Martin H. Voss, MD
Department of Medicine
Memorial Sloan Kettering Cancer Center
New York, New York
In this review, current information on the diagnosis, monitoring, and management of immune-related adverse reactions of anti-PD-1 antibody therapy is presented. Recent literature highlights optimal strategies for managing specific adverse events related to antibodies that target this pathway.
In only a few years immune checkpoint blockade has rapidly moved from the bench to a transformative position in cancer therapy, and by 2017, molecularly targeted immunotherapeutics directed against Programmed Death 1 (PD1), its ligand PD-L1 and Cytotoxic T-Lymphocyte-Associated protein 4 (CTLA4) have become an approved standard across a number of solid tumor malignancies, including melanoma, non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), bladder cancer and head and neck cancer.
This new generation of drugs augments cancer-directed immune response of the host by modulating the effects of regulatory surface receptors on human immune cells, so-called immune checkpoints. Through activation of cancer-antigen specific T effector cells these agents can achieve powerful anti-cancer effect and induce long-lasting treatment responses. A growing list of targets is being explored in the treatment of RCC. The PD-1 directed humanized monoclonal antibody nivolumab is FDA approved for the treatment of tyrosine kinase inhibitor (TKI) pretreated advanced RCC.
Exploiting function of immune regulators therapeutically can lead to treatment induced adverse events (AE) via immune-activation and resulting inflammatory changes in healthy tissues. Immune-related adverse events (irAEs) can affect any organ system, most commonly the skin, gastrointestinal, hepatic, and endocrine systems. Early data suggest that temporary use of immunosuppressive medications administered to suppress these side effects does not eliminate the possibility of a favorable antitumor effect. Our review of current literature offers important perspectives from which to explore the principles of immune-related adverse events recognition and management. These are increasingly important considerations beyond kidney cancer as the use of these antibodies expands. Although guidelines are emerging on the optimal management of irAEs, there is a relative scarcity of prospective trials on evaluating the best treatment approaches to manage these unique side effects.
Treatment Administration and Safety: The Pivotal Nivolumab Study
The phase 3 CheckMate 025study reported by Motzer et al1 established the benefits of nivolumab for RCC and delineated the safety profile of this agent in the largest cohort reported to date. It showed that patients with advanced RCC who had received previous antiangiogenic treatment achieved longer overall survival (OS) with nivolumab treatment than with everolimus treatment. The separation of the OS curves occurred early in the study, and there was a 5.4 months absolute difference in median OS with nivolumab than with everolimus (25.0 months vs. 19.6 months), a difference that crossed the prespecified boundary for significance at the time of the interim analysis.1
The median duration of treatment was 5.5 months (range, <0.1 to 29.6) with nivolumab and 3.7 months (range, 0.2 to 25.7) with everolimus. While the protocol did not allow dose reductions for AEs, 51% patients treated with nivolumab (51%) had at least one dose delay, and 66% patients treated with everolimus (66%) had dose delays (including interruptions). A total of 102 of the 397 patients in the everolimus group (26%) had at least one dose reduction.
The authors reported that treatment-related adverse events of any grade occurred in 79% of patients treated with nivolumab versus 88% of those having received everolimus. The most common treatment-related adverse events with nivolumab were fatigue (134 patients, 33%), nausea (57 patients, 14%), and pruritus (57 patients, 14%); among patients who received everolimus, the most common events were fatigue (134 patients, 34%), stomatitis (117 patients, 29%), and anemia (94 patients, 24%). Grade 3 or 4 treatment-related adverse events occurred in 19% and 37% of patient treated with nivolumab and everolimus, respectively; the most common grade 3 or grade 4 event was fatigue (10 patients, 2%) with nivolumab.1
Treatment-related adverse events leading to treatment discontinuation occurred in 8% of patients treated with nivolumab and in 13% of patients treated with evero-limus. No deaths from study-drug toxic effects were reported in the nivolumab group, and two deaths were reported in the everolimus group (one from septic shock and one from acute bowel ischemia).
In a subsequent presentation the authors reported on the timing of onset and resolution of select AEs, addressing the unique nature of immune-mediated toxicties.2 While the median time to onset was <12wks for hepatic, skin, GI, renal irAEs, it tended to be later in immune endocrinopathies (median 16.4 weeks) and pneumonitis (median 17.4 weeks). Notably, the range of symptom onset was wide for each organ, several patients developing irAEs >100 weeks into treatment.2 Similarly, time to resolution of AE varied greatly across patients with some subject for all reported AEs requiring >1y until reported resolution. Importantly, the primary publication for Checkmate025 provided no details on the management of irAEs beyond the general rate of dose delays and treatment discontinuations. On the dose-randomized phase II study of nivolumab in metastatic RCC the rate of giving systemic corticosteroids for the management of AEs (regardless of causality) was 15-33% across three different dosing groups.3
This can be put in context with data from patients with advanced melanoma treated on clinical trials. Weber et al. reported on over 500 patients treated with single agent nivolumab across four trials.4 The authors found that the kinetics of onset and resolution of irAEs varied with distinct patterns across different organ systems, e.g. hepatic, skin and gastrointestinal toxicity emerging earlier, renal toxicity later. While many of these lingered for extended periods of time, no new-onset treatment related AEs were documented in patients 80 weeks or longer on therapy.4 Similarly, McDermott et al. recently presented long-term outcomes for RCC patients who received nivolumab on one other original phase I and phase II monotherapy studies. No new-onset irAEs across organ domains of interest (endocrine, gastrointestinal, hepatic, pulmonary, renal, and skin) were recorded beyond 30 months from treatment start.I will also provide you with a final design for your business card, your letterhead, and a #10 envelope.5 Such data suggest that organ-specific immune toxifies can be delayed and in some patients persist for extended periods of time; however, they are unlikely to newly develop late in the course of those patients who have achieved extended benefit from therapy.
In the above cited report for nivolumab-treated melanoma patients,4 24% of subjects received systemic immunomodulatory (IM) drugs to treat adverse effects. This was not associated with an apparent loss in treatment benefit, the objective response rate being 29.8% in IM-treated patients vs. 31.8% in others. In fact, adjusting for number of doses, response rate was higher in patients who experienced treatment related AEs in this dataset.
These findings add to a growing body of safety data collected on studies performed in other diseases using this class of agents. Eigentler et al6 reviewed pooled data from pivotal trials, conducted not only in advanced RCC but also melanoma and non-small-cell lung cancer (NSCLC) as reported by the European Medicines Agency. The authors scrutinized incidence and kinetics of onset and resolution of immune-mediated ‘‘adverse events of specific interest” (AEOSI) for the two PD-1 inhibitors nivolumab and pembrolizumab. They found that the severity of AEOSI was generally mild to moderate (grade 1–2); the frequency of grade 3–4 adverse drug reactions was rarely >2% for any event term, the exception being grade 3 fatigue which was reported in >2% of patients in NSCLC and RCC. The onset of irAEs was highly variable across organ systems and underlying malignancies.
On further analysis, the authors made recommendations for the diagnosis, monitoring and management of relevant dermatological, gastrointestinal, pulmonary, endocrine, renal and hepatic toxicities, including the use of topical and systemic corticosteroids as well as non-steroidal immunosuppressants.
Most Common Types of Immune-Related Adverse Events
Dermatologic events. Dermatologic toxicity is among the most common adverse events and typically observed to have early onset; 10% of patients developed treatment-related rashes with nivolumab on CheckMate 025 with median onset at 8.4 weeks.2 With checkpoint blockade, the sign of an adverse event is most likely to emerge as a faintly erythematous rash. Reticular and maculopapular, it is generally observed on the trunk and extremities.6 The incidence of pruritus is similarly high (14% of patients on CheckMate 025), often presenting is an isolated symptom without rash.
The initial approach for dermatologic toxic effects is supportive. Topical corticosteroid creams of medium to high potency can be used for rash.7 Cold compresses, oatmeal baths, and topical corticosteroids may be helpful in relieving symptoms of pruritus in addition to systemic antihistamines such as diphenhydramine hydrochloride and hydroxyzine hydrochloride. Oral or topical doxepin hydrochloride, a tricyclic antidepressant, has also been used with some success for pruritic symptoms as has oral aprepitant.7 Anti–CTLA-4 or anti–PD-1 therapy can be continued while managing grade 1 to 2 skin toxic effects. Severe rash (grade 3 or higher) should be treated with systemic corticosteroids, usually at an equivalent dose of prednisone 1-mg/kg daily.
In such cases, treatment checkpoint inhibitor therapy should be interrupted until symptoms improve to baseline or grade 1 or lower before more treatment can be considered. In the event of severe rashes, not responsive to oral corticosteroids, clinicians should consider dermatology consultation and the addition of immunosuppressive medications such as infliximab, mycophenolate mofetil, or cyclophosphamide. Treatment with immune checkpoint inhibitors should be permanently discontinued if cutaneous symptoms fail to improve after 12 weeks of supportive management due to the risk of more severe symptoms.
Diarrhea/colitis. Diarrhea/colitis with CTLA-4 blockade is more common than with PD-1/PD-L1 blockade. The rate of grade 3/4 diarrhea in patients treated with PD-1/PD-L1 agents is very low across diseases, including RCC where treatment related diarrhea with nivolumab was reported in 12%, but only 1% grade ¾. For any patient with treatment-emergent diarrhea, clinicians should consider other etiologies that may be responsible, such as Clostridium diffıcile infection or other bacterial/viral pathogens. Patients should be counseled on the importance of maintaining oral hydration. Some clinicians fınd that the American Dietary Association’s colitis diet and antimotility agents (oral diphenoxylate HCl and atropine sulfate 4 times a day) can be helpful. For persistent mild diarrhea the use of oral budesonide can be considered (see below). For patients with symptoms refractory to these interventions, and for those with grade 3 diarrhea and negative infectious workup the use of oral or intravenous corticosteroids is required.8
When symptoms are refractory to oral corticosteroids, hospitalization for intravenous corticosteroids, hydration, and electrolyte management is required. Endoscopic workup can be reserved for situations when the diagnosis is unclear. If intravenous corticosteroids (up to 2 mg/kg methylprednisolone twice a day) do not lead to symptom resolution, infliximab (Remicade; Janssen Biotech, Horsham, PA) at a dose of 5 mg/kg, once every 2 weeks can be effective in patients with steroid-refractory colitis.9-11 The use of infliximab in this setting is based on its use in patients with inflammatory bowel diseases.12 In very rare cases, colitis can result in bowel perforation and require surgical intervention, and in some cases colostomy.
In patients with low-grade events and those with prompt response to immunosuppressive therapy, anti-PD-1 therapy may be resumed after glucocorticoid taper, which should be carried out over at least 1 month to prevent symptom rebound. In high-grade and steroid-refractory cases, therapy must be permanently discontinued.12,13 Unfortunately, there are no proven treatments to prevent the occurrence of diarrhea. In one study, prophylactic use of the matrix-release corticosteroid budesonide was not found to be helpful.14
Hepatic events. Hepatitis, as determined by elevations in aspartate aminotransferase (AST), aminotransferase (ALT) and less commonly, total bilirubin, can develop in patients treated with checkpoint blockade. Although most episodes present only as asymptomatic laboratory abnormalities, some patients have an associated fever. Rates of AST and ALT elevations with CTLA-4 blockade vary among clinical trials, but they typically have been reported in less than 10% of patients.15 In large trials of PD-1–blocking antibodies, the rates of hepatitis were lower(below 5%) and grade ¾ toxicity was even less common.11,12 On the RCC registration trial the rate of immune-related hepatitis was low (1.5%, and early in onset (median 7.3 weeks) reference.2
Radiographic fındings are not typical. In severe cases, however, fındings on CT scans may include mild hepatomegaly, periportal edema, or periportal lympha-denopathy.14 Liver biopsies have described pathologic changes that include severe panlobular hepatitis with prominent perivenular infıltrate with endothelialitis or a primary biliary pattern with mild portal mononuclear infıltrate around bile ductules.14,16
Hepatic function (transaminases and bilirubin) should be monitored before each dose of checkpoint inhibitor therapy. In the setting of rising transaminases, viral and other drug-induced causes of hepatitis should be excluded. Patients with grade 1 elevations may not need treatment-interruption, but should we closely monitored for further enzyme rise, e.g. with once-twice weekly blood draws. For patients with grade ≥2 events treatment should be interrupted, alternative etiologies should be investigated, and prompt treatment with systemic corticosteroids is advised (e.g. starting dose prednisone 1mg/kg QD or equivalent) with close monitoring of liver function, ideally daily blood draws. Typically, responses are swift Once liver function tests have improved to within grade 1, steroids can be tapered, typically over a minimum of 3-4 weeks. In rare cases, elevations in AST and ALT are steroid-refractory and 500 mg every 12 hours of mycophenolate mofetil (CellCept; Genentech, South San Francisco, CA) may be helpful. The use of antithymocyte globulin therapy also was described in a case report.8 Unlike for patients with diarrhea/colitis, infliximab should not be given to patients with hepatitis because infliximab carries a risk of hepatotoxicity.
Endocrinopathy. Immune-related adverse events that affect the pituitary, adrenal, and thyroid glands often present with nonspecifıc symptoms such as nausea, headache, and fatigue.8 Despite difficulties in determining the incidence of such AEs—due to the variable methods of assessment, diagnosis, and monitoring in each clinical trial, new data are emerging. For example, hypophysitis (pituitary inflammation) and hypothyroidism are the most common endocrinopathies and reportedly occur in up to 10% of patients treated with CTLA-4 blockade.8
The most frequent AE is thyroid dysfunction, which is seen in approximately 10% of RCC patients receiving nivolumab17; typically, a transient period of subclinical hyperthyroidism proceeds a drop in function, ultimately requiring thyroid replacement therapy. A report of lung cancer patients treated with the PD1 inhibitor pembrolizumab recently reported that many patients with new thyroid dysfunction developed new thyroid antibodies.18 Development of isolated thyroid dysfunction does not require initiation of systemic corticosteroids in addition to thyroid replacement therapy.
Immune mediated hypophysitis is the most feared endocrinopathy, in which all hormones released by the pituitary may be reduced simultaneously (adrenocortico- tropic hormone [ACTH], thyroid stimulating hormone [TSH], follicle stimulating hormone, luteinizing hormone, growth hormone, prolactin). Typically, hypo-physitis presents with headache, skin and constitutional changes, labile blood pressure, clinical hypogonadism and general malaise. Laboratory abnormalities include hyponatremia, secondary hypothyroidism, low ACTH and gonadotropins and sex hormones. A sellar MRI should be obtained which typically reveals inflammatory sequelae with enhancement and enlargement of the pituitary gland itself19,20 (low ACTH and TSH). Biochemical tests associated with hypophysitis are distinct from primary adrenal insuffıciency (low cortisol or inappropriate cortisol stimulation test; high ACTH) and primary hypothyroidism (low free T4; high TSH).
If hypophysitis is suspected, anecdotal reports suggest that a course of high-dose corticosteroids (1 mg/kg of prednisone daily) given during the acute phase can reverse the inflammatory process and prevent the need for longer-term hormone replacement.21 In almost all patients, however, longer-term supplementation of affected hormones is necessary because of secondary hypothyroidism (treated with levothyroxine) or secondary hypoadrenalism (treated with replacement doses of hydro- cortisone, typically 20 mg each morning and 10 mg each evening). Some authors have described that patients can be successfully weaned from replacement corticosteroids over time, but this is likely the exception.21 The immunologic mechanisms of hypophysitis are unknown, but they may be related to the development of humoral (antibody) immunity against the pituitary gland and subsequent complement activation.22 Urgent care for endocrinopathy is warranted when an adrenal crisis associated with dehydration, hypotension, and electrolyte imbalances such as hyperkalemia and hyponatremia occur.
In this event, patients need to be hospitalized with intravenous corticosteroids administered. Consultation with an endocrinologist, aggressive hydration, and evaluation for sepsis is critical.
For many patients the presentation is subclinical: Since routine monitoring of thyroid function tests (TSH) is frequently performed by oncologists, patients often are diagnosed with thyroid abnormalities (hyperthyroidism and hypothyroidism) as a result of checkpoint blockade. oxine).
Hypophysitis rarely has been described in published trials of PD-1 blockade for patients with advanced melanoma.9,11 and was reported in only 0.5% of patients receiving niviolumab on the RCC registration trial.17
Pneumonitis. There is a broad spectrum of less common AEs associated with checkpoint blockade; although they are rare, the toxicities may take the form of pancreatitis, hematologic AEs, neurologic events, pneumonitis, and nephritis. Pneumonitis is of particular concern because it may worsen despite immunosuppression and may result in infection and/or death. In RCC pneumonitis was reported in 4.4% of patients receiving nivolumab on the pivotal trial,17 high grade pneumonitis was only seen in 1% of patients.1
A report by Naidoo et al24 is noteworthy because it is a relatively large study and the clinical experience of patients with anti-PD-1/PD-L1 associated pneumonitis has not been comprehensively described. The study also addresses another gap in the literature because management and outcomes have not been thoroughly addressed. Naidoo described the clinical, radiologic, and pathologic features and management of 43 cases of pneumonitis from two separate institutions, Memorial Sloan Cancer Center and the Melanoma Institute of Australia. Patients received anti-PD-1/PDL1 monotherapy or a combined regimen with anti-cytotoxic T cell lymphocyte-4 mAb. Any grade pneumonitis developed in approximately 5% of patients treated with anti–PD-1/PD-L1 mAbs, and grade 3 and higher pneumonitis developed in 1%. Pneumonitis was more common in patients treated with anti–PD-1/PD-L1 mAbs plus anti–CTLA-4 mAb compared with anti–PD-1/PD-L1 monotherapy.24
Clinically, nearly all cases of pneumonitis improved/ resolved with drug holding and/or immunosuppression. However, some cases worsened and were fatal. In this series, worsening cases were restricted to current and former smokers and were more common in patients with underlying lung conditions; such patients may require particularly careful management. Among patients in whom pneumonitis improved/resolved, 12 (all with grade 1 to 2) underwent rechallenge with anti–PD-1/PD-L1 mAbs, and recurrent pneumonitis occurred in three (25%).
This may suggest that in mild cases, one may cautiously resume therapy after pneumonitis has improved/ resolved and after careful discussion with the patient. Although most instances of pneumonitis were not severe, five deaths occurred, and in three cases, infection from prolonged immunosuppression contributed to death. No patient who received immunosuppression beyond corticosteroids (infliximab with or without cyclophosphamide) recovered from pneumonitis.
Improvement is needed in the choice, dose, and duration of therapies for pneumonitis with consideration of the role of antimicrobial prophylaxis.
Renal events: acute interstitial nephritis. Immune-induced nephritis is uncommon (related all-grade events on CheckMate025 3.2%, per FDA label), but likely occurs fairly early in most patients (median time 10.6 weeks).2 As an acute tubulo-interstitial nephritis, it typically manifests with urinalysis demonstrating WBC, RBC, and WBC casts.25 Renal biopsy is rarely considered in RCC patients, the majority of which have solitary kidneys. In the event of severe acute kidney injury (AKI) checkpoint inhibitor therapy should immediately be discontinued, and corticosteroid therapy should be initiated promptly (e.g. 1mg/kg per day during 1 month followed by rapid tapering). The choice of withdrawing or reintroducing ICI should be decided upon after multidisciplinary discussion that includes defining the cancer status and its prognosis, the risk of end-stage renal disease account.
The advent of immune checkpoint inhibition in the treatment of RCC has helped to usher in a new era in managing this disease. With that, oncologists are facing a new spectrum of class specific toxicities, immune mediated adverse events Additional checkpoint inhibitors and numerous combination regimens are under investigation. Early data suggests that particularly the combination of two such immunomodulators may increase the incidence of immune related toxicities,26 highlighting the relevance of understanding and better managing these phenomena. As the clinical experience with immune checkpoint inhibitors grows, it is imperative to rapidly identify side effects and promptly initiate adequate management to improve outcomes while not detracting from the efficacy of checkpoint inhibition. Prospective data are still needed to further elucidate optimal strategies for specific immunosuppressive treatment; however, by adhering to established guidelines for such therapy, clinicians are more likely to realize the potential benefits of checkpoint blockade.
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2. Plimack ER, et al. 15th Intl Kidney Cancer Symposium. Nov 2016, Miami, FL.
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16. Kleiner DE, Berman D. Pathologic changes in ipilimumab-related hepatitis in patients with metastatic melanoma. Dig Dis Sci. 2012;57: 2233-2240.
17. FDA prescribing information for nivolumab. Reference ID: 3932569 -FDAhttps://www.accessdata.fda.gov/drugsatfda_docs/label/2016/ 125554s0 19lbl.pdf.
18. Osorio JC, Ni A, Chaft JE, et al. Antibody-mediated thyroid dysfunction during T-cell checkpoint blockade in patients with non-small-cell lung cancer. Ann Oncol. 2017;28:583-589.
19. Blansfıeld JA, Beck KE, Tran K, et al. Cytotoxic T-lymphocyte associated antigen-4 blockage can induce autoimmune hypophysitis in patients with metastatic melanoma and renal cancer. J Immunother. 2005; 28:593-598.
20.Dillard T, Yedinak CG, Alumkal J, et al. Anti-CTLA-4 antibody therapy associated autoimmune hypophysitis: serious immune-related adverse events across a spectrum of cancer subtypes. Pituitary. 2010;13: 29-38.
21. Sarnaik AA, Yu B, Yu D, et al. Extended dose ipilimumab with a peptide vaccine: immune correlates associated with clinical benefıt in patients with resected high-risk stage IIIc/IV melanoma. Clin Cancer Res. 2011;17:896-906.
22. Iwama S, De Remigis A, Callahan MK, et al. Pituitary expression of CTLA-4 mediates hypophysitis secondary to administration of CTLA-4 blocking antibody. Sci Transl Med. 2014;6:230ra45.
23. Topalian SL, SznolM,McDermott DF, et al. Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. J Clin Oncol. 2014;32:1020-1030.
24. Naidoo J, Wang X, Woo KM, et al. Pneumonitis in Patients Treated With Anti-Programmed Death-1/Programmed Death Ligand 1 Therapy. J Clin Oncol. 2017;35:709-717.
25. Cortazar FB, Marrone KA, Troxell ML, et al. Clinicopathological features of acute kidney injury associated with immune checkpoint inhibitors. Kidney Int. 2016 Sep;90(3):638-47.
26. Hammers HJ, Plimack ER, Infante JR, et al. Phase I study of nivo-lumab in combination with ipilimumab in metastatic renal cell carcinoma (mRCC). ASCO Meeting Abstracts. 2014;32(15_suppl):4504. http://meeting.ascopubs.org/cgi/content/ abstract/32/15_ suppl/4504. KCJ
Keywords: Immune checkpoint blockade, immune-related adverse events, PD1, PD-L1, nivolumab, dermatologic, hepatic, endocrino-pathy, diarrhea, colitis, pneumonitis.
Address for reprints and correspondence: Martin H. Voss, MD, Memorial Sloan Kettering Cancer Center, 1275 York Ave., New York, NY, 10065. Email: email@example.com