TY - JOUR
T1 - Influence of Genomic Landscape on Cancer Immunotherapy for Newly Diagnosed Ovarian Cancer
T2 - Biomarker Analyses from the IMagyn050 Randomized Clinical Trial
AU - Landen, Charles N.
AU - Molinero, Luciana
AU - Hamidi, Habib
AU - Sehouli, Jalid
AU - Miller, Austin
AU - Moore, Kathleen N.
AU - Taskiran, Cagatay
AU - Bookman, Michael
AU - Lindemann, Kristina
AU - Anderson, Charles
AU - Berger, Regina
AU - Myers, Tashanna
AU - Beiner, Mario
AU - Reid, Thomas
AU - Van Nieuwenhuysen, Els
AU - Green, Andrew
AU - Okamoto, Aikou
AU - Aghajanian, Carol
AU - Thaker, Premal H.
AU - Blank, Stephanie V.
AU - Khor, Victor K.
AU - Chang, Ching Wei
AU - Lin, Yvonne G.
AU - Pignata, Sandro
N1 - Publisher Copyright:
© 2023 The Authors.
PY - 2023/5/1
Y1 - 2023/5/1
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85159254986
U2 - 10.1158/1078-0432.CCR-22-2032
DO - 10.1158/1078-0432.CCR-22-2032
M3 - Article
C2 - 36595569
AN - SCOPUS:85159254986
SN - 1078-0432
VL - 29
SP - 1698
EP - 1707
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 9
ER -