Systematic Review and Network Meta-Analysis of Immune Checkpoint Inhibitors in Combination with Chemotherapy as a First-Line Therapy for Extensive-Stage Small Cell Carcinoma

Hsiao-Ling Chen; Yu-Kang Tu; Hsiu-Mei Chang; Tai-Huang Lee; Kuan-Li Wu; Yu-Chen Tsai; Mei-Hsuan Lee; Chih-Jen Yang; Jen-Yu Hung; Inn-Wen Chong

doi:10.3390/cancers12123629

Systematic Review and Network Meta-Analysis of Immune Checkpoint Inhibitors in Combination with Chemotherapy as a First-Line Therapy for Extensive-Stage Small Cell Carcinoma

Cancers (Basel). 2020 Dec 3;12(12):3629. doi: 10.3390/cancers12123629.

Authors

Hsiao-Ling Chen¹, Yu-Kang Tu^{2

3}, Hsiu-Mei Chang¹, Tai-Huang Lee⁴, Kuan-Li Wu⁵, Yu-Chen Tsai⁵, Mei-Hsuan Lee⁵, Chih-Jen Yang^{5

6

7

8}, Jen-Yu Hung^{4

5

7}, Inn-Wen Chong^{6

7

8

9}

Affiliations

¹ Department of Pharmacy, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung 80145, Taiwan.
² Institute of Epidemiology and Preventive Medicine, National Taiwan University, Taipei 100225, Taiwan.
³ Department of Medical Research, National Taiwan University Hospital, Taipei 100225, Taiwan.
⁴ Department of Internal Medicine Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University, Kaohsiung 88145, Taiwan.
⁵ Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 88708, Taiwan.
⁶ Department of General Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 88708, Taiwan.
⁷ Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 88708, Taiwan.
⁸ Respiratory Therapy, College of Medicine, Kaohsiung Medical University, Kaohsiung 88708, Taiwan.
⁹ Department of Biological Science & Technology, National Chiao Tung University, Hsinchu 300, Taiwan.

Abstract

Patients with extensive-stage small cell lung cancer (ED-SCLC) have a very short survival time even if they receive standard cytotoxic chemotherapy with etoposide and platinum (EP). Several randomized controlled trials have shown that patients with ED-SCLC who received a combination of EP plus immune checkpoint inhibitors (ICIs) had superior survival compared with those who received EP alone. We conducted a systematic review and network meta-analysis to provide a ranking of ICIs for our primary endpoints in terms of overall survival (OS), progression free survival (PFS), and objective response rate (ORR), as well as our secondary endpoint in terms of adverse events. The fractional polynomial model was used to evaluate the adjusted hazard ratios for the survival indicators (OS and PFS). Treatment rank was estimated using the surface under the cumulative ranking curve (SUCRA), as well as the probability of being best (Prbest) reference. EP plus nivolumab, atezolizumab or durvalumab had significant benefits compared with EP alone in terms of OS (Hazard Ratio HR = 0.67, 95% Confidence Interval CI = 0.46-0.98 for nivolumab, HR = 0.70, 95% CI = 0.54-0.91 for atezolizumab, HR = 0.73, 95% CI = 0.59-0.90 for durvalumab) but no significant differences were observed for pembrolizumab or ipilimumab. The probability of nivolumab being ranked first among all treatment arms was highest (SCURA = 78.7%, Prbest = 46.7%). All EP plus ICI combinations had a longer PFS compared with EP alone (HR = 0.65, 95% CI = 0.46-0.92 for nivolumab, HR = 0.77, 95% CI = 0.61-0.96 for atezolizumab, HR = 0.78, 95% CI = 0.65-0.94 for durvalumab, HR = 0.75, 95% CI = 0.61-0.92 for pembrolizumab), and nivolumab was ranked first in terms of PFS (SCURA = 85.0%, Prbest = 66.8%). In addition, nivolumab had the highest probability of grade 3-4 adverse events (SUCRA = 84.8%) in our study. We found that nivolumab had the best PFS and OS in all combinations of ICIs and EP, but nivolumab also had the highest probability of grade 3-4 adverse events in our network meta-analysis. Further head-to head large-scale phase III randomized controlled studies are needed to verify our conclusions.

Keywords: atezolizumab; chemotherapy; durvalumab; extensive-stage small cell lung cancer; immune checkpoint inhibitors; ipilimumab; nivolumab; pembrolizumab.