Reference Detail

Ref Type

Journal Article

PMID

(34103352)

Authors

Antill Y, Kok PS, Robledo K, Yip S, Cummins M, Smith D, Spurdle A, Barnes E, Lee YC, Friedlander M, Baron-Hay S, Shannon C, Coward J, Beale P, Goss G, Meniawy T, Lombard J, Andrews J, Stockler MR, Mileshkin L, Australia New Zealand Gynaecological Oncology Group (ANZGOG)

Title

Clinical activity of durvalumab for patients with advanced mismatch repair-deficient and repair-proficient endometrial cancer. A nonrandomized phase 2 clinical trial.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Journal for immunotherapy of cancer	9	6	2021 06		J Immunother Cancer

URL

Abstract Text

In this study, we assessed the activity of durvalumab, an antibody to programmed death ligand-1, in two cohorts of women with advanced endometrial cancers (AEC)-mismatch repair proficient (pMMR) and mismatch repair deficient (dMMR).A multicenter phase two study was performed in women with AEC with pMMR tumor progressing after one to three lines of chemotherapy and women with AEC with dMMR tumor progressing after zero to three lines of chemotherapy. Mismatch repair status was based on immunohistochemistry expression. All women received durvalumab 1500 mg given every 4 weeks until progression or unacceptable toxicity. The primary endpoint was objective tumor response by RECIST V.1.1 modified for immune-based therapeutics.Seventy-one women were recruited: 35 dMMR and 36 pMMR. Median follow-up was 19 vs 21 months in dMMR versus pMMR, respectively. Median age was 67 years. Histology in dMMR versus pMMR included endometrioid (94% vs 57%) and serous (0% vs 31%) and was high grade in 26% vs 74%. The objective tumor response rate (OTRR) in the dMMR cohort was 47% (17/36, 95% CI 32 to 63), including 6 complete responses and 11 partial responses (PRs)) vs 3% in the pMMR cohort (1/35, 95% CI 1 to 15, PR). In the dMMR cohort, durvalumab was the first-line therapy in 58% (OTRR 57%) and the second-line therapy in 39% (OTRR 38%). Median progression-free survival was 8.3 months in the dMMR cohort vs 1.8 months in the pMMR cohort. The 12-month overall survival (OS) rate was 71% in dMMR vs 51% in pMMR, with median OS not reached for dMMR vs 12 months for pMMR. Immune-related adverse events occurred in 14 women, mostly grades 1-2.Durvalumab monotherapy showed promising activity and acceptable safety in AEC with dMMR regardless of prior lines of chemotherapy, but activity was limited in AEC with pMMR.ANZGOG1601, ACTRN12617000106336, and NCT03015129.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
MSH6 negative	endometrial cancer	predicted - sensitive	Durvalumab	Phase II	Actionable	In a Phase II trial (PHAEDRA), Imfinzi (durvalumab) treatment resulted in superior objective tumor response rate (47%, 17/36, 6 complete responses, 11 partial responses (PR) vs 3%, 1/35, 1 PR) and median progression-free survival (8.3 vs 1.8 mo) in patients with mismatch repair deficient (dMMR, defined by the loss of MLH1, PMS2, MSH2, or MSH6 expression by IHC) advanced endometrial cancer compared to mismatch repair proficient patients (PMID: 34103352; NCT03015129).	34103352
MLH1 negative	endometrial cancer	sensitive	Durvalumab	Phase II	Actionable	In a Phase II trial (PHAEDRA), Imfinzi (durvalumab) treatment resulted in superior objective tumor response rate (47%, 17/36, 6 complete responses, 11 partial responses (PR) vs 3%, 1/35, 1 PR) and median progression-free survival (8.3 vs 1.8 mo) in patients with mismatch repair deficient (dMMR, defined by the loss of MLH1, PMS2, MSH2, or MSH6 expression by IHC) advanced endometrial cancer compared to mismatch repair proficient patients (PMID: 34103352; NCT03015129).	34103352