991O - First-in-human (FIH) phase I data of HST-1011, an oral CBL-B inhibitor, in patients with advanced solid tumors

Background

The E3 ligase Casitas B-lineage lymphoma proto-oncogene B (CBL-B) is a master negative regulator of the immune system. Inhibition of CBL-B may elicit and sustain effective anti-tumor immunity. HST-1011 is a novel, potent, selective, oral allosteric small molecule CBL-B inhibitor previously shown to have robust preclinical activity.

Methods

SOLAR1 (NCT05662397) is a first-in-human, multicenter Ph1/2 trial investigating safety (primary), pharmacokinetics (PK), target engagement (TE), pharmacodynamics (PD), and anti-tumor activity (secondary) of HST-1011 monotherapy and an HST-1011/anti-PD-1 combination. Eligibility: Patients (pts) with advanced solid tumors and a) progression on PD-(L)1-based standard-of-care regimens OR b) selected tumor types (ovarian, prostate, rectal, anal). Design: In Part A1, HST-1011 monotherapy dose escalation utilized a Bayesian optimal interval design. Data cut-off was April 22, 2024.

Results

28 pts with various solid tumors received oral doses from 5 to 40 mg twice weekly. Pts had a median of 4 (2-13) prior systemic therapies (89% with prior immunotherapy; 50% with ³ 2 prior lines of immunotherapy). There were no dose-limiting toxicities. Gastrointestinal toxicities were the most common treatment-emergent adverse events (TEAEs), and HST-1011-related Grade 3 or higher TEAEs were observed in 5 pts (18%). All HST-1011 related TEAEs were clinically manageable, and only 1 patient discontinued therapy for patient preference. Translational analyses showed dose-related PK, peripheral TE, and gene expression/cytokine changes consistent with CBL-B inhibition. Despite extensive pre-treatment history, tumor shrinkage or stasis was observed in 10 pts (36%), including 3 non-small cell lung cancer patients with prior progression on chemo/immunotherapy regimens. Stable disease was also seen in head and neck, rectal, and ovarian cancer (longest duration 194 days).

Conclusions

HST-1011 monotherapy has a manageable safety profile with correlative evidence of PK-TE-PD and early signs of single-agent activity in heavily pre-treated solid tumor patients, supporting its ongoing evaluation in dose optimization and PD-1 combination.

Clinical trial identification

NCT05662397.

Editorial acknowledgement

Legal entity responsible for the study

HotSpot Therapeutics.

Funding

HotSpot Therapeutics.

Disclosure

R.E. Sanborn: Financial Interests, Personal and Institutional, Other, Funding for Investigator-Sponsored Trial: Merck, AstraZeneca; Financial Interests, Personal, Steering Committee Member: GSK, Janssen Oncology, Daiichi, BeiGene; Financial Interests, Personal, Advisory Board, Also Steering Committee Member: AstraZeneca; Financial Interests, Personal, Advisory Board: Macrogenics, Sanofi, Gilead, Regeneron, Targeted Oncology, G1 Therapeutics, GE Healthcare, Amgen, Lilly Oncology; Financial Interests, Personal, Other, Consulting for manuscript: EMD Serono; Other, Personal, Other, Educational Presentation: Illumina, GameOn!, OncLive, Binary; Financial Interests, Personal, Other, Educational Presentation: APP Oncology. M.R. Patel: Financial Interests, Personal, Stocks or ownership: ION Pharma; Financial Interests, Personal, Other, Honoraria: Janssen; Financial Interests, Personal, Advisory Role: Olema, Daiichi Sankyo, Kura Oncology, Accutar Biotech, Nurix; Financial Interests, Institutional, Research Funding: Acerta Pharma, ADC Therapeutics, Agenus, AstraZeneca, BioNTech AG, Boehringer Ingelheim, Celgene, Cyteir, Daiichi Sankyo, Lilly, Genentech/Roche, Gilead Sciences, GSK, H3 Biomedicine, Hengrui Therapeutics, Hutchison MediPharma, Janssen, Klus Pharma, Kymab, Loxo, LSK Biopartners, Macrogenics, Merck, Millennium, Moderna Therapeutics, Pfizer, Prelude Therapeutics, Ribon, Seven and eight BioPharmaceuticals, Syndax, Taiho Pharmaceutical, Tesaro, ORIC, Artios, Mabspace, Puretech, BioTheryx, Novartis, Nurix, Treadwell Therapeutics, Zymeworks, Olema, Adagene, Astellas, Compugen, Immunogen, Blueprint Pharmaceuticals, Cullinan Oncology, Erasca, Immune-Onc Therapeutics, Immunitas, Pionyr, Step Pharma, Bristol Myers Squibb/Celgene, Incyte, Kineta, HotSpot Therapeutics, Conjupro Biotherapeutics, Allorion Therapeutics, Vividion, Georgiamune, Kura Therapeutics. J. Rodon: Financial Interests, Personal, Advisory Board: Ellipses Pharma, iOnctura SA, Aadi Bioscience, Envision Pharma, Molecular Partners, Mekanistic, Amgen; Financial Interests, Personal, Other, Consultancy: Clarion Healthcare, Debiopharm, Cullgen, Pfizer, Macrogenics, Oncology One, Columbus Venture Partners, Sardona Therapeutics, Avoro Capital Advisors, Vall d’Hebron Institute of Oncology/Ministero De Empleo Y Seguridad, Chinese University of Hong Kong, Boxer Capital, Llc, Tang Advisors, Llc, Alnylam Pharmaceuticals, Bridgebio Pharma; Financial Interests, Personal, Other, Consultancy/Advisory Board: Monte Rosa Therapeutics, Merus N.V., Incyte; Financial Interests, Institutional, Other, Clinical Research: Novartis, Spectrum Pharmaceuticals, Symphogen, BioAtla, Pfizer, GenMab, CytomX, Kelun-Biotech, Takeda-Millenium, GSK; Financial Interests, Institutional, Other, Research Funding: Blueprint Medicines, Black Diamond, Merck Sharp & Dohme; Financial Interests, Institutional, Research Grant, Research Funding/Clinical Research: Hummingbird, Yingli; Financial Interests, Institutional, Research Grant, Research Funding: Vall d’Hebron Institute of Oncology/Cancer Core Europe; Financial Interests, Institutional, Research Grant, Clinical Research: Bicycle Therapeutics, Taiho, Roche Pharmaceuticals, Merus, Curis, AadiBioscience, Nuvation, ForeBio, BioMed Valley Discoveries, Loxo Oncology, Cellestia, Deciphera, Ideaya, Amgen, Tango Therapeutics, Mirati, Linnaeus Therapeutics, Bayer, Hutchinson MediPharma; Other, Other: VHIO/Ministero De Empleo Y Seguridad Social; Other, Travel: European Society for Medical Oncology, Loxo Oncology. C. Friedman: Financial Interests, Personal, Advisory Board: Loxo@Lilly; Financial Interests, Personal, Other, One time consulting meeting: Johnson and Johnson; Financial Interests, Institutional, Local PI: AstraZeneca, Hotspot Therapeutics, Immunocore, Mersana, Volastra; Financial Interests, Personal, Steering Committee Member: Marengo, Genentech/Roche; Financial Interests, Institutional, Steering Committee Member: Merck; Other, Travel Support: PUMA. E. Friedman, H. Danaee, S. Jaeger, H. Sun, E. Debanne, J. Dunn, E. Wright, A. Redig: Financial Interests, Personal, Full or part-time Employment: HotSpot Therapeutics. T. Reilly: Financial Interests, Personal, Full or part-time Employment: Hotspot Therapeutics; Financial Interests, Personal, Member of Board of Directors: Hookipa Pharma; Financial Interests, Personal, Advisory Role: Diagonal Therapeutics, Third Harmonic, Atlas Venture. J.J. Luke: Other, Personal and Institutional, Other, DSMB, consultancy, institutional research support: AbbVie; Other, Personal, Other, DSMB, consultancy: Agenus; Other, Personal, Other, DSMB: Immutep, Evaxion; Financial Interests, Personal, Advisory Board: 7 Hills, Affivant, BioCytics, Bright Peak, Exo, Inzen, RefleXion, Xilio; Financial Interests, Personal and Institutional, Advisory Board, Institutional Research Support: Fstar; Financial Interests, Personal, Other, advisory board/stock: Actym, Alphamab, Arch Oncology, Duke Street Bio, Kanaph, Mavu, NeoTx, Onc.AI, OncoNano, physIQ, Pyxis, Saros, Stipe, Tempest; Financial Interests, Personal, Other, Consultancy: Alnylam, Atomwise, Bayer, Castle, Checkmate, Codiak, Crown, Cugene, Curadev, Lisa, Endeavor, Flame, G1 Therapeutics, Gilead, Glenmark, Ko Bio Labs, Krystal, KSQ, Janssen, Inzer, Immunocore, Instil, IO Biotech, LegoChem, Mersana, Partner, Pioneering Medicines, PsiOxus, Regeneron, Ribon, Roivant, STINGthera, Sumitomo, Synthekine, Teva; Financial Interests, Personal and Institutional, Other, Consultancy, Institutional Research Support: AstraZeneca, Bristol Myers Squibb, Day One, EMD Sorono, HotSpot Therapeutics, Kadmon, Ikena, Immatics, Incyte, Macrogenics, Merck, Nektar, Novartis, Pfizer, Replimune, Servier, Synlogic; Financial Interests, Personal, Other, Consultancy: Genetech; Financial Interests, Institutional, Research Funding: Astellas, Corvus, Genmab, Kahr, Moderna, Numab, Palleon, Rubius, Scholar Rock, Takeda, Trishula, Tizona, Xencor. All other authors have declared no conflicts of interest.