Efficacy and safety of first-line immunotherapy plus chemotherapy in treating patients with extensive-stage small cell lung cancer: a Bayesian network meta-analysis

Abstract

Background: Despite numerous immunotherapy and chemotherapy regimens available for patients with extensive-stage small cell lung cancer (ES-SCLC), it remains unclear which regimen is the most effective and safest; relative studies comparing such regimens are scarce.

Objective: The aim of this study was to investigate the efficacy and safety of first-line immunotherapy combinations with chemotherapy for patients with extensive-stage small cell lung cancer. In addition, for the first time, comparisons among the first-line systemic regimens on OS and PFS in ES-SCLC by each time node were made.

Methods: Databases including PubMed, Embase, Cochrane Library, Scopus, Google Scholars, and ClinicalTrials.gov, and major international conferences were searched for randomized controlled trials (RCTs) regarding comparing immunotherapy combinations with chemotherapy as first-line treatments for patients with advanced ES-SCLC from inception to 1 November. Hazard ratios (HRs) and odds ratios (ORs) were generated for dichotomous variants by RStudio 4.2.1. The outcomes comprised overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and adverse events of grade 3 or higher (Grade ≥ 3 AEs).

Results: Eventually, a total of nine RCTs reporting 4,352 individuals with nine regimens were enrolled. The regimens were ipilimumabnu (Ipi), atezolizumab (Atez), durvalumab plus tremelimumab (Durv-Trem), durvalumab (Durv), pembrolizumab (Pemb), adebrelimab (Adeb), serplulimab (Serp), atezolizumab plus tiragolumab (Atez-Tira), and nivolumab (Nivo). With regard to OS, serplulimab (HR = 0.63, 95% CI: 0.49 to 0.81) was found to yield the best OS benefit when compared with chemotherapy. Meanwhile, serplulimab had the highest probability (46.11%) for better OS. Furthermore, compared with chemotherapy, serplulimab significantly increased the OS rate from the 6th to the 21st month. With regard to PFS, serplulimab (HR = 0.47, 95% CI: 0.38 to 0.59) was found to yield the best PFS benefit when compared with chemotherapy. Simultaneously, serplulimab had the highest probability (94.48%) for better PFS. Serplulimab was also a long-lasting first-line regimen in both OS and PFS from a longitudinal perspective. In addition, there was no significant difference among the various treatment options for ORR and grade ≥3 AEs.

Conclusion: Considering OS, PFS, ORR, and safety profiles, serplulimab with chemotherapy should be recommended as the best therapy for patients with ES-SCLC. Certainly, more head-to-head studies are needed to confirm these findings.

Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42022373291.

Keywords: efficacy; extensive-stage small cell lung cancer; immunotherapy; network meta-analysis; safety.

Figure 1

PRISMA flowchart illustrating the selection of studies included in our analyses.

Figure 2

Network meta-analysis of comparisons on different outcomes of first-line treatments in different groups of ES-SCLC patients. (A) Comparison of overall survival (OS). (B) Comparison of progression-free survival (PFS). (C) Comparison of objective response rate (ORR). (D) Comparison of grade 3 or more adverse events. Direct comparisons are represented by the color lines connecting the treatments. Line width is proportional to the number of trials including every pair of treatments, whereas circle size is proportional to the total number of patients for each treatment in the network. Nivo, Nivolumab; Atez-Tira, Atezolizumab + Tiragolumab; Atez, Atezolizumab; Serp, Serplulimab; Durv, Durvalumab; Durv-Trem, Durvalumab + Tremelimumab; Pla, Placebo; Adeb, Adebrelimab; Pemb, Pembrolizumab; Ipi, Ipilimumab.

Figure 3

Efficacy and safety profiles of the Bayesian network meta-analysis in patients with ES-SCLS. (A) HRs and 95% CI for overall survival (upper triangle in blue) and progression-free survival (lower triangle in yellow), and a hazard ratio < 1.00 provides better survival benefits. (B) ORs and 95% CI for objective response rate (upper triangle in blue) and grade ≥ 3 adverse events (lower triangle in yellow), and an OR < 1.00 indicates a better efficacy or more toxicity. The results are presented as column-defined treatment versus row-defined treatment. Significant results are in bold. Nivo, Nivolumab; Atez-Tira, Atezolizumab + Tiragolumab; Atez, Atezolizumab; Serp, Serplulimab; Durv, Durvalumab; Durv-Trem, Durvalumab + Tremelimumab; Pla, Placebo; Adeb, Adebrelimab; Pemb, Pembrolizumab; Ipi, Ipilimumab.

Figure 4

Bayesian ranking profiles for immunotherapy combinations on efficacy and safety for patients with ES-SCLC. Ranking plots indicate the probability of each comparable immunotherapy combination being ranked from first to last on OS, PFS, ORR, and grade ≥ 3 AEs. Nivo, Nivolumab; Atez-Tira, Atezolizumab + Tiragolumab; Atez, Atezolizumab; Serp, Serplulimab; Durv, Durvalumab; Durv-Trem, Durvalumab + Tremelimumab; Pla, Placebo; Adeb, Adebrelimab; Pemb, Pembrolizumab; Ipi, Ipilimumab.

Figure 5

Rank-heat plot of multiple therapies in first-line treatment of patients with ES-SCLC. Each sector was colored according to the surface under the cumulative ranking (SUCRA) value of the corresponding treatment and outcome. (A) Rank-heat plot based on SUCRA on OS. (B) Rank-heat plot based on SUCRA on PFS. Circles from outside to inside refer to SUCRA value of OS on 3rd, 6th, 9th, 12th, 15th, 18th, 21st, and 24th month for immunotherapy combinations compared to chemotherapy, and SUCRA value of PFS on 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, and 12th month. The closer the color is to red, the greater the probability of ranking first, and the closer the color is to green indicates 0% probability of being ranked first. Nivo, Nivolumab; Atez-Tira, Atezolizumab + Tiragolumab; Atez, Atezolizumab; Serp, Serplulimab; Durv, Durvalumab; Durv-Trem, Durvalumab + Tremelimumab; Pla, Placebo; Adeb, Adebrelimab; Pemb, Pembrolizumab; Ipi, Ipilimumab.

Figure 6

Bayesian network meta-analysis in patients with ES-SCLC. Hazard ratios and 95% CIs for patients with the baseline CNS metastases (upper triangle in blue) and for patients without baseline CNS metastases (lower triangle in yellow), and a hazard ratio < 1.00 provides better survival benefits. Hazard ratios less than 1 favor row defining treatment. Significant results are in bold. Nivo, Nivolumab; Atez-Tira, Atezolizumab + Tiragolumab; Atez, Atezolizumab; Serp, Serplulimab; Durv, Durvalumab; Durv-Trem, Durvalumab + Tremelimumab; Pla, Placebo; Adeb, Adebrelimab; Pemb, Pembrolizumab; Ipi, Ipilimumab.