恶性胸膜间皮瘤免疫检查点抑制剂疗效及安全性meta分析

doi:10.5246/jcps.2023.04.026

摘要/Abstract

摘要：

本研究旨在评价免疫检查点抑制剂(immune checkpoint inhibitors, ICIs)治疗在恶性胸膜间皮瘤(malignant pleural mesothelioma, MPM)中的疗效和安全性。计算机检索PubMed、Embase、The Cochrane Library、Web of science等数据库, 建库起至2022年10月, 检索ICIs治疗MPM的前瞻性临床研究。按照纳入与排除标准独立筛选文献、提取资料并评价偏倚风险后, 采用Stata17.0软件进行统计分析。结果发现, 共纳入8个单臂研究, 3个随机对照试验, 包括839例患者。Meta分析结果显示, 接受了ICIs治疗的研究合并ORR为37% (95% CI, 23–51), 中位OS为14.02个月 (95% CI, 11.40–17.64), 中位PFS为4.72个月 (95% CI, 3.62–6.16)。根据治疗方法的类型: ICI单药治疗或ICI联合治疗(联合双药ICI/ICI联合化疗)进行亚组分析。结果为ORR 51% (95% CI, 39–62) vs 19% (95% CI, 8–29); OS 18.30个月 (95% CI, 16.42–20.40) vs 11.03个月 (95% CI, 9.46–12.86); PFS 6.78个月 (95% CI, 6.18–7.44) vs 3.40个月(95% CI, 2.41–4.79); 提示ICI联合治疗在ORR、OS、PFS上明显优于ICI单药治疗。所有研究中3–4级AEs发生率为30%, ICIs治疗最常见不良事件为乏力、腹泻、及皮疹。其中联合用药的3–4级AEs高于单药组(35% vs 22%)。因此, ICI联合治疗在MPM患者中有临床应用价值, 支持在MPM患者中大规模临床应用。ICI联合治疗在安全性方面较一线化疗方案3–4级不良反应事件发生率更高。

关键词: 恶性胸膜间皮瘤, 免疫检查点抑制剂, CTLA-4, PD-1/PD-L1, 系统评价

Abstract:

In the present study, we aimed to evaluate the efficacy and safety of immune checkpoint inhibitors (ICIs) in treating malignant pleural mesothelioma (MPM). The PubMed, Embase, Web of science, and Cochrane Library databases were searched for prospective clinical trials evaluating the efficacy and safety of ICIs for the treatment of advanced MPM. The primary outcomes included objective response rate (ORR), overall survival (OS), progression-free survival (PFS), and adverse events (AEs). Eight single-arm studies and three randomized controlled trials were included, including 839 patients. Meta-analysis results showed that the pooled overall ORR of the studies receiving ICIs was 37% (95% confidence interval (CI), 23%–51%), the median OS was 14.02 months (95% CI, 11.40–17.64 months), and the median PFS was 4.72 months (95% CI, 3.62–6.16 months). Subgroup analysis was made according to the type of treatment methods: ICI single-agent immunotherapy or ICI combination therapy (combining ICIs or ICI with chemotherapy). It was suggested that the combination therapy of ICI was superior to the single-agent immunotherapy of ICI in ORR, OS, and PFS. The results were ORR 51% (95% CI, 39%–62%) vs. 19% (95% CI, 8%–29%), OS 18.30 months (95% CI, 16.42–20.40 months) vs. 11.03 months (95% CI, 9.46–12.86 months), and PFS 6.78 months (95% CI, 6.18–7.44 months) vs. 3.40 months (95% CI, 2.41–4.79 months). The incidence of grade 3–4 AEs in all studies was 30%. The most common AEs of ICI treatment were fatigue, diarrhea, and rash. The level 3–4 AEs of the combination group were higher than those of the single-agent group (37% vs. 22%). The combination therapy of ICI had clinical application value in MPM patients and supported large-scale clinical application in MPM patients. However, regarding safety, ICI combination therapy had a higher incidence of grade 3–4 AEs than first-line chemotherapy.

Key words: Malignant pleural mesothelioma, Immune checkpoint inhibitors, CTLA-4, PD-1/PD-L1, Systematic review

Supporting:

吴崇昊, 黄攀杰, 杨春琦, 高川, 曾鸣. 恶性胸膜间皮瘤免疫检查点抑制剂疗效及安全性meta分析[J]. 中国药学(英文版), 2023, 32(4): 291-301.

Chonghao Wu, Panjie Huang, Chunqi Yang, Chuan Gao, Ming Zeng. The efficacy and safety of immune checkpoint inhibitors in malignant pleural mesothelioma: A systematic review[J]. Journal of Chinese Pharmaceutical Sciences, 2023, 32(4): 291-301.

图/表 6

Figure 1. Flow chart of literature screening.

Table 1. Characteristics of the included studies.

Figure 2. Risk of bias summary according to Cochrane risk of the bias assessment tool.

Table 2. Risk bias assessment for single-arm studies.

Figure 3. The pooled efficacy rates in the overall group. The ORR (A), OS (B), and PFS (C). The pooled efficacy rates in the subgroup. The ORR (D), OS (E), and PFS (F).

Figure 4. The pooled efficacy rates in the overall group. The AEs (A); the pooled efficacy rates in the subgroup. The AEs (B); sensitivity analyses of ORR of ICI therapy (C); funnel plot of ORR of ICI therapy (D).

参考文献 20

[1]	Carteni, G.; Manegold, C.; Garcia, G.M.; Siena, S.; Zielinski, C.C.; Amadori, D.; Liu, Y.; Blatter, J.; Visseren-Grul, C.; Stahel, R. Malignant peritoneal mesothelioma-results from the International Expanded Access Program using pemetrexed alone or in combination with a platinum agent. Lung Cancer. 2009, 64, 211–218.
[2]	Chekol, S.S.; Sun, C.C. Malignant mesothelioma of the tunica vaginalis testis: diagnostic studies and differential diagnosis. Arch. Pathol. Lab. Med. 2012, 136, 113–117.
[3]	Treasure, T. What is the best approach for surgery of malignant pleural mesothelioma? It is to put our efforts into obtaining trustworthy evidence for practice. J. Thorac. Cardiovasc. Surg. 2016, 151, 307–309.
[4]	Peters, S.; Scherpereel, A.; Cornelissen, R.; Oulkhouir, Y.; Greillier, L.; Kaplan, M.A.; Talbot, T.; Monnet, I.; Hiret, S.; Baas, P.; Nowak, A.K.; Fujimoto, N.; Tsao, A.S.; Mansfield, A.S.; Popat, S.; Zhang, X.; Hu, N.; Balli, D.; Spires, T.; Zalcman, G. First-line nivolumab plus ipilimumab versus chemotherapy in patients with unresectable malignant pleural mesothelioma: 3-year outcomes from CheckMate 743. Ann. Oncol. 2022, 33, 488–499.
[5]	Yap, T.A.; Nakagawa, K.; Fujimoto, N.; Kuribayashi, K.; Guren, T.K.; Calabrò, L.; Shapira-Frommer, R.; Gao, B.; Kao, S.; Matos, I.; Planchard, D.; Chatterjee, A.; Jin, F.; Norwood, K.; Kindler, H.L. Efficacy and safety of pembrolizumab in patients with advanced mesothelioma in the open-label, single-arm, phase 2 KEYNOTE-158 study. Lancet Respir. Med. 2021, 9, 613–621.
[6]	Miyamoto, Y.; Kozuki, T.; Aoe, K.; Wada, S.E.; Harada, D.; Yoshida, M.; Sakurai, J.; Hotta, K.; Fujimoto, N. JME-001 phase II trial of first-line combination chemotherapy with cisplatin, pemetrexed, and nivolumab for unresectable malignant pleural mesothelioma. J. Immunother. Cancer. 2021, 9, e003288.
[7]	Forde, P.M.; Anagnostou, V.; Sun, Z.X.; Dahlberg, S.E.; Kindler, H.L.; Niknafs, N.; Purcell, T.; Santana-Davila, R.; Dudek, A.Z.; Borghaei, H.; Lanis, M.; Belcaid, Z.; Smith, K.N.; Balan, A.; White, J.R.; Cherry, C.; Ashok Sivakumar, I.K.; Shao, X.M.; Chan, H.Y.; Singh, D.; Thapa, S.; Illei, P.B.; Pardoll, D.M.; Karchin, R.; Velculescu, V.E.; Brahmer, J.R.; Ramalingam, S.S. Durvalumab with platinum-pemetrexed for unresectable pleural mesothelioma: survival, genomic and immunologic analyses from the phase 2 PrE0505 trial. Nat. Med. 2021, 27, 1910–1920.
[8]	Popat, S.; Curioni-Fontecedro, A.; Dafni, U.; Shah, R.; O’Brien, M.; Pope, A.; Fisher, P.; Spicer, J.; Roy, A.; Gilligan, D.; Gautschi, O.; Nadal, E.; Janthur, W.D.; López Castro, R.; García Campelo, R.; Rusakiewicz, S.; Letovanec, I.; Polydoropoulou, V.; Roschitzki-Voser, H.; Ruepp, B.; Gasca-Ruchti, A.; Peters, S.; Stahel, R.A. A multicentre randomised phase III trial comparing pembrolizumab versus single-agent chemotherapy for advanced pre-treated malignant pleural mesothelioma: the European Thoracic Oncology Platform (ETOP 9-15) PROMISE-meso trial. Ann. Oncol. 2020, 31, 1734–1745.
[9]	Nowak, A.K.; Lesterhuis, W.J.; Kok, P.S.; Brown, C.; Hughes, B.G.; Karikios, D.J.; John, T.; Kao, S.C.H.; Leslie, C.; Cook, A.M.; Pavlakis, N.; Briscoe, K.; O’Byrne, K.J.; Karapetis, C.S.; Lam, W.S.; Langford, A.; Yip, S.; Stockler, M.R. Durvalumab with first-line chemotherapy in previously untreated malignant pleural mesothelioma (DREAM): a multicentre, single-arm, phase 2 trial with a safety Run-in. Lancet Oncol. 2020, 21, 1213–1223.
[10]	Disselhorst, M.J.; Quispel-Janssen, J.; Lalezari, F.; Monkhorst, K.; de Vries, J.F.; van der Noort, V.; Harms, E.; Burgers, S.; Baas, P. Ipilimumab and nivolumab in the treatment of recurrent malignant pleural mesothelioma (INITIATE): results of a prospective, single-arm, phase 2 trial. Lancet Respir. Med. 2019, 7, 260–270.
[11]	Scherpereel, A.; Mazieres, J.; Greillier, L.; Lantuejoul, S.; Dô, P.; Bylicki, O.; Monnet, I.; Corre, R.; Audigier-Valette, C.; Locatelli-Sanchez, M.; Molinier, O.; Guisier, F.; Urban, T.; Ligeza-Poisson, C.; Planchard, D.; Amour, E.; Morin, F.; Moro-Sibilot, D.; Zalcman, G.; Debieuvre, D.; Hiret, S.; Cadranel, J.; Fraboulet-moreau, S.; Carmier, D. Nivolumab or nivolumab plus ipilimumab in patients with relapsed malignant pleural mesothelioma (IFCT-1501 MAPS2): a multicentre, open-label, randomised, non-comparative, phase 2 trial. Lancet Oncol. 2019, 20, 239–253.
[12]	Okada, M.; Kijima, T.; Aoe, K.; Kato, T.; Fujimoto, N.; Nakagawa, K.; Takeda, Y.; Hida, T.; Kanai, K.; Imamura, F.; Oizumi, S.; Takahashi, T.; Takenoyama, M.; Tanaka, H.; Hirano, J.; Namba, Y.; Ohe, Y. Clinical efficacy and safety of nivolumab: results of a multicenter, open-label, single-arm, Japanese phase II study in malignant pleural mesothelioma (MERIT). Clin. Cancer Res. 2019, 25, 5485–5492.
[13]	Quispel-Janssen, J.; van der Noort, V.; de Vries, J.F.; Zimmerman, M.; Lalezari, F.; Thunnissen, E.; Monkhorst, K.; Schouten, R.; Schunselaar, L.; Disselhorst, M.; Klomp, H.; Hartemink, K.; Burgers, S.; Buikhuisen, W.; Baas, P. Programmed death 1 blockade with nivolumab in patients with recurrent malignant pleural mesothelioma. J. Thorac. Oncol. 2018, 13, 1569–1576.
[14]	Alley, E.W.; Lopez, J.; Santoro, A.; Morosky, A.; Saraf, S.; Piperdi, B.; van Brummelen, E. Clinical safety and activity of pembrolizumab in patients with malignant pleural mesothelioma (KEYNOTE-028): preliminary results from a non-randomised, open-label, phase 1b trial. Lancet Oncol. 2017, 18, 623–630.
[15]	Beebe-Dimmer, J.L.; Fryzek, J.P.; Yee, C.L.; Dalvi, T.B.; Garabrant, D.H.; Schwartz, A.G.; Gadgeel, S. Mesothelioma in the United States: a Surveillance, Epidemiology, and End Results (SEER)-Medicare investigation of treatment patterns and overall survival. Clin. Epidemiol. 2016, 8, 743–750.
[16]	Zalcman, G.; Mazieres, J.; Margery, J.; Greillier, L.; Audigier-Valette, C.; Moro-Sibilot, D.; Molinier, O.; Corre, R.; Monnet, I.; Gounant, V.; Rivière, F.; Janicot, H.; Gervais, R.; Locher, C.; Milleron, B.; Tran, Q.; Lebitasy, M.P.; Morin, F.; Creveuil, C.; Parienti, J.J.; Scherpereel, A. Bevacizumab for newly diagnosed pleural mesothelioma in the Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS): a randomised, controlled, open-label, phase 3 trial. Lancet. 2016, 387, 1405–1414.
[17]	Milano, M.T.; Zhang, H. Malignant pleural mesothelioma: a population-based study of survival. J. Thorac. Oncol. 2010, 5, 1841–1848.
[18]	Hazarika, M.; White, R.M. Jr, Booth, B.P.; Wang, Y.C.; Lee Ham, D.Y.; Liang, C.Y.; Rahman, A.; Gobburu, J.V.S.; Li, N.; Sridhara, R.; Morse, D.E.; Lostritto, R.; Garvey, P.; Johnson, J.R.; Pazdur, R. Pemetrexed in malignant pleural mesothelioma. Clin. Cancer Res. 2005, 11, 982–992.
[19]	Vogelzang, N.J.; Rusthoven, J.J.; Symanowski, J.; Denham, C.; Kaukel, E.; Ruffie, P.; Gatzemeier, U.; Boyer, M.; Emri, S.; Manegold, C.; Niyikiza, C.; Paoletti, P. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J. Clin. Oncol. 2003, 21, 2636–2644.
[20]	Nakajima, E.C.; Vellanki, P.J.; Larkins, E.; Chatterjee, S.; Mishra-Kalyani, P.S.; Bi, Y.W.; Qosa, H.; Liu, J.; Zhao, H.; Biable, M.; Hotaki, L.T.; Shen, Y.L.; Pazdur, R.; Beaver, J.A.; Singh, H.; Donoghue, M. FDA approval summary: nivolumab in combination with ipilimumab for the treatment of unresectable malignant pleural mesothelioma. Clin. Cancer Res. 2022, 28, 446–451.