IgE blockade with omalizumab reduces pruritus related to immune checkpoint inhibitors and anti-HER2 therapies

Abstract

Background: Immunoglobulin E (IgE) blockade with omalizumab has demonstrated clinical benefit in pruritus-associated dermatoses (e.g. atopic dermatitis, bullous pemphigoid, urticaria). In oncology, pruritus-associated cutaneous adverse events (paCAEs) are frequent with immune checkpoint inhibitors (CPIs) and targeted anti-human epidermal growth factor receptor 2 (HER2) therapies. Thus, we sought to evaluate the efficacy and safety of IgE blockade with omalizumab in cancer patients with refractory paCAEs related to CPIs and anti-HER2 agents.

Patients and methods: Patients included in this multicenter retrospective analysis received monthly subcutaneous injections of omalizumab for CPI or anti-HER2 therapy-related grade 2/3 pruritus that was refractory to topical corticosteroids plus at least one additional systemic intervention. To assess clinical response to omalizumab, we used the Common Terminology Criteria for Adverse Events version 5.0. The primary endpoint was defined as reduction in the severity of paCAEs to grade 1/0.

Results: A total of 34 patients (50% female, median age 67.5 years) received omalizumab for cancer therapy-related paCAEs (71% CPIs; 29% anti-HER2). All had solid tumors (29% breast, 29% genitourinary, 15% lung, 26% other), and most (n = 18, 64%) presented with an urticarial phenotype. In total 28 of 34 (82%) patients responded to omalizumab. The proportion of patients receiving oral corticosteroids as supportive treatment for management of paCAEs decreased with IgE blockade, from 50% to 9% (P < 0.001). Ten of 32 (31%) patients had interruption of oncologic therapy due to skin toxicity; four of six (67%) were successfully rechallenged following omalizumab. There were no reports of anaphylaxis or hypersensitivity reactions related to omalizumab.

Conclusions: IgE blockade with omalizumab demonstrated clinical efficacy and was well tolerated in cancer patients with pruritus related to CPIs and anti-HER2 therapies.

Keywords: IgE; bullous pemphigoid; cutaneous adverse event; eczema; pruritus; urticaria.

Figure 1.. Clinicopathologic features of patients receiving IgE blockade with omalizumab for pruritus related to immune checkpoint inhibitors and anti-HER2 therapies.

(A) Urticaria with (B) interface dermatitis and superficial perivascular lymphoeosinophilic infiltrate (×200 magnification). (C) Bullous pemphigoid with (D) subepidermal vesicle with eosinophils and lymphocytes (×100 magnification). (E) Eczema with (F) slight spongiosis with superficial perivascular lymphoeosinophilic infiltrate (×200 magnification). Anti-HER2, anti-human epidermal growth factor receptor 2; IgE, immunoglobulin E.

Figure 2.. Time course and efficacy of IgE blockade in patients receiving omalizumab for pruritus related to CPIs and anti-HER2 therapies.

Anti-HER2, anti-human epidermal growth factor receptor 2; CPI, checkpoint inhibitor (e.g. PD-1, PD-L1, CTLA-4); CTLA-4, cytotoxic T-lymphocyte-associated protein 4; paCAEs, pruritus-associated cutaneous adverse events; PD-1, programmed cell death protein 1; PD-L1, programmed cell death-ligand 1. ^a Median (min-max), 93 days (4–820 days) in 32 patients. ^b median (min-max), 62 days (0–440 days) in 34 patients.

Figure 3.. Clinical manifestation of paCAEs before (left) and after (right) IgE blockade with omalizumab.

(A) Patient with metastatic breast cancer and CTCAE grade 2 dermatographic urticaria related to anti-HER2 therapy (resistant to alclometasone dipropionate, clobetasol, diphenhydramine, hydroxyzine, levocetirizine, pregabalin). Two subcutaneous 300-mg doses of omalizumab resulted in complete response with reduction of paCAE to CTCAE grade 0. (B) Patient with advanced melanoma and CTCAE grade 3 bullous pemphigoid related to anti-PD-1 + anti-CTLA-4 immune checkpoint inhibition (resistant to cetirizine, diphenhydramine, mycophenolate mofetil, rituximab, prednisone, pregabalin). One subcutaneous 300-mg injection of omalizumab resulted in partial response with reduction of paCAE to CTCAE grade 1. Anti-HER2, anti-human epidermal growth factor receptor 2; CTCAE, Common Terminology Criteria for Adverse Events; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; IgE, immunoglobulin E; paCAEs, pruritus-associated cutaneous adverse events; PD-1, programmed cell death protein 1.

Figure 4.. Pre- to post-omalizumab changes in the proportion of patients requiring supportive treatments to manage paCAEs related to immune checkpoint inhibitors and anti-HER2 therapies.

Anti-HER2, anti-human epidermal growth factor receptor 2; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; GABAlogs, gamma-aminobutyric acid analogs; IMs, immunomodulators; OAH, oral antihistamine; OCS, oral corticosteroids; paCAEs, pruritus-associated cutaneous adverse events; PD-1, programmed cell death protein 1; PD-L1, programmed cell death-ligand 1; TCS, topical corticosteroids.

Figure 5.. Pre- to post-omalizumab changes in total serum IgE and blood eosinophils of patients with paCAEs related to immune checkpoint inhibitors and anti-HER2 therapies.

Measured analytes correspond to total serum IgE and absolute count of blood eosinophils. The upper limit of normal (ULN) values were established a priori at 213 kU/l and 699 cells/μl, respectively, as per our institutional laboratory services provider (Mayo Clinic Laboratories, Rochester, MN). Anti-HER2, anti-human epidermal growth factor receptor 2; IgE, immunoglobulin E; paCAEs, pruritus-associated cutaneous adverse events.