Immune-related adverse events associated with programmed cell death protein-1 and programmed cell death ligand 1 inhibitors for non-small cell lung cancer: a PRISMA systematic review and meta-analysis

Abstract

Background: Programmed cell death protein-1 (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitors have remarkable clinical efficacy in the treatment of non-small cell lung cancer (NSCLC); however, the breakdown of immune escape causes a variety of immune-related adverse events (irAEs). With the increasing use of PD-1/PD-L1 inhibitors alone or in combination with other therapies, awareness and management of irAEs have become more important. We aimed to assess the incidence and nature of irAEs associated with PD-1 and PD-L1 inhibitors for NSCLC. Methods: Articles from the MEDLINE, EMBASE, and Cochrane databases were searched through December 2017. The incidence of overall and organ-specific irAEs was investigated in all clinical trials with nivolumab, pembrolizumab, atezolimumab, durvalumab, and avelumab as single agents for treatment of NSCLC. We calculated the pooled incidence using R software with package Meta. Results: Sixteen trials were included in the meta-analysis: 10 trials with PD-1 inhibitors (3734 patients) and 6 trials with PD-L1 inhibitors (2474 patients). The overall incidence of irAEs was 22% (95% confidence interval [CI], 17-28) for all grades and 4% (95% CI, 2-6) for high-grade irAEs. The frequency of irAEs varied based on drug type and organ, and patients treated with PD-1 inhibitors had an increased rate of any grade and highgrade irAEs compared with patients who received PD-L1 inhibitors. Organ-specific irAEs were most frequently observed in, in decreasing order, the endocrine system, skin, pulmonary tract, and gastrointestinal tract. The total number of patients whose death was attributed to irAEs was 14 (0.34%), and most (79%) of these patients died because of pneumonitis. The median time to the onset of irAEs after the initiation of treatment was 10 weeks (interquartile range, 6-19.5 weeks) and varied depending on the organ system involved. Conclusions: The specificity of irAEs was closely associated with the mechanism of PD-1/PD-L1 antibodies involved in restarting anticancer immune attacks. Comprehensive understanding, timely detection, and effective management could improve the compliance of patients and guide the interruption of treatment.

Changing Body Weight–Based Dosing to a Flat Dose for Avelumab in Metastatic Merkel Cell and Advanced Urothelial Carcinoma

“…Specifically, in the lightest weight quartile, the mean probability of irAEs was numerically higher with flat dosing compared with weightbased dosing (14.3% vs. 10.0%, respectively); however, this projected difference is not expected to be clinically meaningful because this rate is similar to or lower than rates of irAEs seen with other approved anti-PD-1/PD-L1 antibodies. 21,22 In contrast, in the heaviest weight quartile, the probability of irAEs was lower for flat dosing compared with weight-based dosing.…”

Imaging of tumour response to immunotherapy

“…They generally start the first few weeks after treatment; nevertheless, they can occur at any time, even after treatment discontinuation [37][38][39]. Their incidence and severity depend on the agent, with higher all-grade rates reported with anti-CTLA4 (up to 80%) compared to anti-PD1 (27%) and anti-PDL1 (17%) [39][40][41][42]. Different tissues and organs may be affected and multisystem toxicities are common, with a spectrum of imaging manifestations in each organ [43].…”

“…Different tissues and organs may be affected and multisystem toxicities are common, with a spectrum of imaging manifestations in each organ [43]. Fatigue, cutaneous toxicities, colitis, and endocrine dysfunctions are the most frequent events, followed by hepatitis and pneumonitis [39][40][41][42]. Other rare irAEs include nephrologic, neurologic, cardiologic, and haematologic toxicities [37,[40][41][42].…”

“…Fatigue, cutaneous toxicities, colitis, and endocrine dysfunctions are the most frequent events, followed by hepatitis and pneumonitis [39][40][41][42]. Other rare irAEs include nephrologic, neurologic, cardiologic, and haematologic toxicities [37,[40][41][42]. Although they are generally manageable mild toxicities, severe and lifethreatening events may occur in up to 7%, 3%, and 30% of patients receiving anti-PD1, anti-PDL1, and anti-CTLA4, respectively, reaching up to 55% with combined immunotherapy [39][40][41][42].…”

“…Other rare irAEs include nephrologic, neurologic, cardiologic, and haematologic toxicities [37,[40][41][42]. Although they are generally manageable mild toxicities, severe and lifethreatening events may occur in up to 7%, 3%, and 30% of patients receiving anti-PD1, anti-PDL1, and anti-CTLA4, respectively, reaching up to 55% with combined immunotherapy [39][40][41][42]. IrAEs generally respond to immunotherapy holding and require corticosteroids and immunosuppressive treatment in more severe cases along with organ-specific treatment.…”