Influence of Genomic Landscape on Cancer Immunotherapy for Newly Diagnosed Ovarian Cancer: Biomarker Analyses from the IMagyn050 Randomized Clinical Trial

Charles N. Landen, Luciana Molinero, Habib Hamidi, Jalid Sehouli, Austin Miller, Kathleen N. Moore, Cagatay Taskiran, Michael Bookman, Kristina Lindemann, Charles Anderson, Regina Berger, Tashanna Myers, Mario Beiner, Thomas Reid, Els Van Nieuwenhuysen, Andrew Green, Aikou Okamoto, Carol Aghajanian, Premal H. Thaker, Stephanie V. BlankVictor K. Khor, Ching Wei Chang, Yvonne G. Lin, Sandro Pignata

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

Purpose: To explore whether patients with BRCA1/2-mutated or homologous recombination deficient (HRD) ovarian cancers benefitted from atezolizumab in the phase III IMagyn050 (NCT03038100) trial. Patients and Methods: Patients with newly diagnosed ovarian cancer were randomized to either atezolizumab or placebo with standard chemotherapy and bevacizumab. Programmed deathligand 1 (PD-L1) status of tumor-infiltrating immune cells (IC) was determined centrally (VENTANA SP142 assay). Genomic alterations, including deleterious BRCA1/2 alterations, genomic loss of heterozygosity (gLOH), tumor mutation burden (TMB), and microsatellite instability (MSI), were evaluated using the FoundationOne assay.HRDwas defined as gLOH ≥ 16%, regardless of BRCA1/2 mutation status. Potential associations between progression-free survival (PFS) and genomic biomarkers were evaluated using standard correlation analyses and log-rank of Kaplan-Meier estimates. Results: Among biomarker-evaluable samples, 22% (234/1,050) harbored BRCA1/2 mutations and 46% (446/980) were HRD. Median TMB was low irrespective of BRCA1/2 or HRD. Only 3% (29/1,024) had TMB ≥10 mut/Mb, and 0.3% (3/1,022) were MSIhigh. PFS was better in BRCA2-mutated versus BRCA2-nonmutated tumors and in HRD versus proficient tumors. PD-L1 positivity (≥1% expression on ICs) was associated with HRD but not BRCA1/2 mutations. PFS was not improved by adding atezolizumab in BRCA2-mutated or HRD tumors; there was a trend toward enhanced PFS with atezolizumab inBRCA1-mutated tumors. Conclusions: Mostovariantumorshave lowTMBdespiteBRCA1/ 2mutations orHRD. NeitherBRCA1/2mutation norHRDpredicted enhanced benefit from atezolizumab. This is the first randomized double-blind trial in ovarian cancer demonstrating that genomic instability triggered by BRCA1/2 mutation or HRD is not associated with improved sensitivity to immune checkpoint inhibitors.

Original languageEnglish
Pages (from-to)1698-1707
Number of pages10
JournalClinical Cancer Research
Volume29
Issue number9
DOIs
StatePublished - May 1 2023

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