Efficacy and safety of immunotherapy or antiangiogenic agent-based treatment strategies versus chemotherapy as first-line treatment for extensive-stage small cell lung cancer: a network meta-analysis

Abstract

Objective: Immune checkpoint inhibitors (ICIs) combined with etoposide-platinum are recommended as the standard first-line therapy for extensive-stage small cell lung cancer (ES-SCLC). Despite the potential of antiangiogenic agents to enhance treatment efficacy, the optimal combination pattern remains unclear. This meta-analysis explores existing treatment strategies involving ICIs or antiangiogenic agents in ES-SCLC.

Methods: Hazard ratios (HRs) and odds ratios (ORs) were generated by R software. The outcomes of overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and adverse events of grade 3 or higher (Grade ≥3 AEs) were analyzed. The included trials were classified in terms of different treatment strategies, including ICI + Chemotherapy (ICI + Chemo), ICI + ICI + Chemotherapy (ICI + ICI + Chemo), ICI + Antiangiogenic agent + Chemotherapy (ICI + Antiangio + Chemo), Antiangiogenic agent + Chemotherapy (Antiangio + Chemo), and Chemotherapy (Chemo).

Results: A total of 13 randomized controlled trials (RCTs) involving 6,822 patients were included in the analysis. The drug combination patterns included ipilimumab, durvalumab, adebrelimab, atezolizumab, socazolimab, pembrolizumab, serplulimab, tislelizumab, toripalimab, durvalumab + tremelimumab, tiragolumab + atezolizumab, benmelstobart + anlotinib, bevacizumab + atezolizumab, anlotinib, bevacizumab in combination with chemotherapy. The antiangiogenic agent-containing regimen benmelstobart + anlotinib + chemotherapy demonstrated the highest potential to achieve superior PFS and OS versus chemotherapy. The group meta-analysis also showed that ICI + Chemo, ICI + ICI + Chemo, and ICI + Antiangio + Chemo presented significantly better OS. Additionally, ICI + Antiangio + Chemo achieved better PFS with the lowest HR of 0.37 and the best ORR of 2.08 versus chemotherapy. Patients treated with benmelstobart + anlotinib + chemotherapy, durvalumab + tremelimumab + chemotherapy, and anlotinib + chemotherapy experienced a higher likelihood of grade ≥3 AEs.

Conclusion: For individuals with ES-SCLC, ICI + Antiangio + Chemo was identified as an optimal treatment option due to better OS, PFS, and ORR. Benmelstobart + anlotinib + chemotherapy demonstrated a better survival benefit than chemotherapy. The toxicity of ICI + Antiangio + Chemo was acceptable but needed careful attention. These findings clarified the roles of ICIs and antiangiogenic agent-based treatment strategies in this population.

Keywords: antiangiogenesis; chemotherapy; immunotherapy; network meta-analysis; small cell lung cancer.

FIGURE 1

Flow diagram of eligible studies in our analysis.

FIGURE 2

Network meta-analysis of comparisons of different outcomes of first-line treatments in various groups of ES-SCLC patients. Each circle represents a treatment, and the line between the two points represents a comparison between the two treatments. Chemo, chemotherapy; OS, overall survival; PFS, progression-free survival; ORR, objective response rate; AEs, adverse events. Ade + chemo, adebrelimab + chemotherapy; Ate + chemo, atezolizumab + chemotherapy; Dur + Tre + chemo, durvalumab + tremelimuamb + chemotherapy; Dur + chemo, durvalumab + chemotherapy; Ipi + chemo, ipilimumab + chemotherapy; Pem + chemo, pembrolizumab + chemotherapy; Ser + chemo, serplulimab + chemotherapy; Ben + Anl + chemo, benmelstobart + anlotinib + chemotherapy; Tis + chemo, tislelizumab + chemotherapy; Tir + Ate + chemo, tiragolumab + atezolizumab + chemotherapy; Tor + chemo, toripalimab + chemotherapy; Anl + chemo, anlotinib + chemotherapy; Bev + Ate + chemo, bevacizumab + atezolizumab + chemotherapy; Soc + chemo, socazolimab + chemotherapy; Bev + chemo, bevacizumab + chemotherapy; Chemo, chemotherapy.

FIGURE 3

Efficacy and safety summaries from Bayesian network meta-analysis in ES-SCLC patients: (A) OS, (B) PFS, (C) ORR, and (D) AEs. The data in each cell represent the HR or OR values that compare treatment effects as defined by the columns and rows. The cells are color-coded according to the HR or OR values: those with HR or OR below 0.5 are highlighted in orange, those ranging from 0.5 to 1 in tan, from 1 to 1.5 in light red, from 1.5 to 2 in purple, and those exceeding 2 in blue. The important HRs (or ORs) and 95% confidence interval are highlighted in red and bold. OS, overall survival; PFS, progression-free survival; ORR, objective response rate; AE, adverse event; ICIs, immune checkpoint inhibitors; HR, Hazard ratio; OR, Odds ratio; CI, confidence interval; Ade + chemo, adebrelimab + chemotherapy; Ate + chemo, atezolizumab + chemotherapy; Dur + Tre + chemo, durvalumab + tremelimuamb + chemotherapy; Dur + chemo, durvalumab + chemotherapy; Ipi + chemo, ipilimumab + chemotherapy; Pem + chemo, pembrolizumab + chemotherapy; Ser + chemo, serplulimab + chemotherapy; Ben + Anl + chemo, benmelstobart + anlotinib + chemotherapy; Tis + chemo, tislelizumab + chemotherapy; Tir + Ate + chemo, tiragolumab + atezolizumab + chemotherapy; Tor + chemo, toripalimab + chemotherapy; Anl + chemo, anlotinib + chemotherapy; Bev + Ate + chemo, bevacizumab + atezolizumab + chemotherapy; Soc + chemo, socazolimab + chemotherapy; Bev + chemo, bevacizumab + chemotherapy; Chemo, chemotherapy.

FIGURE 4

Subgroup analysis of OS from Bayesian network meta-analysis in ES-SCLC patients: (A) Pooled HRs and 95%CI in patients with no brain metastasis, (B) Pooled HRs and 95%CI in patients with brain metastasis, (C) Pooled HRs and 95%CI in patients with no liver metastasis, and (D) Pooled HRs and 95%CI in patients with liver metastasis. The data in each cell represent the HR values that compare treatment effects as defined by the columns and rows. The cells are color-coded according to the HR values: those with HR below 0.5 are highlighted in orange, those ranging from 0.5 to 1 in tan, from 1 to 1.5 in light red, from 1.5 to 2 in purple, and those exceeding 2 in blue. The important results are highlighted in red and bold. HRs, hazard ratios; CI, confidence interval; y, years; Ade + chemo, adebrelimab + chemotherapy; Ate + chemo, atezolizumab + chemotherapy; Dur + Tre + chemo, durvalumab + tremelimuamb + chemotherapy; Dur + chemo, durvalumab + chemotherapy; Ipi + chemo, ipilimumab + chemotherapy; Pem + chemo, pembrolizumab + chemotherapy; Ser + chemo, serplulimab + chemotherapy; Ben + Anl + chemo, benmelstobart + anlotinib + chemotherapy; Tis + chemo, tislelizumab + chemotherapy; Tir + Ate + chemo, tiragolumab + atezolizumab + chemotherapy; Tor + chemo, toripalimab + chemotherapy; Anl + chemo, anlotinib + chemotherapy; Bev + Ate + chemo, bevacizumab + atezolizumab + chemotherapy; Soc + chemo, socazolimab + chemotherapy; Bev + chemo, bevacizumab + chemotherapy; Chemo, chemotherapy.

FIGURE 5

Forest plot of survival outcomes from integrated analysis of different therapy strategies (excluding ipilimumab + chemotherapy) in ES-SCLC patients: (A) OS, (B) PFS, (C) ORR, (D) AEs. OS, overall survival; PFS, progression-free survival; ORR, objective response rate; AE, adverse event; HR, hazard ratio; CI, confidence interval; ICI, immune checkpoint inhibitor; ICI + Chemo, ICI + chemotherapy; ICI + ICI + Chemo, ICI + ICI + chemotherapy; ICI + Antiangio + Chemo, ICI + antiangiogenic agent + chemotherapy; Antiangio + Chemo, antiangiogenic agent + chemotherapy; Chemo, chemotherapy.

FIGURE 6

Network meta-analysis of comparisons of each outcome in various treatment strategies (excluding ipilimumab + chemotherapy) of ES-SCLC patients. Each circle represents a treatment strategy, and the line between the two points represents a comparison between the two treatment strategies. The numbers represent the count of involved studies, with the thickness of the lines proportional to the number of studies included. ICI, immune checkpoint inhibitor; ICI + Chemo, ICI + chemotherapy; ICI + ICI + Chemo, ICI + ICI + chemotherapy; ICI + Antiangio + Chemo, ICI + antiangiogenic agent + chemotherapy; Antiangio + Chemo, antiangiogenic agent + chemotherapy; Chemo, chemotherapy.

FIGURE 7

Efficacy and safety summaries from Bayesian network meta-analysis of different treatment strategies (excluding ipilimumab + chemotherapy) in ES-SCLC patients. (A) OS, (B) PFS, (C) ORR, (D) AEs. The data in each cell represent the HR or OR values that compare treatment effects as defined by the columns and rows. The cells are color-coded according to the HR or OR values: those with HRs or ORs below 0.5 are highlighted in orange, those ranging from 0.5 to 1 in tan, from 1 to 1.5 in light red, from 1.5 to 2 in purple, and those exceeding 2 in blue. The important results are highlighted in red and bold. ICI, immune checkpoint inhibitor; ICI + Chemo, ICI + chemotherapy; ICI + ICI + Chemo, ICI + ICI + chemotherapy; ICI + Antiangio + Chemo, ICI + antiangiogenic agent + chemotherapy; Antiangio + Chemo, antiangiogenic agent + chemotherapy; Chemo, chemotherapy.

FIGURE 8

Bayesian ranking profiles indicate the effectiveness of treatment strategies or the likelihood of causing fewer grade ≥3 adverse events (AEs) (excluding ipilimumab + chemotherapy), ranked from most likely to least likely in the overall population. The top illustrates the possibility of improving overall survival (OS), extending progression-free survival (PFS), or causing fewer grade ≥3 adverse events (AEs). Under the premise of the same level, different image areas represent different possibilities of causing the outcome, and the corresponding values are presented in the table. ICI, immune checkpoint inhibitor; ICI + Chemo, ICI + chemotherapy; ICI + ICI + Chemo, ICI + ICI + chemotherapy; ICI + Antiangio + Chemo, ICI + antiangiogenic agent + chemotherapy; Antiangio + Chemo, antiangiogenic agent + chemotherapy; Chemo, chemotherapy.