma who have received at least three prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitorproteasome inhibitor, and an anti-CD38 antibody.4 TECVAYLI® was recommended by the National Comprehensive Cancer Network® (NCCN®) as a treatment option for these patients.5
TECVAYLI® is a first-in-class, bispecific T-cell engager antibody therapy which uses innovative science to activate the immune system by binding to the CD3 receptor expressed on the surface of T cells and to the B cell maturation antigen (BCMA) expressed on the surface of multiple myeloma cells and some healthy B-lineage cells.3
Talquetamab is a bispecific T-cell engaging antibody that binds to the CD3 receptor expressed on the surface of T cells and G protein-coupled receptor class C group 5 member D (GPRC5D), a novel multiple myeloma target that does not shed and is highly expressed on the surface of multiple myeloma cells and non-malignant plasma cells, as well as some healthy tissues such as epithelial cells of the skin and tongue.6  CD3 is involved in activating T-cells, and GPRC5D is highly expressed on multiple myeloma cells.7,8
In May 2021 and August 2021, talquetamab was granted Orphan Drug Designation for the treatment of multiple myeloma by the U.S. FDA and the European Commission, respectively. Talquetamab was also granted Breakthrough Therapy Designation from the U.S. FDA in June 2022 for the treatment of adult patients with relapsed or refractory multiple myeloma who have previously received at least four prior lines of therapy, including a proteasome inhibitorproteasome inhibitor, an immunomodulatory agent, and an anti-CD38 antibody. In December 2022, Janssen submitted a Biologics License Application (BLA) to the FDA seeking approval of talquetamab for the treatment of patients with relapsed or refractory multiple myeloma.
A Phase 1/2 clinical study of talquetamab for the treatment of relapsed or refractory multiple myeloma (NCT03399799) is currently underway. Talquetamab is also being explored in combination studies (NCT04586426, NCT04108195, NCT05050097, NCT05338775) and in a randomized Phase 3 study (NCT05455320). In January 2021, talquetamab was granted PRIME designation by the European Commission.
Multiple myeloma is an incurable blood cancer that affects a type of white blood cell called plasma cells, which are found in the bone marrow.9 In multiple myeloma, these plasma cells change, spread rapidly and replace normal cells in the bone marrow with tumors.10 Multiple myeloma is the third most common blood cancer and remains an incurable disease. In 2023, it is estimated that more than 35,000 people will be diagnosed with multiple myeloma in the U.S. and more than 12,000 people will die from the disease.11 People living with multiple myeloma have a 5-year relative survival rate of 53 percent. While some people diagnosed with multiple myeloma initially have no symptoms, most patients are diagnosed due to symptoms that can include bone fracture or pain, low red blood cell counts, tiredness, high calcium levels, kidney problems or infections.12
Please read full Prescribing Information including Boxed Warning for TECVAYLI®.
At Janssen, we're creating a future where disease is a thing of the past. We're the Pharmaceutical Companies of Johnson & Johnson, working tirelessly to make that future a reality for patients everywhere by fighting sickness with science, improving access with ingenuity, and healing hopelessness with heart. We focus on areas of medicine where we can make the biggest difference: Cardiovascular, Metabolism & Retina; Immunology; Infectious Diseases & Vaccines; Neuroscience; Oncology; and Pulmonary Hypertension.
Learn more at www.janssen.com. Follow us at @JanssenUS and @JanssenGlobal. Janssen Research & Development, LLC is one of the Janssen Pharmaceutical Companies of Johnson & Johnson.
†Dr. Cohen has served as a paid consultant to Janssen; he has not been paid for any media work.
1 Cohen Y 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). 2023 ASCO Annual Meeting – American Society of Clinical Oncology. June 2023.
2 A Study of the Combination of Talquetamab and Teclistamab in Participants With Relapsed or Refractory Multiple Myeloma. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT04586426?term=RedirecTT-1&draw=2&rank=1. Accessed June 2023
3 TECVAYLI® [Prescribing Information]. Janssen Biotech, Inc.
4 Tecvayli. European Medicines Agency. www.ema.europa.eu/en/medicines/human/EPAR/tecvayli. Accessed June 2023
5 NCCN® Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Multiple Myeloma V3.2023. National Comprehensive Cancer Network. Accessed June 2023
6  Pillarisetti K et al. Blood. 2020;135(15):1232-1243.
7  Labrijn AF et al. Proc Natl Acad Sci USA. 2013;110:5145.
8  Cohen, Y., et al. Hematology. 2013 Nov; 18(6):348-51.
9 Rajkumar SV. Multiple myeloma: 2020 update on diagnosis, risk-stratification and management. Am J Hematol.2020;95(5):548-5672020;95(5):548-567. http://www.ncbi.nlm.nih.gov/pubmed/32212178.
10 National Cancer Institute. Plasma Cell Neoplasms. Accessed September 2022. https://www.cancer.gov/types/myeloma/patient/myeloma-treatment-pdq.
11 American Cancer Society. "Key Statistics About Multiple Myeloma." Available at: https://www.cancer.org/cancer/multiple-myeloma/about/key-statistics.html#:~:text=Multiple%20myeloma%20is%20a%20relatively,men%20and%2015%2C370%20in%20women). Accessed June 2023
12 American Cancer Society. "What Is Multiple Myeloma?" Available at: https://www.cancer.org/cancer/multiple-myeloma/about/what-is-multiple-myeloma.html. Accessed September 2023
SOURCE: Janssen
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