First-line therapies with maintenance regimens for driver gene-negative advanced non-small cell lung cancer (NSCLC): a systematic review and network meta-analysis of 61 randomized trials.

Background: Does efficacy differ among first-line treatment strategies that include maintenance therapy (MT) in patients with advanced driver-gene wild-type non-small cell lung cancer (NSCLC)? Few studies have directly compared these MT-containing strategies, and the optimal regimen for this population remains uncertain. In this Bayesian network meta-analysis (NMA), we aimed (I) to compare the efficacy and safety of available first-line regimens incorporating MT and to rate the certainty of evidence, and (II) to compare outcomes across chemotherapy (CT) backbones when combined with MT. Methods: We systematically searched PubMed, Embase and the Cochrane Library. We included randomized controlled trials (RCTs) that randomized patients before first-line treatment initiation and included MT in at least one study arm. We assessed risk of bias for each RCT and used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework to rate certainty of evidence. We performed a Bayesian NMA and compared MT-containing regimens across CT backbones using prespecified subgroup analyses. This review was registered in PROSPERO (CRD42021215862). Results: We included 61 RCTs. Certainty of evidence for primary outcomes was mostly moderate to low. Continuous dual immunotherapy [DI; anti-PD-(L)1 plus anti-CTLA-4] ranked highest for overall survival (OS) in the overall population. In patients with programmed cell death ligand 1 (PD-L1) <1%, DI remained preferred because it was associated with improved OS, regardless of histology. In non-squamous (NSQ) NSCLC with PD-L1 ≥1%, pemetrexed-platinum plus single immunotherapy (SI), with maintenance pemetrexed plus anti-PD-(L)1, may be the most appropriate option. By contrast, in squamous (SQ) NSCLC with PD-L1 ≥1%, platinum-based CT plus SI, with maintenance anti-PD-(L)-1, may be optimal. Conclusions: Among all available first-line therapies incorporating MT for advanced driver-gene wild-type NSCLC, immunotherapies play a central role. DI was associated with an OS advantage over CT in patients with PD-L1 <1%. With increasing PD-L1 expression, chemo-immunotherapy [CT plus a single anti-PD-(L)1 antibody] was associated with durable clinical benefit. However, additional evidence is needed to compare continuous DI with other MT-containing strategies, particularly for progression-free survival in key subgroups.