Management of Adverse Events Following Treatment With Anti-Programmed Death-1 Agents

Abstract

: Immune checkpoint inhibitors have emerged as a mainstay of melanoma therapy and are playing an increasingly important role in the treatment of other tumor types. The clinical benefit afforded by these treatments can be accompanied by a unique spectrum of adverse events, called immune-related adverse events (irAEs), which reflect the drug's immune-based mechanism of action. IrAEs typically originate in the skin, gastrointestinal tract, liver, and endocrine system, although other organ systems may also be affected. This article provides an overview of irAEs associated with anti-programmed death-1 (anti-PD-1) antibodies (nivolumab and pembrolizumab) as monotherapy or in combination with anti-cytotoxic T-lymphocyte antigen-4 inhibition (ipilimumab), followed by a discussion of irAEs of special clinical interest based on the potential for morbidity, frequent steroid use, and inpatient admission. We review clinical trial data and provide recommendations on how to manage irAEs associated with anti-PD-1 agents based on clinical experience and established management guidelines. We further illustrate the practical considerations of managing irAEs by presenting three cases of immune-related toxicity in melanoma patients treated with nivolumab or pembrolizumab. A better understanding of the identification and management of irAEs will help inform health care providers about the risks associated with anti-PD-1 treatment, to ensure the safe and appropriate use of these important new treatments.

Implications for practice: Immune checkpoint inhibitors have demonstrated significant clinical benefit in advanced melanoma and other tumor types. These treatments are associated with immune-related adverse events (irAEs), which most commonly affect the skin and gastrointestinal tract, and, to a lesser extent, the liver, endocrine system, and other organs. This review focuses on the management of irAEs after treatment with anti-programmed death-1 (anti-PD-1) antibodies (nivolumab or pembrolizumab) as monotherapy or in combination with anti-cytotoxic T-lymphocyte antigen-4 inhibition (ipilimumab) in patients with advanced melanoma. A better understanding of the management of irAEs will help ensure the safe and appropriate use of anti-PD-1 agents in melanoma and other tumor types.

Keywords: Drug-related side effects and adverse reactions; Melanoma; Nivolumab; Pembrolizumab; Programmed cell death 1 receptor.

Figure 1.

Management algorithms for GI (A), endocrine (B), hepatic (C), and pulmonary (D) irAEs. Abbreviations: ADL, activities of daily living; ALT, alanine aminotransferase; AST, aspartate aminotransferase; b.i.d., twice daily; CTCAE, Common Terminology Criteria for Adverse Events; fT4, free T4; G3, grade 3; GI, gastrointestinal; ID, infectious disease; I-O, immuno-oncology; IVIG, i.v. immunoglobulin; LFT, liver function test; LLN, lower limit of normal; MRI, magnetic resonance imaging; NCI, National Cancer Institute; p.o., orally; T. bili, total bilirubin; TSH, thyroid-stimulating hormone; ULN, upper limit of normal; v4, version 4.

Figure 1.

Management algorithms for GI (A), endocrine (B), hepatic (C), and pulmonary (D) irAEs. Abbreviations: ADL, activities of daily living; ALT, alanine aminotransferase; AST, aspartate aminotransferase; b.i.d., twice daily; CTCAE, Common Terminology Criteria for Adverse Events; fT4, free T4; G3, grade 3; GI, gastrointestinal; ID, infectious disease; I-O, immuno-oncology; IVIG, i.v. immunoglobulin; LFT, liver function test; LLN, lower limit of normal; MRI, magnetic resonance imaging; NCI, National Cancer Institute; p.o., orally; T. bili, total bilirubin; TSH, thyroid-stimulating hormone; ULN, upper limit of normal; v4, version 4.

Figure 1.

Management algorithms for GI (A), endocrine (B), hepatic (C), and pulmonary (D) irAEs. Abbreviations: ADL, activities of daily living; ALT, alanine aminotransferase; AST, aspartate aminotransferase; b.i.d., twice daily; CTCAE, Common Terminology Criteria for Adverse Events; fT4, free T4; G3, grade 3; GI, gastrointestinal; ID, infectious disease; I-O, immuno-oncology; IVIG, i.v. immunoglobulin; LFT, liver function test; LLN, lower limit of normal; MRI, magnetic resonance imaging; NCI, National Cancer Institute; p.o., orally; T. bili, total bilirubin; TSH, thyroid-stimulating hormone; ULN, upper limit of normal; v4, version 4.

Figure 1.

Management algorithms for GI (A), endocrine (B), hepatic (C), and pulmonary (D) irAEs. Abbreviations: ADL, activities of daily living; ALT, alanine aminotransferase; AST, aspartate aminotransferase; b.i.d., twice daily; CTCAE, Common Terminology Criteria for Adverse Events; fT4, free T4; G3, grade 3; GI, gastrointestinal; ID, infectious disease; I-O, immuno-oncology; IVIG, i.v. immunoglobulin; LFT, liver function test; LLN, lower limit of normal; MRI, magnetic resonance imaging; NCI, National Cancer Institute; p.o., orally; T. bili, total bilirubin; TSH, thyroid-stimulating hormone; ULN, upper limit of normal; v4, version 4.

Figure 2.

Colonoscopy and histopathology results for case history 1. (A): Colonoscopy in August 2014. Discontinuous areas of small and large, deeply cratered ulcerated mucosa are seen throughout entire colon. Mucosa diffusely erythematous with altered vascular pattern, edematous and friable (black arrow). (B): Histopathology (hematoxylin and eosin stain) of right-sided colon (×200). Lamina propria lymphoplasmacytosis and intensely regenerative epithelium (black arrow). Deep crypts contain apoptotic debris (white arrow). (C): Colonoscopy in March 2015. Patchy mild inflammation characterized by pseudopolyps, aphthous ulcers (black arrow), and shallow ulcerations scattered throughout colon. (D): Histopathology (hematoxylin and eosin stain) of cecum (×200) in March 2015. Mild architectural distortion and lamina propria chronic inflammation (similar to quiescent ulcerative colitis). Basal lymphoid aggregate is seen in deep mucosa and submucosa (black arrow).

Figure 3.

Images for case history 3. (A, B): Liver biopsy pathology of (peri-) portal and lobular hepatitis with abundant eosinophils (white arrows) captured at ×200 and ×400, respectively. (C, D): The patient experienced a partial response following a single dose of pembrolizumab treatment.