Abstract 689P
Background
The combination therapy durvalumab (anti PD-L1) plus metformin (oral anti-hyperglycemic) targets multiple facets of the immunosuppressive tumor microenvironment (TME) in HNSCC to promote anti-tumor immunity. Characterization of the TME is crucial for understanding tumor-immune interactions underlying effective therapies.
Methods
Eight responders (two major and six minor; pathologic response at primary site) from the durvalumab-metformin window of opportunity trial (NCT03618654) were selected for DSP analysis of RNA expression by using Nanostring’s GeoMx platform. Unbiased gene set enrichment analysis (GSEA) of expressed genes was performed by query with >22,000 gene sets encompassing cell type signatures, canonical pathways, and biologic processes. On-treatment effects were observed by longitudinal post- vs. pre-treatment contrast for all GSEA runs.
Results
Two independent GeoMx DSP runs revealed corroborating gene sets in cell type signature and gene ontology collections. In the stromal segment, treatment enriched the following gene sets: dendritic cells (normalized enrichment score (NES) >3.63; FDR q-value (q) = 0.0), Kupffer cells (NES >3.53; q = 0.0), microglia (NES >3.47; q = 0.0), macrophages (NES >3.38; q = 0.0), and antigen processing and presentation (NES >2.85; q = 0.0). In the tumor segment, treatment depleted a multicancer invasive signature in three patients (two major and one minor responder) (NES -2.50; q = 0.0). The leading edge of this invasive signature was replete with known cancer-associated fibroblast markers.
Conclusions
GeoMx DSP/GSEA of Durvalumab-metformin combination therapy is consistent with the enrichment of antigen-processing and presentation by macrophages and dendritic cells in the stromal segment of HNSCC. Simultaneously, therapy depletes the invasive signature of the tumor segment.
Clinical trial identification
NCT03618654.
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
AstraZeneca.
Disclosure
D. Cognetti: Financial Interests, Personal, Other, Honoraria: Intuitive Surgical; Financial Interests, Personal, Advisory Role: Rakuten Medical. M. Mahoney: Financial Interests, Personal, Full or part-time Employment: Bristol Myers Squibb Foundation (I); Financial Interests, Personal, Stocks/Shares: Bristol Myers Squibb Foundation (I); Financial Interests, Personal, Royalties: Bristol Myers Squibb Foundation (I). A. South: Financial Interests, Personal, Stocks/Shares: Krystal Biotech, Zikani Therapeutics; Financial Interests, Personal, Advisory Role: Zikani Therapeutics; Financial Interests, Personal, Funding: Zikani Therapeutics. A. Argiris: Financial Interests, Personal, Advisory Role: Aspyrian Therapeutics, Bristol Myers Squibb, Debiopharm Group, Merck Serono, Roche, Seattle Genetics; Financial Interests, Personal, Speaker’s Bureau: Bristol Myers Squibb, Merck Serono; Financial Interests, Personal, Funding: Bristol-Myers Squibb, Genentech/Roche; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Bristol Myers Squibb, Merck Serono. J.M. Johnson: Financial Interests, Personal, Advisory Role: Bristol Myers Squibb, Foundation Medicine, Rakuten Medical; Financial Interests, Personal, Funding: AstraZeneca, Bristol Myers Squibb, Merck; Non-Financial Interests, Personal, Other, Uncompensated Relationship: Taproot Health Inc. J.M. Curry: Financial Interests, Personal, Advisory Role: Rakuten Medical, Sanofi; Financial Interests, Personal, Funding: AstraZeneca, Castle Biosciences. All other authors have declared no conflicts of interest.