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2022-RA-1198-ESGO Post hoc analysis of objective response rate by mismatch repair protein dimer loss/mutation status in patients with mismatch repair deficient endometrial cancer treated with dostarlimab
  1. Anna V Tinker1,
  2. Renaud Sabatier2,
  3. Adriano Gravina3,
  4. Lucy Gilbert4,
  5. Jubilee Brown5,
  6. Vanessa Samouëlian6,
  7. Clare J Reade7,
  8. Cara Mathews8,
  9. Susan Ellard9,
  10. Susana Banerjee10,
  11. Maria Pillar Barretina-Ginesta11,
  12. Rowan Miller12,
  13. Charles Leath13,
  14. Bhavana Pothuri14,
  15. Tao Duan15,
  16. Xinwei Han16,
  17. Eleftherios Zografos17,
  18. Jennifer Veneris16 and
  19. Ana Oaknin18
  1. 1Department of Medicine, British Columbia Cancer, Vancouver Centre, University of British Columbia, Vancouver, BC, Canada
  2. 2Department of Medical Oncology, Institut Paoli Calmettes, Aix-Marseille University, Marseille, France
  3. 3Clinical Trial Unit, Istituto Nazionale Tumori Fondazione G. Pascale, Naples, Italy
  4. 4Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, McGill University Health Centre, Montreal, QC, Canada
  5. 5Division of Gynecologic Oncology, Levine Cancer Institute, Atrium Health, Charlotte, NC
  6. 6Gynecologic Oncology Division, Centre Hospitalier de l’Université de Montréal (CHUM), Centre de Recherche du CHUM (CRCHUM) et Université de Montréal, Montreal, QC, Canada
  7. 7Gynecologic Oncology, Juravinski Cancer Center, Hamilton Health Sciences, Hamilton, ON, Canada
  8. 8Women and Infants Hospital of Rhode Island, Providence, RI
  9. 9BC Cancer-Kelowna, Kelowna, BC, Canada
  10. 10Gynaecology Unit, The Royal Marsden NHS Foundation Trust and Institute of Cancer Research, London, UK
  11. 11Medical Oncology Department, Institut Català d’Oncologia, Girona Biomedical Research Institute (IDIBGI), Girona University, Girona, Spain
  12. 12University College London, St. Bartholomew’s Hospitals London, London, UK
  13. 13University of Alabama at Birmingham, Birmingham, AL
  14. 14Gynecologic Oncology Group (GOG) and Department of Obstetrics/Gynecology, Laura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York, NY
  15. 15GSK, Pennington, NJ
  16. 16GSK, Waltham, MA
  17. 17GSK, London, UK
  18. 18Gynaecologic Cancer Programme, Vall d’Hebron Institute of Oncology (VHIO), Hospital Universitari Vall d’Hebron, Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain ed *Employed by GSK at the time the study was conduct


Introduction/Background Mismatch repair (MMR) deficiency is caused by loss of expression of MMR proteins, MLH1, PMS2, MSH2, and/or MSH6, that function as heterodimers (MLH1/PMS2 and MSH2/MSH6) to mediate DNA repair. Loss of function caused by mutation or epigenetic methylation leads to defective MMR and genomic instability. MMR deficient (dMMR) tumours can respond to anti-programmed death 1 (anti-PD-1) therapy. We report a post hoc analysis of objective response rate (ORR) with loss of MMR dimers and mutation status of MMR genes in patients with dMMR endometrial cancer (EC) treated with dostarlimab.

Methodology GARNET is a multicentre, open-label, single-arm phase 1 study. Cohort A1 enrolled patients with dMMR advanced/recurrent EC. Patients received 500 mg of dostarlimab intravenously Q3W for 4 cycles, then 1000 mg Q6W until disease progression, discontinuation, or withdrawal. MMR protein status (presence or loss) was determined by local immunohistochemistry. MMR gene mutation was determined by FoundationOne. MLH1 loss without MMR gene mutation was a surrogate indicator for epigenetic methylation.

Results Cohort A1 included 143 patients; MMR gene mutation data were available for 101 patients (table 1). Cohort A1 ORR was 45.5%. 66% of patients had loss of MLH1/PMS2; ORR was 48.9%. 11.2% of patients had loss of MSH2/MSH6; ORR was 56.2%. ORR was 41.7% for MLH1 loss with MMR gene mutation and 39.4% for MLH1 loss without MMR gene mutation.

Abstract 2022-RA-1198-ESGO Table 1

Conclusion Patients with dMMR advanced/recurrent EC benefitted from dostarlimab, with no noticeable difference by dimer-pair loss or MMR gene methylation/mutation status. These data suggest the route to MMR deficiency does not influence response to dostarlimab.

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