Yusuke Inoue1,2, Naoki Inui3,4, Masato Karayama3,5, Kazuhiro Asada6, Shun Matsuura7, Masaki Ikeda8, Tomohiro Uto9, Masato Fujii10, Dai Hashimoto11, Takashi Matsui12, Hiroyuki Matsuda13, Nao Inami14, Mikio Toyoshima15, Yusuke Kaida16, Hideki Yasui3, Hironao Hozumi3, Yuzo Suzuki3, Kazuki Furuhashi3, Noriyuki Enomoto3, Tomoyuki Fujisawa3, Takafumi Suda3. 1. Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, 431-3192, Japan. yinoue@hama-med.ac.jp. 2. Department of Clinical Pharmacology and Therapeutics, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu, 431-3192, Japan. yinoue@hama-med.ac.jp. 3. Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, 431-3192, Japan. 4. Department of Clinical Pharmacology and Therapeutics, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu, 431-3192, Japan. 5. Department of Clinical Oncology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu, 431-3192, Japan. 6. Department of Respiratory Medicine, Shizuoka General Hospital, 4-27-1 Kita-ando, Shizuoka, 420-8527, Japan. 7. Department of Respiratory Medicine, Fujieda Municipal General Hospital, 4-1-11 Surugadai, Fujieda, 426-8677, Japan. 8. Department of Respiratory Medicine, Shizuoka Saiseikai General Hospital, 1-1-1 Oshika, Shizuoka, 422-8527, Japan. 9. Department of Respiratory Medicine, Iwata City Hospital, 512-3 Ohkubo, Iwata, 438-8550, Japan. 10. Department of Respiratory Medicine, Shizuoka City Shizuoka Hospital, 10-93 Otemachi, Shizuoka, 420-8630, Japan. 11. Department of Pulmonary Medicine, Seirei Hamamatsu General Hospital, 2-12-12 Sumiyoshi, Hamamatsu, 430-8558, Japan. 12. Department of Respiratory Medicine, Seirei Mikatahara General Hospital, 3453 Mikatahara, Hamamatsu, 433-8558, Japan. 13. Department of Respiratory Medicine, Japanese Red Cross Shizuoka Hospital, 8-2 Otemachi, Shizuoka, 420-0853, Japan. 14. Department of Respiratory Medicine, Shizuoka City Shimizu Hospital, 1231 Miyakami, Shizuoka, 424-8636, Japan. 15. Department of Respiratory Medicine, Hamamatsu Rosai Hospital, 25 Shougen-cho, Hamamatsu, 430-8525, Japan. 16. Department of Respiratory Medicine, Ensyu Hospital, 1-1-1 Chuou, Hamamatsu, 430-0929, Japan.
Abstract
PURPOSE: Identifying patients at high risk of immune-related adverse events (irAEs) that impede the achievement of durable efficacy of programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1) blockade therapy is important in improving their management. Identification of a novel predictive factor of therapeutic benefit is also important in improving patient selection for treatment with PD-1/PD-L1 inhibitors. Further determinants driving response and linking with irAEs are urgently required. METHODS: To address these unmet needs in the field, we explored whether 27 soluble checkpoint proteins and immunomodulatory proteins in serum at the therapy baseline and after week 3 were associated with irAE onset and therapeutic efficacy using MILLIPLEX Human Immuno-Oncology Checkpoint Protein Panel assays in a prospective, multicenter cohort of 81 patients with non-small cell lung cancer (NSCLC) receiving atezolizumab monotherapy. RESULTS: By competing-risks regression analysis, we identified that high levels of B cell-activating factor (BAFF) at baseline were a significant and strong risk factor of irAEs (hazard ratio, 5.61; 95% confidence interval, 2.43-12.96; P < 0.0001). We also identified that increased inducible T cell co-stimulator (ICOS) during the first therapeutic cycle was an independent factor associated with prolonged progression-free survival and overall survival. CONCLUSION: These findings are in keeping with the reported mechanistic basis of these molecules and may provide potential guidance for clinical decision-making to improve patient care. Further validation studies are warranted. Trial registration UMIN000035616 (January 28, 2019).
PURPOSE: Identifying patients at high risk of immune-related adverse events (irAEs) that impede the achievement of durable efficacy of programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1) blockade therapy is important in improving their management. Identification of a novel predictive factor of therapeutic benefit is also important in improving patient selection for treatment with PD-1/PD-L1 inhibitors. Further determinants driving response and linking with irAEs are urgently required. METHODS: To address these unmet needs in the field, we explored whether 27 soluble checkpoint proteins and immunomodulatory proteins in serum at the therapy baseline and after week 3 were associated with irAE onset and therapeutic efficacy using MILLIPLEX Human Immuno-Oncology Checkpoint Protein Panel assays in a prospective, multicenter cohort of 81 patients with non-small cell lung cancer (NSCLC) receiving atezolizumab monotherapy. RESULTS: By competing-risks regression analysis, we identified that high levels of B cell-activating factor (BAFF) at baseline were a significant and strong risk factor of irAEs (hazard ratio, 5.61; 95% confidence interval, 2.43-12.96; P < 0.0001). We also identified that increased inducible T cell co-stimulator (ICOS) during the first therapeutic cycle was an independent factor associated with prolonged progression-free survival and overall survival. CONCLUSION: These findings are in keeping with the reported mechanistic basis of these molecules and may provide potential guidance for clinical decision-making to improve patient care. Further validation studies are warranted. Trial registration UMIN000035616 (January 28, 2019).
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