Ogsiveo (nirogacestat) / EMD Serono - LARVOL DELTA

Pharmacodynamic Immune Changes and Cell Type Correlates of Response, Cytokine Release Syndrome (CRS), and Infection Across Linvoseltamab (LINVO) Combination Regimens in RRMM (LINKER-MM2) (IMS 2026) - P1 | "Introduction: L INVO (BCMA×CD3) in combination with anti-CD38 m onoclonal antibodies ( m Abs ) , proteasome inhibitors (PIs), immunomodulatory drugs ( IMiDs ) , immune checkpoint inhibitors ( ICIs ) , and a gamma secretase inhibitor ( nirogacestat ) i s being evaluated in relapsed/refractory multiple myeloma ( RRMM ; LINKER-MM2; NCT05137054 ). LINVO combinations induce diverse T-cell activation patterns, including cytotoxic effector, differentiated, and senescent cells, with distinct features per regimen. Response was associated with more cytotoxic CD8 EM/EMRA prior to treatment; suppressive Tregs and CD4 ⁺ T-cell dysfunction characterized nonresponse."

Cytokine release syndrome • PK/PD data • Infectious Disease • Inflammation • Multiple Myeloma • B3GAT1 • CD27 • CD28 • CD8 • CXCL8 • ICOS • IFNG • IL10 • IL2 • KLRG1 • PD-1 • TNFA

Nirogacestat Compared With a Historical Sorafenib Cohort Selected for Disease Control in Desmoid Tumors: A Single-Center Real-World Experience (ESMO 2026) - No abstract available

Clinical • Real-world • Real-world evidence • Desmoid Tumors • Oncology • Sarcoma

Effect of dose reduction on the safety and efficacy of nirogacestat in patients with desmoid tumors: post hoc analyses of the DeFi trial (ESMO 2026) - No abstract available

Clinical • Retrospective data • Desmoid Tumors • Oncology • Sarcoma

Severe Nirogacestat-Induced Colitis Responsive to Budesonide After Failure of Standard Therapies (ACG 2026) - "Despite treatment with cholestyramine, loperamide, dicyclomine, tincture of opium, octreotide, and high-dose hydrocortisone, diarrhea persisted at 3-5 L/day. Budesonide's potent local anti-inflammatory activity and limited systemic absorption may make it a valuable treatment option for inflammatory chemotherapy-related colitis, particularly when associated with targeted therapies. Further studies are needed to evaluate its efficacy in similar cases."

Desmoid Tumors • Fibrosis • Gastroenterology • Gastrointestinal Disorder • Immunology • Sarcoma • Solid Tumor • CRP

Desmoid-Type Fibromatosis for the Gastroenterologist: A Practical Review of Diagnosis, Molecular Stratification, and Evidence-Based Management With Comparative Focus on Sporadic and FAP-Associated Disease (ACG 2026) - "For progressive or symptomatic disease, sorafenib improved 2-year progression-free survival compared with placebo (81% vs 36%; HR 0.13), while nirogacestat improved progression-free survival (HR 0.29) and objective response rate (41% vs 8%). The selected evidence supported active surveillance as initial management for most patients without imminent organ threat; prospective data showed spontaneous stability or regression in approximately 60%. Sporadic DTF is usually driven by CTNNB1 mutations, whereas FAP-associated disease reflects germline APC inactivation and preferentially involves the mesentery. CTNNB1 subtype may inform postoperative recurrence counseling, while APC mutation location contributes to desmoid risk stratification in FAP."

Review • Desmoid Tumors • Fibrosis • Gastrointestinal Disorder • Genetic Disorders • Sarcoma • Short Bowel Syndrome • Solid Tumor • APC • CTNNB1

An Unusual Presentation of Small Bowel Obstruction Following Liver Transplantation (ACG 2026) - "Complications include persistent ascites, treated with furosemide; acute kidney injury; and urinary retention...The patient receives a standard immunosuppressive regimen of tacrolimus following discontinuation of everolimus due to side effects...Nirogacestat, a ɣ-secretase inhibitor, targets aberrant Notch signaling in tumor proliferation. Radiation may offer a non-surgical alternative. Furthermore, an intestinal or multivisceral transplant may be considered, particularly when removal of desmoid tumors leads to short bowel syndrome."

Acute Kidney Injury • Desmoid Tumors • Fibrosis • Gastrointestinal Disorder • Hepatology • Immunology • Nephrology • Renal Disease • Sarcoma • Short Bowel Syndrome • Solid Tumor • Transplantation • CCND1 • NOTCH1

Under Pressure: Ischemic Hepatitis Secondary to SMA Compression by a Sporadic Mesenteric Desmoid Tumor (ACG 2026) - "This approach is supported by the Phase 3 DeFi trial. The partial radiographic response we observed suggests that nirogacestat may hold value in cases where surgical options are prohibited by vascular encasement (5)."

Desmoid Tumors • Fibrosis • Genetic Disorders • Hepatology • Oncology • Sarcoma • Solid Tumor • APC

When Targeted Therapy Targets the Pancreas: A Case of Nirogacestat-induced Acute Pancreatitis (ACG 2026) - "Although Nirogacestat related gastrointestinal, hepatic and cutaneous adverse effects have been previously reported in the literature; disruption of pancreatic hemostasis is not previously documented. To the best of our knowledge, this case may be the first reported instance of Nirogacestat-induced acute pancreatitis."

Clinical • Cardiovascular • Desmoid Tumors • Gastroenterology • Hepatology • Mood Disorders • Ovarian Cancer • Pancreatitis • Pulmonary Embolism • Respiratory Diseases • Sarcoma • Solid Tumor

Venetoclax rewires Notch signaling to drive resistance in North American adult T-cell leukemia/lymphoma (AACR 2026) - "Venetoclax shows a significant effect in NA-ATLL both at preclinical and clinical settings, but emerging adaptive Notch signaling activation represents a crucial resistance mechanism. Our study supports evaluating Notch-directed agents (γ-secretase inhibitors/Nirogacestat) in combination with Venetoclax to overcome therapeutic resistance and improve outcomes in NA-ATLL."

Clinical • IO biomarker • Adult T-Cell Leukemia-Lymphoma • Hematological Malignancies • Leukemia • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • CASP3 • HES1 • JAG1 • NOTCH1 • NOTCH2 • TP53

Notch Inhibition by Nirogacestat Attenuates Fibrotic Processes in Fibroblasts from Patients with Systemic Sclerosis and Localized Scleroderma (ESDR 2026) - No abstract available

Clinical • Fibrosis • Immunology • Scleroderma • Systemic Sclerosis

Nirogacestat Ameliorates Fibrosis in Murine Recessive Dystrophic Epidermolysis Bullosa (ESDR 2026) - No abstract available

Preclinical • Fibrosis • Immunology

Nirogacestat Ameliorates Fibrosis in Murine Recessive Dystrophic Epidermolysis Bullosa (ESDR 2026) - "Sponsored by Debra"

Preclinical • Fibrosis • Immunology

DeFi: A phase III, randomized controlled trial of nirogacestat versus placebo for progressing desmoid tumors (DT) (ESMO 2022) - P3 | "Table: LBA2 Primary and secondary efficacy endpoints a - indicates improvement. b + indicates improvement."

Clinical • Late-breaking abstract • P3 data • Desmoid Tumors • Oncology • Sarcoma

DEFI: A PHASE 3, RANDOMIZED, DOUBLE-BLIND TRIAL OF NIROGACESTAT VERSUS PLACEBO FOR PROGRESSING DESMOID TUMORS/AGGRESSIVE FIBROMATOSIS (CTOS 2022) - No abstract available

Clinical • P3 data • Desmoid Tumors • Fibrosis • Oncology • Sarcoma • Solid Tumor

Nirogacestat, a γ-Secretase Inhibitor for Desmoid Tumors. (PubMed, N Engl J Med) - P3 | "Nirogacestat was associated with significant benefits with respect to progression-free survival, objective response, pain, symptom burden, physical functioning, role functioning, and health-related quality of life in adults with progressing desmoid tumors. Adverse events with nirogacestat were frequent but mostly low grade. (Funded by SpringWorks Therapeutics; DeFi ClinicalTrials.gov number, NCT03785964.)."

Journal • Desmoid Tumors • Fatigue • Oncology • Pain • Renal Disease • Sarcoma • Solid Tumor

Tumor volume and T2 hyperintensity changes from DeFi: A phase 3, randomized, controlled trial of nirogacestat in patients with desmoid tumors. (ASCO 2023) - P3 | "In DeFi, nirogacestat demonstrated substantial reduction of tumor volume and T2 hyperintensity of the largest target tumors by MRI compared with placebo in adults with DT. These results are consistent with the significant improvement in ORR achieved with nirogacestat. These data suggest that volumetric MRI and T2 hyperintensity might provide additional information in the evaluation of treatment response in DT."

Clinical • P3 data • Desmoid Tumors • Oncology • Sarcoma

TECLISTAMAB (TEC) + NIROGACESTAT (NIRO) IN RELAPSED/REFRACTORY MULTIPLE MYELOMA (RRMM): THE PHASE 1B MAJESTEC-2 STUDY (EHA 2023) - "The combination of tec + niro yielded response rates of 57–92% across 3 dose levels assessed. This initial experience with tec + niro provides insights on the combination of BCMA-directed therapies with a gamma secretase inhibitor. Phase I, Bispecific, Multiple myeloma, B-cell maturation antigen"

P1 data • Anemia • Cardiovascular • Dermatology • Fatigue • Hematological Disorders • Hematological Malignancies • Immune Modulation • Infectious Disease • Multiple Myeloma • Neutropenia • Novel Coronavirus Disease • Oncology • Septic Shock

EFFICACY OF NIROGACESTAT IN PATIENTS WITH DESMOID TUMORS AND POOR PROGNOSTIC FACTORS: PATIENT-REPORTED OUTCOMES, PROGRESSION-FREE SURVIVAL, AND OBJECTIVE RESPONSE RATE IN THE PHASE 3 DEFI TRIAL (CTOS 2024) - No abstract available

Biomarker • Clinical • P3 data • Patient reported outcomes • Desmoid Tumors • Oncology • Sarcoma

NIROGACESTAT TREATMENT IN ADULT PATIENTS WITH DESMOID TUMORS: LONG-TERM EFFICACY AND SAFETY FROM THE PHASE 3 DEFI TRIAL (CTOS 2024) - No abstract available

Clinical • P3 data • Desmoid Tumors • Oncology • Sarcoma

Efficacy and Safety of Long-Term Continuous Nirogacestat Treatment in Adults With Desmoid Tumors: Results From the DeFi Trial. (PubMed, J Clin Oncol) - P3 | "Since the primary analysis, four patients discontinued nirogacestat because of TEAEs between years 2 and 4. In conclusion, long-term continuous nirogacestat treatment was associated with further tumor size reductions, durable objective responses, sustained PRO benefits, and a manageable safety profile consistent with the primary analysis."

Journal • Desmoid Tumors • Oncology • Sarcoma

A phase I/II trial of FOG-001, a first-in-class direct β-catenin:TCF4 inhibitor - Safety and preliminary antitumor activity in patients with desmoid tumors (ESMO 2025) - P1/2 | "Clinical trial identification NCT05919264. Tumor reductions were seen in all pts, including a PR in a pt who progressed on prior nirogacestat. Dose expansion in a desmoid-specific cohort is currently ongoing."

Clinical • P1/2 data • Colorectal Cancer • Desmoid Tumors • Oncology • Sarcoma • APC • CTNNB1 • TCF4

A PHASE 1/2 TRIAL OF FOG-001, A FIRST-IN-CLASS DIRECT β-CATENIN:TCF4 INHIBITOR: SAFETY AND PRELIMINARY ANTITUMOR ACTIVITY IN PATIENTS WITH DESMOID TUMORS (DT) (CTOS 2025) - "Preliminary data show that FOG-001 has acceptable tolerability in pts with DT. Tumor reductions were seen in all pts, including multiple PRs in pts who progressed on nirogacestat. Dose expansion in a DT-specific cohort is currently ongoing."

Clinical • P1/2 data • Desmoid Tumors • Oncology • Sarcoma • Solid Tumor • APC • CTNNB1 • TCF4

Belantamab mafodotin, nirogacestat, and pomalidomide in patients with relapsed/refractory multiple myeloma (ASH 2025) - P1 | "Median priorlines of therapy was 5; 100% were triple exposed (PI, IMiD, anti-CD38 monoclonal antibody), and 5patients had prior high dose melphalan with autologous stem cell transplant. Two patients had priorBCMA treatment; 1 patient had received a BCMA CAR T and a GPRC5D CAR T, and 1 patient had receiveda BCMA CAR T and a BCMA bispecific antibody.The overall response rate (ORR) was 66% including 3 with partial response (PR) and 3 with very goodpartial response (VGPR)...The rate of ocular AEs wassimilar to prior belantamab mafodotin trials and real-world studies. The significant increase inmembrane bound BCMA after starting nirogacestat indicates a possible therapeutic synergy betweenGSIs and BCMA targeted therapies."

Clinical • IO biomarker • Age-related Macular Degeneration • Infectious Disease • Macular Degeneration • Multiple Myeloma • Neutropenia • Ophthalmology • Renal Disease • Retinal Disorders • Thrombocytopenia

Percutaneous Management of Desmoid Tumors. (PubMed, Curr Oncol Rep) - "An important consideration involves the level of data, comprised predominantly of retrospective data, without direct comparative date. The ongoing prospective CRYODESMO-02 trial will help define optimal sequencing and strengthen the evidence base underpinning guideline recommendations."

Journal • Review • Desmoid Tumors • Fibrosis • Oncology • Pain • Pediatrics • Sarcoma • Soft Tissue Sarcoma • Solid Tumor

Progressive Pelvic and Gluteal Desmoid Tumor in a 16-Year-Old Female: A Five-Year Multimodal Imaging Follow-Up. (PubMed, Cureus) - "Serial MRI, fluorine-18 fluorodeoxyglucose PET/CT (18F-FDG PET/CT), and CT performed from 2024 to 2026 documented progressive enlargement of a right gluteal mass and a large presacral pelvic mass despite sequential treatment with imatinib, sorafenib, and off-label nirogacestat. This case illustrates the refractory behavior of adolescent pelvic desmoid tumors and the central role of longitudinal multimodal imaging in tracking progression and detecting complications amenable to interventional management. It adds to the limited experience with off-label nirogacestat in adolescents, for whom prospective pediatric data remain limited."

Journal • Desmoid Tumors • Fibrosis • Oncology • Pediatrics • Sarcoma • Solid Tumor