Efficacy and Safety of First-Line Treatment Strategies for Anaplastic Lymphoma Kinase-Positive Non-Small Cell Lung Cancer: A Bayesian Network Meta-Analysis

Ling Peng; Dafeng Lu; Yang Xia; Shaodong Hong; Giovanni Selvaggi; Justin Stebbing; Yilan Sun; Fei Liang

doi:10.3389/fonc.2021.754768

Efficacy and Safety of First-Line Treatment Strategies for Anaplastic Lymphoma Kinase-Positive Non-Small Cell Lung Cancer: A Bayesian Network Meta-Analysis

Front Oncol. 2021 Nov 8:11:754768. doi: 10.3389/fonc.2021.754768. eCollection 2021.

Authors

Ling Peng¹, Dafeng Lu², Yang Xia³, Shaodong Hong⁴, Giovanni Selvaggi⁵, Justin Stebbing⁶, Yilan Sun¹, Fei Liang⁷

Affiliations

¹ Department of Respiratory Disease, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, China.
² School of Public Health, Nanjing Medical University, Nanjing, China.
³ Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
⁴ Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China.
⁵ Xcovery Holdings, Palm, Beach Gardens, FL, United States.
⁶ Division of Cancer, Department of Surgery and Cancer, Imperial College London, London, United Kingdom.
⁷ Department of Biostatistics, Zhongshan Hospital, Fudan University, Shanghai, China.

Abstract

Background: Targeted therapies have led to significant improvement in the management and prognosis of anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC). We performed a network meta-analysis of frontline treatment options of ALK-positive NSCLC to provide clinical guidance.

Methods: PubMed, Embase, ClinicalTrials.gov, and international conference databases were searched to identify relevant trials from inception to June 30, 2021. Phase III randomized controlled trials (RCTs) comparing treatments for patients with ALK-positive advanced NSCLC in the first-line setting were included in a Bayesian network meta-analysis. Eligible studies reported at least one of the following clinical outcomes: progression-free survival (PFS), overall survival (OS), risk of the central nervous system (CNS) progression, adverse events (AEs) of grade (G) 3 or higher (G3 AEs), or serious AEs (SAEs). Hazard ratios (HRs) and CI for primary outcome of PFS and secondary outcome of OS and risk of CNS progression were obtained. A multivariate, consistency model, fixed-effects analysis was used in the network meta-analysis. Data on G3 AEs and SAEs were abstracted and meta-analyzed. Risk of bias (RoB) was assessed using the Cochrane Collaboration's tool.

Results: Nine RCTs comprising 2,484 patients were included with seven treatments: alectinib, brigatinib, ceritinib, crizotinib, ensartinib, lorlatinib, and chemotherapy. Compared with chemotherapy, ALK-tyrosine kinase inhibitors (TKIs) significantly prolong PFS and reduced risk of CNS progression except for ceritinib. Lorlatinib appears superior at reducing risk of CNS progression. None of the ALK-TKIs have a significantly prolonged OS as compared with chemotherapy. Lorlatinib increases the risk of G3 AEs as compared with alectinib (odds ratio 4.26 [95% CrI 1.22 to 15.53]), while alectinib caused the fewest G3 AEs.

Conclusions: Lorlatinib is associated with the highest PFS benefit and lowest risk of CNS progression benefits for patients with advanced ALK-positive NSCLC, compared with other first-line treatments, but with higher toxicity. The implementation of a newer generation of ALK-TKIs in the first-line treatment of ALK-positive NSCLC into current clinical practice is evolving rapidly.

Keywords: ALK; first-line; network meta-analysis; non-small cell lung cancer; tyrosine kinase inhibitor.

Publication types

Systematic Review