Integrative tumor immunohistochemical, genomic, and transcriptomic analyses found T cell density, SETD2 mutational status, high inflammatory response and oxidative stress to be associated with NIVO+CABO outcomes versus sunitinib. EMT and CAF pathways were associated with resistance to NIVO+CABO. Further, clinical outcomes were improved with NIVO+CABO versus sunitinib across 6 transcriptomically-defined clusters; T-effector/proliferative cluster was enriched for c-MET positivity which differentiated NIVO+CABO outcomes. Among circulating factors, high IL-6, TN-C, and TIMP-1 were predictive of NIVO+CABO outcomes versus SUN. NIVO+CABO increased levels of cytokines associated with immune activation/inflammation/oxidative stress These results support metabolic/immune pathway activation within the tumor and peripheral circulation as possible contributors to PD-1 based efficacy.
DNA was extracted from tumor samples and blood samples using the Qiagen DNA FFPE and Qiagen DNA Blood Mini Kit, respectively (Qiagen, Germantown, CA). Whole-exome libraries for tumor and blood DNA samples were prepared using the SureSelectXT v5 Kit (Agilent) following validated standard operating procedures for DNA extracted from tumors and germline control samples. Libraries sequenced using the Illumina HiSeq2500 (Illumina, San Diego, CA) following 2 × 100 paired-end sequencing, targeting a depth of coverage of 100×. Sequence alignment and variant calling were performed using a published WES processing pipeline[Chang H, Sasson A, Srinivasan S, et al. Bioinformatic methods and bridging of assay results for reliable tumor mutational burden assessment in non-small cell lung cancer. Mol Diagn Ther 2019;23:507–20] based on Human Build 37 (GRCh37). A maf file is provided.
