Influence of genomic landscape on cancer immunotherapy for newly diagnosed ovarian cancer: biomarker analyses from the IMagyn050 randomized clinical trial

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.
This work was supported by F. Hoffmann-La Roche Ltd. The trial was sponsored, designed, and conducted by F. Hoffmann-La Roche/Genentech in collaboration with the Gynecologic Oncology Group Foundation (GOG-F) and the European Network for Gynaecological Oncological Trial Groups (ENGOT) according to what was subsequently described in 2019 as ENGOT model C. The sponsor (F. Hoffmann-La Roche/Genentech) was involved in data collection, analysis, and interpretation. Medical writing assistance was provided by Jennifer Kelly, MA (Medi-Kelsey Ltd, Ashbourne, UK), funded by F. Hoffmann-La Roche Ltd. No grant number is applicable. We thank the patients and their families and the investigators, study groups, and clinical sites for their contributions to the IMagyn050 trial and this analysis. IMagyn050/GOG 3015/ENGOT-OV39 is sponsored by F. Hoffmann-La Roche Ltd. The publication costs of this article were defrayed in part by the payment of publication fees. Therefore, and solely to indicate this fact, this article is hereby marked “advertisement” in accordance with 18 USC section 1734.