Outcomes of acral, mucosal, and uveal melanoma with treatment from checkpoint inhibitors - spoiler alert - get the immunotherapy combo!!!!

As I've said many times, Melanoma sucks great big hairy green stinky wizard balls.  Sadly, ocular, mucosal, and acral (think -fingers, palms, soles, nail beds) sucks even more.  Here are some prior reports:  https://chaoticallypreciselifeloveandmelanoma.blogspot.com/search?q=mucosal+melanoma

Now, there's this ~

Survival after checkpoint inhibitors for metastatic acral, mucosal and uveal melanoma.  Klemen, Wang, Rubinstein...Sznol.  J Immunother Cancer. 2020 Mar 8.

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.

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.

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, 18 months for mucosal, and 12 months for uveal. 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 and 20 months after combination therapy. 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.

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.

In this report 90 patients with "sun shielded melanoma" (either acral, mucosal, or uveal) first treated with anti-PD-1 or anti-PD-L1 had median survival of 9 months vs OS of 18 months with anti-CTLA-4 vs 20 months OS with combination therapy.  21 of these 90 patients achieved 3 year survival, with 20 of those getting both anti-CTLA-4 and anti-PD-1 either sequentially or together.  80% of the 3-year survivors were also treated with local therapy after immunotherapy.

My take - if you have this sort of melanoma.  Get the combo - from the start!!!

For what it's worth.  Take care.  - c

Late addition:  

Ipilimumab plus nivolumab for patients with metastatic uveal melanoma: a multicenter, retrospective study.  Najjar, Navrazhina, Ding, et al.  J Immunother Cancer.  June 2020.

Background: Uveal melanoma (UM) is the most common intraocular malignancy in adults. In contrast to cutaneous melanoma (CM), there is no standard therapy, and the efficacy and safety of dual checkpoint blockade with nivolumab and ipilimumab is not well defined.

Methods: We conducted a retrospective analysis of patients with metastatic UM (mUM) who received treatment with ipilimumab plus nivolumab across 14 academic medical centers. Toxicity was graded using National Cancer Institute Common Terminology Criteria for Adverse Events V.5.0. Progression-free survival (PFS) and overall survival (OS) were calculated using Kaplan-Meier methodology.

Results: 89 eligible patients were identified. 45% had received prior therapy, which included liver directed therapy (29%), immunotherapy (21%), targeted therapy (10%) and radiation (16%). Patients received a median 3 cycles of ipilimumab plus nivolumab. The median follow-up time was 9.2 months. Overall response rate was 11.6%. One patient achieved complete response (1%), 9 patients had partial response (10%), 21 patients had stable disease (24%) and 55 patients had progressive disease (62%). Median OS from treatment initiation was 15 months and median PFS was 2.7 months. Overall, 82 (92%) of patients discontinued treatment, 34 due to toxicity and 27 due to progressive disease. Common immune-related adverse events were colitis/diarrhea (32%), fatigue (23%), rash (21%) and transaminitis (21%).

Conclusions: Dual checkpoint inhibition yielded higher response rates than previous reports of single-agent immunotherapy in patients with mUM, but the efficacy is lower than in metastatic CM. The median OS of 15 months suggests that the rate of clinical benefit may be larger than the modest response rate.

For what it's worth - c