Enhanced understanding of the TME can enable precision medicine–driven patient (pt) selection to identify pts more likely to benefit from IO therapy (Hellman MD, et al. N Engl J Med 2018; Overman MJ, et al. Lancet Oncol 2017).
The Cancer Genome Atlas (TCGA) RNA data (melanoma, NSCLC, RCC, UC, SCCHN, GEJ) were normalized and grouped as inflamed (INF), intermediate (INT), or non-INF. Binary associations of PD1 with IO targets (LAG3, IDO1, FOXP3, GITR, CSF1R, KIRDL1, CTLA4) were studied. Unsupervised clustering and pt-level gene expression profiling (GEP) were performed. A separate set of tumors was analyzed by IHC (N = 228; LAG-3, IDO-1, FOXP3, GITR, CSF-1R, NKp46, PD-L1, MHCI, MHCII, CD8, CD68, CD163) and matched mRNA analysis (EdgeSeq; n = 128). IHC results were integrated into an algorithm for IO combination selection.
TCGA analysis showed associations of IO targets and PD1 (mean Pearson r ± SEM = 0.62 ± 0.03; P < 0.0001). Unsupervised clustering revealed discrete groups of INT tumors with high T-cell anergy, regulatory T cell, or myeloid signatures. Pt-level GEP showed INT/low-PDL1 tumors as most likely to have outlier IO targets suggestive of functional relevance. IHC showed clustering of IO targets by INF level, with outliers in INT/low-INF tumors and variability by tumor type. Observations were verified by selected IHC markers showing significant association of expression level and INF score: IDO-1, LAG-3 (non-INF vs INT P = 0.17–1.9E-04; INT vs INF P = 0.001–0.03); FOXP3, GITR, NKp46 (INT vs INF P = 0.001–0.049). CSF-1R did not show significant associations. These data aided in the design of the ADaptiVe biomarker trial that InformS Evolution of therapy (ADVISE; NCT03335540), where prospective treatment selection (nivolumab + second IO agent) is driven by analysis of pretreatment biopsies. Initial clinical implementation will also be presented.
Translational data reveal potentially actionable biomarkers, which are being assessed in the ongoing ADVISE trial as an initial clinical foray into personalized IO therapy.
Clinical trial identification
Legal entity responsible for the study
Writing and editorial assistance was provided by Larra Yuelling, PhD of Chrysalis Medical Communications, Inc., funded by Bristol-Myers Squibb.
J.J. Luke: Consultancy: 7 Hills, Actym, Amgen, Array, AstraZeneca, BeneVir, Bristol-Myers Squibb, Castle, CheckMate, Compugen, EMD Serono, Gilead, Janssen, Merck, NewLink, Nimbus, Novartis, Palleon, RefleXion, Syndax, Tempest, TTC Oncology, WntRx; Research support: AbbVie, Array, Boston Biomedical, Bristol-Myers Squibb, Celldex, CheckMate, Corvus, Delcath, Five Prime, Genentech, Immunocore, Incyte, MedImmune, Macrogenics, Novartis, Pharmacyclics, Palleon, Merck, Tesaro, Xencor; Travel: Amgen, Array, AstraZeneca, BeneVir, Bristol-Myers Squibb, Castle, CheckMate, EMD Serono, Gilead, Janssen, Merck, NewLink, Novartis, RefleXion. R. Edwards, C. Hedvat, D. Pandya, R. Meier, C.T. Harbison, P. Szabo: Employment: Bristol-Myers Squibb; Stock: Bristol-Myers Squibb. S. Ely: Employment: Bristol-Myers Squibb; Stock: Bristol-Myers Squibb; Patents/Royalties/Property: Cornell University. D. McDonald, G. Lee: Employment: Bristol-Myers Squibb; Stock: Bristol-Myers Squibb; Travel and accommodations: Bristol-Myers Squibb. V. Baxi, T.P. Reilly: Employment: Bristol-Myers Squibb; Stock: Bristol-Myers Squibb. E. Jaffee: Consulting/Advisory: Aduro Biotech, MedImmune, Incyte, Genocea; Research funding: Bristol-Myers Squibb, Aduro Biotech, Amgen; Patents/Royalties: Potential royalties from Aduro for GVAX. F.S. Hodi: Consulting/Advisory role: Novartis, Amgen, EMD Serono, Celldex, Merck, Bristol-Myers Squibb; Research funding: Bristol-Myers Squibb; Patents, royalties, other intellectual property: Dana-Farber Cancer Institute. All other authors have declared no conflicts of interest.