27O - First-in-class first-in-human phase I trial of RBN-2397 in patients with advanced solid tumors validates PARP7 as a novel anticancer therapeutic target

Background

RBN-2397 is a first-in-class PARP7 inhibitor that restores type I interferon signaling and induces an adaptive immune response. Elevated PARP7 expression in cancers of squamous histology and selected other tumor types has identified a potential target population for RBN-2397.

Methods

Patients (pts) with advanced solid tumors were treated with RBN-2397 in the dose escalation phase, followed by dose expansion in 3 tumor-specific cohorts: squamous cell carcinoma of the lung (SCCL), head and neck squamous cell carcinoma (HNSCC), and hormone receptor–positive breast cancer (HR+ BC).

Results

During dose escalation, 50 pts received doses from 25 to 500 mg twice daily (BID); the recommended phase 2 dose was 200 mg BID. Preliminary antitumor activity was observed, with 1 partial response (PR) in HR+ BC and 10 pts with stable disease (SD) >4 months. As of 2 July 2022, 31 pts have been treated at 200 mg BID in 3 expansion cohorts: SCCL (n=13), HNSCC (n=10), and HR+ BC (n=8). Median age (range) was 66 years (43-83) and the median number of prior therapies was 4 (1-8). The disease control rate in response-evaluable pts was 44% in SCCL (SD in 4/9 pts), 71% in HNSCC (RECIST PR for 12+ months in 1/7 [paranasal sinus primary]; SD in 4/7), and 29% in HR+ BC (SD in 2/7). In the overall study population (N=81), RBN-2397–related AEs (all grades >10%) were dysgeusia (40%), fatigue and nausea (20% each), and decreased appetite (14%); Grade 3/4 events (≥2 pts) were diarrhea, anemia, and AST increase (3% each). No significant chronic toxicities were observed. Biomarker analysis showed PARP7 expression in all baseline biopsies evaluated, with expression consistently higher in tumor cells than in stromal cells. On-treatment biopsies confirmed induction of adaptive immunity following RBN-2397 treatment, as evidenced by increases in CD8+ T cells and/or granzyme B expression in most pts across tumor types.

Conclusions

RBN-2397 was well tolerated, and preliminary antitumor activity was observed in both the escalation and expansion cohorts. Biomarker studies confirmed the immunomodulatory mechanism of RBN-2397 and support the ongoing trial in combination with pembrolizumab (NCT05127590).

Clinical trial identification

NCT05127590.

Editorial acknowledgement

Patrick Barry, Acumen Medical Communications.

Legal entity responsible for the study

Ribon Therapeutics, Inc. Cambridge, MA.

Funding

Ribon Therapeutics, Inc.

Disclosure

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, OncoSec, Nexys, Novocure, OHSU, Ono Pharma, Pegascy, PER, Piper-Sandler, Prolynx, resTORbio, Theragnostics, Versant, Vibliome, Xinthera, ZielBio; 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, GlaxoSmithKline, 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, Zenith, Tesaro, Vivace, Acrivon. A. Cervantes: Financial Interests, Institutional, Advisory Board: MerckSerono, Amgen, Roche, Transgene, AnHeart Therapeutics; Financial Interests, Institutional, Invited Speaker: Amgen, Roche, Merck Serono, Foundation Medicine; Financial Interests, Personal, Other, Associate Editor: Annals of Oncology, ESMO Open; Financial Interests, Personal, Other, Editor: Cancer Treatment Reviews; Financial Interests, Institutional, Research Grant, Principal Investigator: Actuate Therapeutic, Amgen, Astellas Pharma, BeiGene, Bayer, Astra Zeneca, BMS, Amcure, FibroGen, Lilly, Genentech, MedImmune, Merck Serono, Novartis, Natera, MSD, Servier, Sierra Oncology, Adaptimmune, Takeda; Non-Financial Interests, Personal, Other, General and Scientific Director: INCLIVA Biomedical Research Institute. G. Falchook: Financial Interests, Personal, Royalties: Wolters Kluwer; Financial Interests, Institutional, Advisory Role: AbbVie, Silicon, Navire, Turning Point, Predicine, Inspirna, Regeneron, Jubilant, Boston Gene, Teon; Financial Interests, Personal, Advisory Role: EMD Serono; Financial Interests, Personal, Other, Travel: Amgen, Synthorx/Sanofi, EMD Serono; Financial Interests, Institutional, Research Grant: 3-V Biosciences, Abbisko, AbbVie, ADC Therapeutics, ABL Bio, Accutar, Agenus, Aileron, American Society of Clinical Oncology, Amgen, ARMO/Eli Lilly, Artios, AstraZeneca , BeiGene, Bioatla, Bioinvent, Biothera, Bicycle, Black Diamond, Boehringer Ingelheim, Celgene, Celldex, Ciclomed, Curegenix, Curis, Cyteir, Daiichi, DelMar, eFFECTOR, Eli Lilly, EMD Serono, Epizyme, Erasca, Exelixis, Freenome, Fujifilm, Genmab, GlaxoSmithKline, Hutchinson, MediPharma, IGM Biosciences, Ignyta, Immunitas, ImmunoGen/MacroGenics, Incyte, Jacobio, Jazz, Jounce, Jubilant, Koltan, Loxo/Bayer, MedImmune, Merck, Metabomed, Millennium, Mirati, mRNA Therapeutics, Molecular Templates, National Institutes of Health, Navire, NiKang, Novartis, OncoMed, Oncorus, Oncothyreon, Poseida, Precision Oncology, Prelude, PureTech, Pyramid, RasCal, Regeneron, Relay, Rgenix, Ribon, Samumed, Sapience, Seagen, Silicon, Simcha, Sirnaomics, Strategia, Syndax, Synthorx/Sanofi, Taiho, Takeda, Tallac, Tarveda, Teneobio, Tesaro, Tocagen, Turning Point, UT MD Anderson Cancer Center, Vegenics, Xencor, Zhuhai Yufan. M. Patel: Financial Interests, Institutional, Funding, paid to institution: See https://coi.asco.org/share/BLY-NDGV/Manish%20Patel. D. Juric: Financial Interests, Personal, Research Grant: Ribon Therapeutics, Novartis, Genetech, Syros, Eisai, Pfizer, Amgen, InventisBio, Arvinas, Takeda, Blueprint, AstraZeneca, Infinity; Financial Interests, Personal, Other, Personal fees: Vibliome, PIC Therapeutics, Mapkure, Relay Therapeutics. S.N. Waqar: Financial Interests, Institutional, Invited Speaker, Institutional PI for Research study: Spectrum Pharmaceuticals, Lilly, Pfizer, Genentech/Roche, Daiichi Sankyo, Newlink Genetics, EMD Serono, Puma Biotechnology, Novartis, Xcovery, Synermore biologics, Celgene, Vertex, Bristol-Myers Squibb, Stem CentRx, Hengrui Therapeutics, Checkpoint Therapeutics, Ignyta, AstraZeneca, ARIAD, Roche, Merck; Financial Interests, Institutional, Other, This funding provides effort for Dr. Waqar to support and oversee the Lung-MAP master protocol and sub study activities: SWOG-Clinical Trials Partnership; Financial Interests, Personal and Institutional, Other, Chair of Data Safety Monitoring Board for Study: Hoosier Cancer Research Network. E. Schenk: Financial Interests, Personal, Other, Honoraria: Takeda, Ideology Health, Horizon CME, OncLive, The Doctor's Channel, Regeneron; Financial Interests, Personal, Advisory Role: AbbVie, Guidepoint Global, Regeneron, Bionest partners, ExpertConnect, FCB Health, The KOL Connection Ltd, Actinium Pharmaceuticals, Prescient Health Care Group, G1 Therapeutics. G. Shapiro: Financial Interests, Personal, Research Grant: Tango, Merck KGaA/EMD-Serono, Bristol-Myers Squibb, Merck & Co, Pfizer, Eli Lilly; Financial Interests, Personal, Advisory Board: Merck KGaA/EMD-Serono, Bicycle Therapeutics, Cybrexa Therapeutics, Bayer, Boehringer Ingelheim, ImmunoMet, Artios, Concarlo Holdings, Syros, Zentalis, CtomX Therapeutics, Blueprint Medicines, Kymera Therapeutics, Janssen, Xinthera; Financial Interests, Personal, Royalties, Patents: Cyclacel Pharmaceuticals. V. Boni: Financial Interests, Personal, Advisory Role: Puma Biotechnology, Loxo Therapeutics, CytomX Therapeutics, Ideaya Biosciences, Eli Lilly, Janssen, Oncoart, Guidepoint, Novaritis; Financial Interests, Personal, Leadership Role, Steering committee: CytomX Therapeutics; Financial Interests, Personal, Other, Honoraria: Eli Lilly, MSD, TACTICS, SOLTI, Getthi, Gedefo; Financial Interests, Personal, Other, Travel: Bayer; Financial Interests, Institutional, Research Grant: AbbVie, ACEO, Adaptaimmune, Ancure, Amgen, Amunix, AstraZeneca, Bicycle, BMS Cytomx, GlaxoSmithKline, Genetech/Roche, Genmab, Incyte, Ipsen, Janssen, Kura, Eli Lilly, Loxo , Nektar, Macrogenics, Menarini, Merck, Merus, Nanobiotix, Novartis, Pfizer, PharmaMar, Principia, Puma, Ryvu, Ribon, Sanofi, Taiho, Tesaro, BeiGene, Transgen, Takeda, Incyte, Innovio, MSD, PsiOxus, Seattle Genetics, Mersana, Daiichi, Astellas, ORCA, Boston Therapeutics, Dynavax, DebioPharm, Regeneron, Boehringer Ingelheim, Rigontec, Millennium, Seagen, Synthon, Spectrum, Urogen, Zenith. C.A. Perez: Financial Interests, Institutional, Research Grant: Accutar Biotech, Kinnate Biopharma, Relay Therapeutics, Seagen Inc, Kura Oncology, Hymab Inc, Xilio Therapeutics, Elucida Oncology, Tallac Therapeutics, Ribon Therapeutics, Mirati Therapeutics, Elpiscience Biopharmaceuticals, Dracen Phramaceuticals, Zhuhai Yurfan Biotechnologies. Y. Najjar: Financial Interests, Institutional, Research Grant: Merck, BMS, Pfizer; Financial Interests, Personal, Advisory Board: Merck, Novartis, Intervenn Bio, Pfizer, BMS; Financial Interests, Personal, Speaker’s Bureau: Pfizer, Immunocore. F.E. Racca: Financial Interests, Personal, Advisory Role: Bristol-Myers Squibb; Financial Interests, Personal, Speaker’s Bureau: Bristol-Myers Squibb, Roche; Financial Interests, Personal, Expert Testimony: Pharmore Research, Psyma; Financial Interests, Personal, Other, Travel: Roche, Bristol-Myers Squibb, Merck Sharp & Dohme. K. Kuplast-Barr, K. McEachern: Financial Interests, Personal, Stocks/Shares: Ribon Therapeutics; Financial Interests, Personal, Full or part-time Employment: Ribon Therapeutics. M. Samant, V. Bozón, S. Parasuraman: Financial Interests, Personal, Full or part-time Employment: Ribon Therapeutics; Financial Interests, Personal, Stocks/Shares: Ribon Therapeutics. M.L. Johnson: Financial Interests, Personal, Advisory Role: AbbVie, Amgen, Astellas, AstraZeneca, Azelia Oncology, Black Diamond, Calithera Biosciences, Checkpoint Therapeutics, CytomX Therapeutics, Daiichi Sankyo, EcoR1, Editas Medicine, Eisai, Genetech/Roche, Genmab, Genocea Biosciences, GlaxoSmithKline, Gritsone Oncology, Ideaya Biosciences, iTeos, Janssen, Lilly, Merck , Mirati Therapeutics, Molecular Axiom, Novartis, Oncorus, Regeneron Pharmaceuticals, Revolution Medicines, Ribon Therapeutics, Sanofi-Aventis, Takeda Pharmaceuticals, Turning Point Therapeutics, VBL Therapeutics; Financial Interests, Institutional, Research Grant: Turning Point Therapeutics, Vyriad, Y-mAbs Therapeutics, AbbVie, Acerta, Adaptaimmune, Amgen, Apexigen, Arcus Biosciences, Array BioPharma, Artios Pharma, AstraZeneca, Atreca, BeiGene, BerGenBio, BioAtla, Black Diamond, Calithera Biosciences, Boehringer Ingelheim, Carisma Therapeutics, Corvus Pharmaceuticals, Curis, CytomX, Daiichi Sankyo, Dracen Pharmaceuticals, Dynavax, Lilly, Elicio Therapeutics, EMD Serono, EQRx, Erasca, Exelixis, Fate Therapuetics, Genetech/Roche, Genmab, Genocea Biosciences, GlaxoSmithKline, Gritstone Oncology, Gurdant Health, Harpoon, Helsinn Healthcare SA, Hengrui Therapeutics, Hutchinson MediPharma, IDEAYA Biosciences, IGM Biosciences, Immunocore, Impact, Incyte, Janssen, Kadmon Pharmaceuticals, Kartos Therapeutics, Loxo Oncology, Lycera, Merck, Merus, Mirati Therapetuics, NeoImmune Tech, Novartis, Neovia Oncology, Numab Therapeutics, Nuvalent, OncoMed Pharmaceuticals, Palleon Pharmaceuticals, Pfizer, PMV Pharmaceuticals, Rain Pharmaceuticals, RasCal Therapeutics, Regeneron Pharmaceuticals, Relay Therapeutics, Revolution Medicines, Ribon Therapeutics, Rubius Therapeutics, Sanofi, Seven and Eight Biopharmaceuticals/Birdie Biopharmaceuticals, Shattuck Labs, Silicon Therapeutics, Stem CentRx, Syntax Pharmaceuticals, Takeda, TCR2 Therapeutics, Tempest Therapeutics, Tizona Therapeutics, TMUNITY Therapeutics. All other authors have declared no conflicts of interest.