DeFi trial: Smart design and impressive results for the benefit of patients with rare cancers

• First phase 3 trial shows targeting the Notch pathway improves outcomes in rare tumours 

• The gamma secretase inhibitor nirogacestat, which targets Notch, increases progression free survival and reduces symptoms in patients with desmoid tumours 

• Designing rigorous randomised controlled phase 3 trials in rare cancers is fundamental to improve patients’ outcomes and quality of life 

 

Paris, France, 10 September 2022 - Significant improvement in progression free survival and response rate combined with reduced symptoms and better quality of life are reported as outcomes of a new treatment approach for patients with desmoid tumours, which are benign, but locally aggressive and invasive soft tissue tumours. By targeting the Notch pathway with the novel gamma secretase inhibitor nirogacestat, researchers from the DeFi trial have obtained positive results for the first time with this approach. The results are reported at the ESMO Congress 2022. (1) 

Desmoid tumours are rare, with an incidence of 3-5 cases per million people worldwide each year (2,3). Patients have an unpredictable disease course and, although not generally fatal, the soft tissue tumours can cause symptoms that greatly impair quality of life. “Due to local and aggressive growth, desmoid tumours can cause pain, disfigurement and functional problems that can be a real burden for patients,” said lead author Bernd Kasper, Mannheim Cancer Center, Germany. 

The DeFi study included 142 patients with progressive desmoid tumours who were recruited from 37 centres across the world. “This is the largest and most rigorous randomised controlled study ever carried out in this tumour type,” reported Kasper. “Results showed a statistically significant improvement in progression-free survival in patients randomised to nirogacestat compared to the placebo group, with a 71% lower risk of disease progression on average.” The response rate was also much higher – 41% in the nirogacestat arm and only 8% in the placebo arm; nearly one in ten patients (7%) showed a complete response with the agent. 

The study measured patient reported outcomes because of the major impact of desmoid tumours on quality of life. “We saw a statistically significant benefit in reduction of pain and symptom burden and improvement in physical and role functioning and in health-related quality of life, which was really impressive,” noted Kasper. “In providing treatment we try to optimise local tumour control and reduce the symptom burden. But we have previously had no approved therapy for desmoid tumours. This study has the potential to lead to the first registration of a drug to treat patients with this disease.” 

“This is a unique study, very important in many aspects,” said Jean-Yves Blay, Cancer Center of Lyon, France, who was not involved in the study. “The results show benefit for the first time with a novel treatment with a new mode of action in patients where treatment options are currently limited.” The Notch signalling pathway is implicated in the development and progression of many tumour types. 

“The findings are practice changing,” added Blay. He predicted: “We are going to use nirogacestat as part of the treatment armamentarium for patients with desmoid tumours. But we will have to figure out how best to use it.” Remaining questions include which patients should be offered this treatment, where it fits in relation to current approaches, how to identify responders and the optimal duration of treatment. DeFi included patients with progressing tumours but both Blay and Kasper said that nirogacestat could also be considered in patients with pain and impaired functioning. 

“This was a very smart study: it demonstrated the feasibility of carrying out a large, placebo-controlled trial - which is the highest quality clinical study to investigate the activity of an agent - in a rare cancer by recruiting patients from a multinational group of reference centres and it demonstrated the importance of targeting the right patients with the right drug when designing clinical trials,” Blay added.  

“The trial included patients with volumetrically progressive disease, which provided a measurable way to select patients in need of treatment.” He added: “The success of this study puts even more emphasis to the concept of having patients with rare cancers referred into reference centres, where clinical studies can be accomplished in record times with the potential to deliver new treatments to patients with orphan diseases.” The number of cancer patients being referred to reference centres is increasing but could still be better in some regions, improving the outlook for patients with rare cancers. (4)  

-END- 

Notes to Editors  
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Disclaimer 
This press release contains information provided by the author of the highlighted abstract and reflects the content of this abstract. It does not necessarily reflect the views or opinions of ESMO who cannot be held responsible for the accuracy of the data. Commentators quoted in the press release are required to comply with the ESMO Declaration of Interests policy and the ESMO Code of Conduct. 

References  
1 LBA2 ‘DeFi: a phase 3, randomized controlled trial of nirogacestat versus placebo for progressing desmoid tumours (DT)’ will be presented by Bernd Kasper during Presidential Symposium 1 on Saturday, 10 September, 16:30 to 18:00 CEST in Paris Auditorium. Annals of Oncology, Volume 33 Supplement 7, September 2022 
2 Orphanet. Prevalence and incidence of rare diseases: Bibliographic data. Orphanet Report Series, Rare Diseases Collection. Orphanet; Number 1, January 2022. http://www.orpha.net/orphacom/cahiers/docs/GB/Prevalence_of_rare_diseases_by_alphabetical_list.pdf [accessed 23 August 2022] 
3 Kasper B, Baumgarten C, Garcia J, et al. An update on the management of sporadic desmoid-type fibromatosis: a European Consensus Initiative between Sarcoma PAtients EuroNet (SPAEN) and European Organization for Research and Treatment of Cancer (EORTC)/Soft Tissue and Bone Sarcoma Group (STBSG). Ann Oncol. 2017;28(10):2399-2408. 
4 The campaign Rare Cancers Europe, developed by ESMO in collaboration with major European stakeholders in rare cancers and rare diseases, is working to address the challenges and develop solutions to eliminate the hurdles faced by patients with rare cancers, healthcare professionals and researchers working in this field. 

About the European Society for Medical Oncology (ESMO) 
ESMO is the leading professional organisation for medical oncology. With nearly 25,000 members representing oncology professionals from over 160 countries worldwide, ESMO is the society of reference for oncology education and information. Driven by a shared determination to secure the best possible outcomes for patients, ESMO is committed to standing by those who care about cancer through addressing the diverse needs of #ONEoncologycommunity, offering #educationforLIFE, and advocating for #accessiblecancerCARE. www.esmo.org   

 

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. Lim^8, 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. Gounder^{18  
1}Mannheim 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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