Analysis of small molecule tyrosine kinase inhibitor combined with monoclonal antibody of programmed death receptor-1 in treatment of patients with advanced malignant tumors of digestive system
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摘要:目的 分析小分子酪氨酸激酶抑制剂（TKI）联合程序性死亡受体-1（PD-1）单抗治疗晚期消化系统恶性肿瘤的疗效及安全性。方法 回顾性分析中国医科大学附属第一医院肿瘤内科2019年3月—2021年2月应用小分子TKI联合PD-1单抗治疗的晚期消化系统恶性肿瘤患者用药后的疗效、不良反应、肿瘤生长速率以及不良反应与疗效的相关性。结果 共纳入30例患者，25例可评价疗效，其中胃肠癌客观缓解率（ORR）、疾病控制率（DCR）分别为0、58.33%，肝癌ORR、DCR分别为50.00%、100.00%，胰腺癌ORR、DCR分别为33.30%、100.00%，食管癌ORR、DCR分别为50.00%、100.00%。肿瘤生长速率、免疫相关不良反应发生情况与DCR存在相关性，差异有统计学意义（P < 0.05）。结论 TKI联合PD-1单抗在晚期消化系统恶性肿瘤的治疗中表现出一定的抗肿瘤活性，并且肝癌患者联合治疗的获益更多。联合治疗过程中，肿瘤生长速率慢的患者疗效较好。Abstract:Objective To analyze the efficacy and safety of small molecule tyrosine kinase inhibitor (TKI) combined with monoclonal antibody of programmed death receptor-1 (PD-1) in the treatment of patients with advanced malignant tumors of digestive system.Methods The efficacy and adverse reactions, tumor growth rate and correlation between adverse reactions and efficacy in the patients with advanced malignant tumors of digestive system by combined treatment of TKI and monoclonal antibody of PD-1 from March 2019 to February 2021 in the Internal Department of Oncology of the First Hospital of China Medical University were analyzed retrospectively.Results Among the 30 included patients, 25 patients were available for efficiency evaluation. The objective response rate (ORR) and disease control rate (DCR) of cases with gastric and intestinal cancers were 0 and 58.33% respectively, the ORR and DCR of cases with liver cancer were 50.00% and 100.00% respectively, the ORR and DCR of cases with pancreatic cancer were 33.30% and 100.00% respectively, and the ORR and DCR of cases with esophageal cancer were 50.00% and 100.00% respectively. There were significant correlations between tumor growth rate, immune related adverse events and DCR (P < 0.05).Conclusion TKI combined with monoclonal antibody of PD-1 shows a certain anti-tumor activity in the treatment of patients with advanced malignant tumors of digestive system, and the patients with liver cancer are prone to have more benefits from combined treatment. In the course of combined therapy, patients with slow tumor growth rate have better curative effect.
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表 1 30例患者的基本临床特征[n(%)]
临床特征 数值 年龄/岁 57(34, 73) 性别 男 21(70.00) 女 9(30.00) ECOG评分 1分 28(93.33) ≥2分 2(6.67) 肿瘤分类 胃癌 3(10.00) 肠癌 13(43.33) 肝癌 8(26.67) 胰腺癌 4(13.33) 食管癌 2(40.00) 既往全身治疗 二线 8(26.67) 三线 12(40.00) 三线以上 10(33.33) 肝转移 是 21(70.00) 否 9(30.00) 分子特征 MSI-H 1(3.33) MSI-L 22(73.33) 未知 7(23.33) PD-L1 CPS < 1 9(30.00) ≥1 5(16.67) ≥10 2(6.67) 未知 19(63.33) TMB情况 < 10突变/Mb 17(56.67) ≥10突变/Mb 4(13.33) 未知 9(30.00) 中位TMB/(突变/Mb) 8(2.88, 17.20) 年龄、TMB以中位数(最小值，最大值)表示。
ECOG: 美国东部肿瘤协作组; TMB: 肿瘤突变负荷。
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表 2 30例患者治疗相关不良反应[n(%)]
不良反应 任何级别 ≥3级 导致停药 蛋白尿 12(40.00) 0 0 骨髓抑制 12(40.00) 3(10.00) 0 肝功能损伤 10(33.33) 0 0 皮疹 4(13.33) 3(10.00) 3(10.00) 甲状腺功能减退 3(10.00) 0 1(3.33) 乏力 3(10.00) 0 0 高血压 3(10.00) 2(6.67) 2(6.67) 声音嘶哑 3(10.00) 0 0 心脏毒性 2(6.67) 1(3.33) 1(3.33) 黏膜损伤 2(6.67) 0 1(3.33) 发热 2(6.67) 1(3.33) 1 (3.33)
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[1] SUNG H, FERLAY J, SIEGEL R L, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries[J]. CA: A Cancer Journal for Clinicians, 2021, 71(3): 209-249. doi: 10.3322/caac.21660
[2] GHAHREMANLOO A, SOLTANI A, MODARESI S, et al. Recent advances in the clinical development of immune checkpoint blockade therapy[J]. Cellular Oncology, 2019, 42(5): 609-626. doi: 10.1007/s13402-019-00456-w
[3] HUANG Y, STYLIANOPOULOS T, DUDA D G, et al. Benefits of vascular normalization are dose and time dependent-letter[J]. Cancer Research, 2013, 73(23): 7144-7146. doi: 10.1158/0008-5472.CAN-13-1989
[4] KATO K, MASUISHI T, FUSHIKI K, et al. Impact of tumor growth rate during preceding treatment on tumor response to nivolumab or irinotecan in advanced gastric cancer[J]. Journal of Clinical Oncology, 2019, 37(Suppl 4): 84-84. http://www.sciencedirect.com/science/article/pii/S2059702921001393
[5] FUKUOKA S, HARA H, TAKAHASHI N, et al. Regorafenib plus nivolumab in patients with advanced gastric (GC) or colorectal cancer (CRC): An open-label, dose-finding, and dose-expansion phase 1b trial (REGONIVO, EPOC1603)[J]. Journal of Clinical Oncology, 2019, 37(Suppl 15): 2522-2522. http://www.researchgate.net/publication/333406836_Regorafenib_plus_nivolumab_in_patients_with_advanced_gastric_GC_or_colorectal_cancer_CRC_An_open-label_dose-finding_and_dose-expansion_phase_1b_trial_REGONIVO_EPOC1603
[6] LWIN Z, GOMEZ-ROCA C, SAADA-BOUZID E, et al. LBA41 LEAP-005: Phase Ⅱ study of lenvatinib (len) plus pembrolizumab (pembro) in patients (pts) with previously treated advanced solid tumours[J]. Annals of Oncology, 2020, 31(Suppl 4): S1170. http://www.sciencedirect.com/science/article/pii/S0923753420423531
[7] XU J, ZHANG Y, JIA R, et al. Anti-PD-1 Antibody SHR-1210 Combined with Apatinib for Advanced Hepatocellular Carcinoma, Gastric, or Esophagogastric Junction Cancer: An Open-label, Dose Escalation and Expansion Study[J]. Clin Cancer Res: an official journal of the American Association for Cancer Research, 2019, 25(2): 515-523. doi: 10.1158/1078-0432.CCR-18-2484
[8] FOLKMAN J. Tumor angiogenesis: therapeutic implications[J]. N Engl J Med, 1971, 285(21): 1182-1196. doi: 10.1056/NEJM197111182852108
[9] JAIN, RAKESH K. Antiangiogenesis strategies revisited: from starving tumors to alleviating hypoxia[J]. Cancer Cell, 2014, 26(5): 605-622. doi: 10.1016/j.ccell.2014.10.006
[10] HENDRY S A, FARNSWORTH R H, SOLOMON B, et al. The Role of the Tumor Vasculature in the Host Immune Response: Implications for Therapeutic Strategies Targeting the Tumor Microenvironment[J]. Frontiers in immunology, 2016, 7: 621.
[11] RINDERT M, MASSIMILIANO M, GABRIELE B. The reciprocal function and regulation of tumor vessels and immune cells offers new therapeutic opportunities in cancer[J]. Seminars in Cancer Biology, 2018, 52(2): 107-116. http://www.onacademic.com/detail/journal_1000040435717410_1ae9.html
[12] VORON T, COLUSSI O, MARCHETEAU E, et al. VEGF-A modulates expression of inhibitory checkpoints on CD8+ T cells in tumors[J]. Journal of Experimental Medicine, 2015, 212(2): 139-148. doi: 10.1084/jem.20140559
[13] HOFF S, GRVNEWALD S, RSE L, et al. 1198PImmunomodulation by regorafenib alone and in combination with anti PD1 antibody on murine models of colorectal cancer[J]. Annals of Oncology, 2017, 28(Suppl 5): 1131-1138.
[14] WANG C, CHEVALIER D, SALUJA J, et al. Regorafenib and Nivolumab or Pembrolizumab Combination and Circulating Tumor DNA Response Assessment in Refractory Microsatellite Stable Colorectal Cancer[J]. The Oncologist, 2020, 25(8): 1188-1194. doi: 10.1634/theoncologist.2020-0161
[15] GIBNEY G T, WEINER L M, ATKINS MBJLO. Predictive biomarkers for checkpoint inhibitor-based immunotherapy[J]. Lancet Oncology, 2016, 17(12): 542-551. doi: 10.1016/S1470-2045(16)30406-5
[16] CHENG A L, HSU C, CHAN S L, et al. Challenges of combination therapy with immune checkpoint inhibitors for hepatocellular carcinoma[J]. Journal of Hepatology, 2020, 72(2): 307-319. doi: 10.1016/j.jhep.2019.09.025
[17] SAMSTEIN R M, LEE C H, SHOUSHTARI A N, et al. Tumor mutational load predicts survival after immunotherapy across multiple cancer types[J]. Nature Genetics, 2019, 51(2): 202-206. doi: 10.1038/s41588-018-0312-8
[18] MASUISHI T, TANIGUCHI H, KAWAKAMI T, et al. Impact of tumour growth rate during preceding treatment on tumour response to regorafenib or trifluridine/tipiracil in refractory metastatic colorectal cancer[J]. ESMO Open, 2019, 4(6): 000584. http://www.sciencedirect.com/science/article/pii/S2059702920300934
[19] PHILIPS G K, ATKINS M. Therapeutic uses of anti-PD-1 and anti-PD-L1 antibodies[J]. International Immunology, 2015, 27(1): 39-46. doi: 10.1093/intimm/dxu095
[20] GUNTURI A, MCDERMOTT D F. Nivolumab for the treatment of cancer[J]. Expert Opinion on Investigational Drugs, 2015, 24(2): 253-60. doi: 10.1517/13543784.2015.991819
[21] TOPALIAN S L, DRAKE C G, PARDOLL D M. Targeting the PD-1/B7-H1(PD-L1) pathway to activate anti-tumor immunity[J]. Current Opinion in Immunology, 2012, 24(2): 207-212. doi: 10.1016/j.coi.2011.12.009
[22] GETTINGER S N, HORN L, GANDHI L, et al. Overall Survival and Long-Term Safety of Nivolumab (Anti-Programmed Death 1 Antibody, BMS-936558, ONO-4538) in Patients With Previously Treated Advanced Non-Small-Cell Lung Cancer[J]. Journal of Clinical Oncology, 2016, 33(18): 2004-2012. http://pubmedcentralcanada.ca/pmcc/articles/PMC4672027/
[23] MCDERMOTT D F, DRAKE C G, SZNOL M, et al. Survival, Durable Response, and Long-Term Safety in Patients With Previously Treated Advanced Renal Cell Carcinoma Receiving Nivolumab[J]. Journal of Clinical Oncology, 2015, 33(18): 2013-2020. doi: 10.1200/JCO.2014.58.1041
[24] TOPALIAN S L, SZNOL M, MCDERMOTT D F, et al. Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab[J]. Journal of Clinical Oncology, 2014, 32(10): 1020-1030. doi: 10.1200/JCO.2013.53.0105
[25] GAUCI M L, LANOY E, CHAMPIAT S, et al. Long-Term Survival in Patients Responding to Anti-PD-1/PD-L1 Therapy and Disease Outcome upon Treatment Discontinuation[J]. Clinical Cancer Research, 2019, 25(3): 946-956. doi: 10.1158/1078-0432.CCR-18-0793
[26] DIAZ L A, LE D T, YOSHINO T, et al. KEYNOTE-177: First-line, open-label, randomized, phase Ⅲstudy of pembrolizumab (MK-3475) versus investigator-choice chemotherapy for mismatch repair deficient or microsatellite instability-high metastatic colorectal carcinoma[J]. 2016.
[27] Chen L T, Kang Y K, Satoh T, et al. A phase 3 study of nivolumab in previously treated advanced gastric or gastroesophageal junction cancer (ATTRACTION-2): 2-year update data[J]. Gastric cancer: official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association, 2020, 23(3): 510-519. http://newmed.wanfangdata.com.cn/Paper/Detail/PeriodicalPaper_PM31863227
[28] POSTOW M A. Managing immune checkpoint-blocking antibody side effects[J]. American Society of Clinical Oncology Educational Book, 2015, 35(1): 76-83. http://pdfs.semanticscholar.org/c4f8/f8c7782857e790fa07e0dbf63df979e78a86.pdf
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