Efficacy and Safety of PD-1/PD-L1 Inhibitors Plus Chemotherapy Versus PD-1/PD-L1 Inhibitors in Advanced Non-Small Cell Lung Cancer: A Network Analysis of Randomized Controlled Trials.

Xiang Li,Nan Wu,Shi Yan,Minglei Zhuo,Jun Zhao,Yaqi Wang,Chao Lv,Shaolei Li,Jichun Yang,Yue Yang

doi:10.3389/fonc.2020.574752

Abstract

Immune checkpoint inhibitors (ICIs) are recommended as first-line treatment for late-stage non-small cell lung cancer (NSCLC), either as monotherapy or in combination with chemotherapy. However, efficacy and safety comparisons between ICIs as monotherapy and ICIs with chemotherapy are lacking. We searched PubMed, Embase, and Cochrane Library for randomized controlled trials published before February 29th, 2020, with the search terms “immunotherapy” and “chemotherapy”. 10 eligible trials were identified with a total of 5,956 patients. Of these patients, 3,204 received immune therapy and 2,752 received chemotherapy. PD-1 inhibitors with chemotherapy improved OS (HR 0.84, 0.77–0.92), PFS (HR 0.80, 0.75–0.85), and objective response rate (ORR) (odds ratio (OR) 2.55, 1.20–5.28) compared to PD-1 inhibitors as monotherapy. In contrast, PD-L1 inhibitors plus chemotherapy showed no significant differences in OS, PFS, or ORR compared with PD-L1 inhibitors as monotherapy. When patients were stratified according to PD-L1 expression level, patients with high PD-L1 expression (≥ 50%) receiving PD-1 inhibitors plus chemotherapy had improved PFS, but not other outcomes, compared to PD-1 inhibitors as monotherapy. In these patients, PD-L1 inhibitors plus chemotherapy showed no significant difference in survival compared with PD-L1 inhibitors. In the low PD-L1 expression group (1%–49%), PD-1 inhibitors plus chemotherapy improved OS and PFS, but no advantage was observed in PD-L1 inhibitors plus chemotherapy in OS, PFS, or ORR compared with PD-L1 inhibitor monotherapy. When comparing PD-1/PD-L1 inhibitors plus chemotherapy with PD-1/PD-L1 inhibitors monotherapy, no significant differences were observed in the rate of immune-related adverse events (AEs). In summary, for treating patients with late-stage NSCLC, PD-1 inhibitors plus chemotherapy have improved efficacy compared with PD-1 inhibitor monotherapy, but PD-L1 inhibitors plus chemotherapy have similar efficacy as PD-L1 monotherapy. Survival benefits of PD-1/PD-L1 inhibitors combined with chemotherapy were particularly significant in patients with low PD-L1 expression levels.Systematic Review RegistrationPROSPERO, identifier CRD42020166678 (https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=166678).

Highlights

Worldwide in 2018, 2,093,876 new lung cancer patients were diagnosed and lung cancer caused 1,761,007 deaths [1]
Head-to-head comparisons revealed that compared with chemotherapy, OS was improved in patients treated with PD-1 inhibitors (HR 0.85, 0.76–0.95), PD-1 inhibitors plus chemotherapy (HR 0.57, 0.48–0.69), and PD-L1 inhibitors plus chemotherapy (HR 0.83, 0.74–0.94)
We considered efficacy outcomes (OS, PFS, and ORR) and safety outcomes (AEs) to compare treatment with PD1/PD-L1 inhibitor plus chemotherapy with PD-1/PD-L1 inhibitors as monotherapy

Summary

Introduction

Worldwide in 2018, 2,093,876 new lung cancer patients were diagnosed and lung cancer caused 1,761,007 deaths [1]. Nonsmall cell lung cancer (NSCLC) accounts for 80%–85% of these cases [2]. Therapeutic regimes for patients with NSCLC in stage III or beyond include radical radiotherapy, chemo-radiotherapy, gene targeted therapy, and immune checkpoint inhibitors (ICIs). ICI therapies, targeting T-cell regulatory pathways to provide significant clinical benefits against cancers [3, 4], have been heralded as a promising treatment for lung cancer. The receptor PD-1 and its ligands PD-L1 and PD-L2 play a vital role in the maintenance of immunologic self-tolerance [5]. Cancers can exploit this pathway to escape T-cell-mediated attack by the immune system. Clinical practice has attempted to enhance anti-tumor immune responses by augmenting costimulatory signals, but coinhibitory signals that block anti-tumor T-cell responses have been shown to be more effective than costimulatory signals [6]

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Conclusion