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ICAR SINONASAL TUMORS

increasing interest and utilization of these agents in mucosal melanoma, as well. Another prevalent immune evasion mechanism involves cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). CTLA-4 is an immune checkpoint receptor protein that also downregulates immune response. 1546 Ipilimumab was developed as a monoclonal antibody that binds CTLA-4, thus blocking inhibitory signals produced by the tumor microenvironment and allowing improved immunosurveillance for tumor cells. 1540,1553,1554 This was one of the first immunotherapies to be approved for advanced or metastatic cutaneous melanoma after phase III clinical trials demonstrated improved OS. 1555 Despite early promising results, ipilimumab response was noted in a relatively small number of patients and the response tended to wane over time, with a distinct plateau noted around year 3 of treatment. 1556 In addition, medication side effects and AEs are not uncommon with ipilimumab including pneumonitis, dermatitis, and enterocolitis, with grade 3–4 AEs occurring in 18% of patients. 1557 In a phase III clinical trial of ipilimumab-resistant patients with metastatic cutaneous melanoma without BRAF mutation, nivolumab demonstrated higher 1-year OS than standard chemotherapy (dacarbazine) (72.9% vs. 42.1%). The median PFS was 5.1 months in the nivolumab group compared to 2.2 months in the dacar bazine group. 1558 Moreover, in a randomized phase III trial CheckMate 037, patients with unresectable or metastatic cutaneous melanoma who progressed through ipilimumab demonstrated a better objective response to nivolumab than standard chemotherapy and fewer grade 3–4 AEs. 1559 Other work has demonstrated superiority of pembrolizumab as monotherapy (OS, PFS, toxicity) in metastatic melanoma (majority of subjects had cuta neous melanoma, but a subset of subjects had mucosal melanoma) compared to ipilimumab monotherapy or other standard chemotherapy regimens in KEYNOTE trials 002 and 006. 1509,1560–1562 Thus, immunotherapy reg imens have become increasingly utilized over traditional chemotherapy regimens for patients with advanced and metastatic melanoma (Table XXIV.D.3). For mucosal melanoma specifically (all sites), the first large, pooled analysis was reported in 2017. In this pooled analysis of mucosal melanoma patients from several phase III clinical trials, combination therapy of nivolumab and ipilimumab (37%) demonstrated superiority compared to monotherapy with either nivolumab (23%) or ipili mumab (8%). Additionally, grade 3–4 adverse treatment events were noted in 8.1% of mucosal melanoma patients receiving nivolumab monotherapy versus 40% receiving combination therapy. 1550 Moreover, pembrolizumab data for mucosal melanoma patients were pooled from all KEYNOTE trials and analyzed. In this pooled analysis,

pembrolizumab monotherapy following previous treat ment failure and disease progression demonstrated a durable response in some patients showing an objective response rate of 19%, disease control rate of 31%, median PFS of 2.8 months, and median OS of 11.3 months. 1560 Although data on immunotherapy specifically for SNMM are scarce, a pooled NCDB data multivariate anal ysis demonstrated that survival following immunotherapy was improved for patients with metastatic disease, but not those without metastases (HR 0.14, 95% CI: 0.04–0.49). 366 A separate NCDB database study comparing the efficacy of immunotherapy for SNMM compared to cutaneous melanoma found that the addition of immunotherapy improved OS in metastatic cutaneous melanoma (HR 0.57; 95% CI: 0.49–0.66; p < 0.0001) but not in metastatic SNMM (HR 1.1; 95% CI: 0.67–1.7; p = 0.75). 1563 Another NCDB anal ysis of head and neck mucosal melanoma (79% of which were sinonasal) found that immunotherapy was associated with improved OS on multivariate analysis after control ling for tumor stage, size, site, age, and comorbidities. 1503 An NCDB study of mucosal melanoma of the head and neck (all sites; 71.8% of which were sinonasal) found that surgery and adjuvant immunotherapy had improved OS compared to surgery alone. An international multicen ter retrospective analysis found that immune checkpoint blockade (e.g., ipilimumab, pembrolizumab, nivolumab) was associated with improved OS when administered for recurrent/persistent disease as compared to no treatment, which in turn had superior OS as compared to cases treated with biochemotherapy (e.g., interleukin, interferon). 1564 Additionally, surgery with adjuvant immunotherapy and RT had improved OS compared to surgery and RT. 1565 Role of immunotherapy in sinonasal mucosal melanoma

Aggregate grade of evidence

C (Level 1: one study; Level 4: seven studies)

Benefit

Immunotherapy has proven efficacy as an adjuvant therapy for metastatic cutaneous melanoma. Early experience has also demonstrated efficacy as an adjunctive therapy for advanced or metastatic SNMM and may improve OS, although the robust responses do not equal the efficacy noted for metastatic cutaneous melanoma. The potential harm of immunotherapy includes rash, fever, nausea, and more severe immune-related adverse events including enterocolitis, pneumonitis, and hepatitis, particularly when used in combination therapy.

Harm

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