603O - First clinical results from a phase I trial of PRT3789: A first-in-class intravenous SMARCA2 degrader, in patients with advanced solid tumors with a SMARCA4 mutation

Background

Genes encoding subunits of the SWI/SNF chromatin remodeling complex are among the most highly mutated in cancer, occurring in 20-24% of all human cancers. The SWI/SNF complex contains either 1 of 2 ATP enzymatic subunits, SMARCA2 or SMARCA4, which function interchangeably. PRT3789 is a potent SMARCA2 degrader with > 1000-fold selectivity for SMARCA4 mutated cancer cell compared to wild-type cells. We hypothesize that selective SMARCA2 degradation through synthetic lethality with PRT3789 will be an effective therapy for SMARCA4 mutated cancer.

Methods

This is a phase 1 dose escalation study with backfill cohorts added at active doses. Patients with any solid tumor and any SMARCA4 mutation (loss-of-function or missense) are eligible. PRT3789 is given intravenously weekly. Primary objectives are safety and determination of a recommended phase 2 dose.

Results

As of 7 Mar 2024, 40 pts have been enrolled (NSCLC [18], pancreatic [5], breast [3], esophageal [2], other [12]); 55% have loss-of-function mutations. Dose escalation has proceeded through 6 levels, from 24-212 mg, with 2 backfill cohorts opened. No DLTs or study drug-related SAEs have been reported. The most common AEs reported, of any grade or relatedness, are nausea (25.0%), constipation and dyspnea (each 17.5%), decreased appetite and fatigue (each 15.0%), and anemia (12.5%). Dose-related increases in AUC were observed. Dose dependent decreases in SMARCA2 levels were seen at all doses with a trend for increasing depth and duration with increasing doses; minimal effects on SMARCA4 levels were seen. Clinical activity of PRT3789 therapy noted to date includes RECIST partial responses, tumor shrinkage and prolonged stable disease (longer than response to most recent therapy) in patients with advanced, heavily pretreated esophageal cancer and NSCLC. A complete analysis of PK, PD, biomarkers, safety, and efficacy will be presented at ESMO.

Conclusions

PRT3789, a first-in-class SMARCA2 degrader, at doses studied to date appears to be well tolerated, with excellent pharmacodynamic effect, and with encouraging signs of anti-tumor activity, even during early dose escalation. Dose escalation and backfill cohorts are ongoing.

Clinical trial identification

NCT05639751.

Editorial acknowledgement

Editorial assistance was provided by Laura S. Moye, PhD, ISMPP CMPP™ of Team 9 Science.

Legal entity responsible for the study

Prelude Therapeutics.

Funding

Prelude Therapeutics.

Disclosure

R. Guo: Financial Interests, Personal, Research Funding: Prelude, Merck, AstraZeneca. A. Dowlati: Financial Interests, Personal, Speaker, Consultant, Advisor: Jazz, AstraZeneca, Ipsen, Amgen, AbbVie. I. Dagogo-Jack: Financial Interests, Personal, Other, Honoraria: OncLive, AscoPost, DAVA, Medscape, Research to Practice, Aptitude, Curio, PeerView; Financial Interests, Personal, Speaker, Consultant, Advisor: AstraZeneca, Bayer, BostonGene, BMS, Genentech, Gilead, Janssen, Merus, Novocure, Pfizer, Roche, ThermoFisher, Lilly; Financial Interests, Personal, Research Funding: Pfizer, Genentech, Novartis, BostonGene, Vivace, Tango, Prelude; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: IASLC, Research to Practice, Novocure. A.I. Spira: Financial Interests, Institutional, Leadership Role: NEXT Oncology-Virginia; Financial Interests, Personal, Officer, Honoraria: CytomX Therapeutics; Financial Interests, Personal, Other, Honoraria: AstraZeneca/MedImmune, Merck, Takeda, Janssen Oncology, Novartis, Bristol Myers Squibb, Bayer, Prelude Therapeutics, AbbVie, Astellas Pharma, Amgen; Financial Interests, Personal, Speaker, Consultant, Advisor: Incyte, Amgen, Novartis, Mirati Therapeutics, Gritstone Oncology Oncology, Jazz Pharmaceuticals, Takeda, Janssen Research & Development, Mersana, Gritstone Bio, Daiichi Sankyo/AstraZeneca, Regeneron, Lilly, Black Diamond Therapeutics, Sanofi, ArriVent Biopharma; Financial Interests, Institutional, Speaker, Consultant, Advisor: AstraZeneca/MedImmune, Merck, Bristol Myers Squibb, Blueprint Medicines; Financial Interests, Personal, Research Funding: LAM Therapeutics; Financial Interests, Institutional, Research Funding: Roche, AstraZeneca, Boehringer Ingelheim, Astellas Pharma, MedImmune, Novartis, Incyte, AbbVie, Ignyta, Takeda, Macrogenics, CytomX Therapeutics, Astex Pharmaceuticals, Bristol Myers Squibb, Loxo, Gritstone Bio, Plexxikon, Amgen, Daiichi Sankyo, ADCT, Janssen Oncology, Rubius, Synthekine, Mersana, Blueprint Medicines, Regeneron, Alkermes, Revolution Medicines, Medikine, Synthekine, Black Diamond Therapeutics, BluPrint Oncology, NALO Therapeutics, Scorpion Therapeutics, ArriVent Biopharma, Revolution Medicines, Prelude Therapeutics. V. Moreno Garcia: Financial Interests, Personal, Advisory Board: BMS, Janssen, Roche, Basilea, Bayer, AstraZeneca; Financial Interests, Personal, Full or part-time Employment: START; Financial Interests, Institutional, Local PI, AbbVie, AceaBio, Adaptimmune, ADC Therapeutics, Aduro, Agenus, Amcure, Amgen, Astellas, AstraZeneca Bayer BeiGene BioInvent International AB, BMS, Boehringer, Boheringer, Boston, Celgene, Daiichi Sankyo, Debiopharm, Eisai, e-Terapeutics, Exelisis, Forma Therapeutics, Genmab, GSK, Harpoon, Hutchison, Immutep, Incyte, Inovio, Iovance, Janssen, Kyowa Kirin, Lilly, Loxo, MedSir, Menarini, Merck, Merus, Millennium, MSD, Nanobiotix, Nektar, Novartis, Odonate Therapeutics, Pfizer, PharmaMar, PharmaMar, Principia, PsiOxus, Puma, Regeneron, Rigontec, Roche, Sanofi, Sierra Oncology, Synthon, Taiho, Takeda, Tesaro, Transgene, Turning Point Therapeutics, Upshersmith.: Multiple. S. Punekar: Financial Interests, Institutional, Local PI, Clinical Trial PI: Revolution Medicine, Simcere Pharmaceuticals, Astellas Pharmaceuticals, Constellation, A2Bio, Vitrac; Financial Interests, Institutional, Local PI, Clinical Tria PI: Neogene, Affini-T, Prelude, Tango; Non-Financial Interests, Principal Investigator, Clinical Trial PI: Revolution Medicine, A2Bio, Simcere, Constellation, Vitrac, Astellas Pharmaceuticals, Neogene; Non-Financial Interests, Principal Investigator, Clinical Tria PI: Affini-T, Prelude, Tango. E. Calvo: Financial Interests, Personal, Advisory Board: Adcendo, Amunix, Anaveon, AstraZeneca, BMS, Boehringer Ingelheim, Chugai, Diaccurate, Elevation Oncology, Ellipses Pharmacy, Genmab, Grey Wolf, Incyte, Janssen, MSD, Merus, MonTa, Nanobiotix, Nouscom, Novartis, Servier, SyneosHealth, T-knife, TargImmune, iTeos, Debio; Financial Interests, Personal, Invited Speaker: OncoDNA, PharmaMar, Roche/Genentech; Financial Interests, Personal, Full or part-time Employment, Director, Clinical Research: HM Hospitales Group; Financial Interests, Personal, Full or part-time Employment, Medical Oncologist, Clinical Investigator, Director, Clinical Research: START Madrid - CIOCC (Centro Integral Oncológico Clara Campal); Financial Interests, Personal, Member of Board of Directors, External Independent member of Board of Directors: PharmaMar; Financial Interests, Personal, Ownership Interest: START, Oncoart Associated; Financial Interests, Personal, Steering Committee Member, Member of Data Monitoring Committee: BeiGene, Sanofi, Merus, Shionogi; Financial Interests, Personal, Steering Committee Member: Novartis; Non-Financial Interests, Other, Non-for-profit Foundation. 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Herzberg: Financial Interests, Personal, Speaker, Consultant, Advisor: Astellas, Eli Lilly, Amgen, MJH Health Lifescience, Guardant; Financial Interests, Personal, Research Funding: Repare Therapeutics, Ideaya Therapeutics, AstraZeneca, Amgen, Revolution Medicines, Astellas, Nested Therapeutics, Monte Rosa Therapuetics. A. Italiano: Financial Interests, Personal, Advisory Board: Bayer, Roche, Philips, Chugai, GSK; Financial Interests, Institutional, Coordinating PI: Bayer, AstraZeneca, Roche, MSD, Ipsen, Merck. A. Swalduz: Financial Interests, Personal, Other, Honoraria: AstraZeneca, Janssen, Roche, Amgen, BMS; Financial Interests, Personal, Speaker, Consultant, Advisor, Honoraria: AstraZeneca, Janssen, Roche, Amgen, BMS, Pfizer, Lilly; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Pfizer, Roche. P. 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E.F. Smit: Financial Interests, Institutional, Advisory Board: AstraZeneca, Daiichi Sankyo, MSD, Boehringer Ingelheim, Roche, Eli Lilly, Takeda, Sanofi, Janssen, BMS; Financial Interests, Personal, Invited Speaker: Daiichi Sankyo, Boehringer Ingelheim; Financial Interests, Personal, Advisory Board: Merck Seranno; Financial Interests, Institutional, Other, DSMB member: DSI; Financial Interests, Institutional, Local PI: Pfizer, AZ, Genmab, DSI, Sanofi. E.B. Garon: Financial Interests, Personal, Advisory Board: Novartis, BMS, EMD Serono, Regeneron, Sanofi, Gilead, Eli Lilly, Zymeworks, AstraZeneca, AbbVie, Sensei, Seagan, Arcus, Summit, Synthekine, BridgeBio, Atreca, Sumitomo, Merus, Hookipa, LianBio; Financial Interests, Personal, Other, DSMB: Nuvalent; Financial Interests, Personal, Other, Independent Medical Education: Daiichi Sankyo; Financial Interests, Institutional, Coordinating PI: Novartis; Financial Interests, Institutional, Steering Committee Member: Merck, EMD Serono, Mirati, AstraZeneca, Arrivent, Regeneron; Financial Interests, Institutional, Local PI: Eli Lilly, Genetech, Iovance, ABL Bio, Daiichi Sanko, Prelude, Synthekine, Gilead; Financial Interests, Institutional, Trial Chair: BMS; Non-Financial Interests, Advisory Role, Scientific Advisory Board: Lungevity. W. Novotny: Financial Interests, Personal, Full or part-time Employment: Prelude Therapeutics; Financial Interests, Personal, Leadership Role: Prelude Therapeutics; Financial Interests, Personal, Stocks/Shares: Prelude Therapeutics; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Prelude Therapeutics. T.A. Yap: Financial Interests, Personal, Other, Consultant: Almac, Aduro, AstraZeneca, Atrin, Axiom, Bayer, Bristol Myers Squibb, Clovis, Cybrexa, EMD Serono, Guidepoint, Ignyta, I-Mab, Jansen, Merck, Pfizer, Repare, Roche, Schrodinger, Varian, Zai Labs, AbbVie, Acrivon, Adagene, Amphista, Artios, Athena, Avoro, Baptist Health Systems, BeiGene, Boxer, C4 Therapeutics, Calithera, Cancer Research UK, Diffusion, F-Star, Genmab, Glenmark, GLG, Globe Life Sciences, GSK, Idience, ImmuneSensor, Institut Gustave Roussy, Intellisphere, Kyn, MEI Pharma, Mereo, Natera, Nexys, Novocure, OHSU, OncoSec, Ono Pharma, Pegascy, PER, Piper-Sandler, Prolynx, resTORbio, Theragnostics, Versant, Vibliome, Xinthera, ZielBio, Radiopharm Theranostics, Sanofi, Ellipses.Life, LRG1, Panangium, Pliant Therapeutics, Synthis, Tessellate Bio, TD2 Theragonostics, Tome Biosciences, Zentalis, Amgen Inc., Astex, Avenzo, BioCity Pharma, Blueprint, Carrick Therapeutics, Circle Pharma, Daiichi Sankyo, Dark Blue Therapeuticcs, Duke Street Bio, 858 Therapeutics, EcoR1 Capital, Entos, FoRx Therapeutics AG, Genesis Therapeutics, Ideaya Biosciences, Impact Therapeutics, Merit, Monte Rosa Therapeutics, Nested Therapeutics, Nimbus, Odyssey, Onxeo, Protai Bio, Ryvu Therapeutics, SAKK, Servier, Synnovation, Tango, TCG Crossover, Terremoto Biosciences, Terns Pharmaceuticals, Tolremo, Tome, Thryv Therapeutics, Trevarx Biomedical, Veeva, Voronoi Inc.; Financial Interests, Personal, Other, University of Texas MD Anderson Cancer Center, where I am Medical Director of the Institute for Applied Cancer Science, which has a commercial interest in DDR and other inhibitors (IACS30380/ART0380 was licensed to Artios): MD Anderson Cancer Center, Institute for Applied Cancer Sciences; Financial Interests, Personal, Stocks/Shares: Seagan; Financial Interests, Institutional, Other, Grant/Research support: Bayer, Cyteir, EMD Serono, GSK, Karyopharm, Pfizer, Repare, Sanofi, Artios, AstraZeneca, BeiGene, BioNTech, Blueprint, BMS, Clovis, Constellation, Eli Lilly, Forbius, F-Star, Genentech, Haihe, ImmuneSensor, Ionis, Ipsen, Jounce, KSQ, Kyowa, Merck, Mirati, Novartis, Ribon Therapeutics, Regeneron, Rubius, Scholar Rock, Seattle Genetics, Tesaro, Vivace, Acrivon, Zenith; Financial Interests, Institutional, Research Grant: Boundless Bio, Ideaya; Financial Interests, Institutional, Other, Grant/Research Support: Insilico Medicine, Tango. All other authors have declared no conflicts of interest.