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Published on: July 25, 2020
Influence of Genomic Landscape on Cancer Immunotherapy for Newly Diagnosed Ovarian Cancer: Biomarker Analyses from
Charles N Landen1, Luciana Molinero2, Habib Hamidi2
1Gynecologic Oncology Group Foundation (GOG-F) and Department of Obstetrics and Gynecology, University of Virginia, Charlottesville, Virginia.
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 death-ligand 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. HRD was 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 MSI-high. PFS was better in BRCA2-mutated versus BRCA2-non-mutated 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 in BRCA1-mutated tumors.
Conclusions:
Most ovarian tumors have low TMB despite BRCA1/2 mutations or HRD. Neither BRCA1/2 mutation nor HRD predicted 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. See related commentary by Al-Rawi et al., p. 1645.
Insights
This study found that adding atezolizumab did not improve progression-free survival in ovarian cancer patients with BRCA1/2 mutations or homologous recombination deficiency (HRD). Genomic instability in these ovarian cancers did not predict response to immune checkpoint inhibitors.
Area of Science:
- Oncology
- Immunotherapy
- Genomics
Background:
- The IMagyn050 trial investigated atezolizumab efficacy in BRCA1/2-mutated or homologous recombination deficient (HRD) ovarian cancers.
- Patients received atezolizumab or placebo alongside standard chemotherapy and bevacizumab.
Discussion:
- Homologous recombination deficiency (HRD) and BRCA1/2 mutations were assessed using genomic assays.
- Tumor mutation burden (TMB) was generally low across patient subgroups.
- Progression-free survival (PFS) was improved in BRCA2-mutated and HRD tumors, but not with atezolizumab addition.
Key Insights:
- Neither BRCA1/2 mutation nor HRD predicted improved PFS with atezolizumab in ovarian cancer.
- A trend towards enhanced PFS was observed with atezolizumab in BRCA1-mutated tumors.
- Low TMB was prevalent in ovarian tumors, even with BRCA1/2 mutations or HRD.
Outlook:
- This trial is the first randomized study in ovarian cancer to show genomic instability does not enhance sensitivity to immune checkpoint inhibitors.
- Further research may explore alternative biomarkers or combination therapies for HRD/BRCA-mutated ovarian cancers.
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