Background Epidemiologic and translational data has suggested that metformin may alter the tumor microenvironment and improve outcomes in cancers including HNSCC through effects on cellular metabolism. Therefore, we sought to explore the potential for benefit in the combined use with immune checkpoint inhibition (ICI) . We conducted a single center, randomized, prospective clinical window of opportunity trial (WOT) of the aPD-L1 ICI durvalumab ± metformin in operable HPV+ and HPV- HNSCC.
Methods The trial was conducted in two parts: 1) a 6 patient safety lead-in with 1 dose of 1500mg of durvalumab plus metformin at 500 mg/day and increased to 1,000 mg twice daily over a rapid taper (D/M), and this was followed by 2) a 3:1 randomized trial of D/M (n=29) vs D alone (n=9) (NCT03618654). Clinical and radiographic response data as well as histologic and cytokine analyses were conducted. Whole exome sequencing (WES) and batch-corrected bulk RNA-seq was generated for downstream analysis. Unbiased and biased gene set enrichment analysis (GSEA) using the molecular signatures database (MSigDB) Hallmark gene set was conducted.1 Spatial transcriptomics (Nanostring GeoMx) was performed of 3 segments of the tumor (CD45, CD163, and PanCK segments).
Results Pathologic treatment effect (pTE) at the primary lesion and/or involved lymph nodes occurred in 54.5% of patients. Sixty percent of patients treated with D/M showed pTE versus 37.5% of those treated with durvalumab alone (p = 0.418). Unsupervised GSEA revealed that in HPV- (NES, 1.57; FDR, 0.023) and HPV+ (NES, 1.75; FDR, 0.004) tumors, responders exhibited increased expression of KRAS signaling posttreatment compared to pretreatment samples. In non-responders, HPV- tumors exhibited a decrease in oxidative phosphorylation (NES, -2.25; FDR, 0.000) and fatty acid metabolism (NES, -1.88; FDR, 0.004) gene set transcripts after treatment with D/M. Supervised GSEA revealed an increase in macrophage related gene sets In CD45 and CD164+ segments post-treatment. WES revealed a correlation between pTE and PIK3CA mutation (amplification) after treatment with D/M (p=0.011). This was corroborated using immunohistochemical staining of downstream protein, phospho-Akt. PD-L1 IHC showed no correlation with pathologic response. There was a significant increase in apoptosis regardless of response status.
Conclusions The addition of metformin was associated with an increased rate of early pathologic response that did not reach statistical significance during a short exposure to aPD-L1 and metformin. Correlative analysis revealed substantial differences in immune and metabolic transcripts on GSEA. Further, we report a unique association of between PI3KCa mutation and response.
Trial Registration ClinicalTrials.gov Identifier: NCT03618654
Nirmal AJ, Regan T, Shih BB, Hume DA, Sims AH, Freeman TC. Immune cell gene signatures for profiling the microenvironment of solid tumors. Cancer Immunology Research. 2018;6:1388–400.
Ethics Approval This clinical trial was approved by the Institutional Internal Review Board at Thomas Jefferson University, and all patients provided informed consent in accordance with the Declaration of Helsinki and the guidelines for Good Clinical Practice.
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