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

Yoland Antill, Peey-Sei Kok, Kristy Robledo, Sonia Yip, Michelle Cummins, Deborah Smith, Amanda Spurdle, Elizabeth Barnes, Yeh Chen Lee, Michael Friedlander, Sally Baron-Hay, Catherine Shannon, Jermaine Coward, Philip Beale, Geraldine Goss, Tarek Meniawy, Janine Lombard, John Andrews, Martin R Stockler, Linda Mileshkin, Australia New Zealand Gynaecological Oncology Group (ANZGOG), Yoland Antill, Peey-Sei Kok, Kristy Robledo, Sonia Yip, Michelle Cummins, Deborah Smith, Amanda Spurdle, Elizabeth Barnes, Yeh Chen Lee, Michael Friedlander, Sally Baron-Hay, Catherine Shannon, Jermaine Coward, Philip Beale, Geraldine Goss, Tarek Meniawy, Janine Lombard, John Andrews, Martin R Stockler, Linda Mileshkin, Australia New Zealand Gynaecological Oncology Group (ANZGOG)

Abstract

Background: 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).

Methods: 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.

Results: 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.

Conclusion: 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.

Trial registration numbers: ANZGOG1601, ACTRN12617000106336, and NCT03015129.

Keywords: clinical trials; immunotherapy; phase II as topic; programmed cell death 1 receptor.

Conflict of interest statement

Competing interests: YA: honoraria from AstraZeneca and research funding from AstraZeneca. P-SK: research funding from AstraZeneca and honoraria from Pfizer. DS: stock or other ownership for SNP Pathology; honoraria from Mark Sharp & Dohme; and patents, royalties, and other intellectual property from Uniquest. MF: honoraria from Pfizer and AstraZeneca; and consulting or advisory role, or AstraZeneca and Pfizer. SB-H: consulting or advisory role from AstraZeneca, Novartis, and Pfizer; and travel and accommodation expenses from Novartis. CS: speakers’ bureau for AstraZeneca olaparib advisory board, Roche HER2+ breast cancer. JC: honoraria from Takeda, MSD; consulting or advisory role from Takeda, MSD; research funding from AstraZeneca; and travel, accommodation, and expenses from AMGEN-ESMO. PB: honoraria from Roche; consulting or advisory role from AstraZeneca; and travel and accommodation expenses from Astra Zeneca. TM: honoraria and research funding from AstraZeneca. MRS: research funding from Astra Zeneca.

© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1
Figure 1
Enrollment and outcomes. MMR, mismatch mutation repair.
Figure 2
Figure 2
Objective tumor responses in dMMR and pMMR advanced endometrial cancer cohorts. Waterfall plots for the maximum decrease in the sum of the target lesions are given in (A) for dMMR (n=32, 2 died prior to reassessment and 1 was not evaluable for target lesions) and (B) for pMMR (n=33, 3 died prior to reassessment), colored by lines of previous chemotherapy, with histology marked. Spider plots for the change in the sum of the target lesions over time are shown for dMMR (n=32) (C) and for pMMR (n=33) (D), colored by lines of previous chemotherapy. dMMR, mismatch repair deficient; pMMR, mismatch repair proficient.
Figure 3
Figure 3
Graphs of (A) PFS (B) OS in dMMR and pMMR cohorts. dMMR, mismatch repair deficient; iRECIST, RECIST V.1.1 modified for immune-based therapeutics; pMMR, mismatch repair proficient. OS, overall survival; PFS, progression-free survival.

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