ADVERTISEMENT
Soluble programmed cell death ligand 1 associated with clinical outcome in gastric cancer patients treated with nivolumab: Blood based biomarker analysis of DELIVER trial (JACCRO-GC08AR)
Background
The potential predictive value of soluble checkpoint molecules for immune checkpoint inhibitor has been shown in several malignancies including non-small cell lung cancer and renal cell carcinoma, but not in gastric cancer. We thus assessed the association of soluble PD-1 (sPD-1), soluble Programmed cell Death Ligand 1 (sPD-L1) and soluble Cytotoxic T-Lymphocyte-Associated protein 4 (sCTLA-4) with efficacy measures including survival in advanced gastric cancer patients treated with nivolumab monotherapy using blood samples collected from a prospective observational and translational study (DELIVER [JACCRO-GC08] trial).
Methods
The DELIVER trial enrolled 501 patients with advanced gastric cancer treated with nivolumab monotherapy between March 2018 to August 2019, in which blood samples were prospectively collected before treatment. Serum levels of soluble markers before nivolumab monotherapy were examined in 439 patients, using an HISCL™ series (Sysmex, Kobe, Japan). Primary endpoint was the association of sPD-1, sPD-L1, and sCTLA-4 with progression-free survival (PFS). Secondary endpoints included several relationships between soluble markers and clinical outcomes. The cutoff values for each soluble marker were determined as the value which maximized the C-statistic calculated by dichotomizing each marker (high and low) with all possible values in the first 180 patients. Validation of such cut off values was performed in the last 258 patients. The Glasgow Prognostic Score (GPS) assigns 1 point for albumin <3.5 g/dL and 1 point for CRP ≥1.0 mg/dL and produces scores of low (0 point), intermediate (1 point), and high risk (2 points).
Results
Among the soluble markers, high sPD-L1 trended to associate with poor PFS (p=.070) but no such association was found in sPD-1 and sCTLA-4. Shorter overall survival (OS) was associated with high sPD-L1(p=.005) and high sCTLA-4(p=.023) but not with high sPD-1(p=.125). No soluble markers were associated with tumor shrinkage or hyper progression. Considering the influence of nutrition and the presence of inflammation on the immune environment where tumor cells and immune cells expressing checkpoint molecules are present, we performed a multivariable analysis including serum albumin (< 3.5 g/dL) and CRP (≥1.0 mg/dL) in addition to sPD-1, sPD-L1 and sCTLA-4 at baseline. We found that sPD-L1, serum albumin and CRP were independently associated with OS. Categorization of patients according to GPS (0, 1, 2) and sPD-L1 (high vs. low) clearly identified the subgroup with worst OS in patients with “GPS2 & high sPD-L1” (2.83 months [95% confidence interval {CI}, 2.40-4.40]) followed by those with “GPS2 & low sPD-L1 / GPS1 & high sPD-L1” (4.24 months [95% CI, 3.75-5.82]), those with “GPS1 & low sPD-L1 / GPS0 & high sPD-L1” (7.75 months [95% CI, 6.18-9.10]), and the best OS was found in those with “GPS0 and low sPD-L1” (12.00 months [95% CI, 9.36-13.54]).
Conclusions
Baseline sPD-L1 levels have the potential to predict survival on PD-1 inhibitor nivolumab in advanced gastric cancer, of which predictive accuracy could be more reliable by combining nutrition and inflammation marker, GPS. Further investigation of this biomarker is warranted in the combination of nivolumab and chemotherapy.
Legal entity responsible for the study
The author.
Funding
SYSMEX.
Disclosures
H. Kawakami: Honoraria (self): Taiho Pharmaceutical Co. Ltd, Ono Pharmaceutical Co. Ltd., Bristol-Myers Squibb Co. Ltd., Daiichi-Sankyo Co. Ltd.; Advisory / Consultancy: Daiichi-Sankyo Co. Ltd.; Research grant / Funding (institution): Taiho Pharmaceutical Co. Ltd, Bristol-Myers Squibb Co. Ltd, Eisai Co. Ltd., Kobayashi Pharmaceutical. Co., Ltd. Y. Sunakawa: Honoraria (self): Bristol-Myers Squibb, Chugai Pharm, Eli Lilly Japan; Advisory / Consultancy: Daiichi-Sankyo, Bristol-Myers Squibb, Guardant Health; Research grant / Funding (self): Chugai Pharm, Takeda, Taiho Pharm. E. Inoue: Speaker Bureau / Expert testimony: Bristol-Myers Squibb. R. Matoba: Shareholder / Stockholder / Stock options: DNA Chip Research Inc.; Officer / Board of Directors: DNA Chip Research Inc. T. Sato: Full / Part-time employment: Sysmex Corporation. C. Suminaka: Full / Part-time employment: Sysmex Corporation. A. Makiyama: Honoraria (self): Ono Pharmaceutical Co. Ltd., Bristol-Myers Squibb Co. Ltd. H. Hayashi: Honoraria (self): AstraZeneca K.K., Boehringer Ingelheim Japan Inc., Bristol-Myers Squibb Co. Ltd., Chugai Pharmaceutical Co. Ltd., Eli Lilly Japan K.K., Kyorin pharmaceutical co. ltd, Merck Biopharma Co., Ltd., MSD K.K., Novartis pharmaceuticals k.k, Ono Pharmaceutic; Advisory / Consultancy: AstraZeneca K.K., Boehringer Ingelheim Japan Inc., Bristol-Myers Squibb Co. Ltd., Chugai Pharmaceutical Co. Ltd., Eli Lilly Japan K.K, Pfizer Japan Inc., Shanghai Haihe Biopharm, Takeda Pharmaceutical Company Limited, Daiichi Sankyo Co. Ltd. and Merc; Research grant / Funding (self): AstraZeneca K.K., Boehringer Ingelheim Japan Inc., Chugai Pharmaceutical Co. Ltd., and Ono Pharmaceutical Co. Ltd.; Research grant / Funding (institution): AstraZeneca K.K., Boehringer Ingelheim Japan Inc., Bristol-Myers Squibb Co. Ltd., Chugai Pharmaceutical Co. Ltd., and Ono Pharmaceutical Co. Ltd. and personal fees from AstraZeneca K.K., Boehringer Ingelheim Japan Inc., Bristol-Myers Squibb Co. Ltd.,. K. Chamoto: Research grant / Funding (self): Sysmex Corporation. T. Honjo: Research grant / Funding (self): Sysmex Corporation, Bristol-Myers Squibb Company, Meiji Seika Pharma Co., Ltd. K. Nakagawa: Honoraria (self): Eli Lilly Japan K.K. , Chugai Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd.; Research grant / Funding (institution): Takeda Pharmaceutical Co.,Ltd., Chugai Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd. W. Ichikawa: Honoraria (self): Chugai Pharma, Merck Biopharma; Research grant / Funding (institution): Taiho Pharma, Chugai Pharma, Takeda Pharma. All other authors have declared no conflicts of interest.
