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.

backgroundAlthough 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.

methodsPubMed, 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.

resultsTwenty-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.

conclusionsA 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.