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Survival after checkpoint inhibitors for metastatic acral, mucosal and uveal melanoma
Nicholas D Klemen1, Melinda Wang1, Jill C Rubinstein2
1Surgery, Yale School of Medicine, New Haven, Connecticut, USA.
Background:
Checkpoint 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.
Methods:
We 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.
Results:
We 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.
Conclusions:
Long 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.
Insights
Checkpoint inhibitors (CPIs) show improved survival in metastatic melanoma, particularly when combining anti-CTLA-4 and anti-PD-1 therapies. Sun-shielded melanomas benefit from this combination, offering hope for long-term survival.
Area of Science:
- Oncology
- Immunology
- Dermatology
Background:
- Cutaneous melanoma's response to checkpoint inhibitors (CPIs) is linked to high neoantigen burden from UV radiation.
- Sun-shielded melanomas (acral, mucosal, uveal) have fewer neoantigens and unique biology, suggesting resistance to immunotherapy.
- Limited evidence exists on CPI efficacy in improving survival for metastatic sun-shielded melanoma.
Purpose of the Study:
- To evaluate the effectiveness of CPIs in patients with metastatic melanoma based on primary tumor site.
- To compare overall survival (OS) outcomes for different melanoma subtypes treated with CPIs.
- To identify factors associated with long-term survival in metastatic melanoma patients receiving CPIs.
Main Methods:
- Retrospective review of 428 metastatic melanoma patients treated with anti-CTLA-4, anti-PD-1, and/or anti-PD-L1 antibodies.
- Categorization of primary tumors into cutaneous, unknown, acral, mucosal, or uveal.
- Analysis of demographic data, treatment characteristics, and overall survival (OS).
Main Results:
- Median OS after CPI was 45 months for cutaneous melanoma versus 17 months (acral), 18 months (mucosal), and 12 months (uveal).
- For sun-shielded melanomas (n=90), median OS was 9 months for anti-PD-1/anti-PD-L1, 18 months for anti-CTLA-4, and 20 months for combination therapy.
- Twenty out of 21 three-year survivors received combination therapy (anti-CTLA-4 and anti-PD-1); over 80% of these survivors with progressive disease received local therapy post-CPI.
Conclusions:
- Combination therapy with anti-CTLA-4 and anti-PD-1 antibodies is associated with improved long-term survival in metastatic melanoma, including sun-shielded subtypes.
- While complete responses are rare, aggressive multidisciplinary approaches, including local therapy, can lead to long-term survival in 25%-32% of sun-shielded melanoma patients.
- Sun-shielded melanomas generally have worse outcomes with CPIs compared to cutaneous melanomas, but combination therapy offers a potential survival benefit.
