Ipilimumab in patients with cancer and the management of dermatologic adverse events

REVIEW

Ipilimumab in patients with cancer and the management of dermatologic adverse events Mario E. Lacouture, MD,a,b Jedd D. Wolchok, MD, PhD,a,b,c Gil Yosipovitch, MD,d Katharina C. K€ahler, MD,e Klaus J. Busam, MD,a and Axel Hauschild, MDe New York, New York; Winston-Salem, North Carolina; and Kiel, Germany Ipilimumab is a fully human monoclonal antibody that blocks cytotoxic T-lymphocyte antigen-4 to augment antitumor T-cell responses. Phase III studies have demonstrated survival benefit in both previously treated and treatment-na€ıve patients with metastatic melanoma. In clinical trials, adverse events (AEs) related to treatment with ipilimumab were mostly grade 1/2 (as per Common Terminology Criteria for AEs, Version 4.02), and mostly reversible with appropriate management. Distinct immune-related AEs that may reflect the mechanism of action of ipilimumab have been identified, and occur commonly in the skin, typically presenting as a maculopapular rash, which can be accompanied by pruritus, pruritus with no skin lesions, alopecia, and vitiligo. Histologic analyses have revealed epidermal spongiosis, and perivascular CD41 T-cell infiltrates with some eosinophils in areas of rash. Timely implementation of toxicity-specific treatment guidelines that emphasize vigilance and early intervention allows mitigation of dermatologic AEs. Adherence to guidelines is necessary to maintain quality of life, ensure consistent dosing, and obtain the best possible clinical outcome. ( J Am Acad Dermatol http://dx.doi.org/10.1016/ j.jaad.2014.02.035.) Key words: adverse event management; dermatologic; immune-related; ipilimumab; melanoma; pruritus; rash; vitiligo.

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pilimumab, a fully human IgG1 monoclonal antibody, blocks cytotoxic T-lymphocyte antigen (CTLA)-4 to augment antitumor T-cell responses.1 Used either alone or in combination with dacarbazine, ipilimumab has demonstrated a statistically significant improvement in overall survival in 2 randomized phase III trials in previously treated and treatment-na€ıve patients with metastatic melanoma.2,3 Ipilimumab is approved at a dose of 3 mg/kg for use in unresectable or metastatic melanoma in more than 40 countries.4-6

In clinical trials, ipilimumab treatment-related adverse events (AEs) are grade 1/2 (as per Common Terminology Criteria for AEs, Version 4.02) in the majority of cases, and most are reversible

From Memorial Sloan Kettering Cancer Center, New Yorka; Weill-Cornell Medical College, New Yorkb; Ludwig Institute for Cancer Research, New Yorkc; Departments of Dermatology, Neurobiology and Anatomy, and Regenerative Medicine, Wake Forest University Health Sciences, Winston-Salemd; and Department of Dermatology University of Kiel.e The authors take full responsibility for the content of this publication and confirm that it reflects their viewpoint and medical expertise. The authors also wish to acknowledge StemScientific, funded by Bristol-Myers Squibb, for providing writing and editorial support. Neither Bristol-Myers Squibb nor StemScientific influenced the content of the manuscript, nor did the authors receive financial compensation for authoring the manuscript. Disclosure: Dr Lacouture received honoraria for advisory board membership and consultancy with Bristol-Myers Squibb and consultancy for Advancell, Amgen, Bayer, Berg, Galderma, Genentech, GSK, Helsinn, Merck, Novartis, Novocure, OSI, and Pfizer. Dr Wolchok received honoraria for consultancy for

AstraZeneca, Bristol-Myers Squibb, and Merck. Dr K€ahler received honoraria for advisory board membership, consultancy, and as a speaker. Dr Hauschild received honoraria for advisory board membership and consultancy as well as payments for lectures including services on speakers’ bureaus and research funding from the following companies: Amgen, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Eisai, GSK, IGEA, Lilly, MelaSciences, Merck Serono, MSD/Merck, Novartis, Oncosec, and Roche Pharma. Drs Yosipovitch and Busam have no conflicts of interest to declare. Accepted for publication February 24, 2014. Reprints not available from the authors. Correspondence to: Mario E. Lacouture, MD, Memorial Sloan Kettering Cancer Center, Suite 228, 160 E 53 St, New York, NY 10022. E-mail: [email protected]. Published online April 23, 2014. 0190-9622/$36.00 Ó 2014 by the American Academy of Dermatology, Inc. http://dx.doi.org/10.1016/j.jaad.2014.02.035

Abbreviations used: AE: CTLA: GI: irAE:

adverse event cytotoxic T-lymphocyte antigen gastrointestinal immune-related adverse event

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using symptom-specific treatment strategies that SAFETY OVERVIEW emphasize close follow-up and the early use of In ipilimumab studies of metastatic melanoma, steroids when appropriate.1-3,7,8 Ipilimumab is the most common treatment-related AEs were associated with immune-related AEs (irAEs) in 64% characterized as irAEs,2,3,10,16-18,21 reflective of 9 of patients. ipilimumab’s mechanism of action.22 A total of 10 A common site of irAEs is the skin, and data 64.2% of patients in a pooled analysis of ipilimumab from trials of ipilimumab 10 mg/kg indicate that clinical trials (N = 1498) experienced an irAE of any dermatologic events often grade, 17.8% were severe manifest earlier in treatment (grade 3-4), and dermatoCAPSULE SUMMARY than other irAEs. Here, we logic irAEs were the most summarize ipilimumab efficommon (44.9%, any Ipilimumab is approved for treatment of cacy results and safety grade).10 In a phase II doseadvanced melanoma. profile, with particular attenranging study, although the The incidence, timing, and tion to cutaneous events. frequency of irAEs increased characterization of dermatologic adverse Management of cutaneous with ipilimumab dose, the events to ipilimumab are reported events will be described, irAE profile remained consisherein. including data that support tent.16 Most irAEs develop current guidelines. during the initial dosing Understanding these is critical for period (first 12 weeks), with dermatologists involved in the care of IPILIMUMAB a median time to onset of 5 to patients, as it allows for counseling and MECHANISM OF 9 weeks, depending on the mitigation of events that may affect ACTION dose of ipilimumab and completing treatment and quality of life. Tumors are immunogenic organ class affected.10 and have a higher propensity Across clinical studies to develop in an immunocompromised state.11 with ipilimumab monotherapy, inflammatory Although a growing body of evidence supports conditions affecting the skin (pruritus, rash) and tumor immune surveillance, a variety of mechanisms gastrointestinal (GI) tract (diarrhea/colitis) were the serve to evade these responses in patients with most frequently reported irAEs ( $ 10%).2,3,16-18,21 advanced disease. These include blockade of T-cell The majority of irAEs in these studies are grade 1/2 in activation by antigenic variation and expression of severity, with diarrhea being the most common of immune-suppressive factors. In addition, expression the skin or GI irAEs, followed by colitis, rash, of CTLA-4 on T cells acts as an inhibitory signal and pruritis.2,16,21 Less commonly reported irAEs 12 to down-regulate T-cell activation. Hence, a affected the endocrine system (eg, hypothyroidism, therapeutic goal is to achieve tumor-specific lysis hypopituitarism) and liver (eg, elevated transamiby tumor antigenespecific T cells, which would nases, hepatitis). result in decreased systemic toxicities compared with cytotoxic chemotherapies. Ipilimumab has SKIN AEs been developed to exploit the body’s antitumor Ipilimumab-induced rash differs from that activity; it binds to and inhibits CTLA-4, leading to observed with targeted anticancer agents (ie, erlotinib, increased T-cell activation and cytokine secretion, cetuximab, panitumumab, vandetanib, pertuzumab). thereby potentiating T-cell responses13 (Fig 1). Epidermal growth factor receptor inhibitors are associated with a characteristic papulopustular IPILIMUMAB EFFICACY IN METASTATIC (acneiform) rash in 68% to 75% of patients, an AE MELANOMA believed to be a class effect of these agents.23,24 The In patients with unresectable stage III or IV rash observed with ipilimumab appears to be similar melanoma, ipilimumab treatment resulted in 4 to maculopapular rashes to commonly used medicapatterns of response in clinical studies.14,15 In tions (ie, antibiotics, nonsteroidal anti-inflammatory phase II and III clinical trials, a prolonged survival drugs) and atopiform dermatitis.25 effect of ipilimumab therapy has been demonstrated in a proportion of patients with metastatic melanoma.2,3,16-19 Furthermore, retreatment with INCIDENCE OF SKIN AEs ipilimumab can re-establish disease control in The efficacy and safety of ipilimumab has been eligible patients who progress after achieving an assessed at both the approved 3-mg/kg dose and the objective response or stable disease for 3 months or investigational 10-mg/kg dose. Commonly, irAEs longer.20 associated with ipilimumab have been described as d

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Fig 1. Mechanism of action of ipilimumab. Two signals are required for full T-cell activation; the first is triggered by binding of a tumor antigen/major histocompatibility complex with the T-cell receptor (TCR) and the second by binding of the CD28 receptor with B7 ligands on antigen-presenting cells (APC ). On activation, cytotoxic T-lymphocyte antigen (CTLA)-4 is up-regulated and migrates to the cell surface where it competes successfully with CD28 for B7 binding, interrupting the second activation signal and ‘‘switching off’’ the T cell. Ipilimumab binds with CTLA-4, restoring ligand availability for CD28 binding and potentiating the T-cell response. Adapted from Seminars in Oncology, Vol 36(5), Hoos A, Ibrahim R, Korman A, Abdallah K, Berman D, Shahabi V, et al, Development of ipilimumab: contribution to a new paradigm for cancer immunotherapy, Pages 533-46, Copyright 2010, with permission from Elsevier.1

dose-dependent, schedule-related, and cumulative.26,27 However, focusing on studies with ipilimumab monotherapy arms,2,16,21 the incidence and severity of pruritus or rash appear to be similar for both ipilimumab doses. More recently, data from the phase III trial of ipilimumab 10 mg/kg plus dacarbazine versus dacarbazine alone indicate that this higher dose was associated with an incidence of grade 3/4 pruritus (2.0%) and rash (1.2%) in the ipilimumab arm.28

PRURITUS Pruritus may have deleterious effects on quality of life of patients.29 Health-related quality of life instruments, including the FACIT Fatigue Scale, were incorporated into the phase III trial of ipilimumab 3 mg/kg in patients with pretreated, metastatic melanoma. The FACIT Fatigue Scale has a range of 0 to 52, with a higher total score being inversely proportional to the level of fatigue. Scores were similar among the 3 treatment arms (ipilimumab alone, ipilimumab plus gp100 vaccine, and gp100 vaccine alone), suggesting no impact of ipilimumab on fatigue.6

RASH The rates of all-grade cutaneous AEs shown in Table I are similar to those in a recent meta-analysis of 19 studies conducted from 1998 to 2011 (N = 1208

patients), which included trials testing ipilimumab as monotherapy and in combination at various doses in randomized multi-arm and single-arm studies.31 All studies included were in metastatic melanoma except 1 trial each that included patients with urothelial carcinoma,21 pancreatic adenocarcinoma,16 renal cell carcinoma,32 and non-small cell lung cancer.33 Based on 760 patients, the overall incidence of all-grade rash was 24.3% (95% confidence interval, 21.4%-27.6%), with a relative risk of 4.00 (range 2.63-6.08, P \ .001) compared with control subjects, ranging from 11.1% to 50.0% between trials. The overall incidence of high-grade rash was 2.4% (95% confidence interval, 1.1%-5.1%), with a relative risk of 3.31 (range 0.70-15.76, P = .13), ranging from 0.7% to 11.8%. Based on 320 patients receiving 3 mg/kg and 440 receiving 10 mg/kg, there was no significant difference between doses in terms of incidence of all-grade (P = .96) or high-grade (P = .57) rash. Analysis of data from 610 patients with metastatic melanoma and 150 patients with other tumor types indicated that the risk of rash was independent of tumor type.31

SEVERE (GRADE $ 3) SKIN irAEs In the phase III trial of ipilimumab 3 mg/kg in patients with pretreated, metastatic melanoma, severe or life-threatening (grade 3/4) skin irAEs occurred in 11 patients.2 Although dermatologic

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Table I. Summary of specific dermatologic immune-related adverse events from phase II or III clinical trials, all grade2,3,16,17,30

Single-arm17 Crossover to 10 mg/kg upon progression16 Randomized phase II30 Randomized phase III2 (registration trial) Randomized phase III3

No. of patients (%) experiencing irAEs

N

Prior therapy

Ipilimumab dose, mg/kg

155 72 72 57 58 380 131 132 247 251

Yes Yes Yes Mix Mix Yes Yes Yes No No

10 10 3 10 1 Placebo 10 1 bd 3 1 gp100 3 1 Placebo Placebo 1 gp100 10 1 Dacarbazine Placebo 1 dacarbazine

Any type

109 50 46 48 47 221 80 42 192 96

(70.3) (70.4) (64.8) (84.2) (81) (58.2) (61.1) (31.8) (77.7) (38.2)

Skin-related

76 33 32 39 35 152 57 22

(49.0) (46.5) (45.1) (68.4) (60.3) (40.0) (43.5) (16.7)

Pruritus

39 23 15 20 20 67 32 14 66 15

(25.2) (32.4) (21.1) (35.1) (34.5) (17.6) (24.4) (10.6) (26.7) (6.0)

Rash

39 16 17 33 25 67 25 6 55 12

(25.2) (22.5) (23.9) (57.9) (43.1) (17.6) (19.1) (4.5) (22.3) (4.8)

Vitiligo

3 (1.9) NR 1 (1.4) 1 (1.8) 2 (3.4) 14 (3.7) 3 (2.3) 1 (0.8)

bd, Twice daily; irAE, immune-related adverse event; NR, not reported.

irAEs did not result in any deaths, 1 patient in the ipilimumab plus gp100 group developed leg lesions on day 14, which were diagnosed as cutaneous allergic angiitis (Bristol-Myers Squibb data on file). This patient deteriorated over several days with progression of the skin lesions to Stevens-Johnson syndrome/toxic epidermal necrolysis. A skin biopsy specimen confirmed grade-4 leukocytoclastic vasculitis and necrosis of keratinocytes. Despite aggressive treatment the patient died shortly afterwards from acute respiratory distress syndrome. Cutaneous allergic angiitis, toxic epidermal necrolysis, leukocytoclastic vasculitis, and acute respiratory distress syndrome were considered as probably related to ipilimumab, although the patient was also receiving lamotrigine for the treatment of epilepsy, which is strongly associated with severe cutaneous AEs, including toxic epidermal necrolysis.34

TYPICAL FEATURES OF IPILIMUMABINDUCED CUTANEOUS AEs Appearance The rash resulting as an irAE of ipilimumab treatment can be asymptomatic or accompanied by pruritus.35-37 The appearance of the rash is typically reticular, erythematous, edematous, and maculopapular,35-38 often on the trunk and extremities35 (Fig 2). Rash can coincide with the regression of subcutaneous disease and may be especially pronounced around nevi, suggesting that the inflammatory response is directed toward melanocytes.36,38 Histology Histologically, perivascular immune cell infiltrates in superficial dermis that extend to the epidermis have been observed with both lymphocytic and

eosinophilic infiltrates (Figs 2 and 3).35-37 The lymphoid aggregates are composed of a mixture of CD41 and CD81 T cells and have been demonstrated to be CD31 CD81 and CD31 CD41.35-37 A reticular dermal infiltrate of CD41 T cells and lesser infiltrate with CD81 T cells have also been observed.39 Histologic analysis of rash biopsy specimens in patients with melanoma receiving ipilimumab 9 mg/kg as part of a phase II, dose-escalation study and presenting with dermatitis revealed CD4-predominant T-cell infiltrates and eosinophils.40 An increase from baseline in the peripheral blood eosinophil frequency was observed in patients at the time of skin eruptions (P = .006).25 Infiltration of ipilimumab-induced rash with Melan-Aespecific CD81 T cells (which were associated with Melan-Aepositive nevoid structures) has also been reported.38 Tumor-infiltrating lymphocytes in patients with melanoma often contain Melan-Aespecific cells. Ipilimumab treatment may have resulted in these cells undergoing expansion and differentiation to cytotoxic effector cells that subsequently migrated to the skin where they induced a transient inflammatory response, and to the tumor, where they mediated tumor regression.38 Indeed, after stimulation with a panel of peptides, the dominant response detected in the skin was similar to response in tumor specimens and elicited toward Melan-A, with smaller responses identified to additional differentiation antigens gp100 and tyrosinase.38 Although the presence of prurigo-like lesions as part of the rash was not reported,38 elevation of CD81 cells associated with subacute prurigo, which is characterized by intensely itchy papular cutaneous lesions, was described.41 Both CD41 and CD81 T cells have been noted next to apoptotic melanocytes in the skin. Furthermore, CD41 forkhead box P31 regulatory

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Fig 3. Hematoxylin-eosin staining of skin biopsy specimen showing evidence of dryness, ecthyma-like ulceration, and inflammation of hair follicles after treatment with ipilimumab.

Fig 4. Proposed time to onset and resolution of immunerelated adverse events with ipilimumab 10 mg/kg by organ system. Reprinted with permission. Ó 2012 American Society of Clinical Oncology. All rights reserved. Weber JS et al: Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol Vol 30(21), 2012:2691-2697.43

Fig 2. Cutaneous adverse events occurring with ipilimumab treatment. Erythematous papular eruption on the left knee, diagnosed as sarcoidosis (A) and maculopapular exanthem (B). C and D, Both diagnoses were confirmed by hematoxylin-eosin staining of skin biopsy specimens.

T cells are abundantly represented in papillary perivascular dermal infiltrates, where they are thought to ameliorate the severity of the reaction. Punch biopsy specimens of skin from patients with melanoma treated within a phase I trial revealed prominent perivascular T-cell infiltrates in the papillary dermis, which extend into the epidermis.35 In addition, 1 previously vaccinated patient with ovarian cancer who received ipilimumab within the same phase I clinical investigation program developed a transient erythematous rash on the

face and trunk. Skin biopsy specimen demonstrated perivascular T-cell infiltrates in the papillary dermis, but no host reactivity toward melanocytes. An intense dermal infiltrate of neutrophils was also observed, with the rash developing to reveal palisading granuloma annulare-like features in the reticular dermis with marked edema of the papillary dermis.37 In 1 adverse case report, mild, focal hypopigmentation of the retinal pigmented epithelium was detected by ophthalmologic examination.35 In addition, both perivascular cuffing, either with vascular involvement or without true vasculitis, and epidermal spongiosis consistent with an ‘‘allergic’’ drug eruption have been observed.37,39 Although these findings demonstrate a loss of tolerance to melanocyte differentiation antigens, neither vitiligo nor alterations in visual acuity ensued, likely reflecting incomplete melanocyte destruction.35

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Table II. Grading of skin immune-related adverse events: rash, alopecia, and hypopigmentation Grade

Rash*

Alopecia

Hypopigmentation

1

Macular or papular eruption covering \10% BSA with or without symptoms (eg, pruritus, burning, tightness)y

Hypopigmentation or depigmentation covering \10% BSA, with no psychosocial impact

2

Macular or papular eruption covering 10%-30% BSA with or without symptoms (eg, pruritus, burning, tightness) and limiting of instrumental ADLy

Hair loss of up to 50% of normal for that individual that is not obvious from a distance but only on close inspection; a different hairstyle may be required to cover the hair loss but it does not require a wig or hairpiece to camouflage Hair loss of [50% of normal for that individual that is readily apparent to others; a wig or hairpiece is necessary if the patient desires to completely camouflage the hair loss or if loss is associated with psychosocial impact

3

Macules/papules covering [30% BSA with or without associated symptoms and limiting of selfcare ADLy Generalized exfoliative, ulcerative, or bullous dermatitis Death

4 5

Hypopigmentation or depigmentation covering [10% BSA or with associated psychosocial impact

ADL, Activities of daily living; BSA, body surface area. *For some clinical trials with ipilimumab, events were graded using the Common Terminology Criteria for Adverse Events, Version 3.0. y According to Common Terminology Criteria for Adverse Events, Version 4.03.

TIME TO ONSET OF irAEs Data from studies of 10 mg/kg of ipilimumab indicate that the median time to onset of moderate, severe, or life-threatening immune-mediated dermatitis was 3 to 4 weeks and ranged up to 17.3 weeks from initiation of ipilimumab.42,43 Of note, skin AEs have shorter time to onset than those affecting the GI tract, liver, or endocrine system.43 Median time to resolution of longest-lasting skin-, GI-, and liver-related events is 2 to 6 weeks; and resolution of endocrine irAEs is approximately 20 weeks (Fig 4).43 Patterns of onset and resolution appear to be consistent among patients treated with either 3 or 10 mg/kg of ipilimumab.44

GRADING AND MANAGEMENT OF SKIN irAEs Evidence Grading of skin irAEs in clinical trials of ipilimumab, including rash, alopecia, and hypopigmentation, can be found in Table II. In early-phase clinical trials of ipilimumab, symptomatic relief for maculopapular rash was provided by oral hydroxyzine or diphenhydramine. All patients were symptom free within weeks. Patients sometimes developed vitiligo on upper extremities over the next 3 weeks.36,37 Rash can resolve with or without

treatment within several weeks.38 Among 63 patients with moderate (grade 2) dermatitis treated with either systemic or topical corticosteroids (51%), or who received no treatment (49%), most (81%) patients had an improvement to grade 1 or achieved complete resolution (grade 0).4 Of 7 patients with severe (grade 3) dermatitis who were treated with high-dose corticosteroids (median dose 60 mg prednisone/d or equivalent), followed by corticosteroid taper, 6 had complete resolution within 15.6 weeks.4 Guidance Ipilimumab has been approved with an associated risk evaluation and mitigation strategy, which highlights the importance of vigilant monitoring and early identification and intervention to prevent decreased quality of life and inconsistent dosing.8 Patients should be evaluated for signs and symptoms of pruritus, vitiligo, or maculopapular rash and advised to report skin-related changes. Useful educational tools are available for health care professionals and patients, and can be found at https://www.hcp.yervoy.com/pages/rems.aspx (Fig 5). Importantly, although there appear to be no reports of severe itch resulting in discontinuation of

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Fig 5. Schematic treatment algorithms for management of rash (A) and pruritus (B) resulting from treatment with ipilimumab.8 ADL, Activites of daily living; BSA, body surface area.

study medication, it is possible that patients with intractable pruritus may require a more aggressive management approach such as oral steroids, gamma-Aminobutyric acid agonists, or high-dose oral antihistamines. Furthermore, the presence of both T-cell infiltration and eosinophilia25,38 may provide support for treatment of rash with systemic steroids. Again, although not reported, for patients who experience rash and itch that interferes with sleep, more aggressive therapies including sedating oral antihistamines, the antidepressant mirtazapine, and oral/topical steroids may be appropriate.45

Conclusions Ipilimumab is a first-in-class anti-CTLA-4 therapy approved by the Food and Drug Administration and has achieved overall survival benefit in patients with unresectable or metastatic melanoma. Ipilimumab therapy is associated with irAEs that reflect the agent’s mechanism of action, but most are low grade and reversible with appropriate treatment according to guidelines developed to aid irAE management, vigilance, and early intervention. Skin irAEs are among the most commonly observed safety event. Although low-grade events can be managed symptomatically, higher-grade events

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