Immune-Related Adverse Events Associated With Immune Checkpoint Inhibitors for Advanced Non-small Cell Lung Cancer: A Network Meta-Analysis of Randomized Clinical Trials

Abstract

Objective: This network meta-analysis will provide a complete toxicity profile, toxicity profile, and safety ranking of immune checkpoint inhibitors (ICIs) for treatment of advanced non-small cell lung cancer (NSCLC).Methods: We found 12 phase II or III randomized clinical trials (RCTs) including 8,453 patients with NSCLC by searching Pubmed, Embase, and ClinicalTrials.gov. Risk ratios (RRs) and 95% confidence interval (CI) were used to compare the rate of immune-related adverse events (irAEs) for different ICIs-based treatments using pairwise and network meta-analysis with random effects.Results: For dermatologic irAEs, the corresponding ranking of incidences of the seven groups from high to low was: nivolumab + ipilimumab (97.4%), pembrolizumab (80.1%), nivolumab (67.1%), pembrolizumab + platinum (43.3%), atezolizumab + platinum (39.9%), durvalumab (17.5%), platinum-based chemotherapy (4.7%). For colitis, the corresponding ranking of incidences of the six groups from high to low was: atezolizumab + platinum (77.1%), nivolumab (67.3%), pembrolizumab (60.5%), durvalumab (45.2%), pembrolizumab + platinum (41.4%), platinum-based chemotherapy (8.5%). For endocrine irAEs, the corresponding ranking of incidences of the seven groups from high to low was: nivolumab + ipilimumab (79.1%), durvalumab (69.1%), pembrolizumab (61.9%), atezolizumab + platinum (60.4%),nivolumab (45.7%), pembrolizumab + platinum (33.5%), platinum-based chemotherapy (0.3%). For pneumonitis, the corresponding ranking of incidences of the seven groups from high to low was: pembrolizumab (99.3%), pembrolizumab + platinum (65.1%), durvalumab (62.2%), atezolizumab + platinum (56%), nivolumab (35.9%), platinum-based chemotherapy (18.1%),atezolizumab (13.3%). For hepatitis, the corresponding ranking of incidences of the six groups from high to low was: pembrolizumab (71.2%), pembrolizumab + platinum (64.3%), durvalumab (56.4%), atezolizumab + platinum (53.8%), nivolumab (44.5%), platinum-based chemotherapy (9.8%).Conlusion: In addition to platinum-based chemotherapy, durvalumab for dermatologic and liver irAEs, pembrolizumab for gastrointestinal irAEs, pembrolizumab + platinum for endocrine irAEs, and atezolizumab for pneumonitis may be associated with lower rates of irAEs than other immune-based regimens. Nivolumab + ipilimumab for dermatologic and endocrine irAEs, atezolizumab + platinum for colitis, and pembrolizumab for pneumonitis and hepatitis may be associated with higher rates of irAEs.

The safety of combining immune checkpoint inhibitors and platinum-based chemotherapy for the treatment of solid tumors: A systematic review and network meta-analysis

“…Moreover, Khoja et al posited that pneumonia and hypothyroidism were complications more commonly observed in the context of PD-1 checkpoint blockade as compared to CTLA-4 checkpoint blockade (62). Zhang et al additionally detected an increase in the risk of pneumonia in individuals undergoing pembrolizumab treatment, while nivolumab was associated with a greater risk of hypothyroidism (63,64). Our results are consistent with these prior findings, as pembrolizumab + chemotherapy and nivolumab + chemotherapy were the most common respective causes of pneumonia and hypothyroidism.…”

“…Zhang et al. additionally detected an increase in the risk of pneumonia in individuals undergoing pembrolizumab treatment, while nivolumab was associated with a greater risk of hypothyroidism ( 63 , 64 ). Our results are consistent with these prior findings, as pembrolizumab + chemotherapy and nivolumab + chemotherapy were the most common respective causes of pneumonia and hypothyroidism.…”

Comparative severe dermatologic toxicities of immune checkpoint inhibitors in malignant melanoma: A systematic review and network meta‐analysis

“…15 In contrast to solid tumors, such as non-small cell lung cancer and renal cell carcinoma, patients with melanoma exhibited a higher frequency of dermatologic irAEs because of ICI application. 43,44 Dostarlimab, a novel anti-PD-1 inhibitor, has been reported to dramatically improve the prognosis of patients suffering from locally advanced rectal cancer with no severe irAEs; however, dermatologic irAEs are the main characteristic toxic reactions associated with this drug. 45 Therefore, ICI-induced skin toxicity in patients with malignant melanoma requires further investigation.…”

Toxicity spectrum of immunotherapy in advanced lung cancer: A safety analysis from clinical trials and a pharmacovigilance system

“…In 2021, an NMA of 12 RCTs was conducted for five ICI agents (nivolumab, pembrolizumab durvalumab, atezolizumab, and ipilimumab) in advanced NSCLC, and compared their irAEs, including colitis, endocrine irAEs, pneumonitis and hepatitis. 19 Another updated NMA involving 14 RCTs further assessed severe irAEs across these ICI agents. 20 These two studies was considered flawed because of the limited number of included trials and omission of ICI agents and specific irAEs, which inevitably led to instability in network construction as well as insufficient evidence for a conclusion.…”