dazostinag (TAK-676) / Takeda - LARVOL DELTA

Dose expansion data from iintune-1, a phase 1/2 study of the STING agonist dazostinag plus pembrolizumab as first-line (1L), in patients with recurrent/metastatic squamous cell carcinoma of the head and neck (RM-SCCHN). (ASCO 2025) - P1/2 | "This early study of dazo 5 mg IV in combination with pembro showed a manageable safety profile with an encouraging ORR in pts with RM-SCCHN. Pharmacodynamic findings demonstrate peripheral and intratumor changes consistent with STING agonism."

Clinical • IO biomarker • Metastases • P1/2 data • Cough • Fatigue • Head and Neck Cancer • Oncology • Pain • Respiratory Diseases • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • CD8 • PD-L1 • STING

Biomarker-guided dose selection in the iintune-1 study of dazostinag,a STING agonist, alone and in combination with pembrolizumab for patients with metastatic solid tumors (AACR 2025) - P1/2 | "Dazostinag combined with pembro enhanced peripheral anti-tumor immune cell activity, CD8 T-cell tumor infiltration, and radiographic responses. Based on the totality of safety, clinical, PK and pharmacodynamics data, 5 mg and 14 mg dazostinag combined with pembro were selected for dose expansion and optimization in head & neck and colorectal tumors."

Biomarker • Clinical • Combination therapy • IO biomarker • Late-breaking abstract • Metastases • Colorectal Cancer • Oncology • Solid Tumor • CD8 • IFNG • PD-L1

Development of a peripheral dazostinag (TAK-676) activation RNASeq signature to evaluate STING pharmacodynamic modulation in human solid tumor clinical trials (AACR 2025) - P1/2 | "Dazostinag, a novel STimulator of INterferon Genes (STING) agonist, is currently being evaluated with pembrolizumab for colorectal and head & neck cancers (iintune-1, NCT04420884). This induction returned to baseline prior to subsequent weekly doses.In summary, we developed a robust RNASeq-based peripheral STING activation PD biomarker using ex vivo treated PBMCs to evaluate the biological response to STING agonist treatment. This framework could be applied for the development of RNASeq based peripheral PD biomarkers for other investigational assets."

Clinical • PK/PD data • Colorectal Cancer • Head and Neck Cancer • Oncology • Solid Tumor • IFNA1 • IFNG • STING

Reversible downregulation of HLA class I in adenoid cystic carcinoma. (PubMed, J Immunother Cancer) - "Low B2M/HLA class I expression may explain why ACCs are immunologically cold and the lack of response to ICIs. Our findings suggest that the normal cell of ACC origin exists in a B2M/HLA-class I low state, and that pharmacologic manipulation with immune activators, such as STING agonists, can restore HLA/B2M in ACCs, as supported by the promising response observed in a patient with metastatic ACC. These findings indicate a potential path to urgently needed immunotherapies."

IO biomarker • Journal • Adenoid Cystic Carcinoma • Head and Neck Cancer • Oncology • Solid Tumor • B2M • GBP1 • IFNG • IRF1 • NFIB • PD-L1 • TAP1 • TP63

Iintune-1: A Study of Dazostinag as Single Agent and Dazostinag in Combination With Pembrolizumab in Adults With Advanced or Metastatic Solid Tumors (clinicaltrials.gov) - P1/2 | N=374 | Active, not recruiting | Sponsor: Takeda | Recruiting ➔ Active, not recruiting

Enrollment closed • Colorectal Cancer • Head and Neck Cancer • Oncology • Oropharyngeal Cancer • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • MSI • PD-L1

Phase 1b study of dazostinag plus pembrolizumab after hypofractionated radiotherapy in patients with non-small-cell lung cancer, triple-negative breast cancer, or head and neck squamous-cell carcinoma (SITC 2024) - P1, P1/2 | "Three of four responses were seen at higher dazostinag dose levels, consistent with predicted active dose range. Pharmacodynamic biomarker induction was shown to be consistent with STING agonism across multiple dose levels.View this table:View inline View popup Download powerpoint Abstract 778 Table1 Patient demographics and key data"

Clinical • IO biomarker • P1 data • Breast Cancer • Head and Neck Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • Triple Negative Breast Cancer • IFNG

Evaluating the mechanism of enhanced responses to the IV STING agonist dazostinag (TAK-676) plus pembrolizumab in neuroendocrine tumors (SITC 2024) - P1, P1/2 | "Conclusions Preclinical STING agonism via dazostinag increased immune trafficking and infiltration into the NET/SCLC microenvironment and enhanced antigenicity and immune recognition leading to sensitization to anti-PD-1 therapy. Our results provide rationale for clinical evaluation of STING agonists as part of a combination strategy for immunotherapy-based treatment of NETs."

IO biomarker • Endocrine Cancer • Lung Cancer • Neuroendocrine Tumor • Oncology • Small Cell Lung Cancer • Solid Tumor • PD-L1 • RB1 • RBL2 • TP53

Phase I/II trial of dazostinag with or without pembrolizumab in advanced solid tumors (YouTube) - "Jason Luke, MD...discusses findings from a Phase I/II trial (NCT04420884) of dazostinag, a STING agonist, as monotherapy and in combination with pembrolizumab in advanced solid tumors. Dazostinag showed manageable safety across all dose levels, with common adverse events being fatigue, nausea, and cytokine release syndrome (CRS). Early clinical responses included complete and partial responses in combination therapy, and this novel strategy has potential in earlier lines of therapy or in combination with other checkpoint inhibitors. This interview took place at the European Society for Medical Oncology (ESMO) 2024 Congress in Barcelona, Spain."

Interview • Video

Dazostinag (TAK-676) alone and in combination with pembrolizumab (pembro) in patients (pts) with advanced/metastatic solid tumors: Data from phase I dose escalation (ESMO 2024) - P1/2 | "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."

Clinical • Combination therapy • Metastases • P1 data • Adenoid Cystic Carcinoma • Bladder Cancer • Cervical Cancer • Genito-urinary Cancer • Neuroendocrine Tumor • Oncology • Solid Tumor • IFNG

Enjoyed #ESMO24 seeing friends/colleagues & contributing to the advancement of cancer treatment. Here phase I of dazostinag (TAK-676) an IV STING agonist. Excellent immune PD biomarkers suggest potential to move this forward. (LinkedIn)

Biomarker

A Study of TAK-676 With Pembrolizumab After Radiation Therapy to Treat a Number of Cancers (clinicaltrials.gov) - P1 | N=34 | Completed | Sponsor: Takeda | Active, not recruiting ➔ Completed | N=65 ➔ 34

Checkpoint inhibition • Enrollment change • Trial completion • Breast Cancer • Head and Neck Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • Triple Negative Breast Cancer

Multiomics analysis of impact of CD8+ and other cell populations in STING agonist treated ex vivo mesothelioma samples (AACR 2024) - "We evaluated immune modulations in mesothelioma after treatment with a systemic STING agonist dazostinag using human tumor ex vivo culture. Innate interferon type I expression was higher in responding samples. TAK-676 efficacy was partially reduced in absence of effector lymphocytes, however other cells, such as immunosuppressive myeloid cells and fibroblasts, can have a negative impact on dazostinag response in mesothelioma."

Preclinical • Mesothelioma • Oncology • Solid Tumor • CD8 • IFNA1 • IFNB1

A Study of TAK-676 With Pembrolizumab After Radiation Therapy to Treat a Number of Cancers (clinicaltrials.gov) - P1 | N=65 | Active, not recruiting | Sponsor: Takeda | Recruiting ➔ Active, not recruiting

Checkpoint inhibition • Enrollment closed • Breast Cancer • Head and Neck Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • Triple Negative Breast Cancer

TAK-500 as a single agent and in combination with pembrolizumab in patients (pts) with advanced solid tumors: Rationale and design of a phase I/II study (ESMO 2023) - P1a/1b | "Background TAK-500 is a novel immune-cell-directed antibody drug conjugate comprising the STING agonist TAK-676 conjugated to a human IgG1 anti-C-C chemokine receptor 2 (CCR2) antibody. A single-stage statistical design will be utilized for 3rd-line NS NSCLC and RCC. As of May 2023, 6 sites in the United States are recruiting; the global phase 2 is planned to start in 2024."

Clinical • Combination therapy • Metastases • P1/2 data • Clear Cell Renal Cell Carcinoma • Gastrointestinal Cancer • Lung Cancer • Lung Non-Squamous Non-Small Cell Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Renal Cell Carcinoma • Solid Tumor • CCR2

Dazostinag (TAK-676) alone and in combination with pembrolizumab (pembro) in patients (pts) with advanced or metastatic solid tumors: Preliminary safety, PK/PD, and anti-tumor activity in a phase I dose escalation study supporting a recommended dose for expansion (RDE) (ESMO 2023) - P1/2 | "Conclusions Preliminary safety, PK/PD data, and anti-tumor activity support the declaration of the RDE of dazostinag 5 mg + pembro 200 mg. Expansion cohorts in colorectal and head and neck cancer are enrolling."

Clinical • Combination therapy • Metastases • P1 data • PK/PD data • Colorectal Cancer • Head and Neck Cancer • Oncology • Solid Tumor • CD8 • IFNG • STING

PBI-MST-01(NCT04541108) Substudy TAK-02: Intratumoral Microdosing of TAK-676 in HNSCC (clinicaltrials.gov) - P1 | N=15 | Completed | Sponsor: Presage Biosciences

New P1 trial • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • CASP3 • CD8 • CD86 • GZMB • TNFA

A Study of TAK-676 as Single Agent and TAK-676 in Combination With Pembrolizumab in Adults With Advanced or Metastatic Solid Tumors (clinicaltrials.gov) - P1/2 | N=368 | Recruiting | Sponsor: Takeda | Phase classification: P1 ➔ P1/2 | Trial completion date: Jul 2025 ➔ Oct 2025 | Trial primary completion date: Jul 2025 ➔ Oct 2025

Combination therapy • Metastases • Phase classification • Trial completion date • Trial primary completion date • Colorectal Cancer • Gastrointestinal Cancer • Head and Neck Cancer • Oncology • Oropharyngeal Cancer • Solid Tumor • Squamous Cell Carcinoma of Head and Neck • MSI • PD-L1 • STING

Targeting STING to CCR2+ Cells via an Immune Cell Directed Antibody Drug Conjugate (iADC) (ADC-USA 2023) - "Narrating an overview of the murine surrogate iADC, mTAK-500, which was designed to selectively deliver the a STING agonist to CCR2+ cells; Discussing the of nonclinical data and mechanistic insight that have motivated design and clinical testing of TAK-500, a CCR2-targeted STING ISAC comprising the clinical STING agonist TAK-676 and a high affinity antibody targeting human CCR2"

Immune cell • CCR2 • STING

Multiplexed trackable intratumor microdosing of the investigational STING agonist TAK-676 alone and in combination in the native tumor microenvironment of patients with head and neck cancer: A phase 0 trial. (ASCO 2023) - P1 | "Microdoses (≤1/100th systemic dose) of TAK-676, carboplatin, 5-FU, paclitaxel, and combinations thereof, were simultaneously injected via CIVO to eligible patients presenting with a surface-accessible primary or metastatic lesion ≥ 2 cm and planned surgical resection of the target lesion at 24 (n=8) or 72–96 (n=7) hours... Intratumor microdosing via CIVO of TAK-676 alone and in combination with chemotherapy was shown to promote an early pro-inflammatory response, providing evidence of an on-target mechanism of action. The absence of effect at the late timepoints could be due to pharmacokinetics of drug exposure or compensatory signaling within the TME. In this Phase 0 clinical trial we safely demonstrated precise, mechanistic effects of TAK-676 on the native TME of intact human tumors."

Biomarker • Clinical • Tumor microenvironment • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • CD8

Preclinical activity of C-C chemokine receptor 2 (CCR2)-targeted immune stimulating antibody conjugate (ISAC), motivating clinical testing of TAK-500 (SITC 2022) - P1a/1b | "Single agent α-PD-1 treatment also resulted in a 12.5% CR rate, however, when combined, mTAK-500 and α-PD-1 treatment achieved enhanced anti-tumor response with a 37.5% CR rate. Conclusions Nonclinical antitumor activity and mechanistic insight have motivated design and clinical testing of TAK-500, a CCR2-targeted STING ISAC comprising the clinical stage STING agonist TAK-676 and a high-affinity antibody targeting human CCR2, as a single agent and in combination with pembrolizumab in adults with select locally advanced or metastatic solid tumors ( NCT05070247 )."

IO biomarker • Preclinical • Oncology • Solid Tumor • CCR2 • CD8 • STING

TAK-676: A Novel Stimulator of Interferon Genes (STING) Agonist Promoting Durable IFN-dependent Antitumor Immunity in Preclinical Studies. (PubMed, Cancer Res Commun) - "TAK-676 is a novel systemic STING agonist demonstrating robust activation of innate and adaptive immune activity resulting in durable antitumor responses within multiple syngeneic tumor models. Clinical investigation of TAK-676 is ongoing."

Journal • Preclinical • Oncology • STING

The IV STING agonist, TAK-676, enhances immune-mediated anti-tumor activity of radiation in syngeneic mouse models (AACR 2022) - P1 | "However, only TAK-676 with fractionated radiation enhanced local IFN-γ production within the tumor, suggesting an enhanced adaptive immune response to this combination that drives the increase in observed efficacy. These studies support the evaluation of TAK-676 in combination with pembrolizumab following fractionated stereotactic body radiation therapy (SBRT) in a dose escalation clinical trial in patients with select advanced tumors (NCT04879849)."

Preclinical • Oncology • CGAS • IFNG • STING

Intratumoral microdosing via the CIVO® Platform reveals anti-tumor immune responses induced by the STING Agonist TAK-676 alone and in combination with chemotherapies (AACR 2022) - P1 | "These studies highlight TAK-676’s potential to promote anti-tumor immunity and the utility of the CIVO platform to reveal and characterize combination-specific responses. This application of CIVO is being further evaluated in an ongoing Phase 0 trial in patients with head and neck squamous cell carcinoma (NCT04541108)."

Combination therapy • Head and Neck Cancer • Melanoma • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • CXCL10 • IFNG • STING

Phase 1 study of TAK-676 + pembrolizumab following radiation therapy in patients with advanced non-small-cell lung cancer (NSCLC), triple-negative breast cancer (TNBC), or squamous-cell carcinoma of the head and neck (SCCHN) (AACR 2022) - P1 | "The primary objective is to determine the safety and tolerability of TAK-676 + pembrolizumab following radiation therapy; secondary objectives are to determine the recommended phase 2 dose of TAK-676 + pembrolizumab following radiation therapy, and to assess preliminary antitumor activity both locally (in the radiation field) and systemically (non-radiated lesions). As of January 2022, nearly 10% of the planned patients have been enrolled."

Clinical • P1 data • Breast Cancer • Head and Neck Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • Triple Negative Breast Cancer • CGAS

TAK-676 in combination with pembrolizumab after radiation therapy in patients (pts) with advanced non–small cell lung cancer (NSCLC), triple-negative breast cancer (TNBC), or squamous-cell carcinoma of the head and neck (SCCHN): Phase 1 study design. (ASCO 2022) - P1 | "The primary objective is to determine the safety and tolerability of TAK-676 plus pembrolizumab following radiation therapy; secondary objectives are to establish the recommended phase 2 dose of TAK-676 plus pembrolizumab following radiation therapy, and to assess preliminary antitumor activity both locally (within the radiation field) and systemically (non-radiated lesions). As of February 2022, we have enrolled ̃10% of the planned pts."

Clinical • Combination therapy • P1 data • Breast Cancer • Head and Neck Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • Triple Negative Breast Cancer • CGAS • STING