On May 26, 2022 SpringWorks Therapeutics, Inc. (Nasdaq: SWTX), a clinical-stage biopharmaceutical company focused on developing life-changing medicines for patients with severe rare diseases and cancer, reported initial clinical data from the Phase 1/2 study evaluating nirogacestat, SpringWorks’ investigational gamma secretase inhibitor, in combination with BLENREP (belantamab mafodotin-blmf), GSK plc’s (LSE/NYSE: GSK) antibody drug conjugate targeting B-cell maturation agent (BCMA), in patients with relapsed or refractory multiple myeloma (RRMM) (Press release, SpringWorks Therapeutics, MAY 26, 2022, View Source [SID1234615161]). In addition, SpringWorks also highlighted long-term follow-up data from a Phase 2 study sponsored by the National Cancer Institute (NCI) evaluating nirogacestat in patients with progressing desmoid tumors, which included follow-up on progression-free survival and long-term safety data.2 These data sets will be shared in poster sessions at the 2022 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting, June 3-7, 2022 in Chicago.
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"We are encouraged by the emerging clinical profile of nirogacestat with low-dose BLENREP given the promising efficacy and safety profile that we have seen to date, and we look forward to the maturation of the Phase 2 portion of the study in parallel with the initiation of new sub-studies to evaluate this combination with standard of care treatments in multiple myeloma," said Saqib Islam, Chief Executive Officer of SpringWorks. "I would also like to thank the NCI for their commitment to evaluating nirogacestat in patients with progressing desmoid tumors. We were very pleased to recently report positive topline data from our Phase 3 DeFi trial and these follow-up data from the NCI-sponsored Phase 2 study provide valuable information on the long-term safety and efficacy profile of nirogacestat in desmoid tumor patients."
Synergistic Effects of Low-Dose Belantamab Mafodotin in Combination with a Gamma-Secretase Inhibitor (Nirogacestat) in Patients with Relapsed/Refractory Multiple Myeloma (RRMM): DREAMM-5 Study (Poster # 443)
The objective of this sub-study of GSK’s DREAMM-5 platform trial (NCT04126200) is to determine if low-dose BLENREP in combination with nirogacestat results in similar efficacy with an improved ocular toxicity profile compared to single-agent BLENREP at its approved dose and schedule. The study opened with a dose-exploration (DE) arm evaluating 0.95 mg/kg BLENREP Q3W combined with 100 mg BID nirogacestat dosed continuously, and subsequently moved into a cohort expansion (CE) arm. The target enrollment for the CE arm of the study is 70 patients randomized either to BLENREP 2.5mg/kg Q3W monotherapy (control arm) or low-dose BLENREP plus nirogacestat combination using the same dose as the DE arm cohort.
The following results of the pre-planned interim analysis will be presented at ASCO (Free ASCO Whitepaper):
The study enrolled patients with relapsed or refractory multiple myeloma who have received at least 3 prior lines of therapy (median: 4.5), including an immunomodulatory agent, proteasome inhibitor, and anti-CD38 antibody. The poster being presented at ASCO (Free ASCO Whitepaper) includes data from a total of 24 patients treated with low-dose BLENREP + nirogacestat across the DE and CE cohorts (N=10 and N=14, respectively) and 14 patients treated with monotherapy BLENREP in the CE cohort.
At the time of the March 4, 2022 data cut-off, the median (range) of follow-up in the low-dose BLENREP plus nirogacestat DE cohort was 34.5 weeks (5-88 weeks), with durations of response exceeding one year in some patients. Data from the CE cohorts are not yet mature with a median duration of follow-up of 12 weeks available at the time of data cut-off.
The CE cohorts utilized the KVA ocular toxicity grading scale; Grade 3 ocular adverse events occurred in 1/14 (7%) patients in the low-dose BLENREP plus nirogacestat combination compared to 7/14 patients (50%) in the BLENREP monotherapy arm. The DE cohort utilized the CTCAE-5 ocular toxicity grading scale; the low-dose BLENREP plus nirogacestat combination demonstrated Grade 3 ocular adverse events in 2/10 (20%) patients.
At the time of data cut-off, the objective response rate (ORR) of low-dose BLENREP plus nirogacestat across the DE and CE cohorts was 38%, with 17% of patients achieving a VGPR or better (N=24). The ORR of the BLENREP monotherapy control arm was 50%, with no patients achieving a VGPR or better (N=14).
These data will be presented in a poster discussion session at ASCO (Free ASCO Whitepaper) on June 4, 2022 from 5:30 – 7:00 p.m. EDT by Sagar Lonial, MD, FACP, Professor and Chair Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University.
Extended Progression-Free Survival and Long-Term Safety of Nirogacestat in Patients with Desmoid Tumors (Poster #449)
The primary objective of this open-label, NCI-sponsored Phase 2 study (NCT01981551) was to assess the RECIST 1.1-determined objective response rate of nirogacestat in patients with progressing desmoid tumors. Seventeen adult patients received 150 mg BID of nirogacestat dosed continuously.
The following results will be presented at ASCO (Free ASCO Whitepaper):
Of the 16 evaluable patients, no disease progression has been observed for any patient while on study.
The median time on treatment for all evaluable patients was 4.4 years (range 0.17-7.99 years) with 4/16 patients remaining on treatment over 7 years. At the time of the Kummar, et. al publication,3 the median time on treatment was >25 months (range: 3-30 months), with 10/16 patients remaining on treatment as of the publication.
The adverse event profile was generally consistent with what was previously reported by Kummar, et. al. Long-term follow-up data reported one new Grade 3 adverse event of diarrhea and one new Grade 3 adverse event of fatigue.
These data will be presented in a poster session on June 5, 2022 from 9:00a.m.-12:00p.m. EDT by Geraldine Helen O’Sullivan Coyne, MD, PhD, Developmental Therapeutics Clinic/Early Clinical Trials Development Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute.
About Multiple Myeloma
Multiple myeloma is the second most common blood cancer in the U.S. and is generally considered treatable, but not curable.4,5 It originates in the bone marrow and is characterized by abnormalities in plasma cells that reproduce uncontrollably in the bone marrow and other disease sites. In the U.S., more than 34,000 people are estimated to be diagnosed with multiple myeloma this year and nearly 13,000 people will die from the disease.6 New therapies are needed as multiple myeloma commonly becomes refractory to available treatments.7
About Desmoid Tumors
Desmoid tumors are rare, aggressive, locally invasive, potentially morbid tumors of the soft tissues.8,9 While they do not metastasize, desmoid tumors are associated with a high rate of recurrence.9,10,11 Sometimes referred to as aggressive fibromatosis, or desmoid fibromatosis, these soft tissue tumors can be serious, debilitating, and in rare cases when vital organs are impacted, they can be life-threatening.9,12
Desmoid tumors are most commonly diagnosed in patients between the ages of 20 to 44 years, with a two-to-three times higher prevalence in females.11,13,14 It is estimated that there are 1,000-1,650 new cases diagnosed per year in the United States.14,15
Historically, desmoid tumors were treated with surgical resection, but this approach has become less favored due to a high recurrence rate after surgery.8,11,16 There are currently no FDA-approved therapies for the treatment of desmoid tumors.
About Nirogacestat
Nirogacestat is an investigational, oral, selective, small molecule gamma-secretase inhibitor in Phase 3 clinical development for desmoid tumors, which are rare and often debilitating and disfiguring soft-tissue tumors. Gamma secretase cleaves multiple transmembrane protein complexes, including Notch, which is believed to play a role in activating pathways that contribute to desmoid tumor growth.
In addition, gamma secretase has been shown to directly cleave membrane-bound BCMA, resulting in the release of the BCMA extracellular domain, or ECD, from the cell surface. By inhibiting gamma secretase, membrane-bound BCMA can be preserved, increasing target density while reducing levels of soluble BCMA ECD, which may serve as decoy receptors for BCMA-directed therapies. Nirogacestat’s ability to enhance the activity of BCMA-directed therapies has been observed in preclinical models of multiple myeloma. SpringWorks is evaluating nirogacestat as a BCMA potentiator and has eight collaborations with industry-leading BCMA developers to evaluate nirogacestat in combinations across modalities, including with an antibody-drug conjugate, two CAR T cell therapies, four bispecific antibodies and a monoclonal antibody. SpringWorks has also formed research collaborations with Fred Hutchinson Cancer Research Center and Dana-Farber Cancer Institute to further characterize the ability of nirogacestat to modulate BCMA and potentiate BCMA-directed therapies using a variety of preclinical multiple myeloma models.
Nirogacestat has received Orphan Drug Designation from the U.S. Food and Drug Administration (FDA) for the treatment of desmoid tumors and from the European Commission for the treatment of soft tissue sarcoma. The FDA also granted Fast Track and Breakthrough Therapy Designations for the treatment of adult patients with progressive, unresectable, recurrent or refractory desmoid tumors or deep fibromatosis.