Comparison of Efficacy and Safety of Single and Double Immune Checkpoint Inhibitor-Based First-Line Treatments for Advanced Driver-Gene Wild-Type Non-Small Cell Lung Cancer: A Systematic Review and Network Meta-Analysis

Abstract

BackgroundImmune checkpoint inhibitors (ICIs) have improved survival for advanced wild-type non-small cell lung cancer (NSCLC) significantly, but few studies compared single ICI (SICI)-based treatments and double ICIs (DICI)-based treatments. We summarized the general efficacy of ICI-related treatments, compared the efficacy and safety of SICI-based [programmed death 1 (PD-1)/programmed death-ligand 1 (PD-L1) or cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) inhibitors ± chemotherapy (CT)] and DICI-based (PD-1/PD-L1 inhibitors+CTLA-4 inhibitors ± chemotherapy) treatments vs. CT in the first-line treatment.MethodsWe included phase II/III randomized controlled trials (RCTs), including patients with histologically confirmed stage IIIB–IV driver-gene wild-type NSCLC who received first-line ICI-related therapy in at least one arm. PubMed, Embase, and Cochrane Library were searched from January 1, 2005, to December 31, 2020. This network meta-analysis was performed in a Bayesian framework using GEMTC and JAGS package in R.3.6.1. The research was registered with PROSPERO (CRD42020184534).ResultsTwenty RCTs were involved, including 13,032 patients and 17 treatment regimens. The results showed that ICI-based therapies could provide a pooled median overall survival (mOS) (POS) of 15.79 (95% CI: 14.85–16.73) months, and there were no significant differences in OS, progression-free survival (PFS), objective response rate (ORR), and grade 3 or higher adverse events (≥3AEs) between DICI-based treatments (POS: 14.81, 12.11–17.52 months) and SICI-based treatments (POS: 16.17, 14.59–17.74 months) in overall patients. However, DICI-based treatments had significantly prolonged the OS over SICI-based treatments in squamous and PD-L1 <1% subgroups. The ranking of OS benefit by Bayesian surface under the cumulative ranking curve (SUCRA) spectrum showed that DICI+chemotherapy ranked first for overall population and subgroups including squamous, non-squamous, any level of PD-L1 expression, smoking, male, Eastern Cooperative Oncology Group performance status (ECOG PS) = 0/1, age < 65/≥65 while SICI+CT for low tumor mutation burden (TMB), non-smoking, and female subgroups, and DICI for high TMB subgroups.ConclusionsIn the first-line therapy for advanced wild-type NSCLC, both SICI- and DICI-based treatments could bring significant overall advantages over chemotherapy, with comparable outcomes of efficacy and ≥3AEs. DICI-based treatments were more effective than SICI-based treatments in squamous and PD-L1 <1% subgroups. For most populations, DICI+chemotherapy could be the best choice with a survival benefit, while SICI+chemotherapy has established its position actually.Systematic Review Registration[PROSPERO], identifier [CRD42020184534].

Combined Immunotherapy with Chemotherapy versus Bevacizumab with Chemotherapy in First-Line Treatment of Driver-Gene-Negative Non-Squamous Non-Small Cell Lung Cancer: An Updated Systematic Review and Network Meta-Analysis

“…In addition, the discussion on how ICIs should be added to the regimen was discussed and a few trials are ongoing to evaluate the efficacy and safety profiles of different interventions. This study confirmed that the use of immunotherapy in driver-gene-negative advanced non-squamous NSCLC would significantly benefit the outcome in terms of survival, which was consistent with several previous studies [ 17 , 18 ]. Based on the Checkmate 227 part one B trial, KEYNOTE-021G trial, and KEYNOTE-189 trials, the combination of nivolumab + CT and pembrolizumab + CT were approved to significantly improve the PFS and OS in patients with driver-gene-negative advanced non-squamous NSCLC [ 19 , 20 , 21 , 22 ].…”

Efficacy and safety of first-line checkpoint inhibitors-based treatments for non-oncogene-addicted non-small-cell lung cancer: a systematic review and meta-analysis

“…48 Moreover, Xu et al. 49 in a recent paper carried out an NMA for frontline treatment of non-oncogene-addicted NCSLC. Our manuscript reports a larger analysis by including published data from several trials updated in 2021 and also included an NMA of patients with BM and LM that have a relevant role in clinical practice and prognosis.…”

“…Unlike previous meta-analyses investigating in this field, our work compared more extensively the available treatment strategies, given the number of included RCTs and most recent updates. 10 , 47 , 48 , 49 Among the most recent meta-analysis, Liu et al. considered only combination strategies, excluding mono-ICI regimens.…”

Identifying optimal PD-1/PD-L1 inhibitors in first-line treatment of patients with advanced squamous non-small cell lung cancer in China: Updated systematic review and network meta-analysis

“…Using OS and PFS HRs in 8 included RCTs, they found combination therapy improved clinical benefits over chemotherapy alone, which were consistent to our results. Xu et al (2021) made comparisons of efficacy and safety of single and double immune checkpoint inhibitors (ICIs)-based first-line treatments for advanced wild-type NSCLC, and they found PD-(L)1 combined with chemotherapy had significant survival benefit compared to chemotherapy alone. Though they reached the same conclusion as ours, they did not compare the efficacy of specific drugs in specific populations.…”