Phase Ib study of MIW815 (ADU-S100) in combination with spartalizumab (PDR001) in patients (pts) with advanced/metastatic solid tumors or lymphomas.
Abstract
2507 Background: MIW815 (ADU-S100) is a novel synthetic cyclic dinucleotide that activates the STimulator of INterferon Genes (STING) pathway impacting tumor cells, tumor microenvironment, vasculature, tumor-associated fibroblasts, and priming APC and CD8+ T cells. Spartalizumab is a humanized IgG4 mAb that blocks the binding of PD-1 to PD-L1/2. Preclinical data support synergistic antitumor effects when MIW815 (ADU-S100) is combined with checkpoint inhibitors. Methods: In this Phase Ib dose escalation study, pts with advanced/metastatic solid tumors or lymphoma received MIW815 (ADU-S100) (intratumoral injections [50–800 µg] either weekly [3 weeks on/1 week off] or Q4W) and spartalizumab (400 mg IV Q4W). Injected and non-injected tumor biopsies were obtained at baseline and on treatment. Primary objectives are to determine safety and identify a dose/schedule for future studies. Preliminary activity, pharmacokinetics (PK), and pharmacodynamics (PD) are also being explored. Results: As of Jan 11, 2019, 66 pts (median age: 61 y) with various solid tumors or lymphomas have been treated. Treatment was discontinued in 49 pts (74%) due to disease progression (n = 28), pt/physician decision (n = 18), AE (n = 2), or death (n = 1). No DLTs were reported during the first cycle at any dose level. Most common (≥5 pts) treatment-related AEs (TRAEs) were injection site pain (12%), pyrexia (11%), and diarrhea (9%). Grade 3/4 TRAEs (in ≥2 pts) were increased AST and ALT (3% each). Serious TRAEs were pyrexia (3%), increased amylase, increased lipase, diarrhea, fatigue, hyperthyroidism, partial seizures, dyspnea, and pneumonitis (all 2%). Partial responses in pts with PD-1–naive TNBC and PD-1–relapsed/refractory melanoma have been observed. MIW815 (ADU-S100) plasma exposure generally increased in a dose-dependent manner with a rapid terminal half-life. Response data, PK and PD analyses will be presented. Conclusions: Thus far, MIW815 (ADU-S100) + spartalizumab has demonstrated antitumor activity in PD-1–naive TNBC and PD-1–relapsed/refractory melanoma. The combination is well tolerated, with no DLTs reported to date. The MTD has not been reached and dose escalation is ongoing. Clinical trial information: NCT03172936.
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Preliminary data showed that some combination therapies (ADU-S100 plus spartalizumab, MK-1454 plus pembrolizumab, manganese plus α-PD-1) had encouraging antitumor activity with a tolerable safety profile.
“The preliminary data showed that some combination therapies (e.g. ADU-S100 plus spartalizumab, MK-1454 plus pembrolizumab, manganese plus α-PD-1) had encouraging antitumor activity with a tolerable safety profile [270, 275, 276].”
From Combination strategies with PD-1/PD-L1 blockade: current advances and future directions (2022) · cites this paper as [275]
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“ADU-S100 plus spartalizumab, MK-1454 plus pembrolizumab, manganese plus α-PD-1) had encouraging antitumor activity with a tolerable safety profile [270, 275, 276].”
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“At the same time, early-phase clinical trials of STING agonists in patients have not yielded sustained clinical remissions (33, 34), indicating a need for improvements in this immunotherapy approach.”
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SHR1032, a novel STING agonist, stimulates anti-tumor immunity and directly induces AML apoptosis
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“ADU-S100 (MIW815) in combination with spartalizumab showed 2 PRs out of 66 patients treated (104).”
BackgroundIf small molecules immunotherapy comes, can the prime be far behind?
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“Systemic delivery of CDN-based STING agonists is limited by their poor PK and instability in plasma ( 34 , 58 – 60 ).”
Type I interferons in pancreatic cancer and development of new therapeutic approaches
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“Although STING agonists have been promising for cancer immunotherapy in clinical trials [10, 32], STING status is crucial for the efficacy of this therapy.”
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- Authors
- Meric-Bernstam, F., Sandhu, S. K., Hamid, O., Spreafico, A., Kasper, S., Dummer, R., Shimizu, T., Steeghs, N., Lewis, N., Talluto, C. C., Dolan, S., Bean, A., Brown, R., Trujillo, D., Nair, N., & Luke, J. J.
- Affiliations
- Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, MD Anderson Cancer Center, Houston, TX;
- The University of Melbourne (AU)
- Angeles Clinic and Research Institute (US)
- Princess Margaret Cancer Centre (CA)
- Essen University Hospital (DE)
- University of Zurich (CH)
- National Cancer Center Hospital (JP)
- The Netherlands Cancer Institute (NL)
- Novartis Pharmaceuticals Corporation, East Hanover, NJ;
- Novartis Institutes for BioMedical Research, Cambridge, MA;
- Aduro BioTech (United States) (US)
- University of Chicago (US)
- ORCID
- Venue
- Journal of Clinical Oncology
- Published
- 2019-05-20
- Volume
- 37
- Issue
- 15_suppl
- Pages
- 2507-2507
- ISSN
- 0732-183X (ISSN-L)
- 1527-7755
- OpenAlex
- W2947265946
- Cited by
- 190
- References
- 0
- Citations by year
- 2026: 14 · 2025: 30 · 2024: 21 · 2023: 17 · 2022: 28 · 2021: 49 · 2020: 27 · 2019: 4
- Type
- conference abstract
- Language
- en
- Open access
- closed
- Locations
- Journal of Clinical Oncology (publishedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- ADU-S100, spartalizumab, cyclic dinucleotides, STING pathway, PD-1/PD-L1 blockade, combination immunotherapy, advanced solid tumors, lymphoma, dose escalation, treatment-related adverse events, pharmacokinetics, pharmacodynamics, triple-negative breast cancer, melanoma, dose-limiting toxicity, intratumoral injection
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