The Risk of Opportunistic Infections and the Role of Antibiotic Prophylaxis in Patients on Checkpoint Inhibitors Requiring Steroids

View More View Less
  • 1 Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York;
  • | 2 Department of Medicine, MedStar Georgetown University Hospital Lombardi Comprehensive Cancer Center, Washington, DC; and
  • | 3 Department of Biostatistics, Bioinformatics and Biomathematics, and
  • | 4 Department of Oncology, Georgetown University Medical Center, Washington, DC.

Background: Immune-related adverse events (irAEs) often require treatment with high-dose systemic steroids (SS) and other immunosuppressive agents (ISAs). NCCN Guidelines recommend prophylactic antibiotics for Pneumocystis jirovecii pneumonia (PJP) for patients receiving prolonged SS/ISAs. However, there is a paucity of evidence regarding the incidence of opportunistic infections (OIs) and non-OIs and the role of prophylactic antibiotics in patients on SS/ISAs for irAEs. Methods: A retrospective analysis was conducted of patients treated using immune checkpoint inhibitor (ICI) therapy at 5 MedStar Health hospitals from January 2011 to April 2018. OIs were defined per the Infectious Diseases Society of America guidelines for the prevention and treatment of OIs in patients with HIV. The study cohort included patients who received ≥20 mg daily of a prednisone equivalent for ≥4 weeks to manage irAEs. Results: The study cohort identified 112 (15%) of 758 total patients treated using ICIs. Baseline characteristics included the following: median age was 64 years, 74% (n=82) of patients were White, 89% (n=100) had an ECOG performance status ≤1, 61% (n=68) had melanoma, 19% (n=21) had non–small cell lung cancer, 45% (n=50) were treated using an anti–PD-(L)1 ICI, and 33% (n=37) were treated using an anti–PD-1/anti–CTLA-4 combination. The median starting SS dose was 100 mg of a prednisone equivalent, and 25% of patients required additional ISAs, with infliximab (n=15) and mycophenolate mofetil (n=9) being the most common. We found that 20% (n=22) of patients developed any infection, including 7% (n=8) with OIs (oral candidiasis [n=4], nondisseminated varicella zoster infection [n=2], PJP [n=1], and Listeria monocytogenes endophthalmitis [n=1]) and 13% (n=14) with non-OIs (most common: Clostridium difficile and pneumonia [n=5 each]). PJP prophylaxis with sulfamethoxazole/trimethoprim was given to 13% (n=14) patients, of whom 43% (n=6) developed OIs/non-OIs. Conclusions: Our study highlights the fundamental issues for patients on ICI therapy who require SS/ISAs for irAEs: the degree of immunosuppression and the relative risk of OI. We noted a low incidence of OIs overall and breakthrough infections despite PJP prophylaxis. We question whether PJP prophylaxis is efficacious or necessary. Prospective trials are required to answer these questions.

Background

Immune checkpoint inhibitor (ICI) therapies have revolutionized the treatment of many advanced cancers. ICIs are monoclonal antibodies that block key immune checkpoints, including PD-1, PD-L1, and CTLA-4,1,2 leading to the restoration of antitumor immunity and cytolysis. Regimens that incorporate ICIs represent the current standard of care in many advanced malignancies, including melanoma,35 non–small cell lung cancer (NSCLC),68 renal cell carcinoma (RCC),911 triple-negative breast cancer,12 and mismatch repair–deficient colorectal cancer.13 However, the antitumor benefit of these agents is tempered by excessive off-target inflammation, characterized as immune-related adverse events (irAEs). Although irAEs can involve any organ, the skin, gastrointestinal tract, liver, thyroid gland, and lungs are the most affected organs. Though less common, irAEs involving the cardiovascular and neurologic systems are associated with high mortality, requiring expeditious diagnosis and prompt treatment.1417

Several expert committees have published guidelines regarding the diagnosis and management of irAEs.14,18,19 Many patients who experience grade 1–2 irAEs can be managed with topical steroids, hormone replacement, and/or withholding ICI therapy. Approximately 20% to 50% of patients will experience grade 3–4 irAEs, which often necessitates multidisciplinary consultation, initiation of high-dose oral or intravenous steroids, and cessation of ICI therapy. For patients with irAE symptoms that persist despite 2 to 5 days of systemic steroids (SS), guidelines recommend the addition of immunosuppressive agents (ISAs), including infliximab, mycophenolate mofetil, or vedolizumab.14,18,19 Once irAE symptoms decrease to grade 1, SS are typically tapered over several weeks to prevent flares. Because of the potential risk of opportunistic infections (OIs) while on prolonged SS, guidelines recommend that patients treated with >20 mg daily of a prednisone equivalent for >4 weeks receive antimicrobial prophylaxis for Pneumocystis jirovecii pneumonia (PJP).

Limited data exist regarding the incidence and outcome of OIs among patients receiving ICIs who need SS and/or ISAs for >4 weeks to manage irAEs. Previously published studies have reported an 18% to 27% incidence of infection with ICI treatment.20,21 The most extensive data come from a single-institution study by Del Castillo et al,22 in which among 740 patients treated using ICIs, they noted 7% of patients with any severe infection and 2% with severe OI (severe infection was defined as infection requiring hospitalization). They also observed that the use of SS (prednisone ≥10 mg) and/or infliximab was associated with a higher risk of infection (odds ratio [OR], 7.71; 95% CI, 3.71–16.18; P≤.001 and OR, 4.74; 95% CI, 2.27–9.45; P≤.001, respectively). In addition, they noted that the combination of nivolumab + ipilimumab was associated with a higher risk of serious infection (OR, 3.26; 95% CI, 1.70–6.27; P≤.002) and that pembrolizumab and nivolumab monotherapy had a lower risk (OR, 0; 95% CI, 0–0.63; P≤.007 and OR, 0.36; 95% CI, 0.3–1.68; P≤.29, respectively). In contrast, Karam et al20 did not find any association between SS or ISA use and infection (P=.37 and P=.22, respectively) in their 200 patients treated using anti–PD-(L)1 ICIs. Thus, further studies are needed to investigate the association between infection and SS and/or ISA use in the context of ICI therapy.

In addition, ongoing research into the gut microbiome’s influence on antitumor response highlights the potentially harmful effects of antibiotic use in conjunction with ICI therapy. For example, Pinato et al23 noted that prior antibiotic use within 30 days of ICI treatment initiation was associated with worse survival for patients with NSCLC. In another study, Derosa et al24 noted that if antibiotics were given within 30 days of the start of ICI treatment, then this treatment was associated with poor survival for patients with NSCLC and patients with RCC. Therefore, it is critical to understand the impact of antibiotics for the prevention of OIs and ICI efficacy.

The fundamental issues for patients on ICI therapy who require SS and ISA for irAE are the degree of immune compromise, the relative risk for OIs, and the impact of prophylactic antibiotics on ICI efficacy. Current expert panel committee guidelines for prophylactic antibiotics are based on historical data for patients requiring prolonged myelosuppressive chemotherapy, patients with HIV, or patients who have had or require organ transplant. Patients on ICI therapy who experience irAE have an excessively active immune system and, in theory, are likely to have a lower risk of OIs. Hence, our study seeks to investigate the impact of SS/ISA and prophylactic antibiotics on the development of OIs in patients receiving ICI therapy.

Methods

We have developed a comprehensive REDCap-based immune-oncology registry (REDCap-based immunotherapy registry) at MedStar Health hospitals (5 community and academic hospitals) to capture real-world data of patients treated using ICI therapy. Pharmacy records were used to identify patients treated using FDA-approved anti–PD-(L)1 inhibitors (pembrolizumab, nivolumab, atezolizumab, avelumab, and durvalumab), CTLA-4 inhibitors (ipilimumab), combinations of PD-1/CTLA-4 inhibitors, and ICI + chemotherapy/targeted therapy from January 2011 to April 2018. irAEs were defined according to CTCAE version 4.03. OIs were defined according to Infectious Diseases Society of America guidelines for the prevention and treatment of OIs in patients with HIV.25 Clostridium difficile (C difficile) infection was considered non-OI due to multiple competing risk factors including age, recurrent hospitalization in our patient population, underlying malignancy and other comorbidities, and antibiotics exposure.

Data sources included inpatient and outpatient records in addition to cancer registries. Patient data, including demographics, comorbidities, and ICI treatment, were compiled through automated extraction with assistance from bioinformatics coinvestigators. Additional patient data including ECOG performance status, irAE diagnosis and grading, SS dosing and duration, and ISA dosing and duration were compiled by study investigators. Steroid dosing was converted into prednisone equivalents for data interpretation. Finally, patient data including noncorticosteroid immunosuppressive medication, prophylactic antibiotic dosing and duration, onset of OIs and non-OIs, and antimicrobial treatment were compiled by study investigators. Infections were included if they occurred during corticosteroid/other immunosuppressive therapy or within 90 days of discontinuation of the aforementioned medications.26

The study cohort was defined as patients treated using ICIs who developed irAEs requiring a starting dose of SS at ≥20 mg (prednisone equivalent) with or without ISAs and continued SS for >4 weeks (28 days). Patients who died before the 4-week cutoff were included to evaluate serious OIs/non-OIs leading to death. Descriptive statistics, including percentages and interquartile range, were used to characterize demographic data, the incidence of irAE, SS use, ISA use, and OIs. Univariate logistic regression models were fitted to use the incidence of non-OIs or OIs as a dependent variable. A multivariate model was fitted for non-OI adjusting for variables with P<.05 in the univariate model. However, no multivariate model was fitted for OIs because none of the variables satisfied P<.05 in the univariate logistic regression model. The Hosmer and Lemeshow goodness-of-fit27 test for a non-OI multivariable model was performed, and ORs and their 95% CIs were reported. A Bonferroni-adjusted type I error 2.5% (5%/2) was used for statistical significance. R version 3.4 (R Foundation for Statistical Computing) was used for all statistical analyses.

Results

Patient Characteristics, irAEs, and Use of SS and ISAs

We identified 758 patients treated with ICIs during the study period. A total of 156 (21%) patients required SS or ISA for the management of irAE, and 112 (15%) met the study eligibility criteria for a starting steroid dose of ≥20 mg daily (prednisone equivalent) and maintained it for ≥4 weeks (Figure 1). Characteristics of the study cohort are described in Table 1. The median age of this cohort was 64 years (interquartile range, 53–71 years), 74% (n=82) were White, 13% (n=15) were Black, 33% (n=37) were female, and 89% (n=100) had an ECOG performance status of ≤1. The most common malignancies were melanoma (61%; n=68), NSCLC (19%; n=21), and RCC (7%; n=8). The most common ICI therapies were anti–PD-(L)1 (45%; n=50), anti–PD-1/anti–CTLA-4 (33%; n=37), and anti–CTLA-4 (22%; n=25). There were 142 irAEs, including 32% at grade 2 (n=45), 60% at grade 3 (n=85), 7% at grade 4 (n=10), and 1% at grade 5 (pneumonitis, n=2). The most common irAEs in the cohort were colitis (32%; n=45), hepatitis (18%; n=26), pneumonitis (15%; n=21), and dermatitis (13%; n=18). The median starting SS dose was 100 mg of a prednisone equivalent, and 25% (n=28) of patients received additional ISAs (infliximab, n=15; mycophenolate mofetil, n=9; vedolizumab, n=3; tocilizumab, methotrexate, adalimumab, and antithymocyte globulin, n=1 each). Three patients needed dual ISA agents (infliximab + vedolizumab for colitis, infliximab + adalimumab for colitis, and infliximab + mycophenolate mofetil for pancreatitis). The most common irAEs requiring ISAs were colitis 36% (n=16), and hepatitis 35% (n=9) (see supplemental eTable 1, available with this article at JNCCN.org). ICI therapy type among those with ISA use was 46% (n=17) anti–PD-1/anti–CTLA-4; 20% (n=10) anti–PD-(L)1; and 16% (n=4) anti–CTLA-4 (supplemental eTable 1). PJP prophylaxis with sulfamethoxazole/trimethoprim (TMP/SMX) was given to 13% (n=14) of patients.

Figure 1.
Figure 1.

Cohort identification: patients receiving corticosteroids or other ISAs.

Abbreviations: ICI, immune checkpoint inhibitor; irAE, immune-related adverse event; ISA, immunosuppressive agent; SS, systemic steroids.

Citation: Journal of the National Comprehensive Cancer Network 20, 7; 10.6004/jnccn.2022.7020

Table 1.

Baseline Patient Characteristics

Table 1.

Infections and OIs

Twenty percent (n=22) of patients required antimicrobial therapy for infections during or within 90 days of SS or ISA discontinuation. The incidence of OIs was 7% (n=8), including oral candidiasis (n=4), nondisseminated varicella zoster infections (n=2), PJP (n=1), and Listeria monocytogenes endophthalmitis (n=1) (Table 2). The incidence of non-OIs was 13% (n=14), including Clostridium difficile (n=5), hospital-acquired pneumonia (n=4), urinary tract infection (n=3), cellulitis (n=2), and community-acquired pneumonia, osteomyelitis/bacteremia, and sinusitis (n=1 each; Table 3). One patient not receiving TMP/SMX prophylaxis developed PJP. Among 14 patients on TMP/SMX prophylaxis, 3 (21%) developed OIs (varicella zoster virus [n=1] and oral candidiasis [n=2]) and 3 (21%) developed non-OIs (sinusitis [n=1], cellulitis and C difficile colitis [n=1], and osteomyelitis with bacteremia [n=1]). All 8 patients who developed OIs had their infections resolve following appropriate antimicrobial treatment, and no fatalities were observed. Similarly, all non-OIs resolved with appropriate antimicrobial treatment except in 1 patient with NSCLC who developed pharyngocutaneous fistula with Gram-positive bacteremia and osteomyelitis, which subsequently improved with intravenous antibiotics, but the patient was discharged on home hospice. Table 4 describes the overall incidence of OIs and non-OIs according to patient characteristics.

Table 2.

Description and Outcomes of OIs

Table 2.
Table 3.

Description and Outcome of Non-OIs

Table 3.
Table 4.

Incidence of OIs and Non-OIs

Table 4.

SS Duration, ISA Use, irAEs, and Association Between OIs and non-OIs

In our cohort, 42% (n=47) of patients required SS for ≥60 days and 22% (n=28) required ISAs. The incidence of non-OIs and OIs was similar between those receiving SS for ≥60 days versus ≥28 to <60 days (non-OIs: 17% vs 9%; OIs: 11% vs 5%; P=.225 and P=.234, respectively; Table 5). The overall incidence of non-OIs and OIs was similar between the ISA and no-ISA cohorts (non-OIs: 11% vs 13%; OIs: 11% vs 6%; P=.742 and P=.403, respectively; Table 5). The only significant baseline variables associated with non-OIs were ECOG performance status and ICI therapy type (P=.031 and P=.023, respectively; Table 5). In multivariable analysis, both ECOG performance status and ICI therapy were not significant (P=.107 and P=.053, respectively; Table 6). We did not detect a difference in the incidence of OIs related to any specific irAE type compared with no irAE: colitis (P=.056), pneumonitis (P=.642), hepatitis (P=.901), or rash (P=.481). Similarly, there was no difference in the incidence of non-OIs whether patients developed a particular irAE compared with no irAE: colitis (P=.174), pneumonitis (P=.784), hepatitis (P=.16), and rash (P=.562).

Table 5.

Univariate Analysis for Factors Influencing the Development of OIs and Non-OIs

Table 5.
Table 6.

Adjusted Multivariable Analysis for Significant Non-OI Patient Characteristics

Table 6.

Discussion

The treatment landscape for patients with advanced malignancies continues to be shaped by the incorporation of ICIs as single agents and in combination regimens. Since 2011, 8 ICI agents have been approved in 77 combination regimens across a variety of disease types and disease stages.2833 The influx of ICI regimens into clinical practice has ushered in a rapid increase in the incidence of irAEs, leading to the characterization of their associated morbidity and mortality.22,34 Several expert panels have posited guidelines for management that emphasize the timely diagnosis of irAEs and prompt the initiation of SS and/or ISAs.14,18,19 Many patients who require SS/ISAs for severe-grade irAEs experience improvement in symptoms and can be weaned from immunosuppressive therapy over 4 to 6 weeks. During this time, patients may be at risk for OIs due to a relative immune suppression attributed to exogenous high-dose SS/ISAs. Expert guidelines recommend the initiation of prophylactic antibiotics for PJP prevention based on historical data from patients with compromised immune systems resulting from HIV infection, organ transplantation, or prolonged myelosuppressive chemotherapy.14,18,19 However, the incidence of OIs in patients on SS/ISAs for irAEs and the utility of prophylactic antibiotics to prevent infection remain areas of investigation.

We report one of the most extensive multicenter retrospective studies investigating associations between ICI therapy, irAEs, SS/ISA use, and OIs. In our study, the incidence of any infection was 20%, similar to that in previously published studies (18%–27%).20,21 Pneumonia and C difficile (n=5, each) were the most common non-OIs, similar to a report by Karam et al.20 We observed a higher incidence of OIs (7%) compared with Del Castillo et al22 (2% with severe OIs). The plausible explanation for the difference between both studies is that Del Castillo et al22 only reported severe OIs requiring hospitalization, whereas we captured all OIs, including mild and severe OIs. Consistent with prior studies, our study showed that baseline patient characteristics (age, sex, race), ECOG performance status, ICI therapy type, irAE, and primary tumor type did not influence the development of OIs or non-OIs. In addition, neither the SS duration nor the type of irAE was correlated with the incidence of OI/non-OIs. Our study differed from that of Del Castillo et al,22 which noted that the type of ICI therapy, SS use, and ISAs influenced the development of OI/non-OIs. The likely explanation could be that patients in the Del Castillo et al22 study had a higher rate of CTLA-4–based ICI therapy (82% vs 55%, respectively) and SS use (43% vs 15%, respectively) and captured only severe infections relative to our study.

Furthermore, we noted that 43% of patients on PJP prophylaxis developed OIs (21%: fungal infection, n=2; viral infection, n=1) and non-OIs (21%: sinusitis, cellulitis and C difficile colitis, and osteomyelitis with bacteremia, n=1 each) that may have been precipitated by antibiotic prophylaxis. Only 1 patient not receiving prophylactic antibiotics developed PJP. Hence, it is unclear to what extent the PJP prophylaxis was beneficial. In addition, the gut microbiome has emerged as a key mediator of ICI efficacy and toxicity.34,35 Prior studies by Pinato et al23 and Derosa et al24 showed that prior or concurrent antibiotic use was associated with worse ICI therapy survival outcomes. The above findings highlight the necessity for a deeper understanding of the impact that prophylactic antibiotics may have on ICI efficacy.

This is the most extensive study to date that examines the incidence and outcome of OIs and non-OIs in patients treated using ICIs who received SS or ISAs for >4 weeks for the management of irAE. In addition, compared with prior studies, our real-world study includes patients across diverse tumor types treated using various ICI regimens. However, our investigation has several limitations. First, the incidence of OIs and non-OIs was relatively low, resulting in underpowered statistical analyses. Second, our investigation did not account for the potential difference in the risk of OI in patients treated using ICIs only relative to ICIs combined with chemotherapy or targeted therapies. Third, melanoma was the predominant tumor in our cohort, and a variety of tumor types may pose a different risk for OIs (eg, lung cancer, hematologic malignancies possibly higher). Despite these limitations, unadjusted and adjusted analyses were performed to minimize the effect of confounding factors.

Conclusions

In this real-world outcome analysis of patients treated using ICI therapies who developed irAE requiring high-dose and prolonged SS/ISAs, the incidence of OIs was 7% and that of non-OIs was 12%. All patients received appropriate antimicrobial therapy leading to resolution of the OI/non-OIs. Patients who received antibiotics for PJP prophylaxis were observed to have breakthrough infections including OIs and non-OIs (eg, fungal infections and C difficile). Our study questions whether PJP prophylaxis is needed and whether it is adequate, and raises concerns about the potential impact on ICI efficacy. Prospective studies are needed to address these concerns.

References

  • 1.

    Curran MA, Montalvo W, Yagita H, et al. PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. Proc Natl Acad Sci U S A 2010;107:42754280.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2.

    Wei SC, Duffy CR, Allison JP. Fundamental mechanisms of immune checkpoint blockade therapy. Cancer Discov 2018;8: 10691086.

  • 3.

    Hodi FS, Sznol M, McDermott DF, et al. Clinical activity and safety of anti-PD-1 (BMS-936558, MDX-1106) in patients with advanced melanoma (MEL) [abstract]. J Clin Oncol 2012;30(Suppl):Abstract 8507.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4.

    Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med 2013;369:122133.

  • 5.

    Weber JS, Minor DR, D’Angelo SP, et al. A phase 3 randomized, open-label study of nivolumab (anti-PD-1; BMS-936558; ONO-4538) versus investigator’s choice chemotherapy (ICC) in patients with advanced melanoma after anti-CTLA-4 therapy. Ann Oncol 2014;25(Suppl 5):v141.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6.

    Reck M, Rodríguez-Abreu D, Robinson AG, et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med 2016;375:18231833.

  • 7.

    Goldberg SB, Gettinger SN, Mahajan A, et al. Pembrolizumab for patients with melanoma or non-small-cell lung cancer and untreated brain metastases: early analysis of a non-randomised, open-label, phase 2 trial. Lancet Oncol 2016;17:976983.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8.

    Paz-Ares L, Luft A, Vicente D, et al. Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer. N Engl J Med 2018;379: 20402051.

  • 9.

    Motzer R, Choueiri TK. Lenvatinib plus pembrolizumab for renal cell carcinoma [letter]. N Engl J Med 2021;385:287.

  • 10.

    Choueiri TK, Tomczak P, Park SH, et al. Adjuvant pembrolizumab after nephrectomy in renal-cell carcinoma. N Engl J Med 2021;385:683694.

  • 11.

    Rini BI, Plimack ER, Stus V, et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med 2019;380: 11161127.

  • 12.

    Cetin B, Gumusay O. Pembrolizumab for early triple-negative breast cancer. N Engl J Med 2020;382:e108.

  • 13.

    André T, Shiu KK, Kim TW, et al. Pembrolizumab in microsatellite-instability-high advanced colorectal cancer. N Engl J Med 2020;383:22072218.

  • 14.

    Weber JS, Kähler KC, Hauschild A. Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol 2012;30:26912697.

  • 15.

    Weber JS, Dummer R, de Pril V, et al. Patterns of onset and resolution of immune-related adverse events of special interest with ipilimumab: detailed safety analysis from a phase 3 trial in patients with advanced melanoma. Cancer 2013;119:16751682.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16.

    Schneider BJ, Naidoo J, Santomasso BD, et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: ASCO guideline update. J Clin Oncol 2021;39:40734126.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17.

    Alsaadi D, Shah NJ, Charabaty A, et al. A case of checkpoint inhibitor- induced celiac disease. J Immunother Cancer 2019;7:203.

  • 18.

    Thompson JA, Schneider BJ, Brahmer J, et al. NCCN Guidelines Insights: Management of Immunotherapy-Related Toxicities, Version 1.2020. J Natl Compr Canc Netw 2020;18:230241.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19.

    Puzanov I, Diab A, Abdallah K, et al. Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group. J Immunother Cancer 2017;5:95.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 20.

    Karam JD, Noel N, Voisin AL, et al. Infectious complications in patients treated with immune checkpoint inhibitors. Eur J Cancer 2020;141:137142.

  • 21.

    Kanjanapan Y, Yip D. Characteristics and risk factors for microbial infections during cancer immune checkpoint therapy. Cancer Med 2020;9:90279035.

  • 22.

    Del Castillo M, Romero FA, Argüello E, et al. The spectrum of serious infections among patients receiving immune checkpoint blockade for the treatment of melanoma. Clin Infect Dis 2016;63:14901493.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23.

    Pinato DJ, Howlett S, Ottaviani D, et al. Association of prior antibiotic treatment with survival and response to immune checkpoint inhibitor therapy in patients with cancer. JAMA Oncol 2019;5:17741778.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24.

    Derosa L, Hellmann MD, Spaziano M, et al. Negative association of antibiotics on clinical activity of immune checkpoint inhibitors in patients with advanced renal cell and non-small-cell lung cancer. Ann Oncol 2018;29:14371444.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25.

    Guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV. Accessed May 9, 2022. Available at: https://clinicalinfo.hiv.gov/en/guidelines/adult-and-adolescent-opportunistic-infection/whats-new-guidelines

    • Search Google Scholar
    • Export Citation
  • 26.

    Waljee AK, Rogers MAM, Lin P, et al. Short term use of oral corticosteroids and related harms among adults in the United States: population based cohort study. BMJ 2017;357:j1415.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27.

    Hosmer DW, Hosmer T, Lemeshow S. A goodness-of-fit tests for the multiple logistic regression model. Commun Stat 1980;9:10431069.

  • 28.

    Durvalumab. Package insert. AstraZeneca; 2018.

  • 29.

    Atezolizumab. Package insert. Genentech, Inc.; 2021.

  • 30.

    Ipilimumab. Package insert. Bristol-Myers Squibb Company; 2015.

  • 31.

    Nivolumab. Package insert. Bristol-Myers Squibb Company; 2018.

  • 32.

    Pembrolizumab. Package insert. Merck Sharp & Dohme Corp; 2021.

  • 33.

    Cemiplimab. Package insert. Regeneron Pharmaceuticals, Inc.; 2018.

  • 34.

    Zhou CB, Zhou YL, Fang JY. Gut microbiota in cancer immune response and immunotherapy. Trends Cancer 2021;7:647660.

  • 35.

    Gopalakrishnan V, Spencer CN, Nezi L, et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science 2018;359:97103.

Submitted February 22, 2022; final revision received April 20, 2022; accepted for publication April 20, 2022.

Author contributions: Study concept and design: Shah, Cook, Lev-Ari, Blackburn, Serzan, Atkins. Data Collection: Shah, Cook, Lev-Ari, Blackburn, Serzan. Data analysis and interpretation: Shah, Cook, Lev-Ari, Blackburn, Serzan, Atkins. Statistical analysis: Wu, Ahn. Bioinformatics support: Alaoui. Database development: Alaoui. Manuscript preparation: All authors.

Disclosures: Dr. Shah has disclosed receiving institutional grant/research support and clinical trial support from Aravive, Inc.; and serving as a consultant for and receiving travel compensation from Merck & Co., Inc. Dr. Atkins has disclosed serving as a scientific advisor for Aveo Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Eisai Co., Ltd., Elpis Pharmaceuticals, Fathom Pharmaceutics, GlaxoSmithKline LLC, Leads Pharma, Merck & Co., Inc., Novartis International AG, PACT Pharma, Inc., Pfizer Inc., Pneuma Respiratory, Inc., Pyxis Oncology, Roche Holding AG, SAB Biotherapeutics, Inc., Scholar Rock, Inc., Simcha Therapeutics, Surface Ophthalmics, Inc., Takeda Pharmaceutical Company, Valo Health, Werewolf Therapeutics Inc., and X4 Pharmaceuticals, Inc.; serving as a consultant for Agenus Inc., Apexigen, Asher Biotherapeutics, Inc., AstraZeneca plc, Bristol-Myers Squibb Company, Calithera Biosciences, Inc., COTA, Inc., Exelixis, Inc., Idera, Inc., Iovance Biotherapeutics, Inc., Merck & Co., Inc., Neoleukin Therapeutics, Novartis International AG, Pfizer Inc., Roche Holding AG, Sanofi S.A., and SeaGen Inc.; receiving institutional grant/research support from Bristol-Myers Squibb Company, Merck & Co., Inc., and Pfizer Inc.; and having stock/stock options in Eplis Pharmaceuticals, Pyxis Oncology, and Werewolf Therapeutics Inc. The remaining authors have disclosed that they have not received any financial consideration from any person or organization to support the preparation, analysis, results, or discussion of this article.

Correspondence: Michael B. Atkins, MD, Georgetown-Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, 3800 Lombardi Cancer Center, Washington DC 20007. Email: mba41@georgetown.edu

Supplementary Materials

  • View in gallery

    Cohort identification: patients receiving corticosteroids or other ISAs.

    Abbreviations: ICI, immune checkpoint inhibitor; irAE, immune-related adverse event; ISA, immunosuppressive agent; SS, systemic steroids.

  • 1.

    Curran MA, Montalvo W, Yagita H, et al. PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. Proc Natl Acad Sci U S A 2010;107:42754280.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2.

    Wei SC, Duffy CR, Allison JP. Fundamental mechanisms of immune checkpoint blockade therapy. Cancer Discov 2018;8: 10691086.

  • 3.

    Hodi FS, Sznol M, McDermott DF, et al. Clinical activity and safety of anti-PD-1 (BMS-936558, MDX-1106) in patients with advanced melanoma (MEL) [abstract]. J Clin Oncol 2012;30(Suppl):Abstract 8507.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4.

    Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med 2013;369:122133.

  • 5.

    Weber JS, Minor DR, D’Angelo SP, et al. A phase 3 randomized, open-label study of nivolumab (anti-PD-1; BMS-936558; ONO-4538) versus investigator’s choice chemotherapy (ICC) in patients with advanced melanoma after anti-CTLA-4 therapy. Ann Oncol 2014;25(Suppl 5):v141.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6.

    Reck M, Rodríguez-Abreu D, Robinson AG, et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med 2016;375:18231833.

  • 7.

    Goldberg SB, Gettinger SN, Mahajan A, et al. Pembrolizumab for patients with melanoma or non-small-cell lung cancer and untreated brain metastases: early analysis of a non-randomised, open-label, phase 2 trial. Lancet Oncol 2016;17:976983.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8.

    Paz-Ares L, Luft A, Vicente D, et al. Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer. N Engl J Med 2018;379: 20402051.

  • 9.

    Motzer R, Choueiri TK. Lenvatinib plus pembrolizumab for renal cell carcinoma [letter]. N Engl J Med 2021;385:287.

  • 10.

    Choueiri TK, Tomczak P, Park SH, et al. Adjuvant pembrolizumab after nephrectomy in renal-cell carcinoma. N Engl J Med 2021;385:683694.

  • 11.

    Rini BI, Plimack ER, Stus V, et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med 2019;380: 11161127.

  • 12.

    Cetin B, Gumusay O. Pembrolizumab for early triple-negative breast cancer. N Engl J Med 2020;382:e108.

  • 13.

    André T, Shiu KK, Kim TW, et al. Pembrolizumab in microsatellite-instability-high advanced colorectal cancer. N Engl J Med 2020;383:22072218.

  • 14.

    Weber JS, Kähler KC, Hauschild A. Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol 2012;30:26912697.

  • 15.

    Weber JS, Dummer R, de Pril V, et al. Patterns of onset and resolution of immune-related adverse events of special interest with ipilimumab: detailed safety analysis from a phase 3 trial in patients with advanced melanoma. Cancer 2013;119:16751682.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16.

    Schneider BJ, Naidoo J, Santomasso BD, et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: ASCO guideline update. J Clin Oncol 2021;39:40734126.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17.

    Alsaadi D, Shah NJ, Charabaty A, et al. A case of checkpoint inhibitor- induced celiac disease. J Immunother Cancer 2019;7:203.

  • 18.

    Thompson JA, Schneider BJ, Brahmer J, et al. NCCN Guidelines Insights: Management of Immunotherapy-Related Toxicities, Version 1.2020. J Natl Compr Canc Netw 2020;18:230241.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19.

    Puzanov I, Diab A, Abdallah K, et al. Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group. J Immunother Cancer 2017;5:95.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 20.

    Karam JD, Noel N, Voisin AL, et al. Infectious complications in patients treated with immune checkpoint inhibitors. Eur J Cancer 2020;141:137142.

  • 21.

    Kanjanapan Y, Yip D. Characteristics and risk factors for microbial infections during cancer immune checkpoint therapy. Cancer Med 2020;9:90279035.

  • 22.

    Del Castillo M, Romero FA, Argüello E, et al. The spectrum of serious infections among patients receiving immune checkpoint blockade for the treatment of melanoma. Clin Infect Dis 2016;63:14901493.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23.

    Pinato DJ, Howlett S, Ottaviani D, et al. Association of prior antibiotic treatment with survival and response to immune checkpoint inhibitor therapy in patients with cancer. JAMA Oncol 2019;5:17741778.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24.

    Derosa L, Hellmann MD, Spaziano M, et al. Negative association of antibiotics on clinical activity of immune checkpoint inhibitors in patients with advanced renal cell and non-small-cell lung cancer. Ann Oncol 2018;29:14371444.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25.

    Guidelines for the prevention and treatment of opportunistic infections in adults and adolescents with HIV. Accessed May 9, 2022. Available at: https://clinicalinfo.hiv.gov/en/guidelines/adult-and-adolescent-opportunistic-infection/whats-new-guidelines

    • Search Google Scholar
    • Export Citation
  • 26.

    Waljee AK, Rogers MAM, Lin P, et al. Short term use of oral corticosteroids and related harms among adults in the United States: population based cohort study. BMJ 2017;357:j1415.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27.

    Hosmer DW, Hosmer T, Lemeshow S. A goodness-of-fit tests for the multiple logistic regression model. Commun Stat 1980;9:10431069.

  • 28.

    Durvalumab. Package insert. AstraZeneca; 2018.

  • 29.

    Atezolizumab. Package insert. Genentech, Inc.; 2021.

  • 30.

    Ipilimumab. Package insert. Bristol-Myers Squibb Company; 2015.

  • 31.

    Nivolumab. Package insert. Bristol-Myers Squibb Company; 2018.

  • 32.

    Pembrolizumab. Package insert. Merck Sharp & Dohme Corp; 2021.

  • 33.

    Cemiplimab. Package insert. Regeneron Pharmaceuticals, Inc.; 2018.

  • 34.

    Zhou CB, Zhou YL, Fang JY. Gut microbiota in cancer immune response and immunotherapy. Trends Cancer 2021;7:647660.

  • 35.

    Gopalakrishnan V, Spencer CN, Nezi L, et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science 2018;359:97103.

All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 3085 3085 2499
PDF Downloads 2006 2006 1657
EPUB Downloads 0 0 0