Phase II Study to Evaluate the Peripheral Blood Mononuclear Cell Biomarker for Nivolumab Efficacy on Previously Treated Non-Small Cell Lung Cancer Subjects (NEJ029B: IMMUNITY-ONE)

Background Although anti-PD-1 antibodies are the most promising agents in advanced non-small cell lung cancer (NSCLC), no definitive biomarkers of efficacy exist. We developed a novel assay for peripheral blood mononuclear cell (PBMC) biomarker using the prediction formula consisting of CD62L-downregulated (CD62Llow) CD4+T cells and CD25+Foxp3+CD4+T cells. This study aimed to validate it. Methods This prospective multicenter phase II study included patients with treated advanced or metastatic NSCLC. After registration and PBMC biomarker analysis, they were classified into responder (RT) or non-responder (NRT) type. Nivolumab was administered every two weeks. The primary endpoint was disease control rate (DCR) at nine weeks after nivolumab treatment in RT patients. Desired and threshold DCR were set at 80% and 60%, respectively. Secondary endpoints were objective response rate (ORR), time to treatment failure, progression-free survival (PFS), overall survival, safety and tolerability, comparison with NRT patients, and PBMC biomarker quality improvement. Results Of the 96 enrolled patients, 95 were eligible for PBMC analysis: 3 were unanalyzable, and 92 were analyzed; however, 40 had a minimal number of live cells. We excluded 19 patients who did not receive nivolumab in NRT and 1 with indeterminable treatment effect at nine weeks, and 72 patients comprised the per protocol set (PPS), of which 43 were RT and 29 NRT. The DCR and ORR in RT patients were 65.1% (95% confidence interval [CI], 50.9-79.4%) and 14.0% (95% CI, 3.6-24.3%), respectively. The PFS in RT patients was 113 days (95% CI, 65-158). As a subset analysis, we examined 45 patients (25 RT and 20 NRT) excluding those with ≥50% dead cell ratio in lymphocyte culture. The DCR was 80.0% (95%CI, 64.3-95.7) in RT and 50.0% (95% CI, 28.1-71.9) in NRT (chi-square test, p = 0.034). Conclusions In alive PBMC analysis, DCR was better in the RT than in the NRT patients. This PBMC biomarker using the ratio of CD62LlowCD4+T cells to CD25+Foxp3+CD4+T cells might be promising for predicting nivolumab efficacy. Clinical trial identification UMIN ID: UMI28468. Legal entity responsible for the study North East Japan Study Group (NEJSG). Funding Ono Pharmaceutical Co., Ltd., Bristol-Myers Squibb K.K. Disclosure O. Yamaguchi: Research grant / Funding (institution): Nihon Medi-Physics Co., Ltd.; Speaker Bureau / Expert testimony: AstraZeneca; Speaker Bureau / Expert testimony: Ono Pharmaceutical; Speaker Bureau / Expert testimony: Bristol-Myers Squibb. T. Kozuki: Honoraria (self), Research grant / Funding (institution): AstraZeneca; Honoraria (self): Nippon Beohringer Ingelheim Co.; Honoraria (self), Research grant / Funding (institution): Bristol-Myers Squibb; Honoraria (self), Research grant / Funding (institution): Chugai Pharmaceutical Co.; Honoraria (self): Kyowa-Hakko Kirin; Honoraria (self), Research grant / Funding (institution): Eli Lilly Japan; Research grant / Funding (institution): Merck Biopharm; Honoraria (self): MSD; Honoraria (self): Ono Pharmaceutical Co.; Honoraria (self): Pfizer; Honoraria (self): Taiho Pharmaceutical Co. N. Furuya: Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Lilly; Honoraria (self): Chugai Pharma ; Honoraria (self): AstraZeneca; Honoraria (self): Pfizer; Honoraria (self): Taiho Pharmaceutical; Honoraria (self): Ono Pharmaceutical. T. Yamada: Research grant / Funding (self): Ono Pharmaceutical Co., Ltd.; Research grant / Funding (self): Boehringer Ingelheim Japan Inc.; Research grant / Funding (self): Takeda Pharmaceutical Co. Ltd.; Research grant / Funding (self): Chugai Pharmaceutical Co., Ltd. R. Ko: Honoraria (self): Ono Pharmaceutical Co., Ltd. T. Harada: Honoraria (institution): Boehringer Ingelheim; Honoraria (institution): Hisamitsu Pharmaceutical Co., Inc; Honoraria (institution): GlaxoSmithKleine K.K. M. Seike: Honoraria (self), Research grant / Funding (institution): Ono Pharmaceutical; Honoraria (self), Research grant / Funding (institution): Bristol-Myers Squibb. K. Yoshimura: Honoraria (self): Chugai Pharma. K. Kobayashi: Speaker Bureau / Expert testimony: AstraZeneca; Speaker Bureau / Expert testimony: Boehringer Ingelheim; Speaker Bureau / Expert testimony: Taiho Pharmaceutical Company; Speaker Bureau / Expert testimony: Ono Pharmaceutical Company. H. Kagamu: Honoraria (self), Research grant / Funding (institution): Ono Pharmaceutical; Honoraria (self), Research grant / Funding (institution): Taiho Pharmaceutical; Honoraria (self), Research grant / Funding (institution): Chugai Pharmaceutical; Honoraria (self): AstraZeneca; Honoraria (self), Research grant / Funding (institution): Boehringer Ingelheim; Honoraria (self), Research grant / Funding (institution): Eli Lilly Japan. All other authors have declared no conflicts of interest.