The safety of first and subsequent lines of PD-1/PD-L1 inhibitors monotherapy in non-small cell lung cancer patients: a meta-analysis

BACKGROUND: In both first or subsequent therapy of patients with non-small cell lung cancer (NSCLC), some programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) inhibitors have shown prominent efficacy and safety. However, the disease spectra of side effects in different therapy time might exist heterogeneity. In this meta-analysis, we assessed and compared the safety of PD-1/PD-L1 inhibitors in first or subsequent line therapy. And the system-specific disease spectra of both treatment-related adverse events (trAEs) and immune-related adverse events (irAEs) were summarized. METHODS: We performed a comprehensive search of online databases. Incidence and its 95% confidence interval (95% CI) were chosen as the main outcome to assess safety. The incidence of trAEs/irAEs was calculated, including discontinuation and death results. Besides, the most common trAEs/irAEs and system-specific treatment-related/immune-related disease spectra in different therapy lines were also collected. RESULTS: In total, 18 studies (5,649 patients) were included. First-line therapy had a higher risk of high-grade trAEs, any-grade irAEs and high-grade irAEs comparing with subsequent therapy (19.4% vs. 13.0%, P<0.001; 30.1% vs. 16.9%, P<0.001; 9.9% vs. 2.4%, P<0.001). The rate of discontinuation in first-line therapy were also higher (9.5% vs. 5.2%, P<0.001). However, the common system-specific trAEs of first-line and subsequent therapy were semblable, including gastrointestinal disorders, general disorders, skin and subcutaneous tissue disorders, investigations. As for irAEs, the frequent system-specific adverse events related to different therapy lines were also similar, including endocrine adverse events, dermatologic adverse events, pulmonary adverse events, and gastrointestinal adverse events. Especially, the incidence of pneumonitis always ranks high in most of the analyses, while for the high-grade toxicities, first-line therapy focuses more on liver-related disorders in trAEs/irAEs. CONCLUSIONS: In summary, the incidence of trAEs in first-line therapy of PD-1/PD-L1 inhibitors in NSCLC is similar to the one in subsequent therapy, while the rate of having any-grade irAEs and high-grade trAEs/irAEs in first-line therapy is higher than the one in subsequent therapy. Meanwhile, there is no obvious heterogeneity for disease spectra in different therapy lines.