伏美替尼联合特瑞普利单抗治疗EGFR基因突变阳性晚期非小细胞肺癌的临床研究

doi:10.3760/cma.j.issn.1007-1245.2024.20.008

摘要/Abstract

摘要：

目的　探讨伏美替尼联合特瑞普利单抗治疗表皮生长因子受体（EGFR）基因突变阳性晚期非小细胞肺癌（NSCLC）的疗效及安全性。方法　本研究为随机对照试验。选取2019年2月至2021年2月安康市中心医院收治的164例EGFR基因突变阳性晚期NSCLC为研究对象。采用随机数字表法将其分为试验组和对照组，每组82例。试验组男45例，女37例；年龄（63.28±6.75）岁。对照组男45例，女37例；年龄（65.02±7.19）岁。基础治疗：静脉滴注培美曲塞500 mg·m^-2，间隔21 d治疗1次，21 d为1个治疗周期。对照组口服甲磺酸伏美替尼片40 mg·次^-1，2次·d^-1。试验组在对照组基础上，静脉滴注特瑞普利单抗注射液3 mg·kg^-1，间隔21 d治疗1次，21 d为1个治疗周期。治疗3个周期后，比较两组的疗效、不良反应、细胞角质蛋白19片段抗原21-1（CYFRA21-1）、糖类抗原-199（CA-199）、CD4⁺、CD4⁺/CD8⁺。随访2年比较两组的生存预后。采用χ²检验、t检验。结果　治疗期间试验组失访5例，收集试验数据77例；对照组失访8例，收集试验数据74例。治疗3个周期后，试验组和对照组的CYFRA21-1分别为（5.18±1.62）µg·L^-1和（7.03±1.89）µg·L^-1，CA-199分别为（36.71±6.93）U·ml^-1和（49.46±8.02）U·ml^-1，CD4⁺分别为（39.06±5.32）%和（31.92±4.15）%，CD4⁺/CD8⁺分别为（1.48±0.53）和（1.05±0.48），两组比较差异均有统计学意义（t=6.467、10.465、9.171、5.219，均P<0.05）。试验组和对照组的疾病控制率分别为88.31%（68/77）、75.68%（56/74），两组比较差异有统计学意义（χ²=4.103，P=0.043）。截至随访结束，试验组死亡30例，中位无进展生存期（PFS）19个月，未达到中位总生存期（OS）；对照组死亡35例，中位PFS 15个月，未达到中位OS；两组PFS比较，差异有统计学意义（Log-rank χ²=2.608，P=0.031）。结论　伏美替尼联合特瑞普利单抗治疗EGFR基因突变阳性晚期NSCLC，能够提高疾病控制率，降低肿瘤标志物CYFRA21-1、CA-199水平，延长PFS，未明显增加药物不良反应发生率，安全性良好。

关键词:

非小细胞肺癌, 晚期, 表皮生长因子受体-酪氨酸激酶抑制剂, 伏美替尼, 特瑞普利单抗

Abstract:

Objective　To explore the efficacy and safety of Furmonertinib combined with Toripalimab in the treatment of advanced non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) gene mutation positivity. Methods　This study was a randomized controlled trial. A total of 164 patients with EGFR gene mutation-positive advanced NSCLC admitted to Ankang Central Hospital from February 2019 to February 2021 were selected as the study objects. They were divided into an experimental group and a control group by the random number table method, with 82 cases in each group. There were 45 males and 37 females in the experimental group, aged (63.28±6.75) years. There were 45 males and 37 females in the control group, aged (65.02±7.19) years. The basic treatment included intravenous infusion of pemetrexed at a dose of 500 mg·m^-2, once every 21 days, with 21 days as a treatment cycle. The control group received oral administration of 40 mg of Furmonertinib mesylate tablets, twice a day. On the basis of the control group, the experimental group received intravenous infusion of Toripalimab injection at a dose of 3 mg·kg^-1 every 21 days, with 21 days as a treatment cycle. After 3 cycles of treatment, the efficacy, adverse reactions, and levels of cytokeratin19 fragment antigen 21-1 (CYFRA21-1), carbohydrate antigen-199 (CA-199), CD4⁺, and CD4⁺/CD8⁺ were compared between the two groups. The survival prognosis of the two groups was compared after 2 years of follow-up. χ² test and t test were used. Results　During the treatment period, 5 cases were lost to follow-up in the experimental group, resulting in data collection from 77 cases; in the control group, 8 cases were lost to follow-up, resulting in data collection from 74 cases. After 3 cycles of treatment, the levels of CYFRA21-1 in the experimental group and the control group were (5.18±1.62) µg·L^-1 and (7.03±1.89) µg·L^-1, the levels of CA-199 were (36.71±6.93) U·ml^-1 and (49.46±8.02) U·ml^-1, the levels of CD4⁺ were (39.06±5.32)% and (31.92±4.15)%, and the levels of CD4⁺/CD8⁺ were (1.48±0.53) and (1.05±0.48), with statistically significant differences between the two groups (t=6.467, 10.465, 9.171, and 5.219, all P<0.05). The disease control rates of the experimental group and the control group were 88.31% (68/77) and 75.68% (56/74), respectively, with a statistically significant difference between the two groups (χ²=4.103, P=0.043). By the end of follow-up, 30 patients in the experimental group died, and the median progression-free survival (PFS) was 19 months, which did not reach the median overall survival (OS). In the control group, 35 patients died, and the median PFS was 15 months, which did not reach the median OS. There was a statistically significant difference in the PFS between the two groups (Log-rank χ²=2.608, P=0.031). Conclusion　In the treatment of EGFR gene mutation-positive advanced NSCLC, Furmonertinib combined with Toripalimab can improve the disease control rate, reduce the levels of tumor markers (CYFRA21-1 and CA-199), and prolong the PFS, which does not increase the incidence of adverse drug reactions, with good safety.

Key words:

Non small cell lung cancer, Advanced stage, Epidermal growth factor receptor-tyrosine kinase inhibitor, Furmonertinib, Toripalimab

李超来静杨俊.

伏美替尼联合特瑞普利单抗治疗EGFR基因突变阳性晚期非小细胞肺癌的临床研究 [J]. 国际医药卫生导报, 2024, 30(20): 3387-3392.

Li Chao, Lai Jing, Yang Jun.

Clinical study of Furmonertinib combined with Toripalimab in the treatment of advanced non-small cell lung cancer with EGFR gene mutation positivity [J]. International Medicine and Health Guidance News, 2024, 30(20): 3387-3392.

参考文献

[1] Wan C, Zhang Y, Liu P, et al. Efficacy and safety of anti-programmed cell death protein 1 antibody combination therapy in patients with advanced experienced epidermal growth factor receptor-tyrosine kinase inhibitor-resistant lung adenocarcinoma: a retrospective cohort study[J]. J Thorac Dis, 2023, 31, 15(10): 5648-5657. DOI: 10.21037/jtd-23-1399.
[2] Planchard D, Jänne PA, Cheng Y, et al. Osimertinib with or without chemotherapy in EGFR-Mutated advanced NSCLC[J]. N Engl J Med, 2023, 389(21):1935-1948. DOI: 10.1056/NEJMoa2306434.
[3] Baglivo S, Mandarano M, Bellezza G, et al. Inflamed tumor phenotype as predictor of long-term response to pembrolizumab in an EGFR-mutated Non-Small Cell Lung Cancer (NSCLC) patient with acquired resistance to afatinib: a case report and review of the literature[J]. Oncol Ther, 2022, 10(1):291-300. DOI: 10.1007/s40487-022-00183-7.
[4] Lu S, Zhang Y, Zhang G, et al. Efficacy and safety of befotertinib (D-0316) in patients with EGFR T790M-mutated NSCLC that had progressed after prior EGFR tyrosine kinase inhibitor therapy: a phase 2, multicenter, single-arm, open-label study[J]. J Thorac Oncol, 2022, 17(10): 1192-1204. DOI: 10.1016/j.jtho.2022.06.002.
[5] Lu S, Wang Q, Zhang G, et al. Efficacy of Aumolertinib (HS-10296) in patients with advanced EGFR T790M+ NSCLC: updated post-national medical products administration approval results from the APOLLO registrational trial[J]. J Thorac Oncol, 2022, 17(3): 411-422. DOI: 10.1016/j.jtho.2021.10.024.
[6] Cheng Y, He Y, Li W, et al. Osimertinib versus comparator EGFR TKI as first-line treatment for EGFR-mutated advanced NSCLC: FLAURA China, a randomized study[J]. Target Oncol, 2021, 16(2): 165-176. DOI: 10.1007/s11523-021-00794-6.
[7] Hartmaier RJ, Markovets AA, Ahn MJ, et al. Osimertinib + Savolitinib to overcome acquired met-mediated resistance in epidermal growth factor receptor-mutated, met-amplified non-small cell lung cancer: TATTON[J]. Cancer Discov, 2023, 13(1): 98-113. DOI: 10.1158/2159-8290.CD-22-0586.
[8] Hayashi H, Sugawara S, Fukuda Y, et al. A randomized phase II study comparing nivolumab with carboplatin-pemetrexed for EGFR-mutated NSCLC with resistance to EGFR tyrosine kinase inhibitors (WJOG8515L) [J]. Clin Cancer Res, 2022, 28(5): 893-902. DOI: 10.1158/1078-0432.CCR-21-3194.
[9] Assessing toripalimab in NSCLC[J]. Cancer Discov, 2022, 12(5): 1176-1177. DOI: 10.1158/2159-8290.
[10] «非小细胞肺癌血液EGFR基因突变检测中国专家共识»制. 非小细胞肺癌血液EGFR基因突变检测中国专家共识[J]. 中华医学杂志,2015,95(46):3721-3726. DOI:10.3760/cma.j.issn.0376-2491.2015.46.001.
[11] Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1) [J]. Eur J Cancer, 2009, 45(2): 228-247. DOI: 10.1016/j.ejca.2008.10.026.
[12] National Institute of Cancer. Common Terminology Criteria for Adverse Events (CTCAE) [S]. U.S.Department of Health and Human Services, NIH Publication, 2010: 1-71. DOI: 1080/00140139.2010.489653.
[13] Zhang M, Cheng Y, Hu Y, et al. Cytokine release syndrome and successful response to pembrolizumab therapy in a patient with EGFR-mutated non-small-cell lung cancer: a case report[J]. Thorac Cancer, 2022, 13(9): 1419-1422. DOI: 10.1111/1759-7714.14390.
[14] Elamin YY, Robichaux JP, Carter BW, et al. Poziotinib for EGFR exon 20-mutant NSCLC: Clinical efficacy, resistance mechanisms, and impact of insertion location on drug sensitivity[J]. Cancer Cell, 2022, 40(7): 754-767.e6. DOI: 10.1016/j.ccell.2022.06.006.
[15] Gomatou G, Syrigos N, Kotteas E. Osimertinib resistance: molecular mechanisms and emerging treatment options[J]. Cancers (Basel), 2023, 15(3):841. DOI: 10.3390/cancers15030841.
[16] Chmielecki J, Gray JE, Cheng Y, et al. Candidate mechanisms of acquired resistance to first-line osimertinib in EGFR-mutated advanced non-small cell lung cancer[J]. Nat Commun, 2023, 14(1):1070. DOI: 10.1038/s41467-023-35961-y.
[17] 董梦媛,罗春香,蔡丽娟,等. 晚期非小细胞肺癌EGFR-TKIs获得性耐药后治疗策略研究进展[J]. 肿瘤药学,2023,13(4):407-423. DOI:10.3969/j.issn.2095-1264.2023.04.03.
[18] 郭峰睿,王慧,易国震,等. 血清AGR2、ESM-1水平对晚期NSCLC患者EGFR-TKI治疗后预后的预测价值[J]. 标记免疫分析与临床,2023,30(9):1485-1489,1520. DOI:10.11748/bjmy.issn.1006-1703.2023.09.010.
[19] Planchard D, Jänne PA, Cheng Y, 等. Osimertinib联合化疗治疗EGFR突变晚期NSCLC患者的临床研究[J]. 中国临床药理学杂志,2023,39(24):3652.
[20] 侯聪霞,孙芳,梁亚林,等. 特瑞普利单抗联合含铂双药化疗治疗TP53基因突变非小细胞肺癌的疗效[J]. 实用癌症杂志,2023,38(4):585-588. DOI:10.3969/j.issn.1001-5930. 2023.04.016.
[21] 魏小丽,任超,王风华,等. 抗PD-1抗体特瑞普利单抗治疗难治性恶性实体瘤的I期研究[J]. 癌症,2021,40(10):426-435.
[22] 张洁,张年宝,雷芳芳. 奥希替尼联合化疗治疗晚期NSCLC患者EGFR基因突变型的近远期疗效[J]. 川北医学院学报,2023,38(4):551-554. DOI:10.3969/j.issn.1005-3697. 2023.04.027.
[23] Zhou C, Wang Z, Fu C, et al. The efficacy and safety of PD-1 inhibitors for EGFR-mutant non-small cell lung cancer after tyrosine kinase inhibitor failure: a retrospective real-world cohort study[J]. Ann Transl Med, 2023, 11(3): 157. DOI: 10.21037/atm-22-6272.
[24] Chen Y, Chen Z, Chen R, et al. Immunotherapy-based combination strategies for treatment of EGFR-TKI-resistant non-small-cell lung cancer[J]. Future Oncol, 2022, 18(14): 1757-1775. DOI: 10.2217/fon-2021- 0862.
[25] Luna HGC, Imasa MS, Juat N, et al. The differential prognostic implications of PD-L1 expression in the outcomes of Filipinos with EGFR-mutant NSCLC treated with tyrosine kinase inhibitors[J]. Transl Lung Cancer Res, 2023, 12(9):1896-1911. DOI: 10.21037/tlcr-23-118.
[26] Patel SA, Nilsson MB, Yang Y, et al. IL6 Mediates Suppression of T- and NK-cell Function in EMT-associated TKI-resistant EGFR-mutant NSCLC[J]. Clin Cancer Res, 2023, 29(7):1292-1304. DOI: 10.1158/1078-0432.CCR-22-3379.
[27] Yu L, Hu Y, Xu J, et al. Multi-target angiogenesis inhibitor combined with PD-1 inhibitors may benefit advanced non-small cell lung cancer patients in late line after failure of EGFR-TKI therapy[J]. Int J Cancer, 2023, 153(3): 635-643. DOI: 10.1002/ijc.34536.
[28] Nishii K, Ohashi K, Tomida S, et al. CD8+ T-cell responses are boosted by dual PD-1/VEGFR2 blockade after EGFR inhibition in EGFR-mutant lung cancer[J]. Cancer Immunol Res, 2022, 10(9):1111-1126. DOI: 10.1158/2326-6066.CIR-21-0751.
[29] Waliany S, Zhu H, Wakelee H, et al. Pharmacovigilance analysis of cardiac toxicities associated with targeted therapies for metastatic NSCLC[J]. J Thorac Oncol, 2021, 16(12):2029-2039. DOI: 10.1016/j.jtho.2021.07.030.
[30] Yin Y, Shu Y, Zhu J, et al. A real-world pharmacovigilance study of FDA Adverse Event Reporting System (FAERS) events for osimertinib[J]. Sci Rep, 2022, 12(1): 19555. DOI: 10.1038/s41598-022-23834-1.