LBA2 – DeFi: a phase 3, randomized controlled trial of nirogacestat versus placebo for progressing desmoid tumours (DT)

B. Kasper1, R. Ratan2, T. Alcindor3, P. Schoeffski4, W.T.A. Van Der Graaf5, B.A. Wilky6, R.F. Riedel7, A. Lim8, L.M. Smith8, S. Moody9, S. Attia10, S.P. Chawla11, G. D’Amato12, N. Federman13, P. Merriam14, B.A. Van Tine15, B. Vincenzi16, S. Kummar17, M.M. Gounder18
1Mannheim Cancer Center (mcc), UMM – Universitaetsklinikum Mannheim, Mannheim/Germany, 2Sarcoma Medical Oncology, MD Anderson Cancer Center, Houston/United States of America, 3Medical Oncology Department, McGill University Health Centre – Glen Site – Royal Victoria Hospital, Montreal/Canada, 4General Medical Oncology, KU Leuven – Laboratory of Experimental Oncology, Leuven/Belgium, 5Medical Oncology, NKI-AVL – Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Amsterdam/Netherlands, 6Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, CO/United States of America, 7Sarcoma Medical Oncology, Duke Cancer Center, Durham/United States of America, 8Clinical Research, SpringWorks Therapeutics, Stamford/United States of America, 9Biostatistics, PharPoint Research, Inc., Durham/United States of America, 10Medical Oncology, Mayo Clinic Cancer Center, Phoenix/United States of America, 11Oncology Dept, Sarcoma Oncology Research Center, Santa Monica/United States of America, 12Medicine Research Interest, Sylvester Comprehensive Cancer Center – University of Miami, Miami/United States of America, 13Pediatric Hematology Oncology, UCLA – David Geffen School of Medicine, Los Angeles/United States of America, 14Sarcoma Medical Oncology Department, Dana Farber Cancer Institute, Boston/United States of America, 15Medical Oncology Department, Washington University School of Medicine in St. Louis, St. Louis/United States of America, 16Medical Oncology Dept, Policlinico Universitario Campus Bio-Medico, Rome/Italy, 17Division Of Hematology/medical Oncology, Oregon Health & Science University, Portland/United States of America, 18Medicine, Memorial Sloan Kettering Evelyn H. Lauder Breast Center, New York/United States of America

Background: DT are rare, locally aggressive soft-tissue tumors without approved systemic therapy. Nirogacestat (niro), a novel oral gamma secretase inhibitor (GSI) has shown antitumor activity in patients with DT.

Methods: DeFi is a global, Phase 3, randomized, double-blind, placebo (pbo)-controlled trial in adults with progressing DT per RECIST v1.1 (NCT03785964). 142 participants were stratified by target tumor location (intra-/extra-abdominal) and randomized 1:1 to niro (n=70) 150 mg or pbo (n=72) BID. The primary endpoint was progression-free survival (PFS) per blinded independent central review. Prespecified secondary endpoints were safety, objective response rate (ORR), and patient-reported outcomes (PROs).

Results: Niro demonstrated significant PFS improvement compared with pbo (hazard ratio [HR], 0.29 [95% CI, 0.15, 0.55; P<0.001]). ORR was significantly improved with niro versus pbo (41% vs 8%; P<0.001), with a median time to response of 5.6 versus 11.1 months. The complete response rate was 7% with niro versus 0% with pbo. Statistically and clinically significant improvements in all prespecified PROs were observed early and sustained on treatment with niro compared with pbo (Table). Of AEs with niro, 95% were grade 1/2, the most frequently reported being diarrhea (84%), nausea (54%), fatigue (51%), hypophosphatemia (42%), and maculopapular rash (32%). Ovarian dysfunction occurred in 75% (27/36) of women of childbearing potential in the niro arm and resolved in 20 (74%), including 11/11 who discontinued niro for any reason.

Conclusions: Niro demonstrated statistically and clinically significant improvements in PFS, ORR, symptom burden, physical/role functioning, and health-related quality of life and had a manageable safety profile in adults with progressing DT. DeFi is the most rigorous randomized controlled trial performed to date in DT and the first positive Phase 3 trial of a GSI in any indication.

Table. Primary and Secondary Efficacy Endpoints

Nirogacestat
 (n=70)

Placebo (n=72)

P value

PFS

HR (95% CI)

0.29 (0.15, 0.55)

<0.001

Confirmed ORR, n (%) (95%CI)

29 (41) (30.2, 54.5)

6 (8) (3.1, 17.3)

<0.001

LS mean change at Cycle 10

Between-arm difference

Brief Pain Index-Short Form Average Pain Intensitya

-1.5

<0.001

GOunder/DT Research Foundation DEsmoid Symptom/Impact Scalea

DT Symptom Scale

-1.6

<0.001

DT Impact Scale

-0.8

<0.001

European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30b

Global health status/quality of life

10.4

0.007

Physical functioning

13.5

<0.001

Role functioning

16.8

<0.001

a– indicates improvement. b+ indicates improvement.

Clinical trial identification: ClinicalTrials.gov Identifier: NCT03785964

Editorial acknowledgement: Editorial assistance was provided under the direction of the authors by MedThink SciCom and funded by SpringWorks Therapeutics, Inc.

Legal entity responsible for the study: SpringWorks Therapeutics, Inc.

Funding: Pharmaceutical, biotech, or other commercial company – SpringWorks Therapeutics, Inc.

Disclosure: B. Kasper: Financial Interests, Personal, Advisory Board: Bayer; Financial Interests, Personal, Advisory Board: Blueprint; Financial Interests, Personal, Advisory Board: Boehringer Ingelheim; Financial Interests, Personal, Advisory Board: Springworks; Financial Interests, Personal, Advisory Board: GSK; Financial Interests, Personal, Advisory Board: PharmaMar; Financial Interests, Personal, Advisory Board: Ayala; Financial Interests, Institutional, Invited Speaker: PharmaMar; Financial Interests, Institutional, Invited Speaker: Springworks; Financial Interests, Institutional, Invited Speaker: Ayala; Non-Financial Interests, , Leadership Role, Chair of the EORTC Soft Tissue and Bone Sarcoma Group (STBSG): European Organisation for Research and Treatment of Cancer (EORTC). R. Ratan: Financial Interests, Personal, Advisory Board: Epizyme; Financial Interests, Personal, Invited Speaker: Epizyme; Financial Interests, Institutional, Invited Speaker: Ayala Pharmaceuticals; Financial Interests, Institutional, Invited Speaker: Springworks Therapeutics; Financial Interests, Institutional, Invited Speaker: C4 Therapeutics. T. Alcindor: Financial Interests, Personal, Advisory Board: Merck; Financial Interests, Personal, Advisory Board: Taiho; Financial Interests, Personal, Advisory Board: Eisai; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Advisory Board: BMS; Financial Interests, Personal, Advisory Board: Astra Zeneca; Financial Interests, Personal, Advisory Board: Bayer; Financial Interests, Institutional, Funding, For investigator-initiated trial: EMD Serono; Financial Interests, Personal and Institutional, Invited Speaker: Astellas; Financial Interests, Institutional, Invited Speaker: Deciphera; Financial Interests, Institutional, Invited Speaker: Epizyme; Financial Interests, Institutional, Invited Speaker: Isofol; Financial Interests, Institutional, Invited Speaker: SpringWorks; Non-Financial Interests, , Leadership Role, Co-chair of Esophago-Gastric Disease Site-Oriented Group: Canadian Cancer Trials Group; Non-Financial Interests, , Advisory Role, Member, Committee for immunotherapy in upper GI cancers: American Society of Clinical Oncology; Non-Financial Interests, , Advisory Role: Colorectal Cancer Canada. P. Schoeffski: Financial Interests, Personal, Advisory Board: Deciphera; Financial Interests, Personal, Advisory Board: BluePrint Medicines; Financial Interests, Personal, Advisory Board: Boehringer Ingelheim; Financial Interests, Personal, Advisory Board: Ellipses Pharma; Financial Interests, Personal, Advisory Board: Transgene; Financial Interests, Personal, Advisory Board: Exelixis; Financial Interests, Personal, Advisory Board: Medscape; Financial Interests, Personal, Advisory Board: Guided Clarity; Financial Interests, Personal, Advisory Board: Ysios; Financial Interests, Institutional, Advisory Board: Blueprint Medicines; Financial Interests, Institutional, Advisory Board: Ellipses Pharma; Financial Interests, Institutional, Advisory Board: Intellisphere; Financial Interests, Institutional, Expert Testimony: Advance Medical/Teladoc Health; Financial Interests, Personal, Advisory Board: Modus Outcomes; Financial Interests, Personal, Advisory Board: Studiecentrum voor Kernenergie; Financial Interests, Personal, Advisory Board: Curio Science; Financial Interests, Institutional, Funding: CoBioRes NV; Financial Interests, Institutional, Funding: Eisai; Financial Interests, Institutional, Funding: G1 Therapeutics; Financial Interests, Institutional, Funding: Novartis; Financial Interests, Institutional, Funding: PharmaMar.
 W.T.A. Van Der Graaf: Financial Interests, Institutional, Advisory Board, One advisory board: Bayer; Financial Interests, Institutional, Invited Speaker: Springworks; Financial Interests, Institutional, Research Grant, IIS grant: Novartis; Financial Interests, Institutional, Research Grant, IIS: Lilly; Financial Interests, Institutional, Other, consultancy work: Springworks; Financial Interests, Institutional, Invited Speaker: AYALA; Non-Financial Interests, , Invited Speaker, President: EORTC; Non-Financial Interests, , Invited Speaker: European Cancer Organisation; Non-Financial Interests, , Invited Speaker, Chair: Dutch Sarcoma Group; Non-Financial Interests, , Invited Speaker, Chair: Dutch AYA ‘Young and Cancer’ Care Network; Non-Financial Interests, , Invited Speaker: Connective Tissue Oncology Society (CTOS). B.A. Wilky: Financial Interests, Personal, Other, consulting for curriculum development: Springworks; Financial Interests, Personal, Advisory Board: Deciphera; Financial Interests, Personal, Advisory Board: Adaptimmune; Financial Interests, Personal, Advisory Board: Daiichi Sankyo; Financial Interests, Institutional, Invited Speaker: Agenus. R.F. Riedel: Financial Interests, Personal and Institutional, Other, Grants or contracts from any entity; Consulting fees: Aadi; Financial Interests, Institutional, Other, Grants or contracts from any entity: AROG; Financial Interests, Institutional, Other, Grants or contracts from any entity: Ayala; Financial Interests, Institutional, Other, Grants or contracts from any entity: BioAtla; Financial Interests, Personal and Institutional, Other, Grants or contracts from any entity; Consulting fees: Daiichi-Sankyo; Financial Interests, Personal and Institutional, Other, Grants or contracts from any entity; Consulting fees: Deciphera; Financial Interests, Institutional, Other, Grants or contracts from any entity: GlaxoSmithKline; Financial Interests, Personal and Institutional, Other, Grants or contracts from any entity; Consulting fees: Ignyta; Financial Interests, Institutional, Other, Grants or contracts from any entity: Inhibrx; Financial Interests, Institutional, Other, Grants or contracts from any entity: Immune Design; Financial Interests, Institutional, Other, Grants or contracts from any entity: Karyopharm; Financial Interests, Personal and Institutional, Other, Grants or contracts from any entity; Consulting fees: Lilly; Financial Interests, Personal and Institutional, Other, Grants or contracts from any entity; Consulting fees: NanoCarrier; Financial Interests, Institutional, Other, Grants or contracts from any entity: Novartis; Financial Interests, Institutional, Other, Grants or contracts from any entity: Oncternal; Financial Interests, Institutional, Other, Grants or contracts from any entity: Philogen; Financial Interests, Institutional, Other, Grants or contracts from any entity: Plexxikon; Financial Interests, Institutional, Other, Grants or contracts from any entity: Rain Therapeutics; Financial Interests, Institutional, Other, Grants or contracts from any entity: Roche; Financial Interests, Personal and Institutional, Other, Grants or contracts from any entity; Consulting fees: SpringWorks; Financial Interests, Institutional, Other, Grants or contracts from any entity: Threshold; Financial Interests, Institutional, Other, Grants or contracts from any entity: Tracon; Financial Interests, Institutional, Other, Grants or contracts from any entity: Trillium; Financial Interests, Personal, Other, Consulting fees: Bayer; Financial Interests, Personal, Other, Consulting fees: Blueprint; Financial Interests, Personal, Other, Consulting fees: EISAI; Financial Interests, Personal, Other, Consulting fees: EMD Serono; Financial Interests, Personal, Other, Consulting fees: Janssen; Financial Interests, Personal, Other, Patents planned, issued or pending: Limbguard, LLC; Other, Personal, Other, Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid: ECOG-ACRIN Sarcoma Working Group. A. Lim: Financial Interests, Personal, Stocks/Shares: SpringWorks; Financial Interests, Personal, Full or part-time Employment: SpringWorks. L..M. Smith: Financial Interests, Institutional, Stocks/Shares: SpringWorks; Financial Interests, Institutional, Full or part-time Employment, Support for attending meetings and/or travel: SpringWorks. S. Attia: Financial Interests, Personal, Funding, Research Funding: Desmoid Tumor Research Foundation; Financial Interests, Institutional, Funding, Research Funding: AB Science; Financial Interests, Institutional, Funding, Research Funding: TRACON Pharma; Financial Interests, Institutional, Funding, Research Funding: Ayala Pharmaceuticals; Financial Interests, Institutional, Funding, Research Funding: Trillium Therapeutics; Financial Interests, Institutional, Funding, Research Funding: Boehringer Ingelheim; Financial Interests, Institutional, Funding, Research Funding: Salarius Pharmaceuticals; Financial Interests, Institutional, Funding, Research Funding: Theseus Pharmaceuticals; Financial Interests, Institutional, Funding, Research Funding: Monopar Therapeutics; Financial Interests, Institutional, Funding, Research Funding: C4 Therapeutics; Financial Interests, Institutional, Funding, Research Funding: InhibRx; Financial Interests, Institutional, Funding, Research Funding: Noxopharm; Financial Interests, Institutional, Funding, Research Funding: Rain Therapeutics; Financial Interests, Institutional, Funding, Research Funding: Bayer; Financial Interests, Institutional, Funding, Research Funding: Novartis; Financial Interests, Institutional, Funding, Research Funding: Lilly; Financial Interests, Institutional, Funding, Research Funding: Immune Design; Financial Interests, Institutional, Funding, Research Funding: Karyopharm Therapeutics; Financial Interests, Institutional, Funding, Research Funding: Epizyme; Financial Interests, Institutional, Funding, Research Funding: Blueprint Medicines; Financial Interests, Institutional, Funding, Research Funding: Genmab; Financial Interests, Institutional, Funding, Research Funding: CBA Pharma; Financial Interests, Institutional, Funding, Research Funding: Merck; Financial Interests, Institutional, Funding, Research Funding: Philogen; Financial Interests, Institutional, Funding, Research Funding: Gradalis; Financial Interests, Institutional, Funding, Research Funding: Deciphera; Financial Interests, Institutional, Funding, Research Funding: Takeda; Financial Interests, Institutional, Funding, Research Funding: Incyte; Financial Interests, Institutional, Funding, Research Funding: Springworks; Financial Interests, Institutional, Funding, Research Funding: Adaptimmune; Financial Interests, Institutional, Funding, Research Funding: Advenchen Laboratories; Financial Interests, Institutional, Funding, Research Funding: Bavarian Nordic; Financial Interests, Institutional, Funding, Research Funding: BTG; Financial Interests, Institutional, Funding, Research Funding: PTC Therapeutics; Financial Interests, Institutional, Funding, Research Funding: GlaxoSmithKline; Financial Interests, Institutional, Funding, Research Funding: FORMA Therapeutics. S.P. Chawla: Financial Interests, Personal and Institutional, Funding: ADI; Financial Interests, Personal and Institutional, Funding: Amgen; Financial Interests, Personal and Institutional, Funding: GlaxoSmithKline; Financial Interests, Personal and Institutional, Funding: Ignyta; Financial Interests, Personal and Institutional, Funding: Immix Bopharma; Financial Interests, Personal and Institutional, Funding: Inhibrx; Financial Interests, Personal and Institutional, Funding: Janssen; Financial Interests, Personal and Institutional, Funding: Karyopharm Therapeutics; Financial Interests, Personal and Institutional, Funding: Roche; Financial Interests, Personal and Institutional, Funding: SARC; Financial Interests, Personal and Institutional, Funding: Tracon. N. Federman: Financial Interests, Personal, Advisory Board, Participation on a Data Safety Monitoring Board or Advisory Board: DSMB participation Ayala Pharmaceuticals; Financial Interests, Personal, Speaker’s Bureau, Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Speaker Bureau, Larotrectinib, Bayer AG. B.A. Van Tine: Financial Interests, Personal, Invited Speaker, Educational Speaker: Targeted Oncology; Financial Interests, Personal, Advisory Board, Also, Travel paid to conference to present abstract: Adaptimmune Limited; Financial Interests, Personal, Invited Speaker, Also attended an Ad Board meeting. Travel was paid to present abstract at conference.: GSK; Financial Interests, Personal, Other, Consulting. Also attended and Ad Board meeting. Travel was paid to attend an Ad board meeting.: Epizyme; Financial Interests, Personal, Other, Consulting- ADRx working on a cancer project and they are requesting my expertise.: ADRx; Financial Interests, Personal, Advisory Board, tenosynovial giant cell tumors (TGCT): Ayala Pharmaceuticals; Financial Interests, Personal, Other, Consulting/Advisor: Cytokinetics Inc; Financial Interests, Personal, Other, Consulting: Bayer; Financial Interests, Personal, Other, 60 minute interview regarding Synovial Sarcoma.: Bionest Partners; Financial Interests, Personal, Other, OncLive Virtual Workshop : Intellisphere LLC; Financial Interests, Personal, Advisory Board, Attended Advisory Board Meeting: Apexigen Inc; Financial Interests, Personal, Advisory Board, Attended an Advisory Board Meeting: Daiichi Sankyo; Financial Interests, Personal, Advisory Board, Attended an Advisory Board Meeting: Deciphera Pharmaceuticals, Inc; Financial Interests, Personal, Advisory Board, Attended an advisory board meeting: Novartis; Financial Interests, Personal, Advisory Board: lilly; Financial Interests, Personal, Advisory Board: PTC Therapeutics; Financial Interests, Personal, Invited Speaker, Sigma-2 Receptor Ligands and Therapeutic uses therefor (006766), • Modular Platform for Targeted Therapeutic Delivery (006755), • Sigma-2 Receptor Ligand Drug Conjugates as Antitumor Compounds, Methods of synthesis and Uses Thereof (014229): Accuronix Therapeutics; Financial Interests, Institutional, Research Grant: Pfizer; Financial Interests, Institutional, Research Grant: Merck; Financial Interests, Institutional, Research Grant: Tracon Pharm; Financial Interests, Institutional, Research Grant: GSK; Non-Financial Interests, , Invited Speaker: Polaris. B. Vincenzi: Financial Interests, Personal, Other, Consultant / Advisory: Eisai; Financial Interests, Personal and Institutional, Other, Consultant / Advisory; Research funds: Eli Lilly; Financial Interests, Personal and Institutional, Other, Consultant / Advisory; Honoraria; Research funds: Novartis; Financial Interests, Personal and Institutional, Other, Consultant / Advisory; Honoraria; Research funds: PharmaMar; Financial Interests, Personal, Other, Consultant / Advisory; Honoraria; Testimony: Abbott; Financial Interests, Personal, Other, Consultant / Advisory; Honoraria; Testimony: GSK; Financial Interests, Personal, Other, Honoraria; Testimony: Accord. S. Kummar: Financial Interests, Personal, Advisory Board: Bayer; Financial Interests, Personal, Advisory Board: Gilead; Financial Interests, Personal, Advisory Board: Mundibiopharma; Financial Interests, Personal, Advisory Board: Boehringer Ingelheim; Financial Interests, Personal, Advisory Board: Springworks Theraepeutics; Financial Interests, Personal, Advisory Board: HarbourBiomed; Financial Interests, Personal, Advisory Board: Boehringer Ingelheim; Financial Interests, Personal, Advisory Board, Spouse: Cadila Pharmaceuticals; Financial Interests, Personal, Ownership Interest: Pahtomiq; Financial Interests, Personal, Other, co-founder: Pathomiq; Financial Interests, Institutional, Invited Speaker: ADC Therapeutics; Financial Interests, Institutional, Invited Speaker: Pionyr Therapeutics; Financial Interests, Institutional, Invited Speaker: Eisai; Financial Interests, Institutional, Invited Speaker: Bristol Myers Squibb; Financial Interests, Institutional, Invited Speaker: Syndax; Financial Interests, Institutional, Invited Speaker: SeaGen; Financial Interests, Institutional, Invited Speaker: ORIC; Financial Interests, Institutional, Invited Speaker: EMD Serono; Financial Interests, Institutional, Invited Speaker: Genome & Company; Financial Interests, Institutional, Invited Speaker: Moderna; Financial Interests, Institutional, Invited Speaker: Amgen; Financial Interests, Institutional, Invited Speaker: ASTX Therapeutics; Financial Interests, Institutional, Invited Speaker: PMV Pharmaceuticals; Financial Interests, Institutional, Invited Speaker: Elevation Oncology; Financial Interests, Institutional, Invited Speaker: VelosBio Inc; Financial Interests, Institutional, Invited Speaker: Gilead; Financial Interests, Institutional, Invited Speaker: Day One Biopharmaceuticals; Financial Interests, Institutional, Invited Speaker: Vincerx Pharma, Inc.  M.M. Gounder: Financial Interests, Personal, Other, Honoraria: Flatiron Health; Financial Interests, Personal, Other, Honoraria: PER; Financial Interests, Personal, Other, Honoraria: Medscape; Financial Interests, Personal, Other, Honoraria: Guidepoint Global; Financial Interests, Personal, Other, Honoraria: touchIME; Financial Interests, Personal, Other, Honoraria: Med Learning Group; Financial Interests, Personal, Other, Honoraria: More Health; Financial Interests, Personal, Advisory Role, Consulting or Advisory Role: Daiichi Sankyo; Financial Interests, Personal, Advisory Role, Consulting or Advisory Role; Speakers’ Bureau: Karyopharm Therapeutics; Financial Interests, Personal, Advisory Role, Consulting or Advisory Role; Travel, Accommodations, Expenses: Epizyme; Financial Interests, Personal, Advisory Role, Consulting or Advisory Role: Bayer; Financial Interests, Personal, Advisory Role, Consulting or Advisory Role: Springworks; Financial Interests, Personal, Advisory Role, Consulting or Advisory Role; Speakers’ Bureau: Boehringer Ingelheim; Financial Interests, Personal, Advisory Role, Consulting or Advisory Role: TYME; Financial Interests, Personal, Advisory Role, Consulting or Advisory Role: Ayala Pharmaceuticals; Financial Interests, Personal, Advisory Role, Consulting or Advisory Role: Rain Therapeutics; Financial Interests, Personal, Speaker’s Bureau: Amgen; Financial Interests, Personal, Royalties, Patents, Royalties, Other Intellectual Property: UpToDate; Financial Interests, Institutional, Royalties, Patents, Royalties, Other Intellectual Property: GODDESS PRO Desmoid Tumor; Financial Interests, Personal, Other: Desmoid Tumor Research Foundation; Non-Financial Interests, Personal, Other, Uncompensated Relationships: Foundation Medicine; Non-Financial Interests, Personal, Other, Uncompensated Relationships: Athenex. All other authors have declared no conflicts of interest.

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