Efficacy and safety of ipilimumab 3 mg/kg in patients with pretreated, metastatic, mucosal melanoma

Abstract

Background

Mucosal melanoma is an extremely rare and aggressive malignancy that often remains undetected until it reaches an advanced stage, when effective treatment options are limited. The activity and safety of ipilimumab were assessed in an Expanded Access Programme (EAP) that included patients with metastatic, mucosal melanoma.

Methods

Ipilimumab was available upon physician request for patients aged ⩾16 years with stage III (unresectable) or IV skin, ocular or mucosal melanoma, who had failed or did not tolerate previous treatments and had no other therapeutic option available. Patients received ipilimumab 3 mg/kg every 3 weeks for four doses. Patients with stable disease or an objective response to ipilimumab were eligible for retreatment upon disease progression. Tumour assessments were conducted at baseline and week 12 using immune-related response criteria. Patients were monitored for adverse events (AEs), including immune-related AEs, within 3 to 4 days of each scheduled visit.

Results

Of 855 patients participating in the EAP in Italy, 71 (8%) had metastatic, mucosal melanoma. With a median follow-up of 21.8 months, the response rate was 12% and the immune-related disease control rate was 36%. Median progression-free survival and overall survival were 4.3 and 6.4 months, respectively. In total, 34% of patients reported treatment-related AEs of any grade, which were grade 3 or 4 in 9% of patients. AEs were generally manageable as per protocol-specific guidelines.

Conclusion/interpretation

Ipilimumab may be a feasible treatment option in pretreated patients with metastatic mucosal melanoma, and warrants further investigation in prospective clinical trials.

Introduction

Mucosal melanoma is an extremely rare and aggressive malignancy that accounts for 1.3–1.4% of all melanomas [1], [2], [3]. Any mucosal membrane can be affected, but melanoma is most commonly found in the head and neck region (31–55% of cases), the anal/rectal tract (17–24% of cases) or the genitourinary tract (21–43% of cases) [1], [3], [4]. Compared with melanoma arising from the skin, mucosal melanoma tends to occur at a later age and is more commonly diagnosed in women and white Caucasians [1].

Usually, mucosal melanoma is associated with a higher mortality rate than its cutaneous counterpart, possibly because an initial absence of symptoms and lack of visibility prevent early diagnosis. In an analysis of patients diagnosed between 1985 and 1989, the 5-year survival rate across all disease stages was 81% for patients with cutaneous melanoma and 25% for those with mucosal melanoma [4]. In the metastatic setting, the prognosis has not been established, as most studies combine data for all patients regardless of primary tumour site [2]. Nevertheless, because the presence of metastatic spread is associated with rapid clinical deterioration and a short survival time, the prognosis is expected to be poor [5], [6].

Treatment options for patients with metastatic mucosal melanoma are limited. Surgical resection or biochemotherapy can be effective; however, supportive evidence is limited and adjuvant therapy may also be required [7], [8]. Commonly, patients are treated with the same regimens used for cutaneous melanoma despite data suggesting they may be less effective in patients with mucosal disease [2], [9], [10].

To improve the prognosis, new treatment options are being explored. Evidence suggests that the biology of non-cutaneous melanoma differs significantly from cutaneous melanoma, which may impact therapeutic opportunities. In an analysis of 45 mucosal melanomas, c-KIT and NRAS mutations were detected in 16% and 25% of tumours, respectively. By contrast, no mutations were observed in the BRAF gene, which is commonly mutated in patients with cutaneous melanoma [11]. Additional studies support this observation [12], [13]; however, in an analysis of another 20 mucosal melanomas, BRAF and NRAS mutations were detected in 11% and 5% of tumours, respectively [14]. The use of appropriately targeted agents (i.e. inhibitors of c-KIT, NRAS/MEK or BRAF) is therefore one therapeutic strategy, although, at present, clinical data are limited.

An alternative strategy is to target the immune system rather than the tumour directly. Ipilimumab is indicated in the European Union at a dose of 3 mg/kg for use in adult patients with unresectable stage III or IV melanoma who have received prior therapy [15]. Ipilimumab inhibits cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), a negative regulator of T-cell activation, thereby potentiating T-cell proliferation and infiltration, leading to tumour cell death [16]. In phase III trials, ipilimumab significantly improved overall survival (OS) compared to control in both pretreated and treatment-naïve patients with metastatic melanoma [17], [18]. Many patients treated with ipilimumab at different doses and combinations have long-term survival, with 5-year survival rates ranging from 13% to 36% in phase II trials [19], [20]. Ipilimumab is generally well tolerated, and most adverse events (AEs) are manageable using treatment guidelines established during clinical development [15], [21], [22].

Because of the rarity of metastatic mucosal melanoma, limited data are available to guide treatment decisions. Reported data are most commonly from single-institution retrospective analyses that include patients treated many years ago [23]. Here, findings are reported for a subset of patients with metastatic mucosal melanoma participating in an Expanded Access Programme (EAP) [24]. The aim of this analysis was to evaluate the potential for using ipilimumab at its licensed dose of 3 mg/kg in this patient population.