key: cord-0877262-gwgn2pbh
authors: Petrelli, Fausto; Morelli, Anna Maria; Luciani, Andrea; Ghidini, Antonio; Solinas, Cinzia
title: Risk of Infection with Immune Checkpoint Inhibitors: A Systematic Review and Meta-analysis
date: 2021-07-05
journal: Target Oncol
DOI: 10.1007/s11523-021-00824-3
sha: c528b7efa4802f1ba0dd8d04d96b3228e8dd64b3
doc_id: 877262
cord_uid: gwgn2pbh

BACKGROUND: The relative risk (RR) of infection for patients treated with immune checkpoint inhibitors (ICIs) is unknown. OBJECTIVES: This study evaluated the risk of infection for patients with solid tumors undergoing ICI therapy based on a systematic review and meta-analysis. PATIENTS AND METHODS: The Cochrane Library, EMBASE, and Pubmed databases were searched up to 1 December 2020. Randomized trials comparing any ICI alone, with chemotherapy (CT), or with other agents versus placebo, CT, or other agents were included. Three independent reviewers extracted the data. The primary outcome was the RR of all-grade (G) and G3–5 infections for patients receiving ICI-based treatments. Random or fixed-effect models were used according to statistical heterogeneity. RESULTS: A total of 21,451 patients from N = 36 studies were eligible. ICIs were associated with a similar risk of all-grade infections (RR = 1.02; 95% CI 0.84–1.24; P = 0.85) versus non-ICI treatments (G1–5 events: 9.6 versus 8.3%). When the ICIs alone were compared to CT, their use was associated with 42% less risk of all-grade infections (RR = 0.58, 95% CI 0.4–0.85; P = 0.01). Compared to CT, the combination of ICIs and CT increased the risk of all-grade (RR = 1.37, 95% CI 1.23–1.53; P < 0.01) and severe infections (RR = 1.52, 95% CI 1.17–1.96; P < 0.01). In anti-PD-1, anti-PD-L1, anti-CTLA-4, monotherapy, and combination trials, the RR of all-grade infections was 0.72 (95% CI 0.49–1.05; P = 0.09), 1.18 (95% CI 0.95–1.46; P = 0.13), 1.74 (95% CI 1.13–2.67; P = 0.01), 0.97 (95% CI 0.79–1.19; P = 0.75) and 2.26 (95% CI 1.34–3.8; P < 0.01), respectively. CONCLUSIONS: Compared to CT alone, ICIs were safer and are recommended for frail patients. Conversely, CT + ICIs or ICIs combinations increased infection risk. Further studies are required to identify high-risk patients and evaluate the need for CT dose reduction or prophylactic myeloid growth factors. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11523-021-00824-3.

An impaired immune response and the loss of barrier integrity due to tumor development and treatments (e.g., those causing myelosuppression) render cancer patients more susceptible to infections. Infections and neutropenia represent some of the most common life-threatening side effects, generating higher mortality and morbidity in patients who are treated with chemotherapy (CT) [1] . Diverse clinical factors identify the patients who have a high risk of developing neutropenia. These factors include: older age, advanced disease, poor performance status, the nature of the anti-cancer treatment, concomitant steroid use, no granulocyte colonystimulating factor (G-CSF) use, underlying chronic lung disease, and hepatic or renal insufficiency [2] .

The use of immune checkpoint inhibitors (ICIs) in monotherapy is associated with a lower risk of all-grade infections.

Chemotherapy combined with ICIs increased the incidence of infections.

ICIs as monotherapy are recommended for frail patients (including: older age, advanced disease, and poor performance status).

We identified all studies that prospectively evaluated the risk of infection in patients with solid tumors treated with an ICI. A systematic search on multiple electronic databases (Pubmed, EMBASE, and the Cochrane Central Register of Controlled Trials) was conducted from inception to 1 December 2020. The search strategy included the following terms: (atezolizumab or nivolumab or pembrolizumab or avelumab or durvalumab or cemiplimab or ipilimumab or tremelimumab) and (fungal or viral or infection or infestation or flu-like symptoms or influenza-like illness or tuberculosis or pneumonia or sepsis or septic shock or infection [MeSH Terms] or abscess). To ensure that any missing studies were included, the references from the included publications were reviewed manually to identify any additional studies.

A total of N = 36 randomized studies was included among the N = 1234 publications retrieved from a systematic search ( Fig. 1 ) . The study types were as follows: N = 29 phase III, N = 1 phase II-III, and N = 6 phase II. Thirteen trials compared CT + ICIs versus CT alone, N = 18 compared ICIs alone versus CT alone or other targeted therapies, and N = 5 compared ICIs alone versus no active treatment (placebo or best supportive care). A total of N = 21,451 patients were analyzed in the quantitative analysis (N = 12,346 and N = 9305 in the experimental and control arms, respectively).

The types of tumors that were treated in the included studies were as follows: lung cancer (N = 18), urothelial cancer (N = 5), breast cancer (N = 4), head and neck and esophageal cancer (N = 3), colorectal carcinoma (N = 2), melanoma (N = 2), prostate cancer (N = 1), and renal cell carcinoma (N = 1). The disease stages were all locally advanced or metastatic, except for N = 2 studies, where the ICIs were added to the standard (neoadjuvant) CT in earlystage breast cancer.

The experimental arms included nivolumab (N = 4), pembrolizumab (N = 9), durvalumab (N = 2), atezolizumab (N = 9), avelumab (N = 2), ipilimumab (N = 2), tremelimumab (N = 1), and a combination of two ICIs (N = 4; durvalumab + tremelimumab in N = 3 studies and nivolumab + ipilimumab in N = 1 study).

In N = 3 studies, targeted therapies were present in the experimental and control arms (atezolizumab + cobimetinib, atezolizumab + trastuzumab emtansine (TDM-1), and pembrolizumab + axitinib versus regorafenib, TDM-1, and sunitinib, respectively).

We included prospective phase II or III randomized clinical trials that reported the risk of infection in adult patients Immune checkpoint inhibitors (ICIs) boost the spontaneous, pre-existing, adaptive anti-tumor immune response by rescuing the activity of the patients' dysfunctional immune cells. The most common adverse events (AEs) linked to ICIs have an autoimmune-like hyperactivation genesis. Interestingly, a stimulus to the function of the T helper-1 (Th1) cells could be responsible for the sporadic reactivation of tuberculosis, as found in several patients who were treated with anti-programmed cell death-1 (PD-1) antibodies [3, 4] . Additionally, a retrospective study on melanoma patients revealed that the immunosuppressive drugs employed for the management of immune-related AEs (e.g., steroids and the tumor necrosis factor-alpha (TNF-α) inhibitor infliximab) represent the main risk factors for the development of infections in patients undergoing ICIs [5] . Furthermore, a recent meta-analysis revealed that patients with solid tumors who were treated with ICIs were less likely to develop severe AEs than those receiving CT [6] .

Currently, ICIs are being used either alone or in combination with other agents, such as CT, and the risk of infection in these patients is unknown. It is not clear which agents (e.g., bacteria, virus, and fungi) or which sites (e.g., lung, urinary system, gastrointestinal tract, skin, etc.) are most associated with infections in patients treated with ICIs.

We performed this systematic review and meta-analysis to evaluate the incidence, grade (G), and relative risk (RR) of infection in patients with solid tumors who were enrolled in randomized trials and receiving ICIs as single agents or in combination with CT versus other treatments (e.g., CT and placebo).

This systematic review was carried out in accordance with the statement in the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [7] . treated with the anti-PD-1 nivolumab, pembrolizumab, or cemiplimab, the anti-CTLA-4 ipilimumab or tremelimumab, or the anti-PD-L1 avelumab, atezolizumab, or durvalumab either alone or in combination with other ICIs (or CT/ other agents) for any solid tumor. The incidence rates were then compared to non-ICI arms (CT or agents alone (e.g., tyrosine kinase inhibitors) or placebo/best supportive care). Studies were included if they reported toxicities according to the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 or 4.0. We excluded studies that included patients who had previously been exposed to the same class(es) of ICI therapy, pediatric patients, or patients with hematological malignancies.

Two investigators (FP and AMM) independently reviewed and identified relevant studies that were eligible for inclusion and used a standardized Microsoft Word template to extract data from each of the included studies. Disagreements on study inclusion were resolved by consensus with a third investigator (CS). The following information was extracted: baseline study characteristics, including primary tumor, author, year of publication, and type of trial, type of disease, type of therapy (experimental and control arms), the incidence of any-G (G1-5), low-G (G1-2), and high-G (G3-4) and fatal-event (G5) infections, and the type of event(s).

The tools in the Cochrane handbook for evaluating randomized controlled trials were used to assess the sources of bias in each study [44] . The bias parameters included random sequence generation and allocation concealment (selection bias), the blinding of the outcome assessment (detection bias), incomplete outcome data (attrition bias), selective reporting (reporting bias), and other biases. Each trial was categorized based on the risk of bias, as follows: low risk of bias (+); high risk of bias (−); and unclear (?). The publication bias was also evaluated by inspecting a funnel plot and using Begg's and Egger's tests (Table 1) . Records excluded because not perƟnent paper (n = 99)

Full-text arƟcles assessed for eligibility (n = 68)

Full-text arƟcles excluded, because they did not report infecƟon events or included immunotherapy in both arms or were older update analyses (n = 32 ) Studies included in qualitaƟve synthesis (n = 36 )

(meta-analysis) (n = 36 )

We used the GRADE system to rate the quality of evidence relating to the estimated treatment effects on the rates of all-grade and G3-5 infections [45] . The GRADE criteria for assessing the quality of evidence included the study design, risk of bias, inconsistency, indirectness, imprecision, suspected publication bias, and other considerations. The assessments of these criteria and corresponding justifications are provided in Table 2 . We performed GRADE assessments separately for selected subgroups related to inconsistency (e.g., heterogeneity) among effect estimates for the primary endpoint.

The number (or rate) of events was compared, and the relative risk (RR with a 95% confidence interval (CI)) was calculated. The primary endpoint was the rate of all-grade infections. The secondary endpoint was the rate of severe infections (G3-5). The following three primary subgroup analyses were performed: ICIs versus CT arms; ICIs versus control arm, including no active treatment (e.g., best supportive care or placebo); and ICIs + CT or other agents versus CT or other agents alone. To account for heterogeneity across the study populations and designs, the incidence of infection was determined using random-or fixed-effects models. We assessed the heterogeneity among the studies in each analysis using a visual inspection and statistically using the Chi-square (Chi 2 ) test and the I-square (I 2 ) statistic. We used a P value threshold of 0.10 to determine statistical significance for the Chi 2 test and considered an I 2 of 50% or more to be a high degree of heterogeneity. The Review Manager (RevMan) (computer program) Version 5.3 (Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014) was used for the statistical analysis.

Overall, the risk of all-grade (G1-5) infections was 9.6% and 8.3% for ICIs and non-ICIs (all studies), respectively. These values were 16.5% in the combination and 11.2% for CT alone, 3.9% in ICIs alone and 6.3% in CT alone comparisons, and 16.2% in ICIs alone versus 9.4% for best supportive care or placebo (no active treatment). The risk of high G infections was 3.1% and 2.6% for ICIs and non-ICIs, respectively. When added to CT, the combination of ICIs + CT was associated with a 4.4% incidence of G3-5 infections compared to 2.4% for CT alone. G5 infections were 0.5% for the experimental and 0.5% for the control group.

In the pooled analysis, the use of ICIs was associated with a similar risk of all-grade infections (RR = 1.02; 95% CI 0.84-1.24; P = 0.85; Fig. 2 ) compared to non-ICIs. Compared to non-ICI arms, the use of ICIs did not increase the risk of severe (G3-5) infections (RR = 0.99; 95% CI 0.74-1.32; P = 0.95; Fig. 3 ). Fatal infections were also lower (albeit non-significantly) for ICIs compared to non-ICIs (RR = 0.77; 95% CI 0.52-1.13; P = 0.18).

Compared to CT, the combination of ICIs and CT increased the risk of all-grade infections (RR = 1.37; 95% CI 1.23-1.53; P < 0.01; N = 13 studies; Fig. 4 ). When ICIs alone were compared to CT, the experimental arms were associated with 42% less risk of G1-5 infections (RR = 0.58; 95% CI 0.4-0.85; P < 0.01; N = 18 studies; Fig. 5 ).

Conversely, compared to non-active treatments (placebo or best supportive care; N = 5 studies), ICIs increased the risk of all-grade infections (RR = 1.53; 95% CI 1.23-1.9; P < 0.01; Fig. 6 ). For G3-5 infections, ICIs alone increased the risk compared to placebo or best supportive care (RR = 2.11; 95% CI 1.04-4.26; P = 0.04; N = 5 studies). Compared to CT alone, ICIs reduced the risk of G3-5 infections (RR = 0.52; 95% CI 0.34-0.78; P < 0.01; N = 18 studies). When added to CT, ICIs increased the risk of severe infection (RR = 1.52; 95% CI 1.17-1.96; P < 0.01; N = 12 studies).

In lung cancer studies, which represented 50% of the total included, the RR of G1-5, G3-5, and G5 infections was not superior in ICIs versus control treatment (data not shown). Similarly, the risk of infection with ICIs was not greater than the control treatments in non-lung cancer trials.

In an exploratory analysis, RR was not correlated to rates of febrile neutropenia or of G3-4 neutropenia.

In anti-PD-1, anti-PD-L1, anti-CTLA-4, monotherapy, and combination trials, the RR of infections at all grades was 0.72 (95% CI 0. 49 

A low risk of bias was observed in N = 23 studies for the unblinding study design (formal absence of a placebo in the control). No relevant biases were found in N = 13 studies. Although Egger's tests for funnel plot asymmetry indicated evidence of publication bias for the all-grade infection Fig. 1 ; P = 0.03), it did not indicate a bias for the G3-5 infection analysis (Online Supplemental Material, Fig. 2 ; P = 0.1).

This systematic review and meta-analysis of 36 randomized clinical trials suggests an association between the use of ICIs administered with CT and an increased risk of infections in patients with solid tumors. Most ICIs + CT-associated infections were pneumonitis and low respiratory tract, viral, urinary, and cutaneous infections. Sepsis was rarely described. Interestingly, our data showed the presence of three cases of tuberculosis reactivation: one in a patient with advanced HER2-positive breast cancer, and two in patients with nonsmall-cell lung cancer. Conversely, compared to CT alone, the ICIs reduced the risk of G3-5 infections. According to type of ICI, combinations (e.g., anti-PD-1 + anti-CTLA-4) were associated with more than double the infections compared to a single agent alone.

The increased risk of infection when ICIs were administered with CT was probably due to the synergistic effects of each agents' specific toxicities, such as pneumonitis (from ICIs), neutropenia (CT and targeted agents), the advanced stage of the disease, and the diagnosis of a lung cancer [46] . Remarkably, regarding this tumor, the occurrence of infections might influence the patient's prognosis, as shown by the severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2), which causes the severe Coronavirus disease 19 (COVID-19) and a higher risk of mortality. In the pandemic era, caution should be used particularly with those patients at risk of COVID-19 infection and mortality when ICI combinations or a CT + ICIs combination is planned in cancer patients. Despite this, larger studies are urgently needed to improve the evaluation of the effects of ICIs in patients with COVID-19 and the use of ICIs during the coronavirus pandemic [47, 48] .

Due to the increased risk of infection observed with the association of CT and ICIs or with ICI combinations, preventive measures in this group of patients may be considered, particularly in those with a higher risk of developing neutropenia (e.g., prior CT or radiotherapy (e.g., to the lung), bone marrow involvement by the tumor, or older age), elderly or frail patients, and subjects with pulmonary, cardiovascular, and metabolic co-morbidities.

In particular, in patients at a higher risk of developing infections, the use of ICIs alone might be safer, given their low hematological toxicity [49] . These risk factors include older age, advanced disease, poor performance status, the nature of the anti-cancer treatment administered, recent surgical procedures, prior prophylactic antibiotics, concomitant steroid use, previous bacteremia or infection with [2, 50] . Furthermore, regarding the use of steroids, the mainstay for the management of most immune-related AEs related to ICIs should be conducted cautiously and with the awareness of creating a higher risk of infection by specific pathogens, such as Pneumocystis jiroveci, fungal infections, and Herpes zoster. In addition, in patients treated with ICIs, infliximab has been associated with the hepatitis B virus and reactivation of tuberculosis [51] . In the trials included in this meta-analysis, no cases of hepatitis B and three tuberculosis reactivations were detected in ICI groups.

Febrile neutropenia (> 38.3 °C or two consecutive readings of > 38 °C over 2 h plus a neutrophil count of < 500/ mm 3 ) is a common complication of cancer CT. In around 30% of febrile episodes in cancer patients, common infections were in the intestinal tract, lungs, and skin, which cause diarrhea, pneumonia, lung infiltrates, and cellulitis, respectively [49] . Further, bacteremia was observed in around 20% of patients with febrile neutropenia. Sepsis can develop in a minority of patients. In our analysis, similar infection sites were observed; therefore, it can be assumed that the risk is likely driven by CT-induced myelosuppression.

The limitations of our work are as follows: we had difficulty finding detailed information on the precise sites of infection (e.g., infections of the respiratory tract versus pneumonia); there was incomplete information on the nature of the agent of the infections (e.g., viral versus fungal versus bacterial); and the use of prophylactic myeloid growth factors was not reported in the primary studies. Furthermore, the present meta-analysis was unable to include an agestratified analysis or other subgroup analyses, as the primary studies were not focused on reporting risk factors for Heterogeneity 54% (P < 0.01) Five studies did not report events in experimental and control arms infections related to age, co-morbidities, or disease-related complications. The causative role of autoimmune AEs (e.g., pneumonitis) or the detrimental effect of steroids may not be elucidated in single publications. Finally, two-thirds of trials showed evidence of some publication bias mostly due to the unblinded randomization design and general heterogeneity explained for different diseases and stage settings.

However, our work is the first to analyze the overall risk of all infections in patients with solid tumors treated with ICIs either alone or in combination with other agents. Among its strengths, we acknowledge the inclusion of data from > 20,000 patients, the variety of tumor types, the homogeneous disease stage (locally advanced and metastatic), and the possibility of calculating the RR for the inclusion of randomized studies. However, the correlation between infections in cancer patients undergoing ICIs needs to be investigated further in dedicated trials.

The challenges for clinical practice include: correct management and differential diagnosis with the involvement of a multidisciplinary team and the aim of selecting the best treatment options (e.g., supportive drugs) for these patients, particularly those at a high risk, while maintaining the antitumor effect.

In conclusion, our study suggests that the use of ICIs may be associated with a higher risk of infection, particularly when provided in association with CT. Whenever the use of ICIs plus CT is indicated, we should consider the employment of myeloid growth factors and dose reductions of ICIs and/or CT.

Considering the disease's stage and prognosis and the significant improvement in overall survival provided by ICIs, the benefits may still outweigh the risk of infection in most patients.

This meta-analysis highlights the need to perform dedicated studies to identify those patients at a higher risk, as they might be candidates for prophylaxis with colony-stimulating factors or (ICI and/or CT) dose reduction. Strategies to prevent infections and identify patients at risk should be developed. 

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