996MO - Dazostinag (TAK-676) alone and in combination with pembrolizumab (pembro) in patients (pts) with advanced/metastatic solid tumors: Data from phase I dose escalation

Background

Dazostinag (dazo), a synthetic carbocyclic pyrimidine cyclic dinucleotide STING agonist, activates innate and adaptive immune responses, including dose-dependent induction of cytokine responses and activation/proliferation of immune cells in preclinical tumor models. We present dose escalation data from iintune-1, a phase 1/2 study of dazo as single-agent (SA) and combined with pembro (combo) in advanced solid tumors (NCT04420884).

Methods

The primary objective was to determine the safety/tolerability of dazo as SA and combo. The study comprised a SA dose escalation of dazo, with combo cohorts starting after no DLTs were seen with ≥2 SA doses. Pts received dazo IV (Days 1, 8, 15) +/- pembro 200 mg IV (Day 1) in 21-day cycles.

Results

As of Mar 2024, 50 and 79 pts had been treated with dazo 0.1–14 mg SA or combo, respectively. Pts had a median 3 prior treatment lines (range, 0–10). Most common AEs (in >25% of pts) were fatigue, nausea, headache, and CRS. There was no increased toxicity with combo vs SA; no MTD was reached with SA or combo. CRS was grade 1–2 and observed across all doses ≥2.5 mg and 1 pt in a <2.5 mg cohort. RECIST responses were observed in 4 combo pts (2 CR, sebaceous carcinoma and small-cell neuroendocrine [SCN] bladder cancer; 2 PR, adenoid cystic carcinoma and SCN carcinoma of the cervix); 6 pts had SD lasting ≥6 months. Dazo at pharmacologically active doses of 3.5–14 mg achieved ≥2.7- and 4.1-fold induction of peripheral STING signature score with SA and combo, respectively, in a dose-dependent fashion. A ≥2-fold dose-dependent increase in IFN-γ and other cytokines (including IP-10) and increased peripheral Ki67+CD8+ T cell proliferation were observed in the SA and combo cohorts. Most on-treatment vs pre-treatment biopsies from pts in ≥5 mg (SA and combo) cohorts showed intratumoral CD8 T cell accumulation.

Conclusions

Dazo IV had a manageable safety profile, as SA and with pembro, across all dose levels. CRS was grade 1–2 and well managed. Early clinical responses and durable SD is encouraging in this heavily pretreated population. Dazo SA and combo demonstrates robust pharmacodynamic modulation consistent with STING agonism. Enrollment into expansion cohorts is ongoing.

Clinical trial identification

NCT04420884.

Editorial acknowledgement

Medical writing was provided by Luisa Madeira, PhD, of Ashfield MedComms, an Inizio company.

Legal entity responsible for the study

Takeda Development Center Americas, Inc. (TDCA).

Funding

Takeda Development Center Americas, Inc. (TDCA).

Disclosure

J.J. Luke: Financial Interests, Other, DSMB: AbbVie, Agenus, Evaxion, Immutep, Shionogi; Financial Interests, Advisory Board: 7 Hills, Affivant, BioCytics, Bright Peak, Exo, Fstar, Inzen, RefleXion, Xilio (stock) Actym, Alphamab Oncology, Arch Oncology, Duke Street Bio, Elipscience, Kanaph, NeoTx, Onc.AI, OncoNano, physIQ, Pyxis, Saros, Stipe, Tempest; Financial Interests, Speaker, Consultant, Advisor: AbbVie, Agenus, Alnylam, AstraZeneca, Askgene, Atomwise, Bayer, Bristol Myers Squibb, Castle, Checkmate, Codiak, Crown, Cugene, Curadev, Day One, Eisai, EMD Serono, Endeavor, Flame, G1 Therapeutics, Genentech, Geneos, Gilead, Glenmark, HotSpot, Kadmon, Ko; Financial Interests, Institutional, Research Funding: AbbVie, Astellas, AstraZeneca, Bristol Myers Squibb, Corvus, Day One, EMD Serono, Fstar, Genmab, Hot Spot, Ikena, Immatics, Imugene, Incyte, Janux, Kadmon, Kahr, Macrogenics, Merck, Moderna, Nektar, Next Cure, Novartis, Numab, Palleon, Pfizer, Replimmune,; Financial Interests, Other, Patents: US-11638728 (Microbiome Biomarkers for Anti-PD-1/PD-L1 Responsiveness: Diagnostic, Prognostic and Therapeutic Uses Thereof). X. Gao: Financial Interests, Personal, Advisory Board: Arvinas, Bayer, Flare Therapeutics, Loxo Oncology; Financial Interests, Personal, Advisory Role: PathAI; Financial Interests, Institutional, Funding: ALX Oncology, Aprea Therapeutics, Aravive, Arvinas, Bayer, Exelixis, Flare Therapeutics, Harpoon Therapeutics, Janssen, Loxo Oncology, Merck, Novartis, Nuvation Bio, Pfizer, Poseida Therapeutics, Regeneron, Takeda, TopAlliance Biosciences. A.J. Olszanski: Financial Interests, Personal, Advisory Board: Merck, BMS, Oncosec, Replimune; Financial Interests, Institutional, Local PI: Antegene, Astellas, Eutilex, GSK, HiFiBio, Immatics, Kezar, Regeneron, Shionogi, Takeda, PI, Viewpoint; Non-Financial Interests, Personal and Institutional, Non remunerated activity, DSMB: Takeda, Pfizer. R.E. Sanborn: Financial Interests, Personal, Advisory Board: AstraZeneca, Macrogenics, Sanofi, Gilead, Regeneron, Targeted Oncology, G1 Therapeutics, GE HealthCare, Amgen, Lilly Oncology; Financial Interests, Personal, Invited Speaker, Educational Presentation: Illumina, OncLive; Financial Interests, Personal and Institutional, Research Funding, Funding for investigator sponsored trials: AstraZeneca, Merck; Financial Interests, Personal, Steering Committee Member: GSK, AstraZeneca, Janssen Oncology, Daiichi Sankyo, BeiGene; Financial Interests, Personal, Writing Engagement, Consultant for manuscript: EMD Serono. G.S. Falchook: Financial Interests, Institutional, Advisory Board, 2018: FujiFilm; Financial Interests, Institutional, Advisory Board, 7/24/2020, 9/17/2021: Silicon; Financial Interests, Institutional, Advisory Board, 3/10/21: Navire; Financial Interests, Institutional, Advisory Board, 4/22/21: Turning Point; Financial Interests, Institutional, Advisory Board, 10/2/21: Predicine; Financial Interests, Institutional, Advisory Board, 10/26/21: Inspirna; Financial Interests, Institutional, Advisory Board, 10/28/21: Regeneron; Financial Interests, Personal, Advisory Board, 6/2010, 3/2011: EMD Serono; Financial Interests, Institutional, Advisory Board, 1/18/22 and 8/17/22: Jubilant; Financial Interests, Institutional, Advisory Board, 6/4/22: BostonGene; Financial Interests, Institutional, Advisory Board, 9/30/22: AbbVie; Financial Interests, Personal, Invited Speaker, 2019: Total Health Conferencing; Financial Interests, Personal, Invited Speaker, 2020: Rocky Mountain Oncology Society; Financial Interests, Personal, Other, Travel, for work and/or research related to institution, 2015: Bristol Myers Squibb; Financial Interests, Personal, Other, Travel, for work and/or research related to institution, 2011, 2012, 2013: EMD Serono; Financial Interests, Personal, Other, Travel, to present research at a conference (Cholangiocarcinoma Foundation meeting), 2018: Fujifilm; Financial Interests, Personal, Other, Travel, to present research at a conference (ESGO), 2013: Millennium; Financial Interests, Personal, Other, Travel, for work and/or research related to institution, at least once yearly: Sarah Cannon Research Institute (employer); Financial Interests, Personal, Other, Travel, to present research at a conference (WCLC), 2022: Amgen; Financial Interests, Personal, Other, Travel, to present research at a conference (ESMO), 2022: Synthorx/Sanofi; Financial Interests, Institutional, Advisory Board, Scientific advisory board 11/18/22: Teon Therapeutics; Financial Interests, Institutional, Advisory Board, 12/8/22: Merck; Financial Interests, Personal, Invited Speaker, CME presentation about NSCLC and thyroid cancer, 2/20/24: Clinical Care Options; Financial Interests, Personal, Royalties: Wolters Kluwer; Financial Interests, Institutional, Local PI, Unknown end date, before 1/2021: 3-V Biosciences, ARMO/Eli Lilly, Celldex, DelMar, eFfector, Kolltan, miRNA Therapeutics, OncoMed, Precision Oncology, Strategia; Financial Interests, Institutional, Local PI, 12/2019 – 6/2023: Abbisko; Financial Interests, Institutional, Local PI, ending 4/2019: AbbVie; Financial Interests, Institutional, Local PI, 8/2021 – present: ABL Bio; Financial Interests, Institutional, Local PI, 12/2021 – 8/2023: Accutar; Financial Interests, Institutional, Local PI: Aileron, Amgen, AstraZeneca, BeiGene, Fujifilm, Jacobio, Jounce, Loxo/Bayer, Merck, Regeneron, Rgenix, Takeda; Financial Interests, Institutional, Local PI, ending 6/2014: American Society of Clinical Oncology, Celgene, EMD Serono, Genmab, MedImmune, National Institutes of Health, Oncothyreon, U.T. MD Anderson Cancer Center, Vegenics; Financial Interests, Institutional, Local PI, 9/2021 – present: Artios, NiKang; Financial Interests, Institutional, Local PI, 4/2019 – present: Bioatla; Financial Interests, Institutional, Local PI, 6/2020 – present: Bioinvent; Financial Interests, Institutional, Local PI, ending 11/2018: Biothera; Financial Interests, Institutional, Local PI, 8/2020 – present: Bicycle; Financial Interests, Institutional, Other, Subinvestigator on a sponsored clinical trial, 3/2022 – present: Black Diamond, Seagen; Financial Interests, Institutional, Local PI, 5/2021 – present: Boehringer Ingelheim, Erasca; Financial Interests, Institutional, Local PI, ending 5/2021: Ciclomed; Financial Interests, Institutional, Local PI, ending 7/2018: Curegenix; Financial Interests, Institutional, Local PI, ending 3/2019: Curis; Financial Interests, Institutional, Local PI, 9/2019 – present: Cyteir, Xencor; Financial Interests, Institutional, Local PI, 11/2019 – present: Daiichi; Financial Interests, Institutional, Local PI, ending 9/2022: Eli Lilly, Tesaro; Financial Interests, Institutional, Local PI, 12/2019 – present: Epizyme; Financial Interests, Institutional, Local PI, ending 10/2023: Exelixis, GSK; Financial Interests, Institutional, Local PI, 7/2021 – present: Freenome, Samumed; Financial Interests, Institutional, Local PI, ending 10/2022: Hutchison MediPharma; Financial Interests, Institutional, Local PI, 10/2020 – present: IGM Biosciences, ImmunoGen/MarcoGenics; Financial Interests, Institutional, Local PI, ending 6/2019: Ignyta; Financial Interests, Institutional, Local PI, ending 9/2019: Incyte; Financial Interests, Institutional, Other, Subinvestigator on a sponsored clinical trial, 04/2022 – present: Jubilant; Financial Interests, Institutional, Local PI, ending 5/2008, when Millennium was purchased by Takeda: Millennium; Financial Interests, Institutional, Local PI, 10/2021 – 6/2023: Molecular Templates; Financial Interests, Institutional, Local PI, 2/2021 – present: Navire; Financial Interests, Institutional, Local PI, ending 2/2024: Novartis; Financial Interests, Institutional, Local PI, 3/2020 – 2/2024: Oncorus; Financial Interests, Institutional, Local PI, 3/2020 – present: Poseida; Financial Interests, Institutional, Local PI, 12/2019 – 2/2024: Prelude; Financial Interests, Institutional, Local PI, 12/2020 – present: PureTech, Silicon; Financial Interests, Institutional, Local PI, 06/2021 – 06/2023: Pyramid; Financial Interests, Institutional, Local PI, 3/2021 – present: RasCal; Financial Interests, Institutional, Other, Subinvestigator on a sponsored clinical trial, 12/2021 – present: Relay; Financial Interests, Institutional, Local PI, 8/2019 – present: Ribon, Turning Point; Financial Interests, Institutional, Local PI, 7/2020 – present: Sapience; Financial Interests, Institutional, Local PI, 12/2021 – present: Simcha; Financial Interests, Institutional, Other, Subinvestigator on a sponsored clinical trial, 11/2021 – present: Sirnaomics; Financial Interests, Institutional, Local PI, ending 5/2019: Syndax; Financial Interests, Institutional, Local PI, 09/2019 – 02/2024: Synthorx/Sanofi; Financial Interests, Institutional, Local PI, ending 12/2017: Taiho; Financial Interests, Institutional, Local PI, ending 7/2022: Tarveda; Financial Interests, Institutional, Local PI, 5/2021 – present. TeneoBio was purchased by Amgen: Teneobio; Financial Interests, Institutional, Local PI, ending 1/2020: Tocagen; Financial Interests, Institutional, Other, Subinvestigator on a sponsored clinical trial, 05/2022-11/2022: Metabomed; Financial Interests, Institutional, Other, Subinvestigator on a sponsored clinical trial, 6/2022 – present: Agenus; Financial Interests, Institutional, Other, Subinvestigator on a sponsored clinical trial. 06/2022 – present: Tallac; Financial Interests, Institutional, Other, Subinvestigator on a sponsored clinical trial. 7/2022 – present: Zhuhai Yufan, Mirati; Financial Interests, Institutional, Other, Subinvestigator on a sponsored clinical trial, 10/2022 – present: Immunitas, Jazz Pharmaceuticals; Financial Interests, Institutional, Other, Subinvestigator on a sponsored clinical trial, 11/2022 – present: Bayer; Financial Interests, Institutional, Local PI, 1/2019 – present: ADC Therapeutics; Financial Interests, Institutional, Other, Subinvestigator on a sponsored clinical trial. 3/2023 – present: Kineta, Roche; Financial Interests, Institutional, Other, Subinvestigator on a sponsored clinical trial. 03/2023 – present: NGM BioPharmaceuticals; Financial Interests, Institutional, Local PI, 4/2023 – present: Tarus; Financial Interests, Institutional, Other, Subinvestigator on a sponsored clinical trial, 05/2023 – present: Pyxis; Financial Interests, Institutional, Other, Subinvestigator on a sponsored clinical trial. 06/2023 – present: Harbour BioMed, Centessa Pharmaceuticals; Financial Interests, Institutional, Local PI, 07/2023 – present: Ideaya, Tango Therapeutics; Financial Interests, Institutional, Other, Subinvestigator on a sponsored clinical trial. 08/2023 – present: Biomea Fusion; Financial Interests, Institutional, Local PI, 09/2023 – present: Conjupro Biotherapeutics; Financial Interests, Institutional, Other, Subinvestigator on a sponsored clinical trial. 09/2023 – present: Phanes Therapeutics; Financial Interests, Institutional, Other, Subinvestigator on a sponsored clinical trial. 9/2023 – present: Sarah Cannon Development Innovations; Financial Interests, Institutional, Local PI, 10/20/23 – present: Nuvectis Pharma; Financial Interests, Institutional, Other, Subinvestigator on a sponsored clinical trial. 1/20/24 – present: Kura Oncology; Financial Interests, Institutional, Local PI, 1/2024 – present: Eikon Therapeutics. S. Patel: Financial Interests, Personal, Advisory Board: Amgen, AstraZeneca, BeiGene, Bristol Myers Squibb, Certis, Eli Lilly, Jazz, Genentech, Illumina, Merck, Pfizer, Signatera, Tempus; Financial Interests, Institutional, Research Funding: Amgen, AstraZeneca/MedImmune, A2bio, Bristol Myers Squibb, Eli Lilly, Fate Therapeutics, Gilead, Iovance, Merck, Pfizer, Roche/Genentech. P.L. Bedard: Financial Interests, Institutional, Local PI: AstraZeneca, Bicara, BMS, Amgen, Novartis, Genentech/Roche, Merck, Pfizer, Zymeworks, Lilly, SeaGen, Medicenna, DayOneBioPharmaceuticals, LegoChem, Takeda, Gilead; Financial Interests, Institutional, Research Grant: Pfizer; Non-Financial Interests, Member of Board of Directors, Executive Board Member: Breast International Group; Non-Financial Interests, Leadership Role, Chair: AACR Project GENIE; Non-Financial Interests, Leadership Role, Past Chair IND CommitteeMember, Breast Site Steering Committee: Canadian Clinical Trials Group; Non-Financial Interests, Advisory Role: SeaGen, Lilly, Amgen, Merck, BMS, Pfizer, Gilead, Janssen, Repare Therapeutics, Roche. J.P. Gibbs, R. Gregory, J. Raizer: Financial Interests, Full or part-time Employment: Takeda; Financial Interests, Stocks or ownership: Takeda. C. Li: Financial Interests, Personal, Stocks or ownership: Takeda Development Center Americas; Financial Interests, Institutional, Full or part-time Employment: Takeda Development Center Americas. Y. Huang, R. Ramesh, B. Wu, K. Ding: Financial Interests, Full or part-time Employment: Takeda. P. Lorusso: Financial Interests, Advisory Role: Genentech, CytomX Therapeutics, Roche/Genentech, Halozyme, Five Prime Therapeutics, Agenus, Agios, Cybrexa Therapeutics, Sotio, AbbVie, Genmab, Takeda, Tyme, Iqvia, Trial to Reduce IDDM in the Genetically at Risk (TRIGR), Pfizer, ImmunoMet, Black Diamond ; Financial Interests, Other, travel/accommodations/expenses: Genentech; Financial Interests, Stocks or ownership: BAKX Therapeutics; Financial Interests, Other, Honoraria: Five Prime Therapeutics; Financial Interests, Institutional, Research Funding: Genentech. All other authors have declared no conflicts of interest.