Interprofessional Collaboration with Immune Checkpoint Inhibitor Therapy: the Roles of Gastroenterology, Endocrinology and Neurology

ARTICLE IN PRESS Seminars in Oncology Nursing, Vol ■■, No ■■ (■■), 2017: pp ■■-■■

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INTERPROFESSIONAL COLLABORATION WITH IMMUNE CHECKPOINT INHIBITOR THERAPY: THE ROLES OF GASTROENTEROLOGY, ENDOCRINOLOGY AND NEUROLOGY VIRGINIA SEERY OBJECTIVES: To discuss immune checkpoint inhibitor therapy and identify opportunities for interprofessional collaboration in the management of toxicities in the areas of gastroenterology, endocrinology, and neurology.

DATA SOURCES: Published research and education articles in oncology, nursing, and various specialties.

CONCLUSION: The use of immune checkpoint inhibitors is expanding; timely management of toxicity is critical for positive patient outcomes. There are many opportunities for interprofessional collaboration in the diagnosis and treatment of immune-related adverse events.

Virginia Seery, RN, MSN, ANP-BC: Oncology Nurse Practitioner, Beth Israel Deaconess Medical Center, Boston, MA. This research did not receive any specific grant from funding agencies in the public, commercial, or not-forprofit sector.

Address correspondence to Virginia Seery, RN, MSN, ANP-BC, Beth Israel Deaconess Medical Center, 375 Longwood Avenue, Boston, MA 02215. e-mail: vseery@ bidmc.harvard.edu © 2017 Elsevier Inc. All rights reserved. 0749-2081 http://dx.doi.org/10.1016/j.soncn.2017.08.002

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IMPLICATIONS

FOR NURSING PRACTICE: Nurses play key roles in recognizing immune-related adverse events, providing patient education, and helping to facilitate interprofessional collaboration.

KEY WORDS: immunotherapy, immune checkpoint inhibitors, interprofessional collaboration.

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ajor breakthroughs in oncology drug development have expanded treatment options for cancer patients, heralding the era of precision cancer therapy. Often, these medications have unique adverse events that are not seen with traditional cytotoxic therapies and they may be unfamiliar to the oncology team. Interprofessional collaboration is critical to improve outcomes and manage patients effectively. The field of immuno-oncology has seen rapid growth in recent years. Immunotherapy is one type of precision cancer treatment; it harnesses a person’s own immune system to help fight cancer.1 Immune checkpoint inhibitors are one type of immunotherapy; they have demonstrated impressive results in different cancer types and have produced durable responses in a subset of patients.2-9 As use of immune therapy moves from academic medical centers to the community, it is important that providers understand drug mechanism of action, potential unique adverse events and their management. This article will focus on the roles of gastroenterology, endocrinology, and neurology in the interprofessional collaborative management of oncology patients receiving immune checkpoint inhibitors.

IMMUNE CHECKPOINT INHIBITORS: INDICATIONS AND MECHANISM OF ACTION Immune checkpoint inhibitors can help restore an immune response against tumors.1 Several of these drugs were extensively tested in melanoma, with more recent expansion to other disease types. Ipilimumab (Yervoy, Bristol Myers Squibb, Princeton, NJ, USA) was the first immune checkpoint inhibitor approved by the US Food and Drug Administration (FDA) in 2011 based on demonstrated overall survival benefit compared with peptide vaccine in patients with advanced melanoma.2 Ipilimumab is a recombinant, human monoclonal antibody that binds to the cytotoxic

T-lymphocyte–associated antigen 4 (CTLA-4). This action blocks the interaction of CTLA-4 with its ligands and promotes T-cell activation and growth, including T-effector cells that infiltrate tumors. Blocking CTLA-4 can also reduce T-regulatory cell function, thereby improving T-cell responsiveness and the anti-tumor immune response.1,10 Ipilimumab later gained FDA approval in 2015 for adjuvant therapy of high-risk stage III melanoma (defined as patients with melanoma involvement of regional lymph nodes of more than 1 mm who have undergone complete resection, including total lymphadenectomy); this approval was based on improved recurrence-free survival compared with observation in a large phase III trial.11 There have been five additional immune checkpoint inhibitors approved by the FDA in the past 3 years, including pembrolizumab (Keytruda, Merck and Co., Inc. Whitehouse Station, NJ, USA), nivolumab (Opdivo, Bristol Myers Squibb, Princeton, NJ, USA), atezolizumab (Tecentriq, Genentech, Inc., South San Francisco, CA, USA), avelumab (Bavencio, EMD Serono, Inc. and Pfizer, Inc., New York, NY, USA), and durvalumab (Imfinzi, AstraZeneca, Wilmington, DE, USA). Pembrolizumab is a humanized monoclonal antibody and nivolumab is a fully human monoclonal antibody; both are antiPD-1 inhibitors. Some tumors can avoid being recognized by the immune system through the Programmed Death receptor-1 (PD-1) pathway because they express Programmed Death ligand (PD-L1) and Programmed Death ligand 2 (PD-L2) which bind with PD-1 receptors on T cells to inactivate them. Anti-PD-1 antibodies bind to the PD-1 receptor to block this interaction, thereby promoting T-cell activity and the immune response.1,12-14 Pembrolizumab was originally approved by the FDA for advanced or unresectable melanoma in 2014 for second-line use after ipilimumab (and, if BRAF V600E mutant, after BRAF inhibitors). It gained approval for first-line use in melanoma regardless of BRAF status in 2015 after demonstrating improved overall and progression-free survival compared with ipilimumab in a large phase III trial.9

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Pembrolizumab was also approved in 2015 for second-line use in advanced squamous nonsmall cell lung carcinoma (NSCLC) expressing PD-L1, moving to first-line approval for that population (with no EGFR or ALK genomic tumor aberrations) in 2016. Also in 2016, it was approved by the FDA for advanced or recurrent head and neck squamous cell carcinoma progressive after standard chemotherapy. In 2017, pembrolizumab gained FDA approval for three additional disease entities, including classical Hodgkin lymphoma in adults and children with refractory classical Hodgkin lymphoma or who have relapsed after three or more prior therapies; for treatment of locally advanced or metastatic urothelial carcinoma ineligible for cisplatin-containing chemotherapy or who have disease progression after platinumcontaining chemotherapy in the primary or adjuvant setting; and for use in unresectable or metastatic microsatellite instability-high or mismatch repair deficient solid tumors progressive after prior treatment without satisfactory alternative treatment options, as well as microsatellite instability-high or mismatch repair deficient colorectal cancer after progression on a fluoropyrimidine, oxaliplatin, and irinotecan.12 Nivolumab was approved by the FDA in 2014 for second-line use in unresectable or advanced melanoma; in 2015, it moved to first-line approval in BRAF wild type melanoma and was approved in 2016 for BRAF mutant melanoma as first-line therapy. Nivolumab was FDA approved in 2015 for advanced renal cell carcinoma after prior antiangiogenic therapy and for metastatic NSCLC with progression on or after platinum-based chemotherapy. It was approved in 2016 by the FDA for treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma with disease progression on or after a platinum-based therapy and for the treatment of patients with classical Hodgkin lymphoma that has progressed after autologous hematopoietic stem cell transplantation and post-transplantation brentuximab vedotin (Adcetris, Seattle Genetics, Inc., Bothell, WA, USA). Nivolumab also gained FDA approval in 2017 in previously treated locally advanced or metastatic urothelial carcinoma after disease progression on platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.13 Atezolizumab, avelumab and durvalumab are anti-PD-L1 antibodies. Atezolizumab is a humanized monoclonal antibody, while avelumab and

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durvalumab are human monoclonal antibodies. They work by binding to PD-L1, preventing its interaction with PD-1 and B7.1 receptors that suppress T-cell activity and proliferation, thereby inducing an anti-tumor immune response.14,15 Atezolizumab was approved by the FDA in 2016 for second-line use in advanced urothelial carcinoma and for second-line use in metastatic NSCLC.14 Avelumab was FDA approved in 2017 for metastatic Merkel cell carcinoma in adults and pediatric patients 12 years and older and for locally advanced or metastatic urothelial carcinoma with disease progression after platinum-based chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.15 Durvalumab was approved by the FDA in 2017 for locally advanced or metastatic urothelial carcinoma with disease progression after platinumbased chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinumcontaining chemotherapy16 (see Table 1). Combination therapy has been investigated as a way to improve the body’s immune response to cancer because blocking multiple pathways could enhance immune activation.17 The combination of nivolumab and ipilimumab was FDA approved in 2015 for advanced or unresectable BRAF V600 wild type melanoma. This was based on several melanoma trials demonstrating improved response rates and progression-free survival with the combination.18-20 This approval was expanded in 2016 to include treatment of BRAF mutant melanoma. Side effects of the combination of nivolumab and ipilimumab were believed to be manageable, but were higher than with either agent alone.18-20 Pembrolizumab was approved by the FDA in 2017 for first-line use in NSCLC (irrespective of PD-L1 expression) in combination with pemetrexed and carboplatin.12 The high number of FDA approvals for immune checkpoint inhibitors over just a few years is both exciting and challenging. These drugs offer the possibility of a durable response for patients with challenging cancer diagnoses. It is expected that other disease improved entities will receive FDA approval for their use; therefore, use of checkpoint inhibitors will become more widespread in the community. In addition, novel drug combinations are being investigated that may have unique adverse events.17,21 The challenge lies in the need to educate all providers about the potentially serious side-effect profile that often requires interprofessional expertise and management.

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TABLE 1. FDA Approved Checkpoint Inhibitors Used in Cancer Treatment

Ipilimumab (Yervoy, Bristol Myers Squibb)10 Nivolumab (Opdivo, Bristol Myers Squibb)13

Type of Drug

Target

Human monoclonal antibody

Cytotoxic T-lymphocyte antigen 4 (CTLA-4) Programmed death receptor-1 (PD-1)

Human monoclonal antibody

FDA Approved Indications -

Unresectable or metastatic melanoma Adjuvant treatment of patients with cutaneous melanoma with pathologic involvement of regional lymph nodes of > 1 mm who have undergone complete resection, including total lymphadenectomy

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BRAF V600 wild-type unresectable or metastatic melanoma, as a single agent BRAF V600 mutation-positive unresectable or metastatic melanoma, as a single agent Unresectable or metastatic melanoma, in combination with ipilimumab Metastatic NSCLC with progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving nivolumab Advanced renal cell carcinoma who have received prior anti-angiogenic therapy cHL in adults that has relapsed or progressed after: • autologous HSCT and brentuximab vedotin, or • 3 or more lines of systemic therapy that includes autologous HSCT Recurrent or metastatic HNSCC with disease progression on or after a platinum-based therapy Locally advanced or metastatic urothelial carcinoma who: • have disease progression during or following platinum-containing chemotherapy, or • have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy (Continued)

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-

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Drug Name

TABLE 1. (Continued) Drug Name

Humanized monoclonal antibody

Programmed death receptor-1 (PD-1)

FDA Approved Indications -

Unresectable or metastatic melanoma NSCLC • as a single agent for the first-line treatment of patients with metastatic NSCLC whose tumors have high PD-L1 expression with no EGFR or ALK genomic tumor aberrations • as a single agent for the treatment of patients with metastatic NSCLC whose tumors express PD-L1, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving pembrolizumab • in combination with pemetrexed and carboplatin, as first-line treatment of patients with metastatic nonsquamous NSCLC - HNSCC for treatment of patients with disease progression on or after platinum-containing chemotherapy. - cHL in adult and pediatric patients who: • have refractory cHL, or • have relapsed after 3 or more prior lines of therapy - Locally advanced or metastatic urothelial carcinoma who: • are not eligible for cisplatin-containing chemotherapy, or • have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy - MSI-H • for the treatment of adult and pediatric patients with unresectable or metastatic, MSI-H or mismatch repair deficient: ○ solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options, or ○ colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan (Continued)

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Target

INTERPROFESSIONAL COLLABORATION WITH IMMUNE CHECKPOINT INHIBITOR THERAPY

Pembrolizumab (Keytruda, Merck Oncology)12

Type of Drug

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TABLE 1. Drug Name Atezolizumab (Tecentriq, Genentech)14

Avelumab (Bavencio, EMD Serono/ Pfizer)15 Durvalumab (Imfinzi, AstraZeneca)16

Type of Drug

Target

Humanized monoclonal antibody

Programmed death-ligand 1 (PD-L1)

Human monoclonal antibody

Programmed death ligand-1 (PD-L1)

Human monoclonal antibody

Programmed death ligand-1 (PD-L1)

FDA Approved Indications -

Locally advanced or metastatic urothelial carcinoma who: • are not eligible for cisplatin-containing chemotherapy, or • have disease progression during or following any platinum-containing chemotherapy, or within 12 months of neoadjuvant or adjuvant chemotherapy - Metastatic NSCLC who: • have disease progression during or following platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA- approved therapy for these aberrations prior to receiving atezolizumab - Adults and pediatric patients 12 years and older with metastatic MCC - Locally advanced or metastatic urothelial carcinoma with disease progression: • during or following any platinum-containing chemotherapy, or • within 12 months of neoadjuvant or adjuvant chemotherapy - Locally advanced or metastatic urothelial carcinoma with disease progression: • during or following any platinum-containing chemotherapy, or • within 12 months of neoadjuvant or adjuvant chemotherapy

Abbreviations: cHL, classical Hodgkin Lymphoma; HNSCC, head and neck squamous cell cancer; HSCT, hematopoietic stem cell transplantation; MCC, Merkel cell carcinoma; MSI-H, microsatellite instability-high; NSCLC, non-small cell lung carcinoma.

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ARTICLE IN PRESS INTERPROFESSIONAL COLLABORATION WITH IMMUNE CHECKPOINT INHIBITOR THERAPY

IMMUNE-RELATED ADVERSE EVENTS The mechanism of action of checkpoint inhibitors explains the more serious side effects associated with treatment. Improvement in T-cell activity heightens an immune response against a tumor, but it can also attack healthy tissues and cause inflammation in any organ system, creating immune-related adverse events (irAEs).22 The most extensive experience with irAEs comes from ipilimumab trials in melanoma patients. Severe irAEs with ipilimumab occur more frequently than with PD-1 or PD-L1 antibodies (10%15% versus 4%10%, respectively).2,22-25 General guidelines for management of irAEs apply to all immune checkpoint inhibitors, despite the difference in incidence of irAEs, and algorithms have been developed to help clinicians manage irAEs effectively.26 They are based on the risk evaluation and mitigation strategies originally developed by the FDA for ipilimumab.27 Toxicity grading is derived from clinical trials; grade 1 is mild, grade 2 is moderate, grade 3 is severe, and grade 4 is life threatening.28 The key to managing irAEs most effectively is prompt recognition, interruption of therapy, and early treatment with steroids or other immunosuppressive therapy.29,30 General management of grade 2 (moderate) irAEs includes symptom management and withholding treatment of the immune checkpoint inhibitor. If symptoms do not resolve within a week, corticosteroids (prednisone 0.5 mg/kg/day or equivalent) are initiated. Therapy cannot be restarted until symptoms are grade 1 (mild) or better. If grade 3 or 4 (severe) irAEs develop, the immune checkpoint inhibitor should be discontinued; higher doses of steroids may be started (prednisone 1 to 2 mg/ kg/day or equivalent) and consideration given for intravenous administration. Once symptoms improve to grade 1 or better, steroids can be slowly tapered over at least 1 month. If a grade 3–4 (severe) irAEs does not improve within 3 days, infliximab (5 mg/kg) is recommended. If symptoms persist after the first dose, a second 5-mg/kg dose should be repeated.10,12-16,29 Clinicians should be aware that irAEs may occur at any point in treatment, including after therapy has been discontinued. It is critical for oncology providers to recognize irAEs promptly and to determine if the patient can be managed safely as an outpatient or whether hospitalization is indicated. Interprofessional management should be considered for any moderate irAEs that

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is not improving or for severe irAEs. Frequent reassessment of confirmed irAEs is critical to ensure clinical improvement and to allow restart of therapy, if indicated. Most irAEs resolve within 12 weeks of onset. 22 It is important to note that steroid use in patients receiving immune checkpoint inhibitor therapy does not appear to negatively impact the tumor immune response.23

Gastrointestinal irAEs The most common gastrointestinal adverse event from immune checkpoint inhibitors is diarrhea (increase in frequency of stools). It generally occurs 4 to 6 weeks into treatment.22,31 The incidence of grade 3–4 diarrhea with ipilimumab 3 mg/kg is approximately 5%.2 Incidence rates for the 10-mg/ kg adjuvant dose are higher, in the 15% range.10 The rate of grade 3–4 diarrhea with anti-PD-1 and anti-PD-L1 antibodies is lower, approximately 1% to 2% in clinical trials.8,9,25 Colitis is characterized by diarrhea, abdominal pain, or cramping and hematochezia or colon inflammation seen radiographically or endoscopically. The incidence of colitis in ipilimumab-treated patients is 5% to 6%.2,18 In a large phase III ipilimumab trial (N = 676), there was a 1% incidence of death associated with irAEs, the majority from colitis and bowel perforation.2,22 In some of those cases, delayed use of steroids was believed to play a role in the negative outcomes.22 The incidence of colitis with anti-PD-1 and anti-PD-L1 antibodies is lower, approximately 1% to 2%.8,9,25 Prompt recognition and treatment of this condition is critical to ensure patient safety. The management of mild diarrhea (grade 1, < four stools/day over baseline) includes ensuring adequate oral hydration and using antidiarrheals such as loperamide or diphenoxylate atropine sulfate. Budesonide could be considered if symptoms remain mild after 2 to 3 days of treatment with antidiarrheals. If symptoms worsen, oral or intravenous corticosteroids should be considered and infectious etiologies of diarrhea ruled out.10,12-16,29,30 Much of the management of immune checkpoint inhibitor colitis comes from treatment of idiopathic inflammatory bowel conditions; therefore, consultation with gastroenterology should be sought in cases of moderate to severe diarrhea that is not responding to therapy.32 Colonoscopy may be indicated for biopsy confirmation of colitis. Hospitalization for severe symptoms (increase of seven

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TABLE 2. Selected Gastrointestinal irAEs of Immune Checkpoint Inhibitors irAEs Diarrhea Grade 1

Grade 2

Colitis Grade 2

Grade 3/4

Hepatitis Moderate

Severe

Signs/Symptoms

General Management

Increase of <4 stools/day over baseline

Antidiarrheals Ensure adequate hydration Consider budesonide

Increase of 4 to 7 stools/day over baseline

Above, plus: Hold ICI therapy If symptoms persist >5–7 days, consider low-dose 0.5–1.0 mg/kg/day prednisone or equivalent Consider infectious work-up

Inflammation of colon: abdominal pain/cramping, blood or mucus in stools

Above, plus: Steroids 1–2 mg/kg/day prednisone or equivalent Consider endoscopic evaluation Consider GI consult Above, plus: Endoscopic evaluation GI consult Consider hospitalization IV steroids; if no improvement in 3 days, administer infliximab

Severe abdominal pain, change in bowel habits, peritoneal signs

ALT/AST 2.5–5.0 x ULN and/or Total bilirubin 1.5–3.0 x ULN ALT/AST >5.0 x ULN and/or Total bilirubin > 3.0 x ULN

Hold ICI therapy Rule out infectious or malignant causes Systemic steroids 0.5–1.0 mg/kg/day prednisone or equivalent Above, plus: Systemic steroids 1–2 mg/kg/day prednisone or equivalent If no improvement, consider mycophenolate Consider GI consult

Nursing Assessment Number of bowel movements daily Assess response to antidiarrheals Daily check in regarding status/ response to treatment Adequate intake and urine output

Above, plus assess level of pain

Above, plus assess need for hospitalization

Assess for increased malaise, dark urine, jaundice

Above, plus assess need for hospitalization

Abbreviations: ALT, aspartate aminotransferase; AST, alanine aminotransferase; GI, gastrointestinal; ICI, immune checkpoint inhibitors; irAEs, immune-related adverse events; ULN, upper limit of normal.

or more stools per day over baseline) is indicated to administer intravenous corticosteroids and hydration. If there is no improvement with intravenous corticosteroids after 3 days, infliximab 5 mg/kg once every 2 weeks is recommended. If this is not effective, mycophenolate may be administered. In cases of severe colitis, immune checkpoint therapy is permanently discontinued.10,12-16,29,30 Immune-mediated hepatitis can occur with immune checkpoint inhibitors. This most often manifests as asymptomatic elevations in aspartate aminotransferase (ALT) or alanine aminotransferase (AST) levels, or less frequently as total bilirubin elevations.10,12-16,27 The incidence with ipilimumab

is dose dependent; there is a 2% incidence with the 3-mg/kg dose and an 11% incidence with the 10mg/kg dose.10 Combination therapy with ipilimumab and nivolumab has a higher rate of hepatitis at 13%.13 The incidence is lower with single-agent anti-PD-1 and anti-PD-L1 inhibitors, in the 1% to 2% range.12-16 Autoimmune hepatitis tends to occur 6 to 12 weeks into therapy.10,12-16,22 Algorithms for management have been developed and follow the general management guidelines noted earlier 27 (see Table 2). Gastroenterology or hepatology consultation should be sought if a patient is clinically deteriorating or not responding to high-dose steroids and/or mycophenolate.

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Endocrinology irAEs Endocrine irAEs with immune checkpoint inhibitors are infrequent, but can be serious if not recognized promptly. The two most common endocrine irAEs are hypophysitis and hypothyroidism. Hypophysitis is inflammation of the pituitary gland that causes glandular malfunction. With singleagent ipilimumab or nivolumab, this was most commonly seen 6 to 8 weeks after initiation of therapy.23,31 The exact incidence of hypophysitis is unknown, but it is believed to occur in 8% to 10% of patients treated with ipilimumab and is dose dependent.33,34 Hypophysitis occurs in less than 1% of patients treated with nivolumab, pembrolizumab, atezolizumab, and durvalumab.7,8,16,25 The incidence is higher (2% to 10%) for the combination of ipilimumab and nivolumab.20 Symptoms of hypophysitis are often vague and include fatigue, headache, nausea, and visual issues. Laboratory studies show low levels of adrenocorticotropic hormone, thyroid-stimulating hormone, luteinizing hormone, follicle-stimulating hormone, growth hormone, and prolactin. Imaging of the brain may show pituitary inflammation.21 Hypophysitis may cause secondary hypothyroidism or secondary hypoadrenalism. If hypophysitis is suspected, corticosteroids should be started (prednisone 1 mg/kg/day or equivalent) and endocrinology consultation obtained. Most patients will require longterm hormone supplementation and ongoing endocrinology management.33,34 Another endocrinopathy seen with immune checkpoint therapy is inflammation of the thyroid, or thyroiditis, which can cause primary hypothyroidism or, less often, primary hyperthyroidism. Thyroiditis is often diagnosed based on thyroid function tests. Variable incidence rates of thyroiditis and hypothyroidism have been reported. Ipilimumab hypothyroidism rates are approximately 2% to 7%; anti-PD-1 and anti-PD-L1 antibody-induced hypothyroidism incidence is 1% to 2%.2,24,25,33 Hypothyroidism is treated with thyroid replacement and can often be treated without endocrine consultation, unless there is difficulty achieving normal thyroid function tests or controlling symptoms. Hyperthyroidism is treated if the patient is symptomatic. Adrenal insufficiency is rare (<1%), but is the most serious endocrine dysfunction seen with immune checkpoint inhibitors.29 Prompt consultation with endocrinology is essential for optimal management. Patients can present with electrolyte abnormalities (hypokalemia, hyponatremia),

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dehydration, or hypotension. If adrenal crisis is suspected, hospitalization and intravenous corticosteroids are necessary. 29 Diabetes mellitus occasionally develops in patients receiving PD-1 or PD-L1 antibodies alone or in combination with ipilimumab, but this is rare.25,35 This also requires endocrinology consultation for optimal management. Most endocrinopathy irAEs are corrected with hormone or steroid supplementation and immune checkpoint inhibitor therapy may be restarted once side effects are adequately controlled. Neurologic irAEs Neurologic irAEs from single-agent immune checkpoint inhibitors are infrequent, with an incidence of 1% to 3%, although higher rates are seen with combination therapy.36 Different types of neurologic conditions have been identified after treatment with immune checkpoint inhibitors, including motor or sensory neuropathies and more serious syndromes that are often published as single case reports.10,12-16 Neurological irAEs should be considered in patients who develop new sensory and/ or motor findings during treatment with immune checkpoint inhibitors.37 Guillain-Barré syndrome has been reported, with one patient death in the adjuvant setting because of this condition.11,38 Myasthenia gravis has developed after immune checkpoint inhibitor therapy and is fatal in some cases.39 Myasthenia gravis should be suspected in patients treated with immune checkpoint inhibitors who develop diplopia, weakness, dysphagia, or dysarthria.39 In these cases, immune checkpoint inhibitor therapy should be discontinued. Corticosteroids may be helpful, as well as plasmapheresis and intravenous immunoglobulin.29,37 More recently, encephalitis has been described as a rare but serious complication of immune checkpoint inhibitor therapy.40 If immunotherapy patients present with headache, fever, fatigue, weakness, altered mental status, stiff neck, speech problems, or seizure, encephalitis should be included in the differential diagnosis.40 Prompt neurologic consultation for these patients is critical to help minimize long-term consequences of neurologic irAEs.39,40

INTERPROFESSIONAL COLLABORATION Interprofessional collaboration is beneficial for oncology patients, especially given the complexity of their health needs.41 Management of immune

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checkpoint inhibitor toxicities is complicated and requires skill.30 Use of checkpoint inhibitor therapy will increase with recently expanded indications; therefore, oncology practices that have less experience administering these treatments will be managing irAEs. This situation lends itself well to interprofessional collaboration between specialists and the oncology team. Specialists familiar with immune checkpoint inhibitor irAEs need to be identified to help facilitate prompt diagnosis and treatment of toxicities because this is critical to their ongoing use and success. Another area of potential interprofessional collaboration is in the care of patients with autoimmune conditions. These patients were largely excluded from clinical trials with immune checkpoint inhibitors because they could theoretically worsen an autoimmune condition. The specialist and oncology team should anticipate and discuss potential issues before treatment and patients should fully understand the potential to exacerbate the condition. In many cases, the benefit of receiving therapy for cancer will outweigh the risks of possibly worsening an autoimmune condition.29,30

THE ROLE OF NURSING Oncology nurses are a key part of the interprofessional team; they play a pivotal role in successfully managing patients on immune checkpoint inhibitors. Nurses are well positioned to identify immune-related toxicity early so that it can be treated effectively and prevent permanent discontinuation of therapy.42-45 They also educate patients and caregivers about potential irAEs, ensuring symptoms are reported promptly. Lastly, nurses help to educate other health care colleagues regarding immune checkpoint inhibitor therapy and irAEs.

CASE STUDIES The following case studies demonstrate interprofessional collaboration among disciplines managing oncology patients receiving immune checkpoint inhibitors. Case 1 A 49-year-old man was diagnosed with metastatic renal cell carcinoma at the time of presentation. He underwent right nephrectomy, but

known pancreatic and lung metastases progressed after surgery. He started nivolumab on a clinical trial in March 2012. Lung metastases resolved and pancreatic masses were stable on serial scans. He developed diabetes mellitus in February 2014. Endocrinology consult was obtained and he was placed on insulin; the etiology of diabetes mellitus was attributed to nivolumab because he did not have risk factors for its development. Nivolumab therapy was continued. In May 2014, he developed bloody diarrhea with abdominal discomfort. Urgent gastroenterology consultation was obtained and a flexible sigmoidoscopy was performed the next day that showed probable colitis with biopsy confirmation. He was initiated on steroids 1 mg/kg with immediate improvement in diarrhea. Nivolumab was held. Steroid taper was initiated 10 days later and continued over 4 weeks without recurrent symptoms. Nivolumab was discontinued per protocol because of prolonged time to recovery. Follow-up scans were stable off therapy until January 2015 when liver and lung metastases were noted. In preparation for high-dose IL-2 therapy, he underwent repeat colonoscopy by gastroenterology that ruled out colitis before IL-2 treatment. This case utilizes the expertise of two specialists to most effectively diagnose and manage irAEs from nivolumab. Interestingly, this patient developed colitis after being on nivolumab therapy for 2 years; evidence that immune checkpoint inhibitor toxicity can occur at any point in treatment. Case 2 A 55-year-old man with metastatic renal cell carcinoma initially failed high-dose Interleukin-2, then started sunitinib therapy. When disease progression was noted, he began nivolumab on a clinical trial in June 2012. He experienced disease progression in October 2013, but was allowed to stay on trial given clinical benefit and prolonged stabilization of disease. He was removed from the study in June 2014 when a second progression was noted. In August 2014, he was admitted to the hospital with a 3-day history of finger paresthesia, incoordination of the extremities, and mild ataxia. Urgent neurology consultation was obtained. Brain MRI was normal and lumbar puncture revealed normal cerebrospinal fluid without infection. He lost reflexes and was believed to have an atypical GuillainBarré syndrome. His symptoms improved without treatment and he was discharged to home 3 days later. Within 1 week he was re-admitted to the neurology service with progressive gait difficulties,

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asthenia, headache, numbness, and diplopia. His exam revealed impairment in left eye abduction, areflexia bilaterally, dysmetria, and dyssynergia bilaterally on finger-nose-finger, mild weakness bilaterally, and absent proprioception of the left great toe. Brain MRI/MRA showed no evidence of metastases or infarct. He underwent treatment with intravenous immunoglobulin, 0.4 mg/kg per day for 5 days to treat atypical Guillain-Barré syndrome (Miller Fisher variant). This led to resolution of weakness, gait difficulties, and loss of left great toe proprioception. Impaired left eye abduction and areflexia initially persisted, but resolved within 2 weeks. His neurologic symptoms completely resolved; he continues to be followed regularly by neurology. This case illustrates that immune checkpoint inhibitor toxicity may occur after therapy is discontinued. Communication about past use of checkpoint inhibitors is critical to consider irAEs in the differential diagnosis of new conditions. Patient and caregiver education about potential autoimmune side effects is extremely important, especially as checkpoint inhibitor use expands to new settings. Ultimately, this patient had a full recovery with the collaborative efforts of neurology and oncology. Case 3 A 76-year-old man with history of BRAF wildtype melanoma metastatic to the lung was treated in the first-line setting with ipilimumab on a clinical trial. He initially tolerated therapy well and received the first four infusions without difficulty, noting fatigue and a mild rash. At week 13, he was noted to have hypotension (systolic blood pressure in the 90s), increased fatigue, asthenia, dizziness with position changes, and increased dyspnea on exertion. Autoimmune hypophysitis was suspected. Labs revealed elevated creatinine to 2.1, elevated potassium to 5.5, low prolactin, low thyroidstimulating hormone, low T4 and free T4, undetectable testosterone, and low random cortisol. Brain MRI showed triangular swelling of the pituitary with homogeneous enhancement without mass effect on the optic chiasm, consistent with hypophysitis. Antihypertensives were held. He was started on prednisone 1 mg/kg and levothyroxine 50 mcg. Urgent endocrinology consult was obtained with additional labs revealing low basal cortisol and indeterminant cortisol stimulation test, consistent with recent-onset central adrenal insufficiency from hypophysitis. His symptoms improved

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within 1 day of starting steroids. Renal insufficiency and hyperkalemia resolved. The endocrinologist initially recommended changing to physiologic doses of prednisone at that time, but a slow steroid taper was planned after discussion with oncology about irAEs management guidelines. The patient gradually decreased to physiologic doses of prednisone, 5 mg daily. Visual field testing was normal and follow-up brain MRI showed improvement in pituitary inflammation. Endocrinology counseled him on need for hydrocortisone in emergencies and sick-day dosing of steroids. He continued on maintenance ipilimumab every 12 weeks per protocol without further endocrine difficulties noted; he stopped therapy 6 months later because of rash and pruritus. He continues to be seen regularly by endocrinology and is maintained on prednisone 5 mg daily. This case is an excellent example of interprofessional collaboration. The oncology team identified an issue and began therapy, but recognized that expert management was indicated. The endocrinology consultant quickly diagnosed hypophysitis (and secondary hypothyroidism and secondary hypoadrenalism) and agreed with corticosteroid and thyroid hormone replacement. A discussion ensued about how to taper steroids and the oncologist’s prior experience managing irAEs informed the decision to slowly taper prednisone to physiologic doses. The endocrinologist highlighted the need for stress dose steroids for emergencies or illness; this might have been overlooked in a busy oncology practice not accustomed to managing hypophysitis.

FUTURE CONSIDERATIONS The future is bright for immunotherapy as new therapies are developed that work on different pathways to augment the immune response. Novel combinations under investigation are showing promise in terms of efficacy and safety.15 Current research is focused on identifying patients who have a predisposition to certain irAEs based on genetics or biomarkers. This approach would better inform decision-making regarding immunotherapy and prospectively identify toxicity issues. The interprofessional collaborative approach to care for today’s oncology patients is essential to manage toxicities and improve patient outcomes.

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V. SEERY

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