Safety of checkpoint inhibitors for cancer treatment: strategies for patient monitoring and management of immune-mediated adverse events

Introduction

Harnessing the power of a patient’s immune system to attack cancer cells has become a reality. In recent years, immune checkpoint inhibitors (ICPIs) have emerged as a new class of drugs capable of augmenting the body’s immune response against several different tumor types.^1–21 ICPIs approved by the US Food and Drug Administration (FDA) include monoclonal antibodies against CTLA-4 (ipilimumab²²), PD-1 (nivolumab,²³ pembrolizumab²⁴), and, most recently, PD-L1 (atezolizumab,²⁵ avelumab,²⁶ and durvalumab²⁷). Additional indications are being explored for approved agents,^28–34 and other ICPIs are in late-stage development, including a new anti-CTLA-4 antibody (tremelimumab; Table 1).³⁵ Furthermore, combination anti-CTLA-4 and anti-PD-L1 antibody therapy (ipilimumab + nivolumab) was recently added to the National Comprehensive Cancer Network Guidelines as a second-line treatment for small cell lung cancer,³⁶ and many combinations are in development.

Table 1 ICPIs approved or in late-stage developmenta Notes: aLate-stage development refers to Phase III sponsored studies that expect to have primary results on or before Q1 2018 in tumor types different from those in which the agents are already approved. bBest overall response rate. cRecurrence-free survival rate. dAccelerated approval for BRAF V600 mutation-positive unresectable/metastatic melanoma; continued approval may be contingent on confirmatory trials. eAccelerated approval; continued approval may be contingent on confirmatory trials. fPembrolizumab is also approved in combination with pemetrexed and carboplatin as 1L treatment for metastatic nonsquamous NSCLC (ORR, 55%).24 gTremelimumab is an anti-CTLA-4 monoclonal antibody currently in late-stage studies in combination with durvalumab. Abbreviations: 1L, first line; 2L, second line; 3L, third line; 4L, fourth line; CRC, colorectal cancer; dMMR, mismatch repair-deficient; HCC, hepatocellular carcinoma; HNSCC, head and neck squamous cell carcinoma; HSCT, hematopoietic stem cell transplant; ICPIs, immune checkpoint inhibitors; MSI-H, microsatellite instability-high cancer; NSCLC, non-small cell lung cancer; ORR, objective response rate; q2w, every 2 weeks; q3w, every 3 weeks; q12w, every 12 weeks; SCLC, small cell lung cancer; TNBC, triple-negative breast cancer; wt, wild type; mut, mutant; –, not available.

ICPIs are monoclonal antibodies targeting CTLA-4, PD-1, or PD-L1, checkpoint proteins known to prevent excessive immune response. ICPIs can influence the body’s immune response against tumor cells by revitalizing suppressed immune cells, hence promoting an antitumor immune response. CTLA-4 and PD-1/PD-L1 are nonredundant T-cell activation checkpoint pathways, acting at different stages of the antitumor immune response. CTLA-4 is primarily involved in the early stages of T-cell activation within the lymph node, whereas the PD-1/PD-L1 pathway acts at late stages of the antitumor immune response within the tumor microenvironment. Therefore, targeting both checkpoints provides the potential for additive or synergistic effects.^37,38

ICPIs have improved the prognosis for patients with advanced melanoma,^{2,4,9,39–42} non-small cell lung cancer (NSCLC),^{6,11,13,16,21,43,44} renal cell carcinoma,⁵ urothelial carcinoma,^{7,8,15,18–20} Hodgkin’s lymphoma,^14,45 head and neck squamous cell carcinoma,^3,12 Merkel cell carcinoma,¹⁰ and microsatellite instability – high or mismatch repair-deficient cancer.¹ Given the current success of ICPIs in an increasingly wide range of tumor types, the approved indications for ICPIs are expected to increase. In fact, ICPIs have shown promising efficacy in clinical studies in many other cancer types including small cell lung cancer,³¹ hepatic cancer,³³ triple-negative breast cancer,²⁸ ovarian cancer,³² colorectal cancer,⁴⁶ gastric cancer,²⁹ and glioblastoma.³⁰

Due to their novel mechanism of action, ICPIs are associated with a spectrum of immune-mediated adverse events (imAEs) that differ from the typical adverse events seen with chemotherapeutic agents.^47,48 By inhibiting the checkpoints for T-cell activation, ICPIs can cause the patient’s immune system to recognize and attack tumor cells. However, this deregulation of the immune system may also lead to immune-mediated toxicities, which can mimic a broad range of autoimmune conditions.⁴⁹ By understanding the signs and symptoms of these unique adverse events, oncology nurses will be better equipped to educate, monitor, and manage cancer patients receiving ICPIs. This article reviews the imAE profile of anti-CTLA-4 and anti-PD-1/PD-L1 antibodies, including an approach for monitoring patients and managing the imAEs associated with this new and growing therapeutic class.

Dosing of ICPIs

Dosage recommendations for ICPIs include both weight-based and fixed doses (Table 1).^22–27 Although imAE risk appears to be greater with the higher dose of anti-CTLA-4 therapy (ipilimumab 10 mg/kg) than with the lower dose (ipilimumab 3 mg/kg),²² a similar dose effect on toxicity has not been observed in clinical studies of the currently marketed anti-PD-1 antibodies (nivolumab, pembrolizumab).^50–53 Available safety data are based on registration studies that included varying dosing regimens for pembrolizumab (2 mg/kg or 10 mg/kg every 2 or 3 weeks)²⁴ and weight-based dosing for nivolumab (3 mg/kg), which was the recommended dose until September 2016 when a 240 mg fixed dose was deemed to provide a similar drug exposure.^23,53 Clinical registration studies of anti-PD-L1 antibodies utilized the current recommended doses (atezolizumab 1200 mg,²⁵ avelumab 10 mg/kg,²⁶ and durvalumab 10 mg/kg²⁷). Combination anti-CTLA-4 and anti-PD-1 therapy is currently dosed as same-day ipilimumab (3 mg/kg) followed by nivolumab (1 mg/kg) every 3 weeks for four doses, followed by nivolumab (240 mg) every 2 weeks thereafter.²³ As this combination regimen is associated with greater toxicity than ICPI monotherapy,^22–26 alternative dosing strategies are being evaluated in clinical studies with the objective of improving the safety/efficacy profile, including lower-dose anti-CTLA-4 antibodies in combination with anti-PD-1/anti-PD-L1 antibodies (nivolumab + ipilimumab,⁵⁴ pembrolizumab + ipilimumab,⁵⁵ durvalumab + tremelimumab⁵⁶). Unlike chemotherapy where it is typical to dose-reduce patients to manage toxicities, the only dose modifications currently allowed with ICPIs are to either delay or discontinue therapy. Therefore, establishing the optimal dosing regimen of checkpoint inhibitors is very important.

imAEs

Typically, imAEs associated with ICPI treatment are low grade and manageable when identified promptly and treated properly.^57,58 In clinical studies reporting the overall rate of imAEs, imAEs occurred in up to 90% of patients receiving ICPI monotherapy (Table 2).^{4,7,9,10,16–18,20,39,40,43,59,60} However, the incidence of high-grade (Grade ≥3) imAEs in these studies was generally much lower, especially with anti-PD-1 or PD-L1 antibodies. Notably, Grade ≥3 imAEs were reported to occur more frequently in patients receiving anti-CTLA-4 monotherapy (ipilimumab, 15–42%)^4,9,39,40 than in those receiving anti-PD-1 (8%, nivolumab;⁴ 5–10%, pembrolizumab^16,20) or anti-PD-L1 (5–7%, atezolizumab;^7,17 2%, durvalumab;⁵⁹ 1–2%, avelumab^10,61) monotherapy, and the highest rate of Grade ≥3 imAEs was reported with combination anti-CTLA-4 and anti-PD-1 therapy (ipilimumab + nivolumab, 40–45%).^4,9 The skin and gastrointestinal tract are the most common sites for imAEs with any of the approved ICPIs, either in monotherapy or in combination, although any organ system can be affected (Table 3).⁵⁷ In this section, we highlight the five most common organ systems affected by imAEs in patients treated with ICPIs: dermatologic, gastrointestinal, endocrine, hepatic, and pulmonary. Less common but clinically important manifestations of imAEs are also briefly reviewed (renal, pancreatic, ocular, musculoskeletal, neurological, cardiovascular, and hematological toxicities).

Table 2 Frequency of organ-specific imAEs in melanoma, NSCLC, and UC registration clinical trialsa Notes: aPivotal trials that led to US FDA approval. bIpilimumab 3 mg/kg. cIpilimumab 10 mg/kg. dNivolumab 3 mg/kg or pembrolizumab 2–10 mg/kg. eIpilimumab 3 mg/kg + nivolumab 1 mg/kg. fAtezolizumab 1200 mg. gNivolumab 3 mg/kg or pembrolizumab 200 mg. hAtezolizumab 1200 mg or durvalumab 10 mg/kg or avelumab 10 mg/kg. iDoes not include Grade 1. jDiarrhea and/or colitis. Abbreviations: ALT, alanine transaminase; AST, aspartate transaminase; FDA, Food and Drug Administration; imAEs, immune-mediated adverse events; NR, not reported; NSCLC, non-small cell lung cancer; UC, urothelial carcinoma.

Table 3 Frequency of organ-specific imAEs in melanoma, NSCLC, and UC registration clinical trialsa Notes: aBased on published management algorithms22–27,88,93–97 and authors’ clinical experience. bGrading based on NCI Common Terminology Criteria for Adverse Events v4.0. cFor Yervoy (ipilimumab): hold ICPI if Grade 2 rash, consider oral systemic steroid (0.5–1.0 mg/kg/day) if persists >1 week or interferes with ADL. dFor Imfinzi (durvalumab): hold ICPI if Grade 2 for >1 week. eFor Yervoy (ipilimumab): permanently discontinue if Grade 2 imAE persists ≥6 weeks or unable to reduce prednisone to ≤7.5 mg prednisone or equivalent per day or to complete four-dose course within 16 weeks. fFor Yervoy (ipilimumab): resume treatment when imAE resolves to Grade 1 or less and is controlled with ≤7.5 mg/kg prednisone or equivalent per day. gFor Keytruda (pembrolizumab): permanently discontinue if any Grade 3 imAE recurs or if any persistent Grade 2 or 3 imAE (excluding endocrinopathies) does not resolve to Grade 1 within 12 weeks with ≤10 mg prednisone or equivalent per day. hFor Imfinzi (durvalumab): resume treatment when imAE resolves to Grade ≤1 and corticosteroid dose has been reduced to <10 mg prednisone or equivalent per day. iFor Yervoy (ipilimumab): initiate 0.5 mg/kg/day prednisone or equivalent if symptoms persist >1 week, worsen, or recur. jFor Yervoy (ipilimumab) or combination Yervoy + Opdivo (ipilimumab + nivolumab): permanently discontinue. kPermanently discontinue Imfinzi (durvalumab) for Grade 3 gastrointestinal imAE. lPermanently discontinue Bavencio (avelumab) if Grade 3 imAE is recurrent. mFor Tecentriq (atezolizumab): resume treatment when imAE resolves to Grade 1 or less and is controlled with ≤10 mg/kg prednisone or equivalent per day. nKeytruda (pembrolizumab) may be continued in cases of Grade 2 hyperthyroidism and all-grade hypothyroidism. oFor Opdivo (nivolumab): no recommended dose modifications for hypothyroidism or hyperthyroidism. pFor Bavencio (avelumab): no recommended dose modifications for Grade 2 endocrinopathies. qFor Tecentriq (atezolizumab): permanently discontinue for Grade 4 hypophysitis. rBegin taper if AE improves to Grade 2 for Opdivo (nivolumab) or if liver function tests improve for Yervoy (ipilimumab). sPermanently discontinue Imfinzi (durvalumab) if Grade 3 with >8 × ULN AST/ALT or >5 × ULN total bilirubin or if Grade 4. Hold if Grade 3 with ≤8 × ULN AST/ALT or ≤5 × ULN total bilirubin. tPermanently discontinue Yervoy (ipilimumab), Keytruda (pembrolizumab), or Imfinzi (durvalumab) for Grade 3 nephritis. uPermanently discontinue Yervoy (ipilimumab) for Grade 3 pancreatitis. Discontinue Keytruda (pembrolizumab) or Opdivo (nivolumab) if recurrent Grade 2 or 3. vFor grade 4 serum amylase or lipase elevation, hold Tecentriq (atezolizumab) and consider resuming treatment once imAE resolves to Grade ≤1 within 12 weeks and corticosteroids reduced to ≤10 mg/day oral prednisone. wHold Imfinzi (durvalumab) for Grade 2–4 type 1 diabetes mellitus; resume treatment if type 1 diabetes mellitus resolves to Grade ≤1. xPermanently discontinue Yervoy (ipilimumab) if Grade ≥2 or Grade 1 not responding to steroids within 2 weeks or requiring systemic therapy. yPermanently discontinue Opdivo (nivolumab), Keytruda (pembrolizumab), Tecentriq (atezolizumab), or Bavencio (avelumab) if Grade 3. zFor Tecentriq (atezolizumab): permanently discontinue for any grade meningitis or encephalitis and treat with steroids (MPS, 1–2 mg/kg/day); use medical intervention as appropriate for myasthenic syndrome/myasthenia gravis or Guillain–Barre syndrome. AFor Yervoy (ipilimumab) and Opdivo (nivolumab): treat symptoms as per institutional guidelines. For Yervoy, begin tapering steroids when Grade 3–4 imAE resolves to Grade 2. For Opdivo (nivolumab), resume ICPI if Grade 2 imAE resolves to baseline. Abbreviations: ACTH, adrenocorticotropic hormone; ADH, antidiuretic hormone; ADL, activities of daily living; AE, adverse event; ALK, alkaline phosphatase; ALT, alanine transaminase; ANC, absolute neutrophil count; AST, aspartate transaminase; BNP, brain natriuretic peptide; CBC, complete blood count; CMP, comprehensive metabolic panel; C&S, culture and sensitivity; CSF, cerebrospinal fluid; CT, computerized tomography; CVA, cerebrovascular accident; DIC, disseminated intravascular coagulation; ECG, electrocardiogram; FSH, follicle-stimulating hormone; GI, gastrointestinal; Hgl, hemoglobin; ICPI, immune checkpoint inhibitor; imAE, immune-mediated adverse event; IV, intravenous; LH, luteinizing hormone; LLN, lower limit of normal; MPS, methylprednisolone; MRI, magnetic resonance imaging; NCI, National Cancer Institute; PFTs, pulmonary function tests; Plt, platelets; PRN, as needed; r/o, rule out; RUQ, right upper quadrant; TSH, thyroid-stimulating hormone; ULN, upper limit of normal; WBC, white blood cell count.

Dermatologic

Rash and pruritus are the most common dermatological adverse events observed in patients receiving ICPI therapy, occurring more frequently with anti-CTLA-4 therapy (ipilimumab: 3 mg/kg [rash, 15–30%; pruritus, 24–35%];^4,9,39,42 10 mg/kg [rash, 34%; pruritus, 40%]⁴⁰) than with anti-PD-1 (nivolumab/pembrolizumab: rash, 4–22%; pruritus, 2–23%)^{2,4,6,11,15,16,41–43,50,51,62} or anti-PD-L1 treatment (atezolizumab/avelumab/durvalumab: rash, 1–7%; pruritus, 1–11%).^{7,10,13,17,59–61} Skin toxicities are typically low grade, often presenting as erythematous macules/papules/plaques on the trunk or extremities with or without pruritus during the early weeks of treatment (Figure 1).^57,63,64 Dermatologic toxicities have been observed more often in patients receiving ICPIs for melanoma than for NSCLC (Table 2).^{2,4,6,9,11,13,16,41–43,50,51,65,66} Vitiligo may occur more frequently in patients receiving anti-PD-1 antibodies (nivolumab/pembrolizumab, 7–11%) than with anti-CTLA-4 therapy (ipilimumab, 2–4%).^4,42 Grade 3/4 skin imAEs are rare, although cases of Stevens–Johnson syndrome and toxic epidermal necrolysis have been reported in patients receiving anti-CTLA-4 (ipilimumab)^22,57 or anti-PD-1 treatments (nivolumab/pembrolizumab).^23,67

Figure 1 Time to onset of immune-mediated toxicities (median and range).22–27 Notes: Onset patterns of imAEs in patients receiving ICPI treatment by organ system and target pathway: CTLA-4 (ipilimumab), PD-1 (nivolumab, pembrolizumab), and PD-L1 (atezolizumab, avelumab, and durvalumab). aDermatitis in ipilimumab studies; immune-mediated rash in nivolumab and nivolumab + ipilimumab studies. bEnterocolitis in ipilimumab studies; colitis in nivolumab, pembrolizumab, avelumab, and nivolumab + ipilimumab studies; colitis or diarrhea in atezolizumab and durvalumab studies. cIncludes hypopituitarism, adrenal insufficiency, hypothyroidism, hyperthyroidism, hypogonadism, thyroiditis, Cushing’s syndrome, and Graves’ ophthalmopathy. dHypothyroidism and hyperthyroidism are combined for avelumab. eHepatitis. fPneumonitis. gNephritis or renal dysfunction in nivolumab and nivolumab + ipilimumab studies; nephritis in pembrolizumab studies. hNeuropathy in ipilimumab studies and encephalitis in nivolumab and nivolumab + ipilimumab studies. Abbreviations: d, days, GI, gastrointestinal; ICPI, immune checkpoint inhibitor; imAEs, immune-mediated adverse events; m, months; T1DM, type 1 diabetes mellitus.

Gastrointestinal

Diarrhea is the most common gastrointestinal adverse event, occurring in 23–41% of patients treated with anti-CTLA-4 (ipilimumab: 3 mg/kg, 23–35%; 10 mg/kg, 41%),^4,9,39,40,42 7–19% of patients treated with anti-PD-1 antibodies (nivolumab, 8–19%;^{4,6,11,15,41,62} pembrolizumab, 7–16%^{2,16,42,43,50,51}), 2–15% of patients receiving anti-PD-L1 therapy (atezolizumab, 7–15%;^7,13,17,44 avelumab, <1–9%;^10,61 durvalumab, 2%⁵⁹), and 44–45% of patients receiving combination anti-CTLA-4 and anti-PD-1 therapy with ipilimumab and nivolumab.^4,9 Colitis has been observed in 7–16% of patients receiving anti-CTLA-4 therapy (ipilimumab: 3 mg/kg, 7–12%;^4,9,39,42 10 mg/kg, 16%⁴⁰), 1–3% of patients treated with anti-PD-1/PD-L1 antibodies (1% for nivolumab,^4,6,11,41,62 atezolizumab,^7,13,17,44 and durvalumab;⁵⁹ avelumab, 2%;²⁶ pembrolizumab, 1–3%^{2,16,18,20,42,43}), and 12–18% of patients treated with combination anti-CTLA-4 and anti-PD-1 therapy (ipilimumab + nivolumab).^4,9 Rates of Grade 3/4 diarrhea or colitis are low (≤4%) in patients receiving anti-PD-1 or anti-PD-L1 monotherapy,^{2,4,6,7,10,11,13,15–17,20,41–44,50,51,59,60,62} but tend to be higher in patients treated with anti-CTLA-4 monotherapy (ipilimumab, 2–11%)^4,9,39,40,42 or combination anti-CTLA-4 and anti-PD-1 therapy with nivolumab and ipilimumab (8–13%).^4,9 The median onset of immune-mediated diarrhea and/or colitis ranges from 21 days to 5.3 months in patients treated with ICPIs in clinical registration studies (Figure 1).^22–27 Deaths from intestinal perforation from colitis have been reported at very low rates (<1%) in anti-CTLA-4 monotherapy studies at both 3 mg/kg and 10 mg/kg doses.^22,40

Endocrine

Autoimmune endocrinopathies (predominantly Grade 1 or 2) have been reported in patients treated with ICPIs in clinical studies, including hypothyroidism, hyperthyroidism, thyroiditis, hypophysitis (pituitary inflammation), and adrenal insufficiency.^22–27 Rates of all-grade endocrinopathies are generally low in patients receiving anti-PD-1/PD-L1 monotherapy, with <10% of patients experiencing each individual endocrinopathy.^23–27 Higher rates are reported in patients treated with anti-CTLA-4 therapy either as monotherapy (ipilimumab 3 mg/kg, 8–15%;^4,9,39 ipilimumab 10 mg/kg, 38%⁴⁰) or in combination with anti-PD-1 therapy (ipilimumab + nivolumab, 30–31%^4,9). Rates of Grade 3/4 endocrinopathies are generally low in patients receiving ICPI monotherapy (anti-CTLA-4: ipilimumab 3 mg/kg, 1.8%;²² anti-PD-1/PD-L1: nivolumab, pembrolizumab, atezolizumab, avelumab, or durvalumab, <1%^4,24–27 for each individual endocrinopathy); however, higher rates have been reported with high-dose anti-CTLA-4 (ipilimumab 10 mg/kg, 8%)²² and combination anti-CTLA-4 and anti-PD-1 (ipilimumab + nivolumab, 5%).^4,9 Most cases of immune-mediated hypothyroidism can be adequately treated with hormone replacement, and ICPI therapy can be continued.

Hypophysitis and thyroid dysfunction are the most common endocrine imAEs associated with ICPI treatment. Hypophysitis (median onset 2–5 months;^23,24,57 Figure 1) rarely occurred in patients treated with anti-PD-1 or anti-PD-L1 monotherapy in clinical studies (<1% for nivolumab, pembrolizumab, atezolizumab, or durvalumab),^23–25,27 but has been observed in 2–7% of patients receiving anti-CTLA-4 therapy (ipilimumab) at the 3 mg/kg dose^4,9,42 and 18% of patients receiving the 10 mg/kg dose,⁴⁰ and in 8–13% of patients treated with combination anti-CTLA-4 and anti-PD-1 therapy (ipilimumab + nivolumab).^4,9 The vast majority of patients who experience Grade ≥2 hypophysitis fail to recover pituitary function and require lifelong hormone replacement therapy.^22,57,68 Adrenal insufficiency can arise secondary to hypopituitarism (≤1%, anti-PD-1 monotherapy [nivolumab]²³ or anti-PD-L1 monotherapy [atezolizumab,²⁵ avelumab,²⁶ durvalumab²⁷]; 5%, combination anti-CTLA-4 and anti-PD-1 [ipilimumab + nivolumab]²³), typically manifesting as dehydration, hypotension, hyponatremia, and/or hyperkalemia similar to sepsis syndrome.⁶⁹

Hypothyroidism has been reported in 9% of patients treated with anti-PD-1 (nivolumab or pembrolizumab)^23,24 or high-dose anti-CTLA-4 monotherapy (ipilimumab 10 mg/kg),⁴⁰ in 2–13% of patients receiving standard-dose anti-CTLA-4 monotherapy (ipilimumab 3 mg/kg),^4,9,39,42 in 4–5% of patients treated with anti-PD-L1 antibodies (atezolizumab, 4%;²⁵ avelumab, 5%;²⁶ durvalumab, 6%²⁷), and in 15–17% of patients receiving combination anti-CTLA-4 and anti-PD-1 therapy (ipilimumab + nivolumab).^4,9 In clinical registration studies, the median onset of hypothyroidism ranged from 1 to 5 months,^23–27 sometimes following a brief period of hyperthyroidism (Figure 1). Hypothyroidism does not resolve for most patients, resulting in the potential need for long-term hormone supplementation.^{23–27,47,70} Hyperthyroidism, which is less common than hypothyroidism, resolves in the vast majority of patients.⁷¹

Hepatic

Hepatotoxicity, including hepatitis and elevated alanine transaminase (ALT)/aspartate transaminase (AST), has been documented in patients treated with ICPIs.^57,58 In patients treated with anti-CTLA-4 therapy, the rate of hepatic adverse events ranged from 4% to 9% (ipilimumab 3 mg/kg)^4,9,39 to 25% (ipilimumab 10 mg/kg),⁴⁰ with Grade 3/4 events occurring in 0% to 2% to 11%, respectively. Hepatotoxicity occurred in 2–6% (0–3% Grade 3/4) of the patients treated with anti-PD-1 monotherapy (nivolumab)^{4,6,11,15,41,62} and in 30–32% (13–19% Grade 3/4) of the patients receiving combination anti-CTLA-4 and anti-PD-1 therapy (ipilimumab + nivolumab).^4,9 Immune-mediated hepatitis, reported in ≤2% of patients treated with ICPI monotherapy^23–27,39 (excluding ipilimumab 10 mg/kg dose, 15%),²² typically presents at 1–3 months and resolves with steroid treatment in most patients (Figure 1).^22–27 Although rare, fatal cases of immune-mediated hepatitis have occurred with ICPI monotherapy (0.2%, ipilimumab 3 mg/kg;²² 0.1%, avelumab;²⁶ 0.5%, durvalumab²⁷). Elevated ALT/AST with concomitant elevated bilirubin may indicate a more serious hepatic injury.^72,73

Pulmonary

Immune-mediated pneumonitis is a rare but potentially serious adverse event, occurring in <1% of patients treated with anti-CTLA-4 antibodies (ipilimumab 3 mg/kg or 10 mg/kg doses),²² in 1–3% of those receiving anti-PD-1/PD-L1 (nivolumab, pembrolizumab, or atezolizumab, 3%;^23–25 avelumab, 1%;²⁶ durvalumab, 0.5%²⁷), and in 6% of those receiving combination anti-CTLA-4 and anti-PD-1 therapy (ipilimumab + nivolumab).²³ Immune-mediated pneumonitis has been reported more frequently in patients receiving anti-PD-1 therapy (nivolumab or pembrolizumab) for NSCLC (3–6%)^{6,11,16,43,50} than for melanoma (1–2%; Table 2).^{2,4,41,42,62,66} Pneumonitis has a median onset ranging from 2 months to 4 months (Figure 1).^23–27

Rare adverse events

A wide array of additional imAEs has been observed at low rates (<2%) in patients receiving ICPI monotherapy across other organ systems, including renal, pancreatic, ocular, musculoskeletal, neurological, cardiovascular, and hematologic toxicities (Table 3).^22–27 In general, rates of these imAEs are similar or slightly higher in patients receiving combination anti-CTLA-4 and anti-PD-1 antibodies.²³

Renal

Immune-mediated nephritis has been observed at low rates in patients receiving anti-CTLA-4 therapy (ipilimumab, <1%),²² anti-PD-1 antibodies (nivolumab, 1.2%;²³ pembrolizumab, <0.3%²⁴), anti-PD-L1 antibodies (avelumab, 0.1%;²⁶ durvalumab, ≤1%²⁷), and combination anti-CTLA-4 and anti-PD-1 therapy (ipilimumab + nivolumab; 2.2%).²³ The onset of renal imAEs typically occurs earlier with anti-CTLA-4 therapy (2–3 months) than with anti-PD-1 antibodies (3–10 months).⁷⁴

Pancreatic

Pancreatic toxicities reported in clinical studies with ICPIs include elevated amylase/lipase, pancreatitis, and type 1 diabetes mellitus. Pancreatitis was observed in ≤1% of patients receiving ICPI monotherapy^23–26 (excluding anti-CTLA-4 therapy with ipilimumab 10 mg/kg, 1.3%)²² or combination anti-CTLA-4 and anti-PD-1 therapy (ipilimumab + nivolumab).²³ Type 1 diabetes mellitus has occurred at low rates in clinical trials of patients receiving anti-PD-1 antibodies (nivolumab, 0.9%; pembrolizumab, 0.2%)^23,24 and anti-PD-L1 antibodies (atezolizumab, avelumab, durvalumab, ≤0.3%),^25–27 and in 1.5% of patients treated with combination anti-CTLA-4 and anti-PD-1 therapy (ipilimumab + nivolumab).²³ Although diabetes mellitus was not observed in clinical trials of anti-CTLA-4 monotherapy (ipilimumab),²² a report has described a case of diabetes insipidus associated with anti-CTLA-4 monotherapy (ipilimumab).⁷⁵

Ocular

Ocular imAEs have been reported at very low rates in clinical studies of ICPI monotherapy^22–27 or combination anti-CTLA-4 and anti-PD-1 therapy (ipilimumab + nivolumab).²³ Ocular imAEs included uveitis, keratitis, iritis, scleritis, episcleritis, and conjunctivitis, occurring in ≤1% of patients.^22–27

Musculoskeletal

Musculoskeletal imAEs have been reported at low rates in ICPI clinical studies, including polymyalgia rheumatica (<1%), myositis (≤1%), and arthritis (<2%).^{22–24,26,27} Although inflammatory arthritis has been reported with ICPI treatment in case series,^76,77 the rate of this adverse event remains unclear due to inconsistent reporting of inflammatory arthritis in ICPI clinical studies.⁷⁸

Neurologic

A wide array of neurologic imAEs has been associated with ICPI treatment, including Guillain–Barre syndrome, myasthenia gravis, encephalitis, motor dysfunction, meningitis, demyelination, neuropathy, and nerve paresis. In clinical trials, these neurologic imAEs occurred in ≤1% of patients.^22–27 A recent case series, however, noted a 14% incidence of neurologic toxicities in patients treated with combination anti-CTLA-4 and anti-PD-1 therapy (ipilimumab + nivolumab).⁷⁹

Cardiovascular

Cardiovascular imAEs occurred in ≤1% of patients treated with ICPIs in clinical studies, including myocarditis, pericarditis, vasculitis, and heart failure.^{22–24,26,27} Case reports and case series have also documented pericardial effusion, cardiomyopathy, and myocardial fibrosis and suggest that patients with preexisting cardiac pathology may be more susceptible to cardiovascular imAEs with ICPI therapy.^80,81

Hematologic

Hematologic imAEs, including hemolytic anemia and thrombocytopenic purpura, occurred in ≤1% of patients treated with ICPIs in clinical studies.^22,24,26,27 Case reports have found hematologic imAEs in patients receiving anti-CTLA-4 or anti-PD-1 monotherapy, as well as combination anti-CTLA-4 and anti-PD-1 therapy (ipilimumab + nivolumab).^82–85

Monitoring and evaluations of patients receiving ICPIs

Prior to initiating treatment and periodically thereafter, the following laboratory parameters should be assessed: complete blood count, comprehensive metabolic panel (including kidney, liver, pancreatic, and thyroid function tests), and baseline oxygen saturation (including a “walking oxygen saturation” test to facilitate detection of a decrease in oxygen saturation levels that might warrant further diagnostic imaging).^22–27,86 Assessment and documentation of baseline symptoms (Table 3) will allow providers to identify even subtle changes in the patient’s status that might represent an early manifestation of an imAE. In addition, oncology nurses could engage in follow-up telephone calls with patients taking ICPIs.⁸⁷ If specific organ toxicity is suspected, careful evaluation strategies, subspecialty consults, and specialized testing (eg, imaging, bronchoscopy, and colonoscopy) may help rule out other possible causes of dysfunction and delineate the extent of the toxicity to determine optimal management strategies. The National Cancer Institute Common Terminology Criteria for Adverse Events v4.0⁸⁸ should be used to grade baseline symptoms as well as any new symptoms because evaluation and management change according to this grading. Detailed information on evaluation strategies is provided in Table 3.

Understanding the typical time of onset for the various imAEs can be helpful, but it is important to note that the range can be quite broad (Figure 1). Due to the variable onset of imAEs, it is critical to conduct ongoing assessment of symptoms during and after treatment. Patient assessment forms can be built into the electronic medical record (EMR) to capture and communicate potential imAEs.

Special considerations for patients with preexisting autoimmune disease

Although patients with preexisting autoimmune conditions were largely excluded from clinical trials, recent retrospective studies suggest that, with close monitoring, ICPIs can be safely and effectively used in this population.^89,90 Of the 52 patients with preexisting autoimmune disease included in a recent retrospective study, the objective response rate with anti-PD-1 (nivolumab or pembrolizumab) therapy was 33%, with 38% of patients experiencing a flare of their underlying autoimmune condition at a median of 38 days from the first dose of ICPI.⁹⁰ The flares were generally mild, with only two patients permanently discontinuing ICPI treatment due to the flare of their autoimmune disorder.⁹⁰ Four patients permanently discontinued ICPI therapy due to the emergence of imAEs.⁹⁰ Due to the potentially higher risk of side effects and exacerbation of the underlying condition in patients with a history of an autoimmune disease, significant caution should be exercised when considering these patients for treatment with ICPIs. Dosing should occur only after a frank discussion between the health care provider and the patient about the nature of the potential risks and benefits of such therapy.

Management of immune-mediated toxicities

For the current FDA-approved ICPIs, clinicians should follow published guidelines for the management of imAEs.^{57,58,91–97} These imAE algorithms vary based on the type and grade of toxicity, with some Grade 3 imAEs managed by holding therapy and others by permanent discontinuation of ICPI (Table 3). Depending on the organ system involved and the specific ICPI, some mild-to-moderate imAEs can be managed symptomatically, with the patient remaining on ICPIs, while others require the ICPI dose be held and treatment with corticosteroids until the imAE resolves to Grade 1 (Table 3). In patients with more severe (Grade 3/4 or prolonged Grade 2) imAEs, ICPIs are typically discontinued while imAEs are managed with corticosteroids or, if needed, other immunosuppressant agents such as infliximab or mycophenolate (Table 3).^{57,58,91–97} The occurrence of an imAE, regardless of the need for immunosuppressant therapy, does not appear to impact the efficacy of ICPI treatment.^65,98 Because ICPI treatment is relatively new, physicians and nurses may find printed materials from product companies,^22–27,99 publications outlining imAE management,^57,58,92,97 and online algorithm tools^{86,93–96,100} helpful in determining optimal imAE management strategies for their patients (Table 4). Daily communication with the patient (in person or by phone) can help track the status of an imAE and may reduce the risk of mild imAEs escalating to more serious events.⁸⁷

Table 4 ICPI imAE management resources Abbreviations: ICPI, immune checkpoint inhibitor; imAE, immune-mediated adverse event.

Patients receiving corticosteroid treatment for an imAE should be closely monitored. For mild imAEs, low doses of steroids are normally utilized (methylprednisolone [MPS] 0.5–1.0 mg/kg/day intravenously or oral prednisone equivalent), while more severe imAEs require higher steroid doses (MPS 1–4 mg/kg/day intravenously or oral prednisone equivalent).^{57,58,91–97} Patients with severe imAEs may require hospitalization, particularly if they are hemodynamically unstable. In patients with serious imAEs, MPS is typically administered intravenously until the toxicity is stable, after which the patient can be transitioned to oral prednisone.^{57,58,91–97} Once the imAE has resolved to Grade 1 per clinical assessment, steroids should be tapered slowly over approximately 1 month or longer, as tapering steroids too quickly may result in a flare of the imAE. Patients should be monitored weekly during and immediately following the steroid tapering. Often ICPIs can be resumed once the imAE has resolved or stabilized to Grade 1.^{57,58,91–97} In some cases, patients may need to remain on physiologic doses of prednisone (≤10 mg) to stabilize imAEs at Grade 1.^57,92 Patients on prolonged corticosteroid treatment (>20 mg prednisone equivalent daily for 4 weeks) may require supportive therapy with a proton pump inhibitor and/or antibiotic prophylaxis.^58,101 In those patients who require long-term steroid use, evaluation by an endocrinologist is recommended, as additional management such as bone density monitoring may be necessary to evaluate the risk of steroid-induced osteoporosis and diabetes and the need for calcium/vitamin D₃ repletion.¹⁰² In general, if a patient requires >10 mg/day of prednisone equivalent for >12 weeks or if there is a persistent Grade 2 or 3 imAE for >12 weeks, then ICPI should be permanently discontinued.^{57,58,91–97} The diagnosis and management of three sample patients with different imAEs are shown in Figure 2, including rash, colitis, and adrenal insufficiency.

Figure 2 Sample imAE case management.a Notes: aCases based on fictitious patients. bIpilimumab + nivolumab. cPermanently discontinue ICPI therapy in patients with Grade 4 colitis. Abbreviations: ACTH, adrenocorticotropic hormone; BID, twice daily; BM, bowel movement; CT, computerized tomography; GI, gastrointestinal; HCl, hydrochloride; ICPI, immune checkpoint inhibitor; imAE, immune-mediated adverse event; IV, intravenous; PPI, protein pump inhibitor; TSH, thyroid-stimulating hormone.

Education of patients, caregivers, and health care providers on the signs and symptoms of immune-mediated toxicities

Most moderate and severe immune-mediated toxicities, if detected and treated early, can be managed effectively with oral or intravenous steroids; in rare steroid-refractory cases, other immunomodulatory agents (eg, infliximab or mycophenolate mofetil) may be used.^57,58 It is critical that oncology nurses and physicians treating patients receiving ICPIs familiarize themselves with the signs and symptoms of serious imAEs (Table 3).

Patient and caregiver education

A sound patient management approach includes comprehensive education of patients and caregivers about how to recognize and report suspected symptoms of immune-mediated toxicities. Nurses are frequently the first and primary contact for patients throughout treatment. They can prepare patients with the knowledge to identify the signs and symptoms of imAEs and can highlight the importance of reporting symptoms immediately. Incorporating a multimodal approach to education, including printed materials, online education modules, or educational group sessions, can support patient education and understanding. Where available, patients may benefit from live group education or videos. Toxicity checklists (available from product companies) may assist patients in recognizing imAE symptoms. Companies’ websites offer online educational resources specifically designed for patients and caregivers. Most importantly, patients should be instructed to call their doctor’s office if they experience any new, worsening, or otherwise concerning symptoms (even when mild) to maximize early recognition of imAEs.

Education of other health care providers

As the use of ICPIs becomes ubiquitous across multiple different cancer diagnoses, it is imperative that all health care providers are informed regarding the potential for imAEs in patients being treated with these agents. Several modalities are available to assist other health care providers identify imAEs in this unique group of patients. Patient immunotherapy drug “wallet safety cards” can be a useful tool to alert other providers to be aware of potential imAEs associated with ICPIs, particularly during urgent visits. Health care professionals can call the phone number provided on the patient wallet safety card and benefit from peer discussion with the oncology team regarding symptoms, evaluation, and appropriate management. All staff members involved in the telephone triage process who might receive incoming patient phone calls must be educated in the use of the guidelines and in communication and documentation of imAEs. The EMR may also serve as a mechanism to alert other care providers that the patient is receiving immunotherapy. Specific alert mechanisms may be incorporated, such as an alert banner on the chart or a caution alert if a provider attempts to enter an order for an immune-modulating agent. A system alert can be sent to the primary oncology team if the patient presents to the emergency room, is hospitalized, or is evaluated by another discipline.

Conclusion

Nurses play a critical role in identifying imAEs, educating patients about the importance of the timely reporting of potential imAE symptoms, and assisting in the management and follow-up of patients who develop imAEs while on ICPI therapy. ICPIs are associated with a unique safety profile, characterized by fewer and more tolerable side effects than chemotherapeutic drugs. With additional indications, combination regimens, and late-stage drugs on the horizon, the clinical use of ICPIs is expected to increase. Although most imAEs are mild and easily managed, to ensure optimal patient outcomes, imAEs must be promptly identified and treated to reduce the risk of developing severe imAEs and increase the likelihood that the patient continues to receive the benefits of ICPI treatment.

Acknowledgments

The authors wish to thank Jennifer Nepo, MS, and Francesca Balordi, PhD, of The Lockwood Group (Stamford, Connecticut, USA) for providing medical writing support, which was according to Good Publication Practice (GPP3) guidelines and funded by AstraZeneca plc (Wilmington, Delaware, USA).

Disclosure

The authors report no conflicts of interest in this work.

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