Immune-related adverse events for anti-PD-1 and anti-PD-L1 drugs: systematic review and meta-analysis

Abstract

ObjectiveTo evaluate rates of serious organ specific immune-related adverse events, general adverse events related to immune activation, and adverse events consistent with musculoskeletal problems for anti-programmed cell death 1 (PD-1) drugs overall and compared with control treatments.DesignSystematic review and meta-analysis.Data sourcesMedline, Embase, Cochrane Library, Web of Science, and Scopus searched to 16 March 2017 and combined with data from ClinicalTrials.gov.Study selectionEligible studies included primary clinical trial data on patients with cancer with recurrent or metastatic disease.Data extractionThree independent investigators extracted data on adverse events from ClinicalTrials.gov and the published studies. Risk of bias was assessed using the Cochrane tool by three independent investigators.Results13 relevant studies were included; adverse event data were available on ClinicalTrials.gov for eight. Studies compared nivolumab (n=6), pembrolizumab (5), or atezolizumab (2) with chemotherapy (11), targeted drugs (1), or both (1). Serious organ specific immune-related adverse events were rare, but compared with standard treatment, rates of hypothyroidism (odds ratio 7.56, 95% confidence interval 4.53 to 12.61), pneumonitis (5.37, 2.73 to 10.56), colitis (2.88, 1.30 to 6.37), and hypophysitis (3.38, 1.02 to 11.08) were increased with anti-PD-1 drugs. Of the general adverse events related to immune activation, only the rate of rash (2.34, 2.73 to 10.56) increased. Incidence of fatigue (32%) and diarrhea (19%) were high but similar to control. Reporting of adverse events consistent with musculoskeletal problems was inconsistent; rates varied but were over 20% in some studies for arthraligia and back pain.ConclusionsOrgan specific immune-related adverse events are uncommon with anti-PD-1 drugs but the risk is increased compared with control treatments. General adverse events related to immune activation are largely similar. Adverse events consistent with musculoskeletal problems are inconsistently reported but adverse events may be common.

Resolution of Pembrolizumab-Associated Steroid-Refractory Lichenoid Dermatitis with Cyclosporine

“…Pembrolizumab, an anti‐PD‐1 monoclonal antibody, is approved by the U.S. Food and Drug Administration for the treatment of multiple malignancies, including advanced melanoma, non‐small cell lung cancer, Hodgkin's lymphoma, primary mediastinal B‐cell lymphoma, urothelial carcinoma, and head and neck cancer. Recent meta‐analyses have shown that anti‐PD‐1 drugs are associated with a higher risk of rash when compared with conventional treatment such as chemotherapy or targeted therapy . We present a case of a patient on pembrolizumab who developed diffuse steroid‐refractory lichenoid dermatitis associated with severe pruritus that was successfully treated with a short course of oral cyclosporine.…”

Nivolumab‐induced celiac‐like enteropathy in patient with metastatic renal cell carcinoma: Case report and review of the literature

“…Nivolumab, an anti‐PD‐1 monoclonal antibody, has shown its efficacy in improving survival in patients with metastatic renal cell carcinoma (RCC), and has been approved as a second‐line treatment, after the failure of angiogenesis‐targeted therapy, in this indication. Even though nivolumab has a relatively good tolerance profile, it may induce severe immunologic toxicities that can occur at any time during or even after the treatment, and these side effects are of crucial importance for patient's care . Immune‐related gastrointestinal toxicities are among the most frequently observed and are dominated by colitis, while small intestine toxicities are much less frequent .…”

“…Even though nivolumab has a relatively good tolerance profile, it may induce severe immunologic toxicities that can occur at any time during or even after the treatment, and these side effects are of crucial importance for patient's care. [3][4][5][6] Immune-related gastrointestinal toxicities are among the most frequently observed and are dominated by colitis, while small intestine toxicities are much less frequent. 7,8 Only one case of diffuse enteropathy, with immune infiltration extended from the duodenum to the colon, has been reported after a long-term course of nivolumab in a patient with lung cancer.…”

Risk of immune‐related pneumonitis for PD1/PD‐L1 inhibitors: Systematic review and network meta‐analysis

“…Although previous data from randomized controlled trials (RCTs) have already shown that PD1/PD‐L1 inhibitor‐related therapeutic regimens are likely to increase the risk of immune‐related pneumonitis, results from these RCTs are not consistent. Traditional systematic reviews and meta‐analyses were conducted to estimate the safety profile of PD1/PD‐L1 inhibitor . However, due to lacking head‐to‐head direct evidence, comparative pneumonitis risk among different PD1/PD‐L1 inhibitor‐related therapeutic regimens have never been systematically studied.…”

“…Traditional systematic reviews and meta-analyses were conducted to estimate the safety profile of PD1/ PD-L1 inhibitor. [13][14][15][16] However, due to lacking head-to-head direct evidence, comparative pneumonitis risk among different PD1/PD-L1 inhibitor-related therapeutic regimens have never been systematically studied.…”