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 - Funding Information:
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.
Funding Information:
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.
Funding Information:
C.N. Landen reports personal fees from Roche during the conduct of the study as well as personal fees from Mercy Bio outside the submitted work. L. Molinero is an employee of Genentech and holds stock in Roche. H. Hamidi is an employee of Roche and holds stock in Genentech. J. Sehouli reports grants from Roche during the conduct of the study as well as grants and personal fees from GSK, AstraZeneca, Clovis, MSD, and Pfizer outside the submitted work. K.N. Moore reports personal fees from AstraZeneca, Aravive, Addi, Alkemeres, Blueprint Medicines, Clovis, Eisai, EMD Serono, GSK/Tesaro, Genentech/Roche, Hengrui, Immunogen, Inxmed, Imab, Lilly, Merck, Mersana, Mereo, Novartis, OncXerna, Onconova, Tarveda, VBL Therapeutics, and Verastem during the conduct of the study as well as personal fees from Genentech/Roche outside the submitted work; in addition K.N. Moore is associate director for GOG Partners and is on the GOG Foundation board of directors (uncompensated). M. Bookman reports advisory board participation with Genentech/Roche and Merck Sharp & Dohme and is chair of an independent data monitoring committee at Immunogen. K. Lindemann reports other support from Roche during the conduct of the study as well as personal fees from MSD, Eisai, AstraZeneca, and Nycode and grants from GSK outside the submitted work. R. Berger reports other support from Roche during the conduct of the study as well as other support from Merck, PharmaMar, AstraZeneca, Novartis, Roche, and BIOCAD outside the submitted work. M. Beiner reports other support from Meir Medical Center during the conduct of the study. A. Okamoto reports grants from Taiho Pharmaceutical Co. Ltd., Fuji Pharma Co. Ltd., Kissei Pharmaceutical Co. Ltd., ASKA Pharmaceutical Co. Ltd., Kaken Pharmaceutical Co. Ltd., Meiji Holdings Co. Ltd., Nippon Shinyaku Co. Ltd., Tsumura & Co., Mochida Pharmaceutical Co. Ltd., Linical Co. Ltd., Daiichi Sankyo Co. Ltd., Pfizer Japan Inc., Terumo Corporation, Eisai Co. Ltd., and Gyne Mom Co. Ltd.; grants and personal fees from MSD K.K., Chugai Pharmaceutical Co. Ltd., Takeda Pharmaceutical Company Ltd., and AstraZeneca K.K.; and personal fees from Zeria Pharmaceutical Co. Ltd. and Johnson & Johnson K.K. outside the submitted work. C. Aghajanian reports personal fees from Eisai/ Merck, Roche/Genentech, AbbVie, AstraZeneca/Merck, and Repare and grants from AbbVie, Roche/Genentech, and AstraZeneca outside the submitted work; in addition, C. Aghajanian serves on the board of directors of GOG Foundation (travel cost reimbursement for attending meetings) and NRG Oncology (unpaid). P.H. Thaker reports grants and personal fees from Merck, and GlaxoSmithKline and personal fees from Clovis Oncology, AstraZeneca, Iovance, Aadi Biosciences, Novocure, Celsion/ Immunon, Immunogen, Seagen, Agenus, Mersana, Eisai, and Incyte outside the submitted work. S.V. Blank reports grants and other support from Roche during the conduct of the study. V.K. Khor is an employee of Genentech and holds stock in Roche. C.-W. Chang is an employee of Genentech and holds stock in Roche. Y.G. Lin is an employee of Genentech and holds stock in Roche. S. Pignata reports grants and personal fees from Roche during the conduct of the study. No disclosures were reported by the other authors.
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 - http://www.scopus.com/inward/record.url?scp=85159254986&partnerID=8YFLogxK
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 -