LBA2 - DeFi: A phase III, randomized controlled trial of nirogacestat versus placebo for progressing desmoid tumors (DT)

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 III, 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 treated with niro 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 III trial of a GSI in any indication. Table: LBA2

Primary and secondary efficacy endpoints

^a- indicates improvement.^b+ indicates improvement.

Clinical trial identification

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

SpringWorks Therapeutics, Inc.

Disclosure

B. Kasper: Financial Interests, Personal, Advisory Board: Bayer, Blueprint, Boehringer Ingelheim, Springworks, GSK, PharmaMar, Ayala; Financial Interests, Institutional, Invited Speaker: PharmaMar, Springworks, 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, Springworks Therapeutics, C4 Therapeutics. T. Alcindor: Financial Interests, Personal, Advisory Board: Merck, Taiho, Eisai, Pfizer, Roche, BMS, AstraZeneca, 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, Epizyme, Isofol, 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, BluePrint Medicines, Boehringer Ingelheim, Ellipses Pharma, Transgene, Exelixis, Medscape, Guided Clarity, Ysios, Modus Outcomes, Studiecentrum voor Kernenergie, Curio Science; Financial Interests, Institutional, Advisory Board: Blueprint Medicines, Ellipses Pharma, Intellisphere; Financial Interests, Institutional, Expert Testimony: Advance Medical/Teladoc Health; Financial Interests, Institutional, Funding: CoBioRes NV, Eisai, G1 Therapeutics, Novartis, PharmaMar. W.T.A. Van Der Graaf: Financial Interests, Institutional, Advisory Board, One advisory board: Bayer; Financial Interests, Institutional, Invited Speaker: Springworks, Ayala; Financial Interests, Institutional, Research Grant, IIS grant: Novartis; Financial Interests, Institutional, Research Grant, IIS: Lilly; Financial Interests, Institutional, Other, consultancy work: Springworks; Non-Financial Interests, Invited Speaker, President: EORTC; Non-Financial Interests, Invited Speaker: European Cancer Organisation, Connective Tissue Oncology Society (CTOS); Non-Financial Interests, Invited Speaker, Chair: Dutch Sarcoma Group, Dutch AYA 'Young and Cancer' Care Network. B.A. Wilky: Financial Interests, Personal, Other, Consulting for curriculum development: Springworks; Financial Interests, Personal, Advisory Board: Deciphera, Adaptimmune, Daiichi Sankyo; Financial Interests, Institutional, Invited Speaker: Agenus. R.F. Riedel: Financial Interests, Personal and Institutional, Grants or contracts from any entity; Consulting fees: Aadi, Daiichi-Sankyo, Deciphera, Ignyta, Lilly, NanoCarrier, SpringWorks; Financial Interests, Institutional, Grants or contracts from any entity: AROG, Ayala, BioAtla, GlaxoSmithKline, Inhibrx, Immune Design, Karyopharm, Novartis, Oncternal, Philogen, Plexxikon, Rain Therapeutics, Roche, Threshold, Tracon, Trillium; Financial Interests, Personal, Consulting fees: Bayer, Blueprint, Eisai, EMD Serono, Janssen; Financial Interests, Personal, Patents planned, issued or pending: Limbguard, LLC; Personal, 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, TRACON Pharma, Ayala Pharmaceuticals, Trillium Therapeutics, Boehringer Ingelheim, Salarius Pharmaceuticals, Theseus Pharmaceuticals, Monopar Therapeutics, C4 Therapeutics, InhibRx, Noxopharm, Rain Therapeutics, Bayer, Novartis, Lilly, Immune Design, Karyopharm Therapeutics, Epizyme, Blueprint Medicines, Genmab, CBA Pharma, Merck, Philogen, Gradalis, Deciphera, Takeda, Incyte, Springworks, Adaptimmune, Advenchen Laboratories, Bavarian Nordic, BTG, PTC Therapeutics, GlaxoSmithKline, FORMA Therapeutics. S.P. Chawla: Financial Interests, Personal and Institutional, Funding: ADI, Amgen, GlaxoSmithKline, Ignyta, Immix Bopharma, Inhibrx, Janssen, Karyopharm Therapeutics, Roche, SARC, 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, 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, Deciphera Pharmaceuticals, Inc; Financial Interests, Personal, Advisory Board, Attended an advisory board meeting: Novartis; Financial Interests, Personal, Advisory Board: lilly, 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, Merck, Tracon Pharm, GSK; Non-Financial Interests, Invited Speaker: Polaris. B. Vincenzi: Financial Interests, Personal, Consultant / Advisory: Eisai; Financial Interests, Personal and Institutional, Consultant / Advisory; Research funds: Eli Lilly; Financial Interests, Personal and Institutional, Other, Consultant / Advisory; Honoraria; Research funds: Novartis, PharmaMar; Financial Interests, Personal, Consultant / Advisory; Honoraria; Testimony: Abbott, GSK; Financial Interests, Personal, Honoraria; Testimony: Accord. S. Kummar: Financial Interests, Personal, Advisory Board: Bayer, Gilead, Mundibiopharma, Boehringer Ingelheim, Springworks Theraepeutics, HarbourBiomed, Boehringer Ingelheim; Financial Interests, Personal, Advisory Board, Spouse: Cadila Pharmaceuticals; Financial Interests, Personal, Ownership Interest: Pahtomiq; Financial Interests, Personal, Co-founder: Pathomiq; Financial Interests, Institutional, Invited Speaker: ADC Therapeutics, Pionyr Therapeutics, Eisai, Bristol Myers Squibb, Syndax, SeaGen, Oric, EMD Serono, Genome & Company, Moderna, Amgen, ASTX Therapeutics, PMV Pharmaceuticals, Elevation Oncology, VelosBio Inc, Gilead, Day One Biopharmaceuticals, Vincerx Pharma, Inc. M.M. Gounder: Financial Interests, Personal, Other, Honoraria: Flatiron Health, PER, Medscape, Guidepoint Global, touchIME, Med Learning Group, More Health; Financial Interests, Personal, Advisory Role, Consulting or Advisory Role: Daiichi Sankyo, Bayer, Springworks, TYME, Ayala Pharmaceuticals, Rain Therapeutics; Financial Interests, Personal, Advisory Role, Consulting or Advisory Role; Speakers' Bureau: Karyopharm Therapeutics, Boehringer Ingelheim; Financial Interests, Personal, Advisory Role, Consulting or Advisory Role; Travel, Accommodations, Expenses: Epizyme; 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: Desmoid Tumor Research Foundation; Non-Financial Interests, Personal, Uncompensated Relationships: Foundation Medicine, Athenex. All other authors have declared no conflicts of interest.