Correlative and spatial transcriptomic analysis of olaparib and durvalumab in patients with recurrent/refractory <i>IDH</i> -mutant gliomas.

Abstract

2075 Background: Combination of immune checkpoint and PARP inhibition has potential synergistic effects in IDH mt gliomas in pre-clinical models. Durvalumab and olaparib demonstrated objective responses in a subset of patients (pts) with IDH mt gliomas (NCT03991832). We report mutational, transcriptomic, and spatial correlative analysis of pts samples from baseline and at time of progression. Methods: Pts with recurrent/refractory IDH mt gliomas received olaparib 300 mg twice daily and durvalumab 1500 mg IV every 4 weeks until disease progression as determined by RANO 2.0 criteria. Whole exome sequencing (WES, n = 28) and total RNA sequencing (RNA-seq, n = 21) were performed on baseline archival formalin-fixed, paraffin-embedded tumor samples. Baseline tumor microenvironment was characterized with multiplex-immunohistochemistry (n = 29). Matched responders (n = 4) and non-responders (n = 6) were further profiled using 10X Visium HD for spatial transcriptomics. An unsupervised deconvolution method was applied using consensus non-negative matrix factorization for de novo discovery of expression programs corresponding to cell types and cell states. Associations with objective response (OR) to therapy were determined using either Fisher’s exact test or rank-sum test. Results: In the 29 pts enrolled between January 2020–February 2023, median age was 40.5 (range 23–66) and 41% were female. The initial tumor grade was 2 (n = 9), 3 (n = 8), and 4 (n = 12). The OR rate was 14% (95% CI 3.9–32%), 1 complete response and 3 partial responses. All cases were mismatch repair proficient. The median tumor mutation burden (TMB) was 16.5, with TMB &gt; 10 in 21 pts (75%). Baseline TMB was not associated with response. The most common co-mutations were TP53 (n = 21, 75%), ATRX (n = 20, 71%), ARID1A (n = 7, 25%), CIC (n = 4, 14%), and NF1 (n = 3, 11%), none were associated with response. There were no canonical mutations in BRCA1 , BRCA2 , or PALB2 . Pathway analysis on differentially expressed genes between responders and non-responders showed convergence on interferon signaling and inflammation among responders (p &lt; 0.001). Lower pre-existing M2-polarized tumor associated macrophages/microglia (high expression of CD68, PDL1, CD163) was associated with response (p &lt; 0.01). These findings were supported by metaprograms in the HD spatial data, which showed higher levels of CD8+ cytotoxic T-cells at baseline in responders. Conversely, M2-polarized macrophage/microglia were enriched in non-responders. Paired progression samples will additionally be presented. Conclusions: Responders to olaparib and durvalumab had decreased baseline M2-polarized macrophages/microglia and increased pre-existing immunogenicity (interferon signaling). Several spatially conserved expression metaprograms targeting baseline immune infiltration were associated with response. Clinical trial information: NCT03991832 .