Abstract 2224: Validated differential expression of immunoregulatory molecules that coincide with targetable mutations may provide novel insights into strategic trial design for therapeutics

Abstract

Abstract Background: Immune checkpoint inhibitors (ICI) are rarely administered as first-line monotherapies for cancer. ICI are currently being trialed as combination ICI therapies, ICI in combination with standard chemo-(or other) therapies, or as second-line therapies following relapse, but many of these trials fail due to lack of optimal design. Here we sought to identify which checkpoint genes are differentially expressed (DE) in the presence of therapeutically targetable DNA mutations prior to treatment in order to facilitate the rational design of clinical trials for first-line ICI combination therapies. Methods: Whole-exome (WES) variant calls and whole-transcriptome expression values (RNAseq) were acquired for 5767 samples across 28 solid tumor subtypes from TCGA sources including breast (N=981), thymic (N=404), melanoma (N=344), prostate (N=331), gliobastoma multiforme (GBM, N=289) among others. A curated list of 274 targetable single nucleotide variants (SNVs) was obtained from ImmunityBio sources based on FDA labels, literature review, and trial notes. Ten checkpoint genes significantly DE between targetable SNV mutant (mt) vs. wild-type (wt) were identified by t-tests corrected for multiple hypothesis testing. Checkpoint DE was then validated as significant in an external cohort of 2739 unselected later-stage clinical cases from the NantHealth database with similarly profiled paired WES & RNAseq, comprised of breast (N=576), colon (N=314), lung (N=283), pancreatic (N=221), ovarian (N=196), among others. Tissue subtype enrichment for targetable mutations was assessed by Fisher's exact test. Results: Twenty-three significant associations between targetable mt and DE checkpoint genes were identified in TCGA cases; 10 were validated in the external cohort. The vemurafenib target BRAF V600E was found coinciding with increased PD1, PDL1, and CTLA4 (adj. p=2.4e-3, 1.1e-23, 6.6e-7 respectively) as well as decreased IDO1 (adj. p=3.4e-6), and the effect size was larger than that of tissue-type. TIM3 was found significantly elevated in lapatinib-sensitive EGFR G598V patients (adj. p=1.0e-5) most prevalent in GBM, and conversely suppressed in FGFR3 S249C patients (adj. p=0.04) that are significantly enriched in bladder cancers. PIK3CA E545K patients, mostly cervical cancers, showed higher IDO1 expression (adj. p=3.3e-4) suggesting sensitivity to combined alpelisib/epacadostat. Conclusions: NGS data inform decisions for use of gene mutation-targeted therapies; use of similar analysis when paired with RNAseq may support efforts to replace chemotherapy with more efficacious/safer combined immuno- and mutation-targeted therapies. Our findings here suggest future studies may result in the optimization of ICI - gene targeted therapy trials. Citation Format: Jacob J. Adashek, Christopher W. Szeto, Saihitha Veerapaneni, Andrea Preble, Sandeep K. Reddy, Philippe E. Spiess. Validated differential expression of immunoregulatory molecules that coincide with targetable mutations may provide novel insights into strategic trial design for therapeutics [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2224.