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713 The impact of cause of mismatch repair deficiency and other molecular markers on clinical outcomes with the use of durvalumab in advanced endometrial cancer in the phase 2 PHAEDRA trial (ANZGOG1601)
  1. Daniel Buchanan1,
  2. Ji-Hoon Eric Joo1,
  3. Khalid Mahmood1,
  4. Peter Georgeson1,
  5. Rommy Walker1,
  6. Kristy Robledo2,
  7. Michelle Cummins2,
  8. Amanda B Spurdle3,
  9. Deborah Smith4,
  10. Mark Clendenning1,
  11. Julia Como1,
  12. Susan Preston1,
  13. Sonia Yip2,
  14. John Andrews5,
  15. Peey-Sei Kok2,
  16. Yeh Chen Lee2,
  17. Martin Stockler2,
  18. Linda Mileshkin6 and
  19. Yoland Antill7
  1. 1University of Melbourne, Melbourne, Australia
  2. 2University of Sydney, Sydney, Australia
  3. 3Queensland Institure of Medical Research – Bergofer, Brisbane, Australia
  4. 4The Mater Hospital, Brisbane, Australia
  5. 5ANZGOG, Sydney, Australia
  6. 6Peter MacCallum Cancer Centre, Melbourne, Australia
  7. 7Cabrini Health, Melbourne, Australia


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; p<0.001). Within the dMMR-MLH1 methylated group, there were 208 hypomethylated CpGs and 107 hypermethylated CpGs significantly enriched in responders compared with non-responders. Of these, BCOR was the most significantly differentially methylated gene promoter, with hypermethylation associated with MLH1 methylated non-response AECs.

Conclusion 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

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