Survival after checkpoint inhibitors for metastatic acral, mucosal and uveal melanoma

Abstract

BackgroundCheckpoint inhibitors (CPIs) are thought to be effective against cutaneous melanoma in part because of the large burden of somatic mutations (neoantigens) generated from exposure to ultraviolet radiation. However, rare melanoma subtypes arising from acral skin, mucosal surfaces, and the uveal tract are largely sun-shielded. Genomic studies show these sun-shielded melanomas have a paucity of neoantigens and unique biology; they are thought to be largely resistant to immunotherapy. It has not been definitively shown that CPI improves survival in metastatic sun-shielded melanoma.MethodsWe reviewed a single institutional experience using antibodies against CTLA-4, PD-1 and/or PD-L1 to treat patients with metastatic melanoma. Primary tumor histology was categorized as cutaneous, unknown, acral, mucosal, or uveal. We studied demographic data, treatment characteristics, and overall survival (OS) after CPI.ResultsWe treated 428 patients with metastatic melanoma from 2007 to 2019. Primary tumors were cutaneous in 283 (66%), unknown in 55 (13%), acral in 22 (5%), mucosal in 38 (9%), and uveal in 30 (7%). Patients with metastatic disease from cutaneous primary tumors had median OS after CPI of 45 months compared with 17 months for acral (p=0.047), 18 months for mucosal (p=0.003), and 12 months for uveal (p<0.001). For all patients with sun-shielded melanoma (n=90), first treatment with anti-PD-1 or anti-PD-L1 was followed by a median OS of 9 months compared with 18 months after anti-CTLA-4 (p=0.010) and 20 months after combination therapy (p=0.003). There were 21 patients who achieved actual 3-year survival; 20 received both anti-CTLA-4 and anti-PD-1, either sequentially or in combination. Over 80% of 3-year survivors with progressive disease were treated with local therapy after CPI.ConclusionsLong survival in patients with metastatic melanoma from acral, mucosal, and uveal primary tumors was associated with receipt of both anti-CTLA-4 and anti-PD-1 antibodies. Complete responses were rare, and local therapy was frequently employed to control disease progression. While sun-shielded melanomas exhibit worse outcomes after CPI than cutaneous melanomas, with an aggressive multidisciplinary approach, 5-year survival is still possible for 25%–32% of these patients.

Biologic subtypes of melanoma predict survival benefit of combination anti-PD1+anti-CTLA4 immune checkpoint inhibitors versus anti-PD1 monotherapy

“…In our study, acral or mucosal melanoma subtypes predicted poor response to anti-PD1 monotherapy, in line with previous studies. 16–18 These tumor types are rare, and the reported numbers of patients with acral or mucosal melanoma that were treated with anti-PD1 ICI were small; our data provide further validation of these observations. The unique genomic make-up of acral and mucosal melanomas, as described above, may explain their relative insensitivity to anti-PD1 ICI compared with cutaneous melanomas.…”

Treatment of Metastatic Uveal Melanoma: Systematic Review

“…For this reason, it has been precisely this immunological field on which studies in recent years have focused their attention in a very noticeable way, as can be seen in the articles included in this review [ 21 , 22 , 50 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 ].…”

“…In this treatment group, it is remarkable how a few exceptional events are observed in certain studies. Extreme survival can be appreciated in the four alive patients at 5 years in the study by Klemen et al [ 85 ] or the 46 months reached by a patient in the study by Bol et al [ 21 ] with ipilimumab.…”

“…Within the group of immunotherapy, it should be highlighted the work of Klemen et al, where 20% of patients reach 5 years of survival; the authors have attributed this result to those patients that have received anti-CTLA-4 and anti-PD-1, either sequentially or in combination. Although they cannot rule out that it is due to the selection of the patients or to a reduced number of the samples [ 85 ].…”

The emerging role of immunotherapy for the treatment of sarcoma

“…For example, cutaneous melanoma, which has a large burden of neoantigens due to UV mutagenesis, is highly sensitive to checkpoint blockade. In contrast, sun‐shielded melanomas including acral lentiginous, mucosal, or uveal melanomas have a paucity of neoantigens and are less responsive 63 . Mismatch repair‐proficient colorectal cancer has a low TMB and is unresponsive to anti‐PD‐1, but mismatch repair‐deficient colorectal cancer has a high TMB and is highly sensitive 60 …”