TY - JOUR
T1 - Analyses of PD-L1 and inflammatory gene expression association with efficacy of nivolumab ± Ipilimumab in gastric cancer/gastroesophageal junction cancer A C
AU - Lei, Ming
AU - Siemers, Nathan O.
AU - Pandya, Dimple
AU - Chang, Han
AU - Sanchez, Teresa
AU - Harbison, Christopher
AU - Szabo, Peter M.
AU - Janjigian, Yelena
AU - Ott, Patrick A.
AU - Sharma, Padmanee
AU - Bendell, Johanna
AU - Jeffry Evans, Thomas R.
AU - de Braud, Filippo
AU - Chau, Ian
AU - Boyd, Zachary
N1 - Funding Information:
This study was supported by Bristol Myers Squibb and by Ono Pharmaceutical Co., Ltd. The authors would like to thank the patients who participated in this trial and their families, as well as the investigators, study coordinators, and study teams, and Dako, an Agilent Technologies Inc. company, for collaborative development of the PD-L1 IHC 28-8 pharmDx assay. The authors acknowledge Scott Chasalow, Abraham Apfel, and Kyung In Kim for their advice on statistical and bioinformatic methods used in the study and contributions to the interpretation of data. All authors contributed to the writing and approval of this manuscript. Writing and editorial assistance were provided by Emily Motola, PharmD, and Matthew Weddig of Spark Medica Inc., funded by Bristol Myers Squibb, according to Good Publication Practice guidelines.
Funding Information:
M.Lei reports personal fees fromBristolMyers Squibboutside thesubmitted work;in addition, M. Lei has a patent for PCT/US2020/025441 pending to Bristol Myers Squibb. N.O. Siemers reports other from Bristol Myers Squibb and Abiosciences, Inc. outside the submitted work; in addition, N.O. Siemers has a patent for PCT patent publications WO2020/198672 and WO2020/198676, filing date March 27, 2020, to Bristol Myers Squibb. D. Pandya reports other from Bristol Myers Squibb outside the submitted work; in addition, D. Pandya has a patent for PCT patent publications WO2020/198672 and WO2020/198676, filing date March 27, 2020, to Bristol Myers Squibb. H. Chang reports other from Bristol Myers Squibb outside the submitted work; in addition, H. Chang has a patent for PCT patent publications WO2020/198672 and WO2020/ 198676, filing date March 27, 2020, to Bristol Myers Squibb. T. Sanchez reports other from Bristol Myers Squibb during the conduct of the study and outside the submitted work; in addition, T. Sanchez has a patent for PCT patent publications WO2020/198672 and WO2020/198676, filing date March 27, 2020, to Bristol Myers Squibb. C. Harbison reports other from Bristol Myers Squibb outside the submitted work. P.M. Szabo reports other from Bristol Myers Squibb during the conduct of the study. Y. Janjigian reports other from Bristol Myers Squibb, Rgenix, Eli Lilly, Merck, Bayer, Merck Serono, Daiichi Sankyo, Pfizer, Imugene, Zymeworks, Seattle Genetics, Basilea Pharmaceutica, AstraZeneca, National Cancer Institute, Department of Defense, Cycle for Survival, Genentech/Roche, and Fred’s Team outside the submitted work. P.A. Ott reports grants and personal fees from Bristol Myers Squibb during the conduct of the study, as well as grants and personal fees from Merck, Genentech, Novartis, Neon Therapeutics, Celldex, and Pfizer GSK; grants from AstraZeneca and ARMO BioSciences; and personal fees from Array outside the submitted work. P. Sharma reports personal fees from Achelois, BioAtla, Lytix, Lava, Glympse, Earli, Marker Therapeutics, Polaris, Jounce, Neon, Oncolytics, Hummingbird, Dragonfly, and Infinity Pharma outside the submitted work. J. Bendell reports grants and other from Gilead, Genentech/Roche, Bristol Myers Squibb, Five Prime Therapeutics, Eli Lilly, Merck, MedImmune, Celgene, Taiho, Macrogenics, GlaxoSmithKline, Novartis, OncoMed, Leap Therapeutics, TG Therapeutics, AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Bayer, Incyte, Apexigen, Array, Sanofi, Agios, ARMO BioSciences, Ispen, Oncogenex, Evelo, Forma Therapeutics, Innate, Arch Oncology, Prelude Therapeutics, Amgen, Pfizer, Seattle Genetics, Bicycle Therapeutics, and Relay Therapeutics; grants from EMD Serono, Kolltan, SynDevRx, Forty Seven, OnyX, Takeda, Eisai, Celldex, CytomX, Nektar, Boston Biomedical, Merrimack, Tarveda, Marshall Edwards, Pieris, Mersana, Calithera, Blueprint, Merus, Jacobio, Effector, Novocare, Arrys, Tracon, Sierra, Unum Therapeutics, Vyriad, Harpoon, ADC, Millennium, ImClone, Acerta Pharma, Rgenix, Bellicum, Gossamer Bio, Arcus Bio, Tempest Tx, Shattuck Labs, Synthorx, Inc., Revolution Medicines, Zymeworks, AtlasMedx, Scholar Rock, NGM Biopharma, Treadwell Therapeutics, IGM Biosciences, MabSpace, Repare Therapeutics, and Neolmmune Tech; and other from Phoenix Bio, Cyteir, Molecular Partners, Torque, Tizona, Janssen, Tolero, TD2 (Translational Drug Development), Moderna Therapeutics, Tanabe Research, BeiGene, Continuum Clinical, Amgen, Evelo, Piper Biotech, Samsung Bioepis, and Fusion Therapeutics outside the submitted work. T.R.J. Evans reports grants, personal fees, and nonfinancial support from Bristol Myers Squibb during the conduct of the study, as well as grants and personal fees from Roche/
Publisher Copyright:
© 2021 American Association for Cancer Research.
PY - 2021/7/15
Y1 - 2021/7/15
N2 - Purpose: In advanced gastric cancer/gastroesophageal junction cancer (GC/GEJC), there is a need to identify biomarkers of response to therapies, such as immune checkpoint inhibitors. Patients and Methods: In post hoc exploratory analyses from CheckMate 032 (GC/GEJC cohort), we evaluated associations between nivolumab ± ipilimumab (NIVO ± IPI) efficacy and programmed death ligand 1 (PD-L1) expression, defined by tumor cells (% TC) or combined positive score (CPS; sum of PD-L1–staining TCs þ immune cells, divided by total viable TCs, × 100) using the Dako PD-L1 IHC 28-8 pharmDx assay, or inflammatory gene expression. Results: There was a trend toward increased efficacy (objective response and overall survival) when PD-L1 expression was determined by CPS compared with % TC at higher cutoffs of ≥5 and ≥10 in the pooled analysis of all treatment regimens. In this analysis, 19% and 26% of patients with PD-L1–positive tumors at a CPS cutoff of ≥5 and ≥10, respectively, had an objective response compared with 8% and 9% of patients at the equivalent % TC cutoffs. Longer survival was demonstrated in patients with PD-L1–positive (defined by CPS cutoffs of ≥5 and ≥10) versus PD-L1–negative status. Similar results were observed in the NIVO 1 mg/kg þ IPI 3 mg/kg subgroup. Multiple inflammatory gene signatures/transcripts, including a signature consisting of four genes (CD274, CD8A, LAG3, and STAT1), showed associations with response to NIVO ± IPI. Conclusions: This study suggests a greater association of PD-L1 expression by CPS with NIVO ± IPI efficacy compared with % TC PD-L1 expression in patients with GC/GEJC. Inflammatory signatures were also associated with NIVO ± IPI response, warranting further investigation.
AB - Purpose: In advanced gastric cancer/gastroesophageal junction cancer (GC/GEJC), there is a need to identify biomarkers of response to therapies, such as immune checkpoint inhibitors. Patients and Methods: In post hoc exploratory analyses from CheckMate 032 (GC/GEJC cohort), we evaluated associations between nivolumab ± ipilimumab (NIVO ± IPI) efficacy and programmed death ligand 1 (PD-L1) expression, defined by tumor cells (% TC) or combined positive score (CPS; sum of PD-L1–staining TCs þ immune cells, divided by total viable TCs, × 100) using the Dako PD-L1 IHC 28-8 pharmDx assay, or inflammatory gene expression. Results: There was a trend toward increased efficacy (objective response and overall survival) when PD-L1 expression was determined by CPS compared with % TC at higher cutoffs of ≥5 and ≥10 in the pooled analysis of all treatment regimens. In this analysis, 19% and 26% of patients with PD-L1–positive tumors at a CPS cutoff of ≥5 and ≥10, respectively, had an objective response compared with 8% and 9% of patients at the equivalent % TC cutoffs. Longer survival was demonstrated in patients with PD-L1–positive (defined by CPS cutoffs of ≥5 and ≥10) versus PD-L1–negative status. Similar results were observed in the NIVO 1 mg/kg þ IPI 3 mg/kg subgroup. Multiple inflammatory gene signatures/transcripts, including a signature consisting of four genes (CD274, CD8A, LAG3, and STAT1), showed associations with response to NIVO ± IPI. Conclusions: This study suggests a greater association of PD-L1 expression by CPS with NIVO ± IPI efficacy compared with % TC PD-L1 expression in patients with GC/GEJC. Inflammatory signatures were also associated with NIVO ± IPI response, warranting further investigation.
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U2 - 10.1158/1078-0432.CCR-20-2790
DO - 10.1158/1078-0432.CCR-20-2790
M3 - Article
C2 - 33782030
AN - SCOPUS:85109490398
SN - 1078-0432
VL - 27
SP - 3925
EP - 3935
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 14
ER -