67MO - Long-term nirogacestat treatment in adult patients with desmoid tumors: Updated efficacy and safety from the phase III DeFi trial

Background

Nirogacestat (niro), an oral, targeted, gamma secretase inhibitor, is the only FDA-approved treatment for adults with progressing desmoid tumors (DT) requiring systemic treatment. DeFi (NCT03785964), a global, randomized, multicenter, phase 3 trial, demonstrated the efficacy and safety of niro. In the primary analysis (data cutoff [DCO] date 07Apr2022), median (range) duration of niro exposure was 20.6 (0.3–33.6) months (mo). This analysis of DeFi evaluated long-term safety and efficacy of continuous niro at a final a DCO date of 19Dec2024.

Methods

Patients initially randomized to niro (N=70) were evaluated by milestone group (years 1, 2, 3, and 4). Tumor response was evaluated by independent central review per RECIST v1.1. Patient-reported outcomes (PROs) were assessed longitudinally as least squares mean change from baseline. Safety was reported as treatment-emergent adverse events (TEAEs).

Results

Median (range) duration of niro exposure was 33.6 (0.3–61.8) mo. There were 46 (66%), 40 (57%), 33 (47%), and 15 (21%) patients who received at least 1, 2, 3, and 4 years of continuous niro treatment, respectively. Objective response rate (ORR) increased from 34.3% (up to 1 year of treatment) to 45.7% (up to 4 years of treatment). Across years 3 and 4, 3 additional partial responses (PRs) and 3 additional complete responses (CRs) occurred, yielding 24 (34.3%) PRs and 8 (11.4%) CRs as of the 19Dec2024 DCO. Improvement in PROs of pain, DT-specific symptom burden, physical and role functioning, and overall quality of life occurred early and were sustained with up to 4 years of niro treatment. For patients who remained on therapy, incidence and severity of TEAEs decreased after year 1. Since the primary analysis, the only dose reductions due to TEAEs that occurred (n=5) were between years 2 and 3. Treatment discontinuations due to TEAEs (pelvic abscess, folliculitis, diarrhea, hidradenitis, and ovarian toxicity) occurred between years 2 and 3 (n=1) and years 3 and 4 (n=3).

Conclusions

Long-term continuous niro treatment was associated with durable objective responses, early improvement and sustained benefit in PROs, and a manageable safety profile consistent with the primary analysis.

Clinical trial identification

NCT03785964.

Editorial acknowledgement

Medical writing support was provided by Saba Choudhary, PhD, from Prescott Medical Communications Group, a Citrus Health Group, Inc., company (Chicago, IL), and was funded by SpringWorks Therapeutics, Inc.

Legal entity responsible for the study

SpringWorks Therapeutics, Inc.

Funding

SpringWorks Therapeutics, Inc.

Disclosure

B. Kasper: Financial Interests, Personal, Other, Honoraria: Bayer; GlaxoSmithKline; Pharmamar-zeltia; Financial Interests, Personal, Advisory Role: Ayala Pharmaceuticals; Bayer; Boehringer Ingelheim; GlaxoSmithKline; SpringWorks Therapeutics, Inc.; Financial Interests, Personal, Funding, Research: Immunome; Cogent Medicine; PharmaMar; SpringWorks Therapeutics, Inc. R. Ratan: Financial Interests, Personal, Stocks/Shares: Johnson & Johnson/Janssen; Medtronic; Financial Interests, Personal, Other, Honoraria: PeerView; touchIME; Financial Interests, Personal, Advisory Role: InhibRx; Ipsen; SpringWorks Therapeutics, Inc.; Financial Interests, Personal, Funding, Research: Ayala Pharmaceuticals; C4 Therapeutics; SpringWorks Therapeutics, Inc.; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: SpringWorks Therapeutics, Inc. T. Alcindor: Financial Interests, Personal, Other, Honoraria: Research to Practice; Financial Interests, Personal, Other, Travel: SpringWorks Therapeutics, Inc. W.T.A. Van der Graaf: Financial Interests, Institutional, Funding, Research: Eli Lilly, SpringWorks Therapeutics, Inc., Immunome, Boehringer Ingelheim. N. Federman: Financial Interests, Personal, Advisory Role: Bayer; SpringWorks Therapeutics, Inc.; Financial Interests, Personal, Speaker’s Bureau: Bayer; Fennec Pharma; Springworks Therapeutics, Inc.; Financial Interests, Personal, Funding, Research: California Institute for Regenerative Medicine; National Institute of Health/National Center for Advancing Translational Sciences. N. Bui: Financial Interests, Personal, Advisory Role: Rain Therapeutics; SpringWorks Therapeutics, Inc.; Boehringer Ingelheim. G. D'Amato: Financial Interests, Personal, Other, Honoraria: a OncLive/MJH Life Sciences, Research to Practice, touchIME; Financial Interests, Personal, Advisory Role: AADi, Bayer, Boehringer Ingelheim, Daiichi Sankyo, Epizyme, Springworks Therapeutics Inc., Deciphera. R.F. Riedel: Financial Interests, Personal, Research Grant, Grants/Contracts: AADi, Adaptimmune, AROG, Ayala, BioAtla, Blueprint, Cogent, Daiichi Sankyo, Deciphera, GlaxoSmithKline, InhibRx, NanoCarrier, Oncternal, PTC Therapeutics, SARC, SpringWorks, Tracon, Trillium; Financial Interests, Personal, Other, Consulting: AADi, Adaptimmune, Bayer, Blueprint, Boehringer Ingelheim, Daiichi Sankyo, Deciphera, GlaxoSmithKline, NanoCarrier, SpringWorks Therapeutics, Inc. S. Attia: Financial Interests, Personal, Research Grant, Grants/Contracts: AB Science, Adaptimmune, Advenchen, Ayala Pharma, Bavarian Nordic A/S, Bayer HealthCare Pharmaceuticals Inc., Blueprint Medicines Corporation, Boehringer Ingelheim, BTG pharma, C4 Therapeutics, CBA pharma, Daiichi Sankyo Inc., Deciphera Pharmaceuticals In. S.P. Chawla: Financial Interests, Personal, Research Grant: Amgen, Roche, GSK, Threshold Pharmaceuticals, CytRx Corporation, Ignyta, Immune Design, TRACON Pharma, Karyopharm Therapeutics, Sarcoma Alliance for Research through Collaboration (SARC), Janssen, Advenchen Laboratories, Bayer, Inhibrx, NKMax, Thyme; Financial Interests, Personal, Other, Consulting Fees: Amgen, Roche, GSK, Threshold Pharmaceuticals, CytRx Corporation, Ignyta, Immune Design, TRACON Pharma, Karyopharm Therapeutics, Sarcoma Alliance for Research through Collaboration (SARC), Janssen, Advenchen Laboratories, Bayer, Inhibrx, NKMax, Thyme; Financial Interests, Personal, Invited Speaker: Amgen, Roche, GSK, Threshold Pharmaceuticals, CytRx Corporation, Ignyta, Immune Design, TRACON Pharma, Karyopharm Therapeutics, Sarcoma Alliance for Research through Collaboration (SARC), Janssen, Advenchen Laboratories, Bayer, Inhibrx, NKMax, Thyme; Financial Interests, Personal, Stocks/Shares: AADi, Cellestia Biotech, CounterPoint, Immix, BioPharma. Y. Chu: Financial Interests, Personal, Other, Consultant: SpringWorks Therapeutics, Inc. R. Cohen, A.B. Oton, S. Zhou, B. Tumminello: Financial Interests, Personal, Full or part-time Employment: SpringWorks Therapeutics, Inc.; Financial Interests, Personal, Stocks/Shares: SpringWorks Therapeutics, Inc. M. Gounder: Financial Interests, Personal, Other, Honoraria: Gerson Lehrman Group; Great Debates and Updates; Guidepoint Global; Med Learning Group; Medscape; MJH/PER; OncLive/MJH Life Sciences; Research to Practice; touchIME; Financial Interests, Personal, Advisory Role: AADi; Ayala Pharmaceuticals; Bayer; Boehringer Ingelheim; Daiichi Sankyo; Epizyme; Ikena Oncology; Karyopharm Therapeutics; Rain Therapeutics; Regeneron; SpringWorks Therapeutics, Inc; TYME; Financial Interests, Personal, Funding, Research: AADi; Athenex; Ayala Pharmaceuticals; Boehringer Ingelheim; Erasca, Inc; Foghorn Therapeutics; GlaxoSmithKline; Ikena Oncology; Kymera; Rain Oncology; Regeneron; SERVIER; SpringWorks Therapeutics, Inc; Tango Therapeutics; Tango Therapeutics; Financial Interests, Personal, Royalties: GODDESS PRO Desmoid Tumor; UpToDate; Financial Interests, Personal, Invited Speaker, Travel, Accommodations, Expenses: Epizyme; Financial Interests, Personal, Other: Desmoid Tumor Research Foundation; Financial Interests, Personal, Other, Uncompensated Relationship: Foundation Medicine.