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Introduction/Background In PHAEDRA, a single arm Phase 2 trial (n=71), MMR deficiency (dMMR) was predictive of response to durvalumab (1500mg IV Q4W), with an objective tumour response rate (OTR; defined by iRECIST) of 47% in dMMR compared with 3% in MMR-proficient (pMMR) women with advanced endometrial cancer (AEC). We investigated tumour genomic and DNA methylation features and their correlation with treatment outcomes. Methodology Germline pathogenic variants in DNA MMR genes (Lynch syndrome) or somatic MMR gene inactivation through somatic mutation or MLH1 methylation were tested to determine dMMR subtypes. Tumour (formalin fixed paraffin embedded) and matched blood DNA from 25 dMMR and 16 pMMR patients were sequenced on a targeted gene panel to determine microsatellite instability (MSI), tumour mutational burden (TMB) and neoantigen load. Tumour DNA from 23 dMMR and 9 pMMR patients were tested on the Illumina EPIC array to identify differentially methylated CpG sites/regions across the methylome. Results The dMMR molecular subtypes comprised 4 (11%) Lynch syndrome, 4 (11%) somatic MMR mutation, 25 (71%) MLH1 methylated and 2 (6%) dMMR-unresolved. The OTR rate was 100% (4/4; 95%CI:40–100%) for dMMR-Lynch, 75% (3/4; 95%CI:22–99%) for dMMR-somatic MMR mutations and 40% (10/25; 95%CI:22–61%) for dMMR-MLH1 methylated groups. The median TMB (assessed in 41/71) was higher in those with a confirmed radiological response (37, IQR=26–50) vs non-responders (16, IQR=9–25; pConclusion dMMR-MLH1 methylated AEC demonstrated greater heterogeneity in OTR to single agent durvalumab than the dMMR-Lynch and dMMR-somatic MMR mutation molecular subtypes. Hypermethylation of the promoter of BCOR was prognostic for non-response to durvalumab in dMMR-MLH1 methylated AECs. Disclosures This study was funded by Astra Zeneca- Investigator Initiated Grant
Buchanan et al. (Fri,) studied this question.
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