Oral Presentation Clinical Oncology Society of Australia Annual Scientific Meeting 2023

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). (#82)

Daniel D Buchanan 1 2 , Peter Georgeson 1 , Khalid Mahmood 1 3 , Jihoon E Joo 1 , Romy Walker 1 , Kristy P Robledo 4 , Michelle M Cummins 4 , Amanda B Spurdle 5 , Deborah Smith 6 , Mark Clendenning 1 , Julia Como 1 , Susan Preston 1 , Sonia Yip 4 , John Andrews 4 , Peey-Sei Kok 4 , Yeh Chen Lee 4 , Martin R Stockler 4 , Linda Mileshkin 7 , Yoland C Antill 8 9
  1. Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Melbourne, VIC, Australia
  2. Genomic Medicine and Family Cancer Clinic, Royal Melbourne Hospital, Parkville, VIC, Australia
  3. Melbourne Bioinformatics, University of Melbourne, Parkville, VIC, Australia
  4. NHMRC Clinical Trials Centre, University of Sydney, Camperdown, NSW, Australia
  5. QIMR Berghofer Medical Research Institute, Herston, QLD, Australia
  6. Mater Pathology, University of Queensland, Brisbane, QLD, Australia
  7. Department of Medical Oncology, Sir Peter MacCallum Cancer Centre, Parkville, VIC, Australia
  8. Faculty of Medicine, Dentistry and Health Sciences, Monash University, Clayton, VIC, Australia
  9. Cabrini Health, Malvern, VIC, Australia

Background: In the single arm phase 2 PHAEDRA trial, 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) advanced endometrial cancer (AEC). This substudy investigates MMR molecular subtypes and other genomic tumor features and their correlation with treatment outcomes.

Methods: Testing was performed to determine molecular subtypes of dMMR, including germline MMR pathogenic variant carriers (Lynch syndrome), biallelic somatic MMR mutations and somatic MLH1 promoter hypermethylation. DNA from FFPE tumour tissue and matched blood was available from 41/71 925dMMR, 16 pMMR) participants for testing on a targeted 298 gene panel including the MMR genes and key somatic AEC driver genes. The derived tumour genomic features included tumour mutational burden (TMB), COSMIC v3.2 tumour mutational signatures and insertion/deletion (Indel) somatic mutation count.

Results: Of the 71 patients recruited, 35 were dMMR and 36 were pMMR. Median follow-up was 44 vs 52 months in dMMR vs pMMR participants, respectively. The dMMR molecular subtypes were 4 (11.4%) Lynch syndrome, 4 (11.4%) somatic MMR mutation, 25 (71.4%) MLH1 methylated and 2 (5.7%) dMMR-uncategorised. The OTR rate was 100% (4/4; 95%CI 40-100%) for Lynch, 75% (3/4; 95%CI 22-99%) for somatic MMR mutations and 40% (10/25; 95%CI 22-61%) for 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 MLH1 methylated group, TMB was also higher in responders vs non-responders (40 v 21; p=0.03). Somatic mutations in KRAS, PTEN, PIK3CA, ARID1A and TP53 were not associated with OTR rate.

 

Conclusions: dMMR-MLH1 methylated AEC demonstrated greater heterogeneity in OTR to single agent durvalumab than the dMMR-Lynch and dMMR-somatic MMR mutation molecular subtypes.  Higher TMB was seen in responders, and specifically within dMMR-MLH1 methylated responders, compared to non-responders