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Improving Efficacy in First-Line Treatment of Advanced Melanoma: Focus on the Role of Immune Checkpoint Inhibitors

Managing Adverse Events of First-line Treatment of Advanced Melanoma (Part 2 of a 2-Part Interactive Monograph Series)

Overview

Survival outcomes for patients with advanced melanoma have dramatically improved with the use of immune checkpoint inhibitors (ICIs).¹ The intent of ICI therapy is to stimulate T-cell activation against cancer by releasing the brakes of natural control mechanisms for the immune system.² However, ICI therapy can also trigger activation against healthy organs and tissues.³ This lack of specificity and predictability in the mechanism of ICIs results in unique challenges with the management of immune toxicity.⁴ Pharmacists can play a key role in advocating for the prompt identification and treatment of immune-related toxicities.⁵ In this module, we will discuss the safety profiles of first-line ICI–containing therapeutics for advanced melanoma, how to recognize immune-related toxicity, and review appropriate strategies for immune toxicity management.

First-line Treatment-Associated Adverse Event Management

Toxicity Profiles of First-line Treatments

ICIs have become the standard of care for first-line treatment of advanced melanoma, with multiple US Food and Drug Administration (FDA)-approved ICI–containing therapy options in this setting.⁶ These include programmed cell death-1 (PD-1) ICI monotherapy with pembrolizumab or nivolumab; PD-1 plus cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) ICI combination therapy with nivolumab and ipilimumab; lymphocyte-activation gene 3 (LAG-3) plus PD-1 ICI combination therapy with relatlimab and nivolumab; and triplet (PD-1 ICI + BRAF/MEK inhibitor) combination therapy with atezolizumab, vemurafenib, and cobimetinib.⁶ Of note, the triplet combination is not a preferred first-line option for metastatic melanoma.⁷ Although PD-1 plus CTLA-4 ICI combination therapy with pembrolizumab and low-dose ipilimumab is listed as an option in the National Comprehensive Cancer Network Guidelines for advanced melanoma, it is a Category 2B recommendation and not FDA approved.⁷

In terms of safety, PD-1 ICI monotherapy is the best tolerated therapy, with an approximately 10% to 15% risk of grade 3 or 4 treatment-related adverse effects (AEs).^4,8 LAG-3 plus PD-1 inhibition with relatlimab and nivolumab carries approximately twice the risk of grade 3 or 4 treatment-related toxicity as PD-1 inhibition with nivolumab alone (18.9% vs 9.7%), with a higher rate of myocarditis (1.7% vs 0.6%) and adrenal insufficiency (4.2% vs 0.8%).⁹ The regimen with the highest risk of immune toxicity is combination PD-1 plus CTLA-4 blockade with nivolumab and ipilimumab, carrying a 59% risk of grade 3 or 4 treatment-related toxicity.¹⁰ Finally, the triplet combination of atezolizumab, vemurafenib, and cobimetinib has a 79% risk of grade 3 or 4 treatment-related AEs.¹¹ This high likelihood of AEs reflects the additive toxicity profiles of both PD-L1 inhibition and BRAF/MEK inhibition; the BRAF/MEK doublet likely accounts for about 65% of observed grade 3 or 4 treatment-related AEs.¹²

Core Principles of Immune-Related Adverse Event Management

Background

Immune toxicities caused by ICIs are referred to as immune-related adverse events (irAEs).⁴ irAEs are caused by uncontrolled immune sensitivity against self-antigen, triggered by T-cell activation from ICIs for cancer (Table 1).⁴ irAEs are inflammatory, thus the suffix “-itis” is used when describing them.¹³ They have symptom profiles that mimic autoimmune diseases, such as inflammatory bowel disease or rheumatoid arthritis, and irAE treatment strategies have been inspired by related autoimmune diseases.¹⁴ Severe and steroid-refractory irAEs often require collaboration with experts from related subspecialties.¹⁵ Consensus guidelines have been published to assist in the management of irAEs and are freely available for reference in clinical practice.^13,15-17

irAE timeline

Unlike the predictable toxicity timeline of other anticancer therapies, the occurrence of irAEs is highly unpredictable, with a delayed risk profile that begins to peak a few months after the start of ICI therapy.⁴ However, irAEs can occur at any time, even months after treatment discontinuation.¹⁴ Due to the underlying mechanism of T-cell activation against self-antigen, severe irAEs are usually not self-limiting and require medical intervention.⁴ Thus, it is imperative to be aware of the potential for an irAE to occur in a patient on an ICI or ICI combination therapy, regardless of the timing from the start of treatment.

Non-endocrine irAE management pearls

For any patient who has received anticancer therapy with an ICI, an irAE should be considered as a possibility in the differential diagnosis of any AEs.⁴ While irAEs are often a diagnosis of exclusion, treatment for suspected severe irAEs should not be delayed in order to obtain results from workup; however, laboratory testing should be obtained and sent before initiation of empiric treatment whenever possible.¹³ If more than 1 diagnosis is a likely culprit, such as in cases of pneumonia versus pneumonitis, both potential diagnoses should be treated until one can be definitively ruled out.^13,15-17 For minor grade 1 irAEs and some grade 2 irAEs, increased monitoring frequency is often preferred before initiation of immunosuppressive treatment.⁴

Supportive care measures, such as loperamide for diarrhea, should be avoided whenever possible or used temporarily with extreme caution for grade 1 symptoms to avoid masking a potentially life-threatening underlying irAE.¹³ However, for grade 2 or higher dermatologic irAEs, high potency topical corticosteroids such as clobetasol are often used as an adjunctive therapy for symptomatic relief. The mainstay of therapy for the majority of persistent grade 2 irAEs and any grade 3 or 4 irAEs is to hold ICI therapy and start a high-dose corticosteroid (0.5-2 mg/kg/day depending on grade) such as prednisone (oral) or methylprednisolone (intravenous).^13,15-17 Ideally, irAEs should be identified as early as possible and treated before the transition to grade 3 or 4 occurs because more severe irAEs often require inpatient care.^13,16 Once an irAE recovers to grade 1 or less, prednisone may be slowly tapered over 4 to 6 weeks, with the hope of avoiding a recurrence of symptoms.¹³

Endocrine irAE management pearls

Endocrine irAEs are a subclass of irAE that affect glands in the body—primarily the thyroid gland, pituitary gland, and pancreatic islet beta cells. Endocrine irAEs occur in more than 1 in 10 patients who receive an ICI, with the highest risk being for thyroiditis (9.2%), followed by hypophysitis (1.2%), adrenal insufficiency (0.7%), and type 1 diabetes (T1D; 0.2%).¹⁸ Although immune-related primary adrenal insufficiency is mentioned in the literature, there is debate as to whether it exists as a separate entity, or is in most cases secondary to corticosteroid usage or other irAEs such as hypophysitis.¹³

Thyroiditis is commonly characterized by temporary, asymptomatic hyperthyroidism (low thyroid-stimulating hormone [TSH] and normal/high free thyroxine [T4]) during immune burnout followed by primary hypothyroidism (high TSH and normal/low free T4) within about 1 month as thyroid function is lost.^13,19 Hypophysitis often presents with mass effect symptoms such as headaches, dizziness, nausea, and light sensitivity from the inflamed pituitary gland.^13,20 Shortly thereafter, these patients demonstrate severe fatigue and evidence of secondary adrenal insufficiency (low corticotropin [ACTH] and low cortisol); some patients may also experience secondary hypothyroidism (low TSH and low T4) or secondary hypogonadism (low luteinizing hormone [LH], low follicle-stimulating hormone [FSH], and low testosterone or estradiol not due to underlying illness or clinical state).^13,20 Finally, patients with immune-related T1D from ICI therapy often present with fulminant diabetic ketoacidosis.²¹

Unlike non-endocrine irAEs, endocrine irAEs are usually permanent and cause partial or total disruption of hormonal release. As such, they are not an indication for permanent discontinuation of ICI therapy.^13,15-17 Management of endocrine irAEs focuses on the replacement of the primary deficient hormone that are causing the symptoms—namely levothyroxine for thyroiditis, hydrocortisone for the secondary adrenal insufficiency caused by hypophysitis (with replacement of other secondary deficient hormones if needed), and insulin for new-onset T1D.

Concerns with immunosuppression

Early use of corticosteroids either before or within the first 8 weeks of ICI initiation has been linked to poor clinical outcomes.^22,23 The use of high-dose corticosteroids for hypophysitis is also associated with worse survival.²⁴ Apart from these data, there has been little evidence to indicate that the use of immunosuppressive agents for irAE treatment affects clinical outcomes. However, corticosteroids are associated with a myriad of other side effects and complications, which prophylactic efforts can help to mitigate.

Pneumocystis jirovecii pneumonia prophylaxis should be considered for all patients receiving an equivalent of 20 mg or more of prednisone daily for 4 or more weeks.^13,16,17 Use of therapeutic anticoagulation or frequent use of nonsteroidal anti-inflammatory drugs in addition to active corticosteroid therapy may require the use of a proton pump inhibitor (PPI) or H2 blocker due to the higher risk of gastritis.^13,16,17 Because patients may experience gastric discomfort on high-dose prednisone even without those risk factors, it may be reasonable to consider a PPI or H2 blocker for any patient starting high-dose prednisone.^13,16 Patients with a history of type 2 diabetes may require escalation of their antihyperglycemic regimens, sometimes necessitating the addition or escalation of an insulin regimen.^13,15-17 Patients with baseline sleep difficulty, or who manifest with insomnia after initiation of high-dose steroids, may require a sleep aid such as trazodone.^15,16 For patients who require extended use of prednisone 20 mg equivalent or more beyond 6 weeks, other measures such as antifungal prophylaxis with fluconazole or bone prophylaxis with calcium and vitamin D supplementation should be considered.^13,16,17

Rare irAEs

Common irAEs include rash (dermatitis), colitis, pneumonitis, hepatitis, and thyroiditis.⁴ However, any organ or tissue in the body can become inflamed by the immune system, and some irAEs occur only rarely. Nonspecific symptoms make rare irAEs even more challenging to identify and treat promptly.²⁵ For example, immune-related myocarditis is a rare irAE with nearly 40% to 50% risk of mortality, which can occur within the first month after starting ICI therapy and may present with nonspecific symptoms such as fatigue, muscle aches, and weakness.²⁶ Examples of additional uncommon or rare irAEs includes those that affect the eyes (uveitis), blood (hemolytic anemia, immune thrombocytopenia), muscles (myositis, myocarditis), nervous system (myasthenia gravis, Guillain-Barré syndrome, peripheral neuropathy, aseptic meningitis, encephalitis, transverse myelitis), kidneys (nephritis), and salivary glands (sicca syndrome).^13,15,25

Triplet (anti–PD-1 plus BRAF/MEK inhibition) combination therapy toxicity

Delineating the underlying cause of toxicity during triplet combination therapy with atezolizumab, vemurafenib, and cobimetinib is challenging due to overlapping symptoms and laboratory values, including joint pain, hepatotoxicity, rash, fatigue, and ocular symptoms.¹¹ For toxicity workup when the causative agent is unknown, holding treatment is appropriate. Persistent or worsening toxicity after withholding of the BRAF and MEK inhibitors would suggest an irAE is the more likely culprit. In contrast, an improvement after withholding the BRAF and MEK inhibitors would suggest that BRAF and MEK inhibition may be the underlying cause; dose reduction upon treatment resumption may be advisable depending on the toxicity, per label guidance.^27,28

Pharmacist Considerations for Optimizing Patient Outcomes

Role of the Pharmacist

Pharmacists and pharmacy technicians serve as advocates for ICI efficacy by facilitating access to first-line ICI therapeutics through formulary decision-making and financial assistance programs. As the medication experts in many varied health care settings, pharmacists must also be aware of the potential for irAEs to occur in patients taking ICIs and advocate for optimal management.²⁹ Pharmacists should be involved in both patient and clinician education regarding ICI mechanisms, irAE symptoms, and appropriate treatment whenever possible.⁵ A recent position statement from the International Society of Oncology Pharmacy Practitioners encourages health institutions to recognize the value of the oncology pharmacy specialty and integrate these specialists into the oncology health care team.³⁰ It has been proposed that the pharmacist is the ideal clinician to help identify, treat, monitor, and manage highly varied and complex irAEs (Table 2).⁵ Furthermore, pharmacists can assist in screening patients, which may help identify challenging patient populations for ICI therapy, including those with preexisting autoimmune disorders, organ dysfunction, solid organ transplant, baseline immunosuppressant use, poor performance status, or pregnancy.^31,32 The support of pharmacists to organize the complex, multifactorial needs of irAE management across disciplines may help improve toxicity management outcomes.

Summary

Management of toxicity for first-line melanoma therapeutics is challenging. Improved awareness of irAEs and toxicity from targeted therapy can begin to bridge the gaps so that patients receive prompt, diligent care. Clinicians must balance the hope of improved efficacy with ICI combination treatments with the increased risk of treatment-related toxicity. Paying close attention to the signs, symptoms, and laboratory values during treatment can help to quickly identify toxicity and guide next steps. Pharmacists can play a key role in the identification, treatment, and management of irAEs in many types of care settings.

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