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Year : 2019  |  Volume : 56  |  Issue : 5  |  Page : 10--22

Adverse effects of immuno-oncology drugs—Awareness, diagnosis, and management: A literature review of immune-mediated adverse events

Shyam Aggarwal 
 Department of Medical Oncology, Sir Ganga Ram Hospital, New Delhi, India

Correspondence Address:
Shyam Aggarwal
Department of Medical Oncology, Sir Ganga Ram Hospital, New Delhi
India

Abstract

Immuno-oncology (IO) approaches such as cytokine therapy, immune-checkpoint blockers (ICBs), cancer vaccines, and cell-based therapies have revolutionized cancer treatment. ICBs provide better response-to-toxicity profile among various IO approaches; however, they can cause dysregulation of host immune system resulting in immune-mediated adverse events (imAEs). The skin and gastrointestinal system are most commonly affected. Although reversible, imAEs may cause life-threatening conditions if untreated. Risk assessment and appropriate patient selection before treatment initiation may prevent most imAEs. Key factors in effectively managing imAEs include baseline clinical evaluation, appropriate diagnostic tests, severity grading, timely decision on discontinuation or reintroduction of ICB treatment, and intervention with immunosuppressive and/or immunomodulatory agents. Patient and healthcare provider awareness is critical for identifying and managing lower grade imAEs. Immediate reporting is important for successfully managing and preventing or worsening of imAEs. Pretreatment sensitization of patients should address barriers to reporting such as fear of ICB discontinuation, ignorance of symptoms, financial constraints, and self-medication. Physicians should rely on clinical presentation and diagnostic work-up (including imaging) to accurately identify, characterize, and differentiate imAEs from metastasis. Treatment-related new symptoms should be dealt with a high level of suspicion. Corticosteroids are initiated if symptoms do not resolve within a week from onset and tapered over a month to avoid rebound of symptoms. ICB therapy should be permanently discontinued in most cases of grade 3-4 imAEs. A multidisciplinary approach involving oncologists, oncosurgeons, primary care physicians, and nurses is necessary in effectively managing imAEs and facilitating better clinical outcomes.



How to cite this article:
Aggarwal S. Adverse effects of immuno-oncology drugs—Awareness, diagnosis, and management: A literature review of immune-mediated adverse events.Indian J Cancer 2019;56:10-22


How to cite this URL:
Aggarwal S. Adverse effects of immuno-oncology drugs—Awareness, diagnosis, and management: A literature review of immune-mediated adverse events. Indian J Cancer [serial online] 2019 [cited 2019 Dec 12 ];56:10-22
Available from: http://www.indianjcancer.com/text.asp?2019/56/5/10/272012


Full Text



 Introduction



Cancer is a leading cause of mortality with an estimated 18.1 million new cases and 9.6 million deaths expected globally in 2018.[1] Several cancers have poor prognosis and/or unacceptable treatment-associated toxicities driving the search for more effective therapies.[2] Immunotherapy, particularly, immune checkpoint blockers (ICBs) have revolutionized the treatment paradigm for various cancers; however, ICBs are associated with unique and sometimes life-threating immune-mediated adverse events (imAEs). This review summarizes the safety profile of ICBs outlining the clinical presentation, diagnosis, and management of imAEs in multiple cancer types.

 Mechanism and Benefits of ICBS



The list of immune-oncology (IO) approaches that have been investigated include cytokines, ICBs, cancer vaccines, and cell-based therapies.[3] IO drugs target immune surveillance mechanisms to resurrect the patient's suppressed immune system and launch a sustained attack against tumors resulting in cancer eradication.[4]

To prevent autoimmunity, the immune system employs major regulations and checkpoints acting as brakes on immune responses. These checkpoints include receptors expressed on T cells such as cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) receptor; receptors expressed on regulatory T cells (Tregs) such as programmed cell death-1 (PD-1) receptor; and PD-1 ligands (PD-L1 and PD-L2) expressed on effector or tumor cells. ICBs are monoclonal antibodies (mAbs) that inhibit these receptors or ligands and release the brakes on immune responses and promote efficient tumoricidal activity.[5] The mechanism of action for ICBs signifies a true shift in oncology, in that, rather than being directed at destroying tumor cells, they target immunosuppression induced by cancer.[6] Six ICBs, that is, ipilimumab (CTLA-4 inhibitor); nivolumab and pembrolizumab (PD-1 receptor inhibitors); and atezolizumab, durvalumab, and avelumab (PD-L1 inhibitors) have been approved by the Food and Drug Administration for various solid tumors in the last decade.

ICBs target specific host immune cells or malignant cells while sparing normal healthy tissues from damage often seen with conventional therapies like radiotherapy (RT) and chemotherapy.[6] Clinical trials have shown promising efficacy in terms of durable, long-term objective responses with ICBs in major cancer types.[7] IO therapies in some indications have “all comer” labels; however, there are quite a few instances where they are restricted to specific populations [e.g., 50% PD-L1 expression for pembrolizumab in first-line metastatic non-small cell lung carcinoma (NSCLC)].[8] With multiple immune checkpoint targets, potential exists to further enhance efficacy through synergistic combination of ICBs.[9] Furthermore, conventional RT and chemotherapy cause immune sensitization and several studies suggest that a combination of ICBs with these conventional therapies may further enhance the antitumor response.[10] Thus, ICBs provide a beneficial tumor response-to-toxicity profile because of their distinct mechanisms that restore tumor-related immune deficiency selectively in the tumor microenvironment. However, because of their novel mechanism, ICBs can dysregulate the host immune system and elicit typical toxicities termed as imAEs; these imAEs mimic other autoimmune and inflammatory conditions and differ from typical adverse events (AEs) seen with conventional cancer therapies.[11]

 Safety Profile of ICBs



AEs associated with ICBs occur because of the broad and, sometimes, nonspecific activation of immunity. ImAEs can affect almost all organ systems and can occur long after treatment initiation due to “immune memory;” in some cases, they occur after treatment discontinuation.[12] Most imAEs are mild or moderate and reversible; rare but severe imAEs are manageable with timely diagnosis and intervention.[7]

The pathophysiology of imAEs is likely due to multiple factors. Moreover, the imAE profile varies considerably between ICBs, based on their mechanism of action, cancer type, or other nonspecific actions.[13] For instance, the frequency of colitis and hypophysitis is higher with CTLA-4 inhibitors compared with placebo, PD-1/PD-L1 inhibitors, or gp100 (a vaccine), in melanoma patients.[13],[14],[15] However, the frequency thyroiditis is higher for PD-1/PD-L1 inhibitor therapy compared with CTLA-4 inhibitor monotherapy or CTLA-4 inhibitor and PD-1/PD-L1 combination therapy in melanoma and NSCLC patients.[13],[16] CTLA-4 expression in a normal pituitary gland and increased cytokine IL-17 may be responsible for hypophysitis and colitis, respectively.[15] Similarly, anti-thyroid antibodies in humoral immune modulation may be responsible for thyroid-related events with PD-1/PD-L1 inhibitors.[16] Vitiligo is observed in melanoma patients treated with ICBs, suggesting cross-reactivity between T cells directed against tumor and T cells directed against normal tissue antigens.[13]

Overview of imAEs

The six most frequently affected organ systems by imAEs are dermatologic, gastrointestinal, endocrine, hepatic, musculoskeletal, and respiratory systems. Rare but clinically important manifestations of imAEs (occurring in ≤1% patients) involve the renal, pancreatic, ocular, neurological, cardiovascular, blood, and lymphatic systems.[12] The most common all-grade imAEs reported in clinical trials with CTLA-4 inhibitors include pruritus, rash, diarrhea, colitis, increased aspartate transaminase (AST) and alanine transaminase (ALT), and hypophysitis; with PD-1 inhibitors include fatigue, increased AST and ALT, hepatitis, vitiligo, dysthyroidism, and pneumonitis; and with PD-L1 inhibitors include pruritus, rash, fatigue, diarrhea, and pneumonitis.[7],[17] A recent systematic review of 28 studies with 3,418 patients of all cancer types reported the most common any grade imAEs (>5% patients) as follows: CTLA-4 inhibitor-pruritus, rash, diarrhea, colitis, and hypophysitis; PD-1 inhibitors-diarrhea, pruritus, rash, and hypothyroidism; and PD-L1 inhibitors-pruritus and rash.[18] Rare neurological imAEs such as polyneuropathy, facial nerve palsy, demyelination, myasthenia gravis, Guillain-Barre' syndrome, posterior reversible leukoencephalopathy, transverse myelitis, enteric neuropathy, encephalitis, and aseptic meningitis have been reported with CTLA-4 (3.8%) and PD-1 inhibitors (6.1%). Rare cardiac imAEs such as myocarditis, pericarditis, arrhythmias, cardiomyopathy, and impaired ventricular function have occurred in <1% of patients treated with CTLA-4 and PD-1 inhibitors. Rare renal imAEs such as nephritis, renal failure, or acute kidney injury have been reported in ≤1% of patients treated with any ICBs. Rare ophthalmic imAEs such as peripheral ulcerative keratitis, uveitis and Vogt-Koyanagi-Harada syndrome, orbital inflammation, and retinal and choroidal disease have been reported in <1% of patients treated with CTLA-4 and PD-1 inhibitors. Allograft rejection with PD-1 inhibitors and hematological imAEs such as lethal aplastic anemia, autoimmune hemolytic anemia, and immune thrombocytopenic purpura with ICBs have also been reported.[19],[20]

Median time to onset of imAEs varies according to the type of organ systems involved [Table 1]. Early occurring imAEs (median time to onset <2 months) include dermatologic (5 weeks), gastrointestinal (7.3 weeks), and hepatic (7.7 weeks) systems, whereas late occurring imAEs include pulmonary (8.9 weeks), endocrine (10.4 weeks), and renal (15.1 weeks) systems; however, owing to “immune memory” immune toxicities can develop at any time: at the beginning, during treatment, and after cessation of immunotherapy.[7] The time to onset of imAEs with PD-1 or PD-L1 inhibitors is less clear, but it occurs slightly later than anti-CTLA-4 toxicity.[12]{Table 1}

Global incidence of imAEs

A meta-analysis of 46 studies including 12,808 cancer patients treated with approved PD1/PD-L1 inhibitors reported a global incidence of any grade imAEs of 26.8% and of severe grade (grade ≥3) imAEs of 6.1%, with lower incidence of severe imAEs for pembrolizumab (5.1%) and atezolizumab (5.3%) than for nivolumab (8.2%).[21]

The PACIFIC trial that used durvalumab in stage III NSCLC patients reported an incidence of any grade imAEs, regardless of cause, of 24.2% in the durvalumab group and 8.1% of patients in the placebo group. Grade 3 or 4 imAEs had incidence of 3.6% in the durvalumab group and 2.4% in the placebo group, respectively.[22]

Information is scarce about the nature and incidence of imAEs in Indian patients. A prospective study of 62 Indian patients with advanced cancer treated with nivolumab or pembrolizumab reported the most frequent any grade AE of fatigue (16.6%) and grade 2-3 AEs of transaminitis (3%) and pneumonitis (3%).[23] A retrospective review of 15 Indian patients with metastatic renal cell carcinoma (RCC) treated with nivolumab reported grade 1 fatigue (33.3%) and skin rash (20%) as the most frequent AEs.[24]

Incidence by grade

All-grade imAEs (all causality) occur in ~90% patients treated with ipilimumab and in ~70% patients treated with any anti-PD-1/anti-PD-L1 antibody.[12] Another review reported any grade imAEs with an incidence of 55-65% for CTLA-4 inhibitors, 30-45% for PD-1 inhibitors, and 16-23% for PD-L1 inhibitors.[17] A meta-analysis reported an overall incidence of <75% with ipilimumab and ≤30% in phase 3 trials of anti-PD-1/PD-L1 agents.[25] El-Osta et al. reported an overall incidence of 53.8%, 26.5%, and 17.1% with CTLA-4, PD-1, and PD-L1 inhibitors, respectively.[18]

Several studies have reported incidences of grade 3-4 imAEs in the range of 10-42%, 3-20%, and 1-9% with CTLA-4, PD-1, and PD-L1 inhibitors, respectively.[12],[17],[18]

Incidence by fatality

ICB treatment-related deaths have been reported in up to 2% of patients in clinical trials.[19] A meta-analysis and systematic review of imAEs in cancer trials reported a total of 31 deaths due to imAEs, of which 21 deaths (68%) were associated with CTLA-4 inhibitors and nine deaths (29%) with PD-1 inhibitors in solid malignancies mainly melanoma (40%).[18] Two (1.0%) deaths (1 each due to pneumonitis and hepatitis) occurred in the durvalumab group in the advanced urothelial carcinoma cohort in study 1,108; four (0.8%) pneumonitis-related deaths occurred in durvalumab group compared with 3 (1.3%) deaths in the placebo group in the PACIFIC trial.[22],[27] A meta-analysis of 112 trials involving 19,217 patients showed imAE-related fatality rates of 1.08% (anti-CTLA-4), 0.36% (anti-PD-1), and 0.38% (anti-PD-L1).[28] A review of the World Health Organization (Vigilyze) database showed that 70% of CTLA-4 inhibitorrelated fatalities were due to colitis [135 (70%)], whereas anti-PD-1/PD-L1-related fatalities were often from pneumonitis [333 (35%)]), hepatitis [115 (22%)], and neurotoxic effects [50 (15%)].[28] A systematic review of seven academic centers with 3,545 ICB-treated patients revealed fatality rates of 0.6% with ICBs; cardiac and neurologic events accounted for ~43% of the fatality rates.[28]

Incidence by dose

In advance melanoma, the incidence of imAEs with ipilimumab increases as the dose increases. All-grade, any causality imAEs varied from 61% (at 3 mg/kg) to 79% at (10 mg/kg).[25] The rate of grade 3-4 drug-related serious imAEs increased from 5% to 18% when the dose was increased from 3 to 10 mg/kg; the rate was 0% at 0.3 mg/kg, with no treatment-related deaths.[29] Wang et al. showed that patients treated with 3 mg/kg ipilimumab had fewer fatal AEs compared with patients treated with 10 mg/kg ipilimumab (0.56% vs. 1.29%; χ2 = 4.9; P = 0.03).[30] By contrast, the incidence of imAEs with anti-PD-1/PD-L1 agents does not seem dose related in patients with melanoma, NSCLC, or RCC.[12]

Incidence of imAEs in ICB combination therapy by grade and fatality

A meta-analysis of 11 randomized control trials involving 5,307 patients treated with an ICB combination (CTLA-4 inhibitor plus PD-1 inhibitor) in all small cell lung cancer, advanced melanoma, refractory melanoma, metastatic melanoma, unresectable melanoma, advanced RCC, or NSCLC found that the pooled incidence of all-grade treatment-related imAEs ranged from 7.38% for pneumonitis to 32.7% for diarrhea. Pooled incidence of treatment-related grade 3 and 4 imAEs ranged from 1.46% for pneumonitis to 8.9% for colitis.[31] El-Osta et al. reported 61.1% incidence of any grade imAEs and 16.5% incidence of grade 3-5 imAEs in patients receiving the tremelimumab-durvalumab combination in NSCLC patients.[18]

In untreated melanoma patients, the incidence of severe imAEs (grade 3 and 4) with the ipilimumab-nivolumab combination was 55%, which is significantly higher than with either agent individually and led to treatment discontinuation in one-third of patients.[32] The CheckMate-067 trial reported 59% grade 3-4 imAEs for the ipilimumab-nivolumab combination in patients with advanced melanoma.[33] Per the meta-analysis, the pooled incidence of grade ≥3 imAEs was 54.8% in patients receiving the CTLA-4 and PD-1 combination.[18]

One death was reported with a CTLA-4PD-L1 inhibitor combination (3%), whereas no deaths were reported in patients receiving PD-L1 inhibitor monotherapy or a CTLA-4PD-1 inhibitor combination.[18] Wang et al. noted an incidence of 1.23% deaths for a CTLA-4-PD-1/PD-L1 inhibitor combination. The same study, in a review of the Vigilyze database, noted 32 (37%) colitis-related and 22 (25%) myocarditis-related deaths with the PD-1-CTLA-4 inhibitor combination.[28]

Safety profile: Comparison between ICBs

The incidence of any grade and grade 3 and 4 imAEs was significantly higher with CTLA-4 inhibitors than with anti-PD-1/PD-L1 agents (P < 0.001) in the meta-analysis by El-Ostaet al.[18] Another review reported that grade ≥3 imAEs occurred more frequently with CTLA-4 inhibitors (ipilimumab, 15-42%) than with PD-1 inhibitors (nivolumab, 8%; pembrolizumab, 5-10%,) or PD-L1 inhibitors (atezolizumab, 5-7%; durvalumab, 2%; avelumab, 1-2%).[11] Wang et al. concluded that PD-1/PD-L1 inhibitors were associated with lower fatal toxic effects rates compared with either CTLA-4 monotherapy or combination (χ2 = 58.8; P < 0.001).[28]

A meta-analysis of 23 studies containing 3,284 PD-1 inhibitor-treated patients and 2,460 PD-L1 inhibitor-treated patients found that the incidence of imAEs (16% [95% Confidence Interval [CI], 14%-17%] vs. 11% [95% CI, 10%-13%]; P = 0.07) and pneumonitis (4% [95% CI, 3%-5%] vs. 2% [95% CI, 1%-3%]; P = 0.01) was slightly increased in PD-1 inhibitor-treated patients compared with PD-L1 inhibitor-treated patients.[34] A detailed safety profile of individual ICBs is presented in [Table 1] and [Table 2].{Table 2}

Pneumonitis is a relatively uncommon but serious and potentially life-threatening imAE. Pneumonitis-related deaths have occurred in several phase I trials of ICBs. Clinical trials using CTLA-4 inhibitors as monotherapy have noted significantly less incidence of pneumonitis (<1% all-grade and grade 3), but the incidence was higher (2-6% for all-grade and ≤2% for grade 3) for PD-1 and PD-L1 inhibitors.[17]

Two systematic reviews and meta-analyses reported the incidence of all-grade pneumonitis as 1.3-5.8%, grade 3-4 pneumonitis as 0-2.6%, and pneumonitis-related death as 0-0.8% with PD-1 inhibitor monotherapy.[35],[36]

Pneumonitis was more frequent during combination therapy than monotherapy for all-grade (6.6% vs. 1.6%; P < 0.001) and grade ≥3 pneumonitis (1.5% vs. 0.2%; P = 0.001). The risk for all-grade (Odds Ratio [OR] 3.54, 95% CI: 1.52-8.23) and high-grade pneumonitis (OR 2.35, 95% CI: 0.45-12.13) was higher for the PD-1-CTLA-4 inhibitor combination than for either monotherapy alone.[35],[36] The OR for PD-1 inhibitor-associated all-grade pneumonitis was 4.59 (95% CI: 2.51-8.37; P < 0.00001) for high-grade pneumonitis was 3.83 (95% CI: 1.54-9.48; P = 0.004), and for pneumonitis-related death was 2.47 (95% CI: 0.41-14.81; P = 0.32). No significant difference was observed between nivolumab and pembrolizumab regarding the risk of pneumonitis.[36] Nishino et al. also noted that the incidence of PD-1 inhibitor-associated all-grade pneumonitis was higher for NSCLC and RCC patients (4.1% vs. 1.6%; P = 0.002) compared with melanoma patients; the incidence of grade ≥3 pneumonitis was higher only for NSCLC patients compared with melanoma patients.[35]

A meta-analysis evaluated and compared 12 trials of PD-1 inhibitor-treated and seven trials of PD-L1 inhibitor-treated patients (n = 3,232 and 1,806, respectively) for the incidence of pneumonitis. Significantly higher incidence of any grade pneumonitis was found with PD-1 inhibitor treatment (3.6%, 95% CI: 2.4-4.9%) compared with PD-L1 inhibitor treatment (1.3%, 95% CI: 0.8-1.9%; P = 0.001). PD-1 inhibitors were also associated with higher incidence of grade 3-4 pneumonitis (1.1%, 95% CI: 0.6-1.7%) compared with PD-L1 inhibitors (0.4%, 95% CI: 0-0.8%, P = 0.02).[37] A retrospective review involving 915 patients treated with PD-1 or PD-L1 inhibitors as monotherapy or in combination with an anti-CTLA-4 inhibitor found no significant difference in the incidence of pneumonitis between PD-1 and PD-L1 inhibitors (monotherapy, 4% vs. 1%; P = 0.13; combination, 10% vs. 5%; P = 0.70). However, the incidence of pneumonitis was significantly greater in patients who received combination therapy than in those who received monotherapy (10% vs. 3%; P < 0.001).[38]

Safety profile of ICBs in combination with conventional therapies

Immune-sensitizing effects of conventional RT have been long known. However, the promising synergistic efficacy with a combination of immunotherapy and RT may also be a safety concern since both RT, especially thoracic radiation, and immunotherapy, especially PD-1/PD-L1 inhibitors, cause pneumonitis, and their combination may increase the risk and/or severity of pneumonitis.[10] A retrospective analysis of 53 advanced melanoma patients receiving extracranial and/or intracranial RT concurrently with an anti-PD1 antibody demonstrated no excess toxicities with the combination of immunotherapy and extracranial RT; however, neurologic AEs, such as severe radiation necrosis, acute neurocognitive decline, and cerebral edema, were seen with the intracranial RT and immunotherapy combination.[39] Ahmed et al. noted severe pneumonitis with concurrent ICBs (anti-PD-1/PD-L1) and thoracic radiation.[40] Secondary analysis of the KEYNOTE-001 study revealed that pulmonary toxicities were more frequent in pembrolizumab-treated patients who had received previous thoracic RT (63%) versus those who had not.[41] A phase I/II study assessing ipilimumab with or without RT in hormone-resistant prostate cancer did not find increased toxicity with the combination therapy.[42] In patients treated with a combination of ipilimumab and stereotactic ablative radiation, no patient showed grade >1 pneumonitis.[43]

Combination with chemotherapy has also been proposed for improved efficacy; however, a study combining ipilimumab with dacarbazine reported a high rate of treatment discontinuations mostly because of increased levels of liver enzymes, a synergistic toxicity, as both drugs have intrinsic hepatotoxicity.[44] A open-label, phase 2, cohort study in 123 patient with advanced NSCLC evaluated the combination of PD-1 inhibitor (pembrolizumab) with chemotherapy (pemetrexed/carboplatin) as a first-line approach. The combination has shown promising outcomes with an improvement in objective response rate in the combination arm (55%) compared with chemotherapy alone (29%). The progression-free survival also increased with pembrolizumab-chemotherapy combination (13 months) compared with chemotherapy alone (8.9 months).[45]

 Diagnosis and Management of ImAEs: An Unmet Need



Although most imAEs are mild to moderate, serious, occasionally life-threatening imAEs (e.g., severe colitis, pneumonitis, encephalitis, toxic epidermal necrolysis, myocarditis, and autoimmune type I diabetes mellitus presenting as diabetic ketoacidosis) have been reported, and treatment-related deaths have been reported in up to 2% patients in clinical trials. As life-threatening imAEs are rare, and may mimic other better-known conditions, the need for instituting urgent and appropriate diagnostic criteria and management guidelines is increasing recognition in oncology and general medical communities.

Management of imAEs

A multidisciplinary guidance to recognize, report, and manage organ-specific toxicities is critical for managing imAEs in early stages. This also includes patient and healthcare provider factors.

Elements of imAE management cycle

The first step in the management cycle of imAEs is selecting right patients who are at minimum risk and will receive the maximum benefit from immunotherapy. Other key factors in effective management include clinical evaluation, appropriate diagnostic tests, severity grading, timely decision on treatment discontinuation or reintroduction (challenge-dechallenge-rechallenge), and intervention with immune suppression and/or other immunomodulatory agents.

Patient selection

A risk assessment for forecasting the development of imAEs is essential before treatment initiation with ICBs. It includes capturing the history or presence of ongoing autoimmune disorder (AD), family history of AD of digestive (Crohn's disease, ulcerative colitis, celiac disease), skin (psoriasis), rheumatic (spondyloarthrtitis, rheumatoid arthritis, lupus), endocrine (diabetes, thyroiditis), respiratory (interstitial pneumonitis, sarcoidosis), pancreatic (pancreatitis), kidney (nephritis), hematological (hemolytic anemia, immunologic thrombocytopenic purpura), neurological (myasthenia, multiple sclerosis), ocular (uveitis, scleritis, retinitis), or cardiovascular (heart failure, left ventricular systolic dysfunction, myocarditis, vasculitis) systems, and history of treatment with CTLA-4 or PD-1/PD-L1 inhibitors.[7] In a retrospective analysis of advanced melanoma patients with preexisting ADs treated with ipilimumab, grade 3 to 5 imAEs occurred in 33% of patients and exacerbations of autoimmune condition necessitating systemic treatment was observed in 27% of patients. However, all imAEs were readily manageable with standard therapies when started in a timely fashion.[46] Similarly, two retrospective analyses of patients with ADs showed that patients that have had imAEs on ipilimumab are at an increased risk of developing imAEs following anti-PD-1 treatment and vice versa. The authors concluded that patients with active AD at immunotherapy initiation have 60% chance of flare in their symptoms.[47],[48] Use of ICBs in patients with immunocompromised status could be a concern. However, PD-1/PD-L1 inhibitors produced good clinical response in patients (n = 42) with human immunodeficiency syndrome, hepatitis B and C, and solid organ transplantation. No patient had immune reconstitution syndrome or immune-related hepatitis except for one patient who developed colitis.[49] Immunosenescence in elderly patients do not seem to play a major role for development of imAEs. No overall differences in safety were reported in elderly patients (≥65 years) compared with those below 65 years of age across the presently approved ICBs. Thus, no dose adjustment is recommended in elderly patients with mild or moderate renal impairment (i.e., ≥30 ml/min creatinine clearance) or mild hepatic impairment (i.e., total bilirubin > upper limit normal to 1.5 N).[7],[50] As per the latest FDA subset analysis, toxicity (grade 3 to 5) with anti-PD-L1 seems similar between younger and older patients with a cutoff of 65 years. However, patients over 70 years of age presented with more grade 3 to 5 AEs than patients <65 years (71.7% vs. 58.4%), along with higher AEs leading discontinuation (19.8% vs. 14.4%) and immunosuppressive needs (51.9% vs. 41.5%).[51] Older patients are known to have a higher prevalence of autoantibodies, thus ICBs may aggravate subclinical ADs. Additionally, the comorbidities may decompensate more easily such as baseline respiratory dysfunction. Furthermore, the symptomatic treatments (such as antihistamine for pruritus) or corticosteroids may expose older patients to iatrogenic events such as diabetes worsening, mental status disturbance, hypertension, and delirium. Chronic infections are known to induce expression of PD-1 and ICB administration in such patients may lead to inflammatory response. Hence, in older adults and patients with respiratory dysfunction and comorbid infections, tolerance to imAEs should be carefully monitored.[7]

Currently, there is no consensus on initiation of ICBs in patients already on corticosteroids because of the concerns related to compromised efficacy outcomes. Use of corticosteroids (≥10 mg of prednisone equivalent daily) at the start of the single-agent PD-L1 blockade was associated with poorer outcomes.[52] Thus, it is debated if clinicians should minimize the use, duration, and dose if they are contemplating the use of ICBs.

Patient education and awareness

Immediate reporting is the key to successfully managing and preventing or worsening of imAEs. Patient awareness about imAEs is a driver for immediate reporting. Generally, patients do not report symptoms because of the fear of treatment discontinuation or in case of mild symptoms, which are perceived as insignificant. Self-medication is sometimes practiced because of financial constraint to seek specialist care. Hence, patient sensitization is important in recognition and reporting of all imAEs. Strong rapport with patients and strong patient-provider relationships aid in optimum patient education. Nurses, pharmacists, and caregivers/family members should be actively involved in the patient education program. Counseling should be holistic covering financial, social, and clinical aspects. Appropriate referral and continuum of care should be assured even in case of imAEs and benefits of AE resolution should be informed to patients. [Table 3] outlines the essential components of patient education.[7],[53]{Table 3}

Diagnosis and pharmacotherapy of imAEs

A combination of clinical presentation and diagnostic workup including imaging should be used for accurately characterizing imAEs. Physicians should be cautious and sensitized about the frequency, onset time, and nature of imAEs. Misdiagnosis of an imAE as infection or disease progression may turn a potentially, easily treatable condition into a life-threatening complication.[54] Thus, imAEs should be identified, graded for severity, and well differentiated from metastatic progression of disease to alert the treating physician and guide the next appropriate strategy. A high level of suspicion is required for new symptoms that are typically treatment related.[7],[17],[19],[20],[53],[55] Severity should be graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.[56] However, imAE grading could be challenging because of arbitrary distinctions between grade 2 and 3 toxicities, for instance, the number of stools in a day, may be affected by recall bias. Grading of skin reactions may require calculation based on the body surface area; thus, CTCAE should not be the standalone criteria to grade all imAEs.[57] Clinical judgment should be used along with grading recommendations. System-specific diagnostic workup and clinical examination play a vital role in the management of these imAEs. Close monitoring of patients is important to prevent worsening of AEs. Generally, ICB therapy is discontinued in grade 3 and 4 imAEs. With early diagnosis and prompt management of these toxicities, patients may have improved treatment outcomes.[58],[59] Corticosteroids form the backbone of treatment for imAEs and are initiated if symptoms do not resolve within a week from onset. Corticosteroids are slowly tapered (over at least a month) to avoid rebound of symptoms. Gastric prophylaxis with a proton pump inhibitor or H2 blocker should be considered when initiating high-dose corticosteroids. In addition, antimicrobial prophylaxis may be required for patients prescribed high-dose corticosteroids, particularly those requiring extended therapy (>20 mg per day for >1 month).[60]

For some grade 3 (severely symptomatic or having largely affecting activities of daily living) or 4 (life-threatening) imAEs, ICBs are often permanently discontinued as dose modulation is not possible with ICBs.[59]

The general principles of imAE management recommended by the National Comprehensive Cancer Network and American Society of Clinical Oncology practice guidelines are summarized in [Table 4].[59]{Table 4}

The diagnosis and management of common imAEs according to organ systems is described in [Table 5]. Skin toxicities such as rash, pruritus, and vitiligo are frequent and the earliest to occur and can cause significant morbidity and impairment of patients' quality of life. Grade 1 skin toxicity can be managed with topical steroids; however, grade ≥2 may require cessation of ICB therapy. Systemic high-dose steroids may be effective for high-grade diarrhea. Adding immunosuppressant agents such as infliximab earlier in the course of treatment, especially for recurrent cases, may lead to better outcomes. Early implementation of computed tomography or colonoscopy may be a valuable decision-making tool regarding treatment direction.[60]{Table 5}

The radiographic findings of pneumonitis are characterized by cryptogenic organizing pneumonia and nonspecific interstitial pneumonia, acute interstitial pneumonia, acute respiratory distress syndrome, and hypersensitivity pneumonitis. Early recognition and prompt initiation of steroids is critical to improve outcome, with additional immunosuppressive agents reserved for more severe cases.[61]

Endocrine imAEs can present as nonspecific symptoms such as behavioral changes, nausea, headache, fatigue, and visual complaints. CTLA-4 blockade is associated with an increased incidence of hypophysitis and primary thyroid dysfunction. Anti-PD-1/PD-L1 agents are predominantly associated with primary thyroid dysfunction from thyroiditis.[62] Diagnosis of endocrine imAEs is based on clinical symptoms with radiographic abnormalities (pituitary enlargement with enhancement) and biochemical test results (low tropic hormones). Symptoms rapidly improve following initiation of steroids with or without thyroid hormone replacement. The role of high-dose glucocorticoids (1 mg/kg prednisone daily) is controversial in cases with suspected hypophysitis.[17]

 Conclusion



ICBs have become a standard of care for various solid tumors in the last decade. Though they have a unique safety profile, ICBs can dysregulate the host immune system and cause imAEs. The skin and gastrointestinal system are the most commonly affected. However, most imAEs can be successfully managed by selecting right patients for immunotherapy, early diagnosis, and effective communication between patient and the healthcare team. Patient and healthcare provider awareness is also critical for identifying and managing lower grade imAEs. Corticosteroids and continuous careful monitoring of symptoms is the cornerstone of managing imAEs, which may facilitate better clinical outcomes.

Acknowledgements

The authors thank AstraZeneca Pharma India Ltd for providing medical writing assistance in the development of this manuscript, in collaboration Sciformix Technologies Pvt. Ltd.

Financial support and sponsorship

Financial support to authors - Nil.

The supplement issue in which this article has been published has been sponsored by AstraZeneca Pharma India Ltd.

Conflicts of interest

There are no conflicts of interest.

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