659P - Combination treatment with TTX-030, a first-in-class anti-CD39 antibody, in patients with advanced pancreatic cancer

Background

Immunotherapy has had limited benefit in pancreatic ductal adenocarcinoma (PDAC). TTX-030 is a first-in-class antibody that inhibits CD39 and increases extracellular ATP and decreases immunosuppressive adenosine, activating antigen-presenting cells (APCs) and promoting anti-tumor T cell activity. HLA-DQ is an HLA class II molecule expressed on APCs.

Methods

Patients were enrolled May 2020 to Feb 2022 and treated with standard dosing of G/nP (d1, 8, 15) and either TTX-030 40mg/kg followed by 20mg/kg every two weeks (n = 31) or TTX-030 every 2 weeks and budigalimab (anti-PD1 Ab) 500mg every 4 weeks (n = 28). The primary endpoint was safety, secondary endpoints included ORR and PFS. Gene expression in pre-treatment tumor biopsies was analyzed retrospectively using the NanoString PanCancer Immune Profiling Panel.

Results

As of Dec 5 2023, 58/59 patients had completed treatment with a median follow-up of 9.8 months. Median age was 67 years, 53% were ECOG 1, 75% had liver metastases. Both combinations were well-tolerated, with 5 patients (8%) discontinuing treatment due to adverse events (AEs). All-cause, clinically significant, and immune-related AEs were qualitatively similar to those expected from G/nP; the most common Grade ≥3 AEs were neutrophil count decreased (41%), neutropenia (22%), anaemia (20%), fatigue (12%) and ALT increased (10%). For the overall efficacy-evaluable population (n=57), confirmed ORR was 30% with 3 complete responses, median PFS 7.5 months (95%CI 5.2, 9.4) and median OS 19.1 months (9.8, NR). Analysis of tumor biopsies identified a subset of patients with high gene expression of HLA-DQ (HLA-DQ^high) and favorable clinical outcomes with TTX-030 combinations. Of the 40 patients with tumors evaluable by NanoString, 28 were HLA-DQ^high with an ORR of 46%, mPFS of 9.6 mo (95% CI 3.9, 11.8), and mOS of 21.9 mo (9.8, NR); for the 12 HLA-DQ^low, ORR, mPFS and mOS were 8%, 5.2 mo (1.6, 7,5), and 6.9 mo (4.1, NR).

Conclusions

TTX-030 combinations show promising clinical activity in 1L PDAC with HLA-DQ^high having marked benefit. A randomized phase 2 study (NCT06119217) is underway to further evaluate TTX-030 combination treatment based on HLA-DQ status in metastatic PDAC.

Clinical trial identification

NCT04306900.

Editorial acknowledgement

Legal entity responsible for the study

Trishula Therapeutics, Inc.

Funding

Trishula Therapeutics, Inc.

Disclosure

Z.A. Wainberg: Financial Interests, Personal, Advisory Board: Amgen, Astellas, Arcus, Bayer, AstraZeneca, Novartis, Roche, Ipsen, Daiichi, Merck, BMS, Merus; Financial Interests, Personal, Other, DMC: Pfizer; Financial Interests, Institutional, Steering Committee Member: Novartis, AstraZeneca; Financial Interests, Institutional, Coordinating PI: Ipsen; Financial Interests, Institutional, Local PI: Merck; Financial Interests, Institutional, Research Grant: BMS, Arcus. Y. Cha: Other, Personal, Speaker, Consultant, Advisor: Roche, MSD Oncology, Merck, IMBdx, CellabMED Inc; Other, Personal, Expert Testimony: Ono Pharmaceutical, GC Biopharma Corp. B. George: Financial Interests, Personal, Invited Speaker, consultant: Ipsen, Taiho Oncology, AstraZeneca; Financial Interests, Personal, Advisory Board, consultant: Roche; Financial Interests, Personal, Other, consultant: Genentech, foundation medicine; Financial Interests, Personal, Invited Speaker: France Foundation; Financial Interests, Personal, Stocks/Shares: xbiotech; Financial Interests, Institutional, Local PI, research support: Genentech, F. Hoffman-La Roche, Taiho Oncology, Mirati Therapeutics, BMS, Carsgen, Helix Biopharma, Tvardi Therapeutics, Pfizer, Glyconex, Faeth Therapeutics, Biontech, Transcenta. J.S. Grewal: Other, Personal, Speaker, Consultant, Advisor: Curio Science, Eisai; Other, Personal, Speaker’s Bureau: Ipsen, Bayer, BMS; Other, Personal, Expert Testimony: Monsanto. J.R. Merchan: Other, Personal, Speaker, Consultant, Advisor: Merck. M. Mckean: Financial Interests, Institutional, Other, Consulting: Pfizer, Castle Biosciences, IQVIA, Merck, Moderna; Financial Interests, Institutional, Research Grant: Acentage Pharma Group, Bicycle Therapeutics, Dragonfly Therapeutics, Epizyme, Exelixis, Genentech, GSK, Ideaya Biosciences, Ikena Oncology, Infinity Pharmaceuticals, Jacobio Pharmaceuticals, Moderna, NBE Therapeutics, Novartis, Oncorus, Plexxicon, Prelude Therapeutics, Regeneron, Sapience Therapeutics, Seattle Genetics, Tizona Therapeutics, Tmunity Therapeutics, TopAlliance Biosciences, Aadi Biosciences, Alpine Immune Sciences, Arcs Biosciences, Arvinas, ASCO, Astellas, Bayer, BioMed Valley Discoveries, BioNTech, C4 Therapeutics, EMD Serono, Erasca, Foghorn Therapeutics, G1 Therapeutics, Gilead Sciences, ImmVira Pharma, Kechow Pharma, Kezar Life Sciences, Kinnate BioPharma, MedImmune, Mereo BioPharma, Metabomed, Nektar, OncoC4, PACT Pharma, Pfizer, Poseida, Pyramid Biosciences, Scholar Rock, Synthrox, Takeda Pharmaceuticals, Teneobio, Tempest Therapeutics, Xilio, Aulos Bioscienc, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, InconVir, Jazz Pharmaceutical, Krystal Biotech, NucMito Pharmaceuticals, OnKure, Remix Therapeutics. H.P. Soares: Other, Personal, Speaker, Consultant, Advisor: TM Isotope Technologies, Ipsen, TerSera, AstraZeneca, Pfizer, Novartis. T.D. Cruz, A.K. Moesta, T.M. Jahn, S. Mitra: Financial Interests, Personal, Full or part-time Employment: Trishula Therapeutics. A.K. Singhal: Financial Interests, Personal, Officer: Trishula Therapeutics. C. Tribouley, S. Kongpachith, D.E. Afar: Financial Interests, Personal, Full or part-time Employment: AbbVie, Inc. D.R. Spigel: Financial Interests, Institutional, Other, Consulting: AstraZeneca, BeiGene, Bristol Myers Squibb, Evidera, GSK, Ipsen BioPharmaceuticals, Janssen, Jazz Pharmaceuticals, Lilly, Molecular Templates, Monte Rosa Therapeutics, Novartis, Pfizer, Regeneron, Sanofi-Aventis, AbbVie, Novocure, Roche/Genentech; Financial Interests, Institutional, Research Grant, Serve as PI: Amgen, Aeglea Biotherapeutics, Agios, Arrys Therapeutics, Astellas, AstraZeneca, Bayer, BeiGene, BIND Therapeutics, Blueprint Medicine, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celldex Therapeutics, Clovis, Daiichi Sankyo, Eisai, Lilly, Genentech/Roche, G1 Therapeutics, Gilead Sciences, GSK, Grail, Hutchinson MediPharma, ImClone Systems, Ipsen, Janssen, Loxo, MacroGenics, MedImmune, Merck, Nektar, Neon Therapeutics, Novartis, Novocure, Rgenix, SeaGen, Taiho Oncology, Tarveda, Tizona Therapeutics, Transgene, UT Southwestern, Verastem, Arcus Biosciences, Molecular Template, Cyteir Therapeutics, BioNTech, Apollomics, Pure Tech Health, Elevation Oncology, Repare Therapeutics, Razor Genomics, Denovo Biopharma, Erasca, Kronos Bio, Zai Laboratory, Faeth Therapeutics, Ascendis Pharma, Lyell Immunopharma, Synthekine, Shenzhen Chipscreen Biosciences, AbbVie, AnHeart Therapeutics, Calithera, Endeavor, FujiFilm Pharmaceuticals, Incyte, Jazz Pharmaceuticals, Millennium Pharmaceuticals, Moderna, Monte Rosa Therapeutics, Peloton Therapeutics, Stemline Therapeutics, Tango Therapeutics, Tesaro. R. Balaraman: Other, Personal, Speaker, Consultant, Advisor: Genentech/Roche, AstraZeneca; Other, Personal and Institutional, Research Funding: Tizona Therapeutics.