The American Cancer Society estimates 236,740 new cases of lung cancer and 130,180 deaths from lung cancer in 2022, second only to prostate cancer in men and breast cancer in women.1 Lung cancer is the leading cause of cancer-related death, contributing to nearly 25% of all cancer deaths. Non–small-cell lung cancer (NSCLC) contributes to 84% of lung cancers, whereas 13% are classified as small-cell lung cancer.
For many patients with lung cancer, the use of immunotherapy, especially immune checkpoint inhibitors (ICIs), may provide an effective treatment approach.2 Both alone and combined with other therapeutic agents, ICIs have contributed to promising outcomes in patients with NSCLC, which have led to 6 ICIs receiving FDA approvals starting with nivolumab in 2015. These ICIs have been shown to act on programmed cell death protein 1 (PD-1), programmed death ligand 1 (PD-L1), or cytotoxic T-lymphocyte–associated protein 4 (CTLA-4). PD-1 inhibitors include nivolumab, pembrolizumab, and cemiplimab; PD-L1 inhibitors include atezolizumab and durvalumab. Ipilimumab is a CTLA-4 inhibitor. CTLA-4 inhibitor tremelimumab and PD-L1 inhibitor avelumab are under investigation for NSCLC treatment.
As with any medication, adverse events (AEs) have been associated with ICIs. Because ICIs function via disruption of the homeostatic mechanisms involved in regulation of immune cell function, which maintains balanced immune responses, these therapies contribute to a unique spectrum of side effects known as immune-related AEs (irAEs) in some patients,3,4 the management of which may be challenging for healthcare providers. This article reviews the most recent data on the identification, mitigation, and management of irAEs in advanced NSCLC, including expert perspectives from Aung Naing, MD, FACP, Professor in the Department of Investigational Cancer Therapeutics, and Amanda L. Brink, DNP, APRN, FNP-BC, AOCNP, an advanced practice nurse, both from the Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston.
Because patients with cancer can present with toxicity as a result of previous therapies, baseline physical examination, laboratory tests, and imaging can be used as a reference for any newly observed AE that occurs during immunotherapy.5 An immunotherapy baseline checklist should be conducted prior to ICI therapy and can be used to assist with the patient’s follow-up (Table 1).5 “In preparation to start patients on immunotherapy, we ask patients about their baseline symptoms such as cough and shortness of breath, in particular, for non–small-cell lung cancer patients,” explained Dr Brink. “This symptom assessment helps us in the future if patients have worsening of their baseline symptoms. We also ask about personal and family history of any autoimmune disorders, and any prior exposure to immunotherapy agents and how the patients tolerated those agents.”
Healthcare providers should compare new laboratory values with baseline values to enable detection of any change over time.5 “If we know that we have a patient with the cardiac risk, we will be a little more inclined to do the EKG,” said Dr Naing. “When we do the imaging, we evaluate the disease status by CT of the chest-abdomen-pelvis, or PET-CT scan. These can help us in the future if we suspect pneumonitis, so we have a baseline PET-CT scan to compare with.”
Certain populations of patients may require additional evaluations prior to initiating immunotherapy, including those with underlying autoimmune diseases or immunodeficiencies.5 “It depends on what type of autoimmune disease and how that autoimmune disease is being treated,” explained Dr Naing. “On top of that, we work very closely with the other subspecialties, and we discuss with them, ‘Is this patient a good fit to receive immunotherapy or not.’”
Data from retrospective studies suggest that ICIs are generally safe and well-tolerated in patients with NSCLC who have underlying autoimmune diseases, with 23% to 38% of patients reporting exacerbations of the autoimmune disease.3,6 Importantly, the reported AEs were manageable, with rare occurrences of permanent ICI discontinuation. In a recent analysis, 14% of patients with autoimmune diseases permanently discontinued treatment as a result of irAEs,6 which is only slightly higher than the discontinuation rates observed in clinical trials that excluded patients with autoimmune diseases (3%-8%).7-9
Populations at higher risk for developing malignancy and autoimmunity include patients with primary and secondary immunodeficiencies.10 This risk is based on the underlying type of autoimmunity, immunodeficiency, and form of cancer. Patients with human immunodeficiency virus have a 28-fold increased risk of autoimmune hemolytic anemia and a 77-fold higher risk of developing non-Hodgkin lymphoma. Compared with the general population of the same age and sex, organ transplant recipients have a 2- to 3-fold higher risk for malignancy.10 Several mechanisms may contribute to an increased risk of autoimmune reactions, including central tolerance failure, immune-mediated clearance defects, or dysregulated innate immune responses.
There is a known risk of immunotherapy in patients with cancer; however, additional concerns have been brought forward related to the efficacy and safety of ICIs in patients with immunodeficiencies.10 Currently, there are limited available data on the use of immunotherapy in immunocompromised patients with cancer. Many clinical trials exclude immunocompromised patients, and of those who receive immunotherapy, many are underdosed, undertreated, or experience premature treatment interruption based on a concern of side effects. “There are some clinical trials specifically looking for patients with a history of autoimmune disease. However, I do not treat patients that require immunosuppressive therapy with immunotherapy,” noted Dr Naing.
Several mechanisms have been proposed to explain the development of irAEs associated with the use of ICIs, including a model involving compromise in immunogenic tolerance and enhancement of the progression of preexisting autoimmunity.11 Another model focuses on host antigen release from tumor cells undergoing cytotoxic attack. In a related mechanism, self-antigens are released when nontransformed tissues in and around the tumor are damaged via innate and adaptive immune cells. Inflammatory mediator release from immune cells may also contribute to immune-mediated tissue damage. Off-target effects of ICIs on nonhematopoietic cells with the targeted immune checkpoint ligand may contribute to irAEs. Finally, enrichment of certain species of gut microbiome may either protect against or enhance the risk for irAEs.
Skin toxicities are often common irAEs with the earliest onset.3 Rash and pruritus are the most common irAEs associated with ICI treatment.12,13 Up to 68% and 40% of patients receiving anti–CTLA-4 antibodies and anti–PD-1/PD-L1 antibodies, respectively, experience skin toxicities of any grade.14 The incidence of rash has been reported in 11% of patients treated with nivolumab and pembrolizumab and 19% of those treated with ipilimumab in clinical trials.12 Although the incidence of rash is lower with anti–PD-1 antibodies, the incidence of grade 3/4 AEs is similar compared with anti–CTLA-4 antibodies (2.6% and 2.4%, respectively).
“The most frequent irAE that we see for both NSCLC patients and other patients that we treat on immunotherapy is dermatitis,” Dr Brink explained. “First and foremost, patients typically will have a maculopapular rash, or colitis with diarrhea as the main symptom, hepatitis, thyroid function abnormalities, and then pneumonitis after that.”
Colitis and diarrhea contribute to most ICI-related gastrointestinal toxicities, and it may be that this is a class effect associated with the use of CTLA-4 inhibitors alone or in combination with PD-1/PD-L1 inhibitors.15 The incidence of colitis among patients receiving combination ICI therapy is 20% to 32%, including grade 3/4 severity in 11% of cases.14 The incidence of hepatotoxicity is higher with CTLA-4 inhibitors than PD-1/PD-L1 inhibitors and occurs in approximately 20% of patients treated with combination strategies. Common musculoskeletal toxicities associated with ICI use include inflammatory arthritis, myalgia/myositis, giant-cell arteritis, and polymyalgia rheumatica.
“It depends on the agent,” explained Dr Naing. “For example, if you are treating a patient with the anti–CTLA-4 antibody ipilimumab, you see more colitis. If you are treating a patient with an anti–PD-1 inhibitor like pembrolizumab or nivolumab, you see pneumonitis more frequently.”
Considering pulmonary toxicities, pneumonitis occurs predominantly in patients receiving anti–PD-1/PD-L1 monotherapy or combination therapy with multiple ICIs.15 The incidence of pneumonitis is low, but there is a high risk of poor clinical outcomes if it is not treated early. The primary symptoms of pneumonitis can include dyspnea and cough, with less frequent occurrences of fever and chest pain, all of which mimic other common conditions. Pneumonitis is the most commonly reported pulmonary irAE. Although some irAEs are more common with CTLA-4 inhibitors than with PD-1 or PD-L1 inhibitors, pneumonitis is more common in patients treated with PD-1 inhibitors, such as nivolumab or pembrolizumab, though the mechanism for this difference is unclear.16 “The thing that we have the most difficulty with for NSCLC patients is pneumonitis, which can be challenging to diagnose and to treat, especially in these patients because they often have impaired lung function at baseline,” Dr Brink explained.
Combination ICI therapy has been associated with the highest incidence of endocrinopathy.14 Because they can impact any part of the endocrine system, including the thyroid, pituitary, adrenals, and pancreas, endocrine irAEs are complex.15 The most common endocrine-related AEs associated with ICI therapy are hyperthyroidism, hypothyroidism, and thyroiditis.14 Hypophysitis occurs mainly in patients treated with CTLA-4 inhibitors or combination ICIs, whereas dysthyroidism is predominant with PD-1/PD-L1 inhibitor use.3
Among patients with NSCLC, fatigue is another common symptom, reported in up to 40% of patients treated with anti–CTLA-4 antibodies and 16% to 24% of patients receiving anti–PD-1/PD-L1 antibodies.14 Severe infusion-related reactions are also commonly reported with CTLA-4 inhibitors, whereas mild reactions have been reported in up to 25% of patients receiving anti–PD-1/PD-L1 inhibitors. Common musculoskeletal toxicities associated with ICI use include inflammatory arthritis, myalgia/myositis, giant-cell arteritis, and polymyalgia rheumatica.
In a study of 623 patients with NSCLC who received anti–PD-1 or anti–PD-L1 monotherapy, the most common irAEs included pneumonitis (12%), thyroiditis (10%), and dermatitis (9%).17 Among those with multisystem irAEs, the most common first irAEs observed were thyroiditis (38%) and dermatitis (22%), and the most common multisystem irAE pattern observed was pneumonitis thyroiditis in 14% of the patients.17 Among patients receiving ICI combination therapy, the most common irAEs were pneumonitis (9%), colitis/diarrhea (5%), and dermatitis (4%). Among 199 patients with complete time-to-onset data, the median time to the first irAE was 1.6 months after ICI initiation, with the second irAE occurring at a median of 3.25 months.
The incidence and kinetics of irAEs are class-dependent (Figure 1).3,18 The median time to onset of irAEs ranges from 4.2 to 20 weeks after initiation of treatment with ICIs.19 The majority of grade ≥3 irAEs occur within 8 to 12 weeks of treatment initiation of anti–CTLA-4 inhibitors, with the most common being diarrhea and/or colitis (occurring in ~20% of patients), and skin rash usually having the earliest onset (Figure 1).3 Colitis associated with ipilimumab therapy typically occurs between 4 and 8 weeks after the first infusion and is not generally observed >2 months after the final dose.
Pneumonitis is less frequent in patients receiving anti–CTLA-4 antibodies compared with patients receiving anti–PD-1/PD-L1 antibodies or combination therapy.3 Among patients receiving any ICIs, the median time to onset has been reported to be 2.5 months, and among patients receiving anti–PD-1 antibodies, onset has been observed as early as 9 days after the first infusion.
Hypophysitis associated with ICIs typically develops between 6 and 14 weeks of treatment.3 The median time to new onset or exacerbation of preexisting thyroid function abnormalities is approximately 4 to 7 weeks after treatment onset in ICI-treated patients. Onset of ICI-associated hepatitis is variable, emerging between 1 and 14 weeks of treatment. Neurologic irAEs occur between 1 and 7 weeks of treatment initiation in patients receiving ipilimumab, after 4.5 weeks in patients receiving anti–PD-1 antibodies, and after 2 weeks in patients receiving ICI combinations.3 Development of acute interstitial nephritis may occur after 2 to 12 weeks in patients receiving ipilimumab, and after 3 to 12 months in patients receiving anti–PD-1 and/or anti–PD-L1 antibodies. Rheumatic irAEs have a wide range of onset, with some events described more than 50 weeks after initiation of ICI therapy.3
“We use the ASCO guidelines,” Dr Brink explained. “So, in general, for grade 1 toxicities, typically we can continue treatment, but there are some exceptions for patients that have neurologic, hematologic, or cardiac toxicities. For grade 2 toxicities, we may consider holding treatment, and then resuming when symptoms or lab values improve to normal or to grade 1, or we may consider low-dose steroids like 0.5 to 1 mg/kg per day of prednisone for grade 2.”
For grade 1, asymptomatic or minimally symptomatic irAEs, or where findings are confined to a radiographic or laboratory change, supportive care and/or localized therapy on an outpatient basis, continuation of the ICI at full dose, and increased frequency of monitoring are recommended.5,15,20 Alternative management considerations are needed for patients experiencing certain neurologic, hematologic, or cardiac toxicities (such as myocarditis, Guillain-Barré syndrome, and aplastic anemia). For myocarditis, all grades result in the need for workup and intervention by a cardiologist due to the potential for cardiac compromise.21 ICIs should be held for grade 1 toxicity with elevated troponin, but may be restarted once normalized or if not thought to be related to ICI treatment. Cardiac symptoms should be managed based on current guidelines and guidance from cardiology specialists. For Guillain-Barré syndrome, there are no grade 1 toxicities; grade 2 toxicity requires discontinuation of ICIs and a neurology consultation. Further management and inpatient treatment may be required for grade 3 to 4 toxicities.21 For aplastic anemia, ICI treatment should be held for grade 1 toxicity, growth factor support should be provided, and patients should be closely followed with regular laboratory evaluations.21
“For grade 3 toxicities, we hold treatment, and then typically initiate higher-dose steroids like prednisone 1 to 2 mg/kg,” explained Dr Brink. “And it’s an important point that usually the steroids are tapered, not on a set schedule, but instead based on the patient’s response. Sometimes we’ll use other immunosuppressive biologic medications (eg, infliximab) if patients don’t have a robust enough response to the steroid therapy.”
In patients experiencing grade 3 moderate-to-severe irAE symptoms, recommended management approaches include the following: (1) delaying ICI therapy or discontinuing ICIs altogether if the toxicity risk exceeds benefit; (2) treating with oral corticosteroids (1-2 mg/kg) as an outpatient; (3) considering intravenous corticosteroids; and (4) considering treatment with immunosuppressive agents (eg, infliximab).5,15,20 Hospitalization should be considered if symptoms persist for 48 to 72 hours, with or without additional immunosuppression, if there has been no response to intravenous corticosteroids. Pneumocystis jiroveci prophylaxis should be provided per institutional guideline and clinical judgment if prednisone ≥20 mg daily is being used for >1 month. Calcium and vitamin D should be supplemented, and prophylaxis provided for lower gastrointestinal bleed if risk factors are present.15 Corticosteroids may be tapered over at least 4 to 6 weeks once the irAE reaches grade 1 or less.
“For grade 4, typically we discontinue the checkpoint inhibitor; however, there are some exceptions,” noted Dr Naing. “For example, if someone has an endocrinopathy, where someone has a problem with the thyroid, we know that the thyroid has been damaged already, and if we are providing thyroid hormone replacement, we are able to continue checkpoint inhibitor therapy.”
Referral to an organ specialist or internist may be needed based on the treating clinician’s comfort and knowledge about drug-mediated toxicities.5 Oncologists should determine a local organ specialist team based on expertise, availability, and responsiveness. It is crucial for oncologists to initiate support from organ specialists as soon as possible once the diagnosis and treatment of irAEs become difficult. Although some toxicities (eg, asymptomatic hypothyroidism or grade 1-2 rash) can be managed easily, most other toxicities, especially if grade >1, often require specialist expertise for appropriate long-term monitoring and optimal patient management.
The American Society of Clinical Oncology recently updated their clinical practice guideline that includes recommendations to be followed irrespective of affected organs.21 Key recommendations include the following:
With the increasing use of ICIs for treatment of cancer, there is a need to further develop effective management strategies for irAEs, both in community settings and in cancer centers.22 To date, several strategies have been proposed (Table 2), including providing patient education; harmonizing irAE management guidelines; standardizing reporting of irAEs; optimizing the choice of immunosuppressive agents; conducting preclinical, clinical, and translational studies to better understand irAEs; incorporating diagnostic tools to personalize irAE management using wireless technology and digital health; providing a platform to hear the patient’s voice; and sharing evolving data to improve the management of irAEs.
Enhanced awareness and conversations regarding expectations during treatment have been shown to encourage coping skills and improve patient resiliency, contributing to treatment adherence and improved outcomes23; however, patients and caregivers have reported difficulty obtaining information about immunotherapy and side-effect management.24 Guidelines for irAE management can be refined by including perspectives of emergency department physicians, surgeons and anesthesiologists, primary care physicians, nurses, and patient advocates.22 The Common Terminology Criteria for Adverse Events (CTCAE), which uses uniform terminology and a grading system for severity, is usually used for standardized AE reporting.25 However, there is growing evidence that the CTCAE is not adequate in capturing the full range of irAEs associated with the use of ICIs, which can potentially lead to misinterpretation of clinical observations.22,26 The Society for Immunotherapy of Cancer CTCAE Task Force is now adding more terms to the CTCAE for standardized capture of all irAEs.
“We discuss possible irAEs with patients, I would say, early and often,” noted Dr Brink. “We discuss it with patients during our initial consultation. We let patients know which irAEs may be most common with a particular treatment regimen, and when those certain irAEs may occur, making sure that patients know that these side effects can occur at any time during the treatment process, even after they’ve been tolerating treatment for an extended period of time. We revisit the discussion when patients come back for cycle 1 to remind patients what to expect or what they may anticipate having in the future. And then we revisit it again as needed if patients have lab abnormalities or any other symptoms that may indicate an early irAE.”
To optimize the choice of immunosuppressive agents, with minimization of steroid use, additional prospective studies are needed with goals of shortening the duration of irAEs and enabling rechallenge after irAE symptom resolution, without dampening the immune response elicited by ICIs.22 Thus, additional preclinical, translational, and clinical studies are needed to improve the understanding of irAEs.
Self-reporting of symptoms using smartphone-based apps may allow healthcare providers to analyze data in real time and improve management of acute events.22 Applications and wearable technology may expand to allow patient monitoring and the identification of emergent irAEs to facilitate earlier treatment.22 Patient self-reporting data are also key to inform clinicians of patient tolerance and to improve patient-centered care. Finally, sharing of data can promote advancement of the field and easy access to clinical trial results and information on irAE development, management, and patient outcomes.
“While you are taking care of the patient, you want to take care of them comprehensively, so you always ask the questions, ‘What is your biggest fear? What are you worried about? What are you concerned about? Are you scared of this?’ and then make sure that you refer those patients to the specialists who can help them,” explained Dr Naing. “We have a very good partnership with the supportive care group.”
“Something that we have to talk with our patients about is how they cope with emotions that they have, particularly if patients are drinking alcohol, then that can have effects on their treatment, and can also have effects on their blood work, that can sometimes influence our treatment,” Dr Brink explained. “So, we always talk with patients about that as well.”
Patients and their caregivers should be informed that most irAEs are manageable if detected early and treated promptly.5,21 Therefore, patients should be educated about signs of organ inflammation that require prompt referral, including digestive (diarrhea, blood or mucus in the stool, severe abdominal pain), endocrine (fatigue, weight loss, nausea, vomiting, thirst or appetite increase, polyuria), skin (extensive rash, severe pruritus), respiratory (shortness of breath, coughing), and neurologic (headache, confusion, muscle weakness, numbness) symptoms; arthralgia or swelling joints; myalgia; unexplained fever; hemorrhagic syndrome; and severe loss of vision in 1 or both eyes. Patients and caregivers should also receive timely and up-to-date education about immunotherapies, their mechanism of action, and the clinical profile of possible irAEs prior to initiating therapy and throughout treatment and survivorship.
“We tell them how these drugs are working,” noted Dr Naing. “We explain it to them. We tell them, ‘This is the way that it works, it can also bring the potential side effects and it could attack any part of the body, and then you might have an adverse event.’ If they have a problem, we assure them that they can reach out to us, and then we communicate—we call them back.”
Although irAEs may pose a challenge in clinical practice, a positive association between some irAEs and treatment outcomes has been reported. A retrospective review of the medical records of 290 patients with advanced cancer, including NSCLC, treated on an immunotherapy-based clinical trial at The University of Texas MD Anderson Cancer Center showed that patients with grade ≥3 irAEs had an improved overall response rate (25% vs 6%; P = .039) and longer median time to progression (30 weeks vs 10 weeks; P = .004) when compared with those without grade ≥3 irAEs, suggesting that the occurrence of irAEs may signal a potential clinical benefit to the patient from immunotherapy (Figure 2).27 Results from multiple clinical studies indicate that patients with advanced cancer who develop irAEs after treatment with an ICI may demonstrate a survival benefit in response to treatment.28-30 Indeed, a systematic review and meta-analysis revealed that patients with lung cancer who developed irAEs had improved objective response rates (41.49% vs 18.01%) and prolonged weighted average progression-free survival (8.97 vs 3.06 months) and overall survival (19.07 vs 7.45 months) compared with those without irAEs.31 “Around 2018, our group reported patients who had some irAEs and had enhanced benefit from the treatment,” explained Dr Naing. “However, not all irAEs are associated with a positive clinical outcome.”
For patients receiving immunotherapy, disruption of homeostatic mechanisms contributes to a unique side-effect spectrum—irAEs. “I would just emphasize that we don’t often have patients that choose not to pursue immunotherapy treatment because of potential side effects, but every once in a while, we will,” noted Dr Brink. “But I just want patients and other providers to know that these side effects are identifiable, and for the most part manageable.” Although most irAEs resolve with corticosteroid treatment, irAEs can become life-threatening if left untreated. To optimize the prevention and management of irAEs, the need for education of patients and caregivers regarding irAE management, awareness of management guidelines, standardized irAE reporting, incorporation of diagnostic tools, and the use of digital health has been suggested. “There is research focused on who will get more side effects and who will not,” said Dr Naing. “The area is evolving with a large amount of research efforts. At the end of the day, the communication between the physician and the treating group and the patient is really important. Communication is the most important thing.”
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