Efficacy and safety of novel immune checkpoint inhibitor-based combinations versus chemotherapy as first-line treatment for patients with extensive-stage small cell lung cancer: A network meta-analysis

Abstract

Background: Patients with extensive-stage small cell lung cancer (ES-SCLC) have an exceptionally poor prognosis and immune checkpoint inhibitors (ICIs) combined with etoposide-platinum is recommended as standard first-line therapy. However, which combination pattern is the best still remains unknown. This network meta-analysis was performed to compare the efficacy and safety of currently available patterns including an antiangiogenic agent containing regimen and probed into the most appropriate therapy for patients.

Methods: Hazard ratios (HRs) and odds ratios (ORs) were generated using 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 adverse events [AEs]) were analyzed.

Results: A total of 10 randomized controlled trials (RCTs) involving 5544 patients were included for analysis. Drug combination patterns included adebrelimab, atezolizumab, durvalumab, durvalumab plus tremelimumab, ipilimumab, pembrolizumab, serplulimab, benmelstobart plus anlotinib, tislelizumab, tiragolumab plus atezolizumab and toripalimab in combination with chemotherapy. The novel antiangiogenic agent containing regimen benmelstobart + anlotinib + chemotherapy showed the highest possibility to present the best PFS and OS versus chemotherapy. Compared with ICI plus chemotherapy, it also achieved significantly better PFS and presented a tendency of OS benefit. As for safety and toxicity, patients treated with benmelstobart + anlotinib + chemotherapy and durvalumab + tremelimumab + chemotherapy suffered a higher likelihood of more grade ≥ 3 AEs without unexpected AEs.

Conclusion: PD-1/PD-L1 inhibitors-based combinations are associated with significant improvement in both PFS and OS for treatment-naïve ES-SCLC patients. Benmelstobart plus anlotinib with chemotherapy (CT) yielded better survival benefit versus CT alone or other ICIs + CT with caution for more adverse effects along with the addition of an antiangiogenic agent.

Keywords: angiogenesis; chemotherapy; immunology; network meta‐analysis; small cell lung cancer.

FIGURE 1

Flow chart of search, inclusion, and exclusion studies.

FIGURE 2

Network meta‐analysis of first‐line treatments for extensive‐stage small cell lung cancer (ES‐SCLC) patients in various groups that included overall survival, progression‐free survival, and grades ≥3 adverse events of the ES‐SCLC and different subgroups by age, gender, and metastasis. Each node 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.

FIGURE 3

Efficacy and safety characteristics of Bayesian network meta‐analysis in patients with extensive‐stage small cell lung cancer (ES‐SCLC). (a) Hazard ratios (HRs) and 95% confidence interval (CI) for overall survival (OS) in ES‐SCLC patients. (b) HRs and 95% CI for progression‐free survival (PFS) in ES‐SCLC patients. (c) ORs and 95% CI for objective response rate (ORR) in ES‐SCLC patients. (d) ORs and 95% CI for grades ≥3 adverse events (AEs_grade ≥3) in ES‐SCLC patients. Significant results are shown in bold and red. Chemo, chemotherapy; 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.

FIGURE 4

The rank‐heat plot presented in this study illustrates the evaluation of various therapies used as first‐line treatment for patients with extensive‐stage small cell lung cancer (ES‐SCLC). The sectors in the plot are color‐coded based on the surface under the cumulative ranking (SUCRA) value, which represents the overall ranking of each treatment and outcome. (a) SUCRA values for overall survival (OS). (b) SUCRA values for progression‐free survival (PFS). The circles in the plot represent the SUCRA values for OS at third, sixth, ninth, 12th, 15th, 18th, 21st, and 24th month for immunotherapy combinations compared to chemotherapy, as well as the SUCRA values for PFS at first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, 10th, 11th, and 12th month. Chemo, chemotherapy; Ade, adebrelimab; Ate, atezolizumab; Dur + Tre, durvalumab + tremelimuamb; Dur, durvalumab; Ipi, ipilimumab; Pem, pembrolizumab; Ser, serplulimab; Ben + Anl, benmelstobart + anlotinib; Tis, tislelizumab; Tir + Ate, tiragolumab + atezolizumab; Tor, toripalimab.

FIGURE 5

Efficacy and safety characteristics of Bayesian network meta‐analysis in patients with extensive‐stage small cell lung cancer (ES‐SCLC). (a) Hazard ratios (HRs) and 95% confidence interval (CI) in male patients with ES‐SCLC. (b) HRs and 95% CI in female patients with ES‐SCLC. (c) HRs and 95% CI in patients aged <65 with ES‐SCLC. (d) HRs and 95% CI in patients aged ≥65 with ES‐SCLC. Significant results are shown in bold and red. Chemo, chemotherapy; 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. OS, overall survival.

FIGURE 6

Efficacy and safety characteristics of Bayesian network meta‐analysis in patients with extensive‐stage small cell lung cancer (ES‐SCLC). (a) Hazard ratios (HRs) and 95% confidence interval (CI) in ES‐SCLC patients with liver metastasis. (b) HRs and 95% CI in ES‐SCLC patients with no liver metastasis. (c) HRs and 95% CI in ES‐SCLC patients with brain metastasis (d) HRs and 95% CI in ES‐SCLC patients with no brain metastasis. Significant results are shown in bold and red. Chemo, chemotherapy; 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. OS, overall survival.

FIGURE 7

Bayesian ranking profiles from the most likely to the least likely to cause less grades ≥3 adverse events (AEs) or from the most effective to the least effective immunotherapies in the overall population. The top spot demonstrates the highest chances of improving overall survival (OS), extending progression‐free survival (PFS), or being the most likely to cause less grades ≥3 AEs.