Efficacy of Immune Checkpoint Inhibitors Against Advanced or Metastatic Neuroendocrine Neoplasms: A Systematic Review and Meta-Analysis

Overview

Journal Cancers (Basel)

Publisher MDPI

Specialty Oncology

Date 2022 Feb 15

PMID 35159061

Authors

Eun-Joo Park

Hyo-Jung Park

Kyung-Won Kim

Chong-Hyun Suh

Changhoon Yoo

Young-Kwang Chae

Sree Harsha Tirumani

Nikhil H Ramaiya

Affiliations

Soon will be listed here.

Abstract

We performed a systematic review and meta-analysis of the treatment efficacy of immune checkpoint inhibitors (ICIs) in advanced/metastatic neuroendocrine neoplasms (NENs). MEDLINE and EMBASE were searched to identify studies that provide data on treatment response and/or survival outcomes of advanced/metastatic NEN patients treated with ICIs. The overall response rate (ORR) was pooled using a random-effects model. Meta-regression was performed to explore factors influencing the ORR. Individual patient data (IPD) meta-analysis of survival was performed using stratified Cox regression. Ten studies (464 patients) were included. The overall pooled ORR was 15.5% (95% confidence interval (CI), 9.5-24.3%), and it varied according to the primary site (thoracic, 24.7%; gastro-entero-pancreatic, 9.5%), tumor differentiation (poorly differentiated, 22.7%; well-differentiated, 10.4%), and drug regimen (combination, 25.3%; monotherapy, 10.1%). All these variables significantly influenced the ORR. Tumor differentiation was associated with both overall survival and progression-free survival (hazard ratio of poorly differentiated tumors, 4.2 (95% CI, 2.0-8.7) and 2.6 (95% CI, 1.6-4.4), respectively). Thus, the treatment efficacy of ICIs for advanced/metastatic NENs varied according to primary site, tumor differentiation, and drug regimen. Poorly differentiated NENs showed a better ORR than well-differentiated NENs but had a negative impact on survival.

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References

Sorbye H, Welin S, Langer S, Vestermark L, Holt N, Osterlund P . Predictive and prognostic factors for treatment and survival in 305 patients with advanced gastrointestinal neuroendocrine carcinoma (WHO G3): the NORDIC NEC study. Ann Oncol. 2012; 24(1):152-60. DOI: 10.1093/annonc/mds276. View

Guyot P, Ades A, Ouwens M, Welton N . Enhanced secondary analysis of survival data: reconstructing the data from published Kaplan-Meier survival curves. BMC Med Res Methodol. 2012; 12:9. PMC: 3313891. DOI: 10.1186/1471-2288-12-9. View

Le Treut J, Sault M, Lena H, Souquet P, Vergnenegre A, Le Caer H . Multicentre phase II study of cisplatin-etoposide chemotherapy for advanced large-cell neuroendocrine lung carcinoma: the GFPC 0302 study. Ann Oncol. 2013; 24(6):1548-52. DOI: 10.1093/annonc/mdt009. View

Rindi G, Klimstra D, Abedi-Ardekani B, Asa S, Bosman F, Brambilla E . A common classification framework for neuroendocrine neoplasms: an International Agency for Research on Cancer (IARC) and World Health Organization (WHO) expert consensus proposal. Mod Pathol. 2018; 31(12):1770-1786. PMC: 6265262. DOI: 10.1038/s41379-018-0110-y. View

Lu M, Zhang P, Zhang Y, Li Z, Gong J, Li J . Efficacy, Safety, and Biomarkers of Toripalimab in Patients with Recurrent or Metastatic Neuroendocrine Neoplasms: A Multiple-Center Phase Ib Trial. Clin Cancer Res. 2020; 26(10):2337-2345. DOI: 10.1158/1078-0432.CCR-19-4000. View

Kulke M, Wu B, Ryan D, Enzinger P, Zhu A, Clark J . A phase II trial of irinotecan and cisplatin in patients with metastatic neuroendocrine tumors. Dig Dis Sci. 2006; 51(6):1033-8. DOI: 10.1007/s10620-006-8001-3. View

Fang L, Arvind D, Dowlati A, Mohamed A . Role of immunotherapy in gastro-enteropancreatic neuroendocrine neoplasms (gep-nens): Current advances and future directions. J Neuroendocrinol. 2021; 33(3):e12943. DOI: 10.1111/jne.12943. View

Stewart L, Clarke M, Rovers M, Riley R, Simmonds M, Stewart G . Preferred Reporting Items for Systematic Review and Meta-Analyses of individual participant data: the PRISMA-IPD Statement. JAMA. 2015; 313(16):1657-65. DOI: 10.1001/jama.2015.3656. View

Scherer R, Saldanha I . How should systematic reviewers handle conference abstracts? A view from the trenches. Syst Rev. 2019; 8(1):264. PMC: 6836535. DOI: 10.1186/s13643-019-1188-0. View

10.

DerSimonian R, Laird N . Meta-analysis in clinical trials. Control Clin Trials. 1986; 7(3):177-88. DOI: 10.1016/0197-2456(86)90046-2. View

11.

Eisenhauer E, Therasse P, Bogaerts J, Schwartz L, Sargent D, Ford R . New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2008; 45(2):228-47. DOI: 10.1016/j.ejca.2008.10.026. View

12.

Barat M, Nguyen T, Hollande C, Coty J, Hoeffel C, Terris B . LI-RADS v2018 major criteria: Do hepatocellular carcinomas in non-alcoholic steatohepatitis differ from those in virus-induced chronic liver disease on MRI?. Eur J Radiol. 2021; 138:109651. DOI: 10.1016/j.ejrad.2021.109651. View

13.

Sherman S, Rotem O, Shochat T, Zer A, Moore A, Dudnik E . Efficacy of immune check-point inhibitors (ICPi) in large cell neuroendocrine tumors of lung (LCNEC). Lung Cancer. 2020; 143:40-46. DOI: 10.1016/j.lungcan.2020.03.008. View

14.

Forde P, Hooker C, Boikos S, Petrini I, Giaccone G, Rudin C . Systemic therapy, clinical outcomes, and overall survival in locally advanced or metastatic pulmonary carcinoid: a brief report. J Thorac Oncol. 2014; 9(3):414-8. PMC: 4322909. DOI: 10.1097/JTO.0000000000000065. View

15.

Yao J, Hassan M, Phan A, Dagohoy C, Leary C, Mares J . One hundred years after "carcinoid": epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol. 2008; 26(18):3063-72. DOI: 10.1200/JCO.2007.15.4377. View

16.

Chauhan A, Kohn E, Del Rivero J . Neuroendocrine Tumors-Less Well Known, Often Misunderstood, and Rapidly Growing in Incidence. JAMA Oncol. 2019; 6(1):21-22. PMC: 9382718. DOI: 10.1001/jamaoncol.2019.4568. View

17.

Schardt C, Adams M, Owens T, Keitz S, Fontelo P . Utilization of the PICO framework to improve searching PubMed for clinical questions. BMC Med Inform Decis Mak. 2007; 7:16. PMC: 1904193. DOI: 10.1186/1472-6947-7-16. View

18.

Kim S, Ha S, Lee S, Ahn S, Lee J, Park S . The Impact of PD-L1 Expression in Patients with Metastatic GEP-NETs. J Cancer. 2016; 7(5):484-9. PMC: 4780123. DOI: 10.7150/jca.13711. View

19.

Strosberg J, Mizuno N, Doi T, Grande E, Delord J, Shapira-Frommer R . Efficacy and Safety of Pembrolizumab in Previously Treated Advanced Neuroendocrine Tumors: Results From the Phase II KEYNOTE-158 Study. Clin Cancer Res. 2020; 26(9):2124-2130. PMC: 7811789. DOI: 10.1158/1078-0432.CCR-19-3014. View

20.

Yoo C, Oh C, Kim S, Bae W, Choi H, Oh D . Systemic Treatment of Advanced Gastroenteropancreatic Neuroendocrine Tumors in Korea: Literature Review and Expert Opinion. Cancer Res Treat. 2021; 53(2):291-300. PMC: 8053871. DOI: 10.4143/crt.2020.1233. View