Selection of optimal first-line immuno-related therapy based on specific pathological characteristics for patients with advanced driver-gene wild-type non-small cell lung cancer: a systematic review and network meta-analysis

Abstract

Background: Although immune checkpoint inhibitors (ICIs) have improved survival for advanced wild-type non-small cell lung cancer (NSCLC), a lack of direct comparisons of various first-line treatments is clouding clinical decision-making. A network meta-analysis was conducted to compare current first-line treatments and identify the optimal regimen for patients with specific characteristics. Methods: PubMed, Embase, the Cochrane Central Register of Controlled Trials, Clinical Trials databases were searched from inception to 31 July 2020. Phase II/III randomized controlled trials (RCTs) comparing first-line treatments including chemotherapy, anti-angiogenesis, ICIs, and their combinations for previously untreated stage IIIB/IV or recurrent driver-gene wild-type NSCLC patients were included. Results: Twenty-six RCTs were identified and included, involving 16,977 patients and a total of 18 regimens. ICI-containing treatments led to significantly prolonged overall survival (OS) compared with ICI-free treatments (0.82, 0.72–0.93). ICI plus chemotherapy had significantly longer progression-free survival (PFS; 0.70, 0.58–0.86) and marginally longer OS (0.90, 0.79–1.05) compared with ICIs alone. Ranking highest in the Bayesian network meta-analysis, pembrolizumab plus chemotherapy, nivolumab plus ipilimumab and chemotherapy, had significantly superior OS than standard chemotherapy with or without bevacizumab treatments. Pembrolizumab-chemotherapy ranked first for OS, 1-year OS rate, and subgroups of non-squamous, PD-L1 ⩾1%, non-smoking, and liver metastasis; while nivolumab–ipilimumab–chemotherapy for squamous, PD-L1 <1%, brain metastasis NSCLC. Furthermore, the ICI-containing bevacizumab-free treatments, such as pembrolizumab plus chemotherapy, nivolumab and ipilimumab with or without chemotherapy, were not significantly different from atezolizumab plus chemotherapy and bevacizumab in OS. Conclusions: A combination of ICIs with chemotherapy, rather than double ICIs, is the best first-line treatment for advanced wild-type NSCLC, with synergy that leads to better long-term survival. The panoramic view of the relative efficacy of any two regimens with different rankings provides strong evidence for selecting optimal first-line ICIs according to patients’ clinical characteristics.

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 apatinib alone or apatinib plus paclitaxel/docetaxel versus paclitaxel/docetaxel in the treatment of advanced non‐small cell lung cancer: A meta‐analysis

“…Targeted treatment can significantly improve the prognosis of NSCLC patients with positive driver gene mutations, but for NSCLC cases with negative driver genes, the target treatment appears to be invalid. 24 , 25 Since the 20th century, a series of clinical studies have confirmed that tumor angiogenesis plays an important part in tumor development. 26 , 27 , 28 The vascular endothelial growth factor (VEGF) pathway plays an important role in the process of tumor angiogenesis.…”

What Is Long-Term Survival and Which First-Line Immunotherapy Brings Long-Term Survival for Advanced Wild-Type Non-Small Cell Lung Cancer: A Network Meta-Analysis Based on Integrated Analysis

“…Immunotherapy combined with CT plays an important role in achieving LS in ITT patients with advanced wild-type NSCLC compared to either single or dual ICIs. The combination of ICIs and CT was superior to CT or ICIs alone ( 32 ), while there was no difference in mOS or survival rates between single ICI or dual ICIs without CT. The addition of CT helps not only overcome the shortcoming of the slow onset and the possible early ICI-related hyper-progression to improve the short-term response rate but also produce in situ vaccines to promote tumor antigen presentation to increase the efficacy of immunotherapy.…”