Abstract
Several studies have evaluated immune checkpoint inhibitors (ICIs) for metastatic uveal melanoma; however, the efficacy of ICIs in the previous studies varied greatly. In this systematic review, we searched for prospective or retrospective studies on single or dual-ICIs for metastatic uveal melanoma treatment. A random-effect model meta-analysis with generic inverse-variance was conducted, and 36 articles representing 41 cohorts of 1414 patients with metastatic uveal melanoma were included. The pooled outcomes were as follows: objective response rate (ORR) was 5.6% (95% confidence interval [95%CI] 3.7–7.5%; I2, 36%), disease control rate (DCR) was 32.5% (95% CI 27.2–37.7%; I2, 73%), median progression-free survival was 2.8 months (95% CI 2.7–2.9 months; I2, 26%), and median overall survival (OS) was 11.2 months (95% CI 9.6–13.2 months; I2, 74%). Compared to single-agent ICI, dual ICI led to better ORR (single-agent: 3.4% [95% CI 1.8–5.1]; dual-agent: 12.4% [95% CI 8.0–16.9]; P < 0.001), DCR (single-agent: 29.3%, [95% CI 23.4–35.2]; dual-agent: 44.3% [95% CI 31.7–56.8]; P = 0.03), and OS (single-agent: 9.8 months [95% CI 8.0–12.2]; dual-agent: 16.3 months [95% CI 13.5–19.7]; P < 0.001). Our analysis provided treatment outcomes as described above. Dual-ICIs appear better than single-agent ICIs for the treatment of metastatic uveal melanoma.
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Introduction
Uveal melanoma is a rare subtype of melanoma; nevertheless, it is the most common primary intraocular malignancy in adults1,2,3. The prognosis for patients with advanced uveal melanoma remains poor4. A systematic review of 78 articles published between 1980 and 2017 presents the median overall survival (OS) of 12.8 months, although many of these studies were conducted before ICI became available5. Uveal melanoma is considered a tumor distinct from cutaneous melanoma based on clinical and genetic heterogeneities6,7. Particularly, uveal melanoma is characterized by few driver mutations and rare passenger mutations, which has made all kinase inhibitors’ reporting ineffective8,9,10. Therefore, patients with metastatic uveal melanoma have often been treated with immune checkpoint inhibitor (ICI) regimens despite the lack of robust evidence. Tebentafusp, a bispecific T-cell engager, demonstrated the first OS benefit for metastatic melanoma in a HLA-A*02:01-positive patient11. However, the treatment strategy for metastatic uveal melanoma in HLA-A*02:01-negative patients remains to be established. In addition, a recently featured oncological topic is the choice between single-agent and combined ICI for cancer treatments12,13,14,15,16. Particularly, combining nivolumab and ipilimumab has been frequently assessed in trials, and dual ICI regimens, rather than monotherapies, are the first choice for cutaneous melanoma17. However, whether dual ICI therapy is the more plausible treatment for metastatic uveal melanoma than single-agent ICI remains controversial.
To date, several clinical trials and observational studies have evaluated ICIs for metastatic uveal melanoma treatment, and ICI efficacy is of considerable interest to all physicians treating patients with metastatic uveal melanoma. However, ICI efficacy, as reported in previous studies, varies greatly. Therefore, we designed a systematic review and meta-analysis to provide novel insights concerning the objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and OS among patients with metastatic uveal melanoma treated with ICIs with a particular interest in the possible difference between single-agent and dual ICI regimens.
Methods
Protocol registration
The protocol of this systematic review was registered as UMIN000047431 on the University Hospital Medical Information Network (UMIN) Registration website on April 7, 2022 (available at https://www.umin.ac.jp/ctr/index.htm). Institutional review board approval and informed consent were not mandatory because the study involved aggregated data. All methods were performed in accordance with the relevant guidelines and regulations.
Study search
Two investigators (K.Y. and M.T.) systematically and independently searched for eligible articles from electronic databases such as PubMed, Web of Science, Cochrane Central Register of Controlled Trials, and EMBASE until April 7, 2022. The following search formula was used for PubMed: (immune checkpoint inhibitor OR immune checkpoint inhibitors OR ICI OR ICB OR immune checkpoint blockade OR immune checkpoint blockades OR nivolumab OR pembrolizumab OR spartalizumab OR cemiplimab OR avelumab OR atezolizumab OR durvalumb OR ipilimumab OR tremelimumab OR camrelizumab OR sintilimab OR sugemalimab) AND (melanoma) AND (ocular OR eye OR ophthalmological OR intraocular OR uveal OR uvea OR iridal OR iris OR ciliary OR choroidal OR choroid OR chorioidea OR ciliochoroidal). The search terms for the other databases are listed in Supplementary Table 1. Two investigators (K.Y. and M.T.) independently performed additional searches manually. In addition, we attempted to have email communication on a few articles.
Study selection criteria
This systematic review included prospective or retrospective studies reported in English that provided data on at least one of the four outcomes of ICIs for patients with metastatic uveal melanoma. Case reports, studies with fewer than five patients, and conference abstracts were excluded. In addition, the duplicate use of the same data was not permitted.
Patient selection criteria
This study focused on patients with metastatic uveal melanoma Studies focused on non-uveal ocular melanomas, such as iridial and ciliary melanomas, were excluded. However, when a study simply dealt with ocular melanoma, it was not excluded because most ocular melanomas were expected to be uveal melanoma. The metastatic organ of uveal melanoma has not been investigated.
Treatment
Anti-programmed cell death protein 1 (PD-1), anti-programmed death ligand 1 (PD-L1), and anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibodies were used. Both the single-agent and dual-ICI regimens were accepted. Even when the drug’s name was unclear, one article was included in our study. Subgroup analyses separately evaluated the patients who received single-agent therapy and combination therapies. When a study collectively analyzed patients with single- and double-ICI regimens, it was grouped as a “mixed” category. Studies/data on patients receiving combination therapy with non-ICI agents, adjuvant therapy, and neo-adjuvant therapy were excluded.
Outcome
The co-primary endpoints of our analysis were single-arm ORR, DCR, median PFS, and median OS. ORR is the sum of complete and partial responses, and DCR is the sum of complete response, partial response, and stable disease18.
Data extraction
Two review authors (K.Y. and M.T.) independently extracted the research data from the original reports using data extraction form (Supplementary Table 2). When an article described clearly different regimens, data of such a study was subdivided into two or more cohorts.
Study quality assessment
The quality of the included studies was assessed using the Newcastle–Ottawa Scale for cohort studies, wherein a maximum score of eight points indicated the best quality19.
Statistics
The main meta-analyses were performed by applying the random-effects model generic inverse variance method20. In addition, sensitivity meta-analysis based on the fixed-effect model was conducted. The binary outcomes, namely ORR and DCR, were pooled after the standard error (SE) was estimated using the Wilson score interval21. ORR is a measure of the proportion of patients who experience partial or complete response on the response evaluation criteria in solid tumors18. Similarly, DCR indicates the proportion of cases with stable disease, partial response, and complete response. Once the median survival time and 95% confidence interval (CI) were logarithmically transformed, the SE for survival data was calculated assuming a normal distribution using the following formula: SE = (log(upper limit of 95% CI) log (lower limit of 95% CI)) /2/1.9622. When necessary, the 95% CI of survival data was obtained as the time point at which the upper and lower 95% CI of survival proportions crossed 50% of survival. The heterogeneity evaluated with the I2 statistics was interpreted in a standard manner23. In short, 0–40% might not be important, 30%–60% may represent moderate heterogeneity, 50–90% may represent substantial heterogeneity, and 75–100% indicates considerable heterogeneity20.
All analyses were performed using Review Manager ver 5.4.1 (Cochrane Collaboration, Oxford, UK). The figures illustrated using Review Manager were adjusted as necessary.
RESULTS
Study search
Of 808 non-duplicated articles that met the preliminary criteria, 369 and 403 were excluded through title/abstract screening and full article reading, respectively. We identified 36 eligible articles representing 41 single-arm-level cohorts (Supplementary Fig. 1 and Table 1)24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59. The total number of patients in all the studies was 1414 (Table 1). No randomized controlled trial was identified. The number of patients in a cohort treated with ICIs was 5–125 (Table 1). The mean or median age of the patients in each study was 42–67 years. The Newcastle–Ottawa Scale score was 5–7 points, suggesting that most studies were of reasonable quality (Table 1).
Of the 41 cohorts, 28 adopted retrospective studies and 7 were derived from phase I or II trials. Patients in 31 cohorts were treated with ICI monotherapy, including ipilimumab (n = 12), nivolumab (n = 4), pembrolizumab (n = 7), tremelimumab (n = 1), or avelumab (n = 1). Each of the six cohorts collectively assessed patients treated with different single-agent ICIs. In contrast, those in six cohorts were treated with a dual ICI regimen, PD-1 (nivolumab or pembrolizumab) plus CTLA-4 (ipilimumab). Four articles collectively presented data on single-agent ICI and dual ICIs.
Objective response rate
Random-model meta-analysis using the generic inverse variance method suggested a pooled ORR with any ICI regimen of 5.6% (95% CI 3.7–7.5%; I2 = 36%, P for heterogeneity = 0.02; Fig. 1). Despite the low ORR by the single-agent ICI (3.4%, 95% CI 1.8–5.1; I2 = 8%, P for heterogeneity = 0.34), that by dual-ICI (12.4%, 95% CI 8.0–16.9; I2 = 0%, P for heterogeneity = 0.66) achieved a higher ORR (subgroup comparison single-agent versus dual ICIs, P < 0.001).
Disease control rate
The estimated DCR from 34 cohorts was 32.5% (95% CI, 27.2–37.7%; I2 = 73%, P for subgroup heterogeneity < 0.001; Fig. 2). Compared to ICI monotherapy (29.3%, 95% CI 23.4–35.2; I2 = 70%, P for subgroup heterogeneity < 0.001), dual ICI (44.3%, 95% CI 31.7–56.8%; I2 = 68%, P for heterogeneity = 0.008) was effective in more patients with metastatic uveal melanoma (subgroup comparison single-agent versus dual ICIs, P = 0.03, Fig. 2).
Median progression-free survival
Median PFS data were available for 22 cohorts. Half (n = 11) of these studies reported similar median PFS in the narrow range of 2.6–3.0 months with a precise 95% CI (Fig. 3). For instance, Joshua et al. reported a median PFS of 2.9 (95% CI 2.8–3.0 months) 33. The Kaplan–Meier curve reveals a sudden nearly vertical decline in the PFS rate of approximately 2.9 months 33.
A meta-analysis incorporating 22 cohorts suggested that the median PFS was 2.8 months (95% CI 2.7–2.9 months, Fig. 3). Neither the cohort (I2 = 26%, P for heterogeneity = 0.13) nor subgroup-level heterogeneity (I2 = 0%, P for heterogeneity = 0.47) was significant. The aggregated PFS from the single-agent ICI (2.8 months, 95% CI 2.7–3.0; I2 = 22%, P for heterogeneity = 0.2) and that from the dual ICI (3.0 months, 95% CI 2.5–3.5; I2 = 58%, P for heterogeneity = 0.07) were compatible (subgroup comparison single-agent versus dual ICIs, P = 0.52).
Median overall survival
In contrast to the median PFS, the cohort-level median OS greatly varied from 3.8 to 28.0 months (Fig. 4). According to a random-model meta-analysis, the aggregated median OS among patients with metastatic ocular melanoma was 11.2 months (95% CI 9.6–13.2 months; I2 = 74%, P for heterogeneity < 0.001). The patients treated using dual ICI (16.3 months, 95% CI 13.5–19.7 months; I2 = 0%, P for heterogeneity = 0.53) survived longer (subgroup comparison single-agent versus dual ICIs, P < 0.001) than those treated using single-agent ICI (9.8 months, 95% CI 8.0–12.2 months; I2 = 77%, P for heterogeneity < 0.001).
Funnel plot
Funnel plots for ORR, DCR, median PFS, and median OS denied clear publication bias (Supplementary Fig. 2).
Sensitivity analysis
Sensitivity analysis based on a fixed-effect model for ORR, DCR, median PFS, and median OS are illustrated in Supplementary Figs. 3–6. The results indicate the same trend as for the main analysis by using the random-effect model.
Discussion
We performed a systematic review and meta-analysis to focus on patients with metastatic uveal melanoma who were treated with ICIs. The key strengths of our study include the large number of included studies despite the rarity of metastatic uveal melanoma and a straightforward clinical question related to anti-cancer medications. We demonstrated the following key efficacy outcomes: ORR = 5.6%, DCR = 32.5%, PFS = 2.8 months, and OS = 11.2 months. No systematic review has compared the efficacy of mono- and dual-ICI regimens in the treatment of metastatic uveal melanoma. Our data clarified that the efficacy of ICI monotherapy and dual therapy differed, suggesting that ORR with single-agent ICI and dual ICIs should be evaluated separately. In addition, our subgroup analyses clarified the superiority of dual ICI over single-agent ICI for the treatment.
ICI treatment for metastatic uveal melanoma has been evaluated in numerous small uncontrolled trials and observational studies. In a meta-analysis conducted in 2019, Rantala et al. compared the OS of patients treated with different strategies by combining individual patient-level data of 2,494 cases from 78 articles published between 1980 and 2017, although those were mainly conducted during the time before ICI became available3. According to Rantala et al., the median OS after ICI was inferior to that after conventional chemotherapy (hazard ratio 1.13, 95% CI 1.06–1.20, P < 0.0001). They included nine ICI-related studies, which all used ICI monotherapy.
However, single- and dual-agent ICI regimens have recently been regarded as different strategies for various malignancies17. The nivolumab plus ipilimumab, the most frequently selected dual ICI therapy, is considered first-line therapy for renal cell carcinoma12, non-small cell lung cancer13, esophageal cancers14, colorectal cancer15, and pleural mesothelioma16. Dual ICI therapy led to better clinical outcomes in cases with cutaneous melanoma and is a better strategy than ICI monotherapy60,61. In a systematic review, Pradeep et al. aggregated data from nine randomized controlled trials that compared “nivolumab plus ipilimumab” and “nivolumab or ipilimumab” for advanced cutaneous melanoma60. Pradeep et al. showed that the dual ICI regimen resulted in longer OS (hazard ratio = 0.65, 95% CI 0.53–0.79, P < 0.0001), longer PFS (hazard ratio = 0.48, 95% CI 0.38–0.60, P < 0.0001), and higher ORR (relative risk = 2.15, 95% CI 1.63–2.84, P < 0.001) for cutaneous melanoma. A recent review of systematic treatment for metastatic uveal melanoma by Petzold et al. reported the median OS of anti-PD-1/PD-L1 antibodies (10.9 months, 95% confidence interval (CI): 9.8–13.4), anti-CTLA4 antibodies (7.8 months, 95% CI: 6.8–9.3), and dual-ICIs (15.7 months, 95% CI: 14.4–17.9), demonstrating a superior efficacy of dual-ICIs when compared with that with single ICIs, which is consistent with the results of the present study62. In addition, although limited to HLA-A*02:01-positive patients, this study demonstrated the longest median OS in tebentafusp (22.4 months, 95% CI: 19.9–29.6)62.
Uveal and cutaneous melanomas originate from melanocytes and have overlapping risk factors. However, both melanomas have major biological inconsistencies. From a clinical point of view, uveal melanoma frequently causes liver metastasis, whereas cutaneous disease does not. Local growth factors, chemokines, and adhesion molecules may facilitate uveal melanoma cell engraftment to the liver6. Regardless of these differences between cutaneous and uveal melanomas, the results from our analysis (Figs. 1, 2, and 4) and that of Pradeep et al. demonstrated the advantage of the combined ICI regimen for melanoma60. CTLA-4 and PD-1 activate immune reactions to tumor cells by blocking different pathways; therefore, dual administration of both ICIs may precipitate powerful anti-tumor reactions63. Inhibiting only one pathway can lead to upregulation of the other mechanism; however, combined CTLA-4 and PD-1 can simultaneously downregulate both pathways60.
The dual-ICI regimen may prompt more frequent immune-related adverse events (irAEs) than single-agent ICI. Based on previous systematic reviews, pooled frequencies of the key AE indicators caused by dual-ICI are as follows: any AEs, 77.8–81.3%; grade ≥ 3 AEs, 29.3–32.7%; serious AEs, 32.7–34.9%; AE leading to discontinuation, 13.3–28.3%; treatment-related deaths, 0.7–1.0%64,65. Considering the increased risk of AEs associated with the combined use of ICI, it is crucial to carefully deliberate and adopt a personalized approach when determining the treatment strategy for uveal melanoma. This approach aims to minimize the development of potential complications in the management of uveal melanoma.
The current study has some limitations. First, a head-to-head regimen comparison was not performed. Second, strong heterogeneities in some outcomes made it challenging to interpret the results. Third, our analysis could not detect a difference in median PFS between single-agent and combined ICIs. Several studies have reported a median PFS of approximately 3 months. These studies may have detected the progressive disease in numerous cases three months after the first course of administration because imaging evaluations were often scheduled just after four cycles of every three-week treatment. Our meta-analysis could not detect PFS differences; nonetheless, the benefits of dual ICI were consistent in ORR, DCR, and OS. Therefore, we believe that dual ICI therapy is superior in treating metastatic uveal melanoma.
Conclusions
We have reported a systematic review and meta-analysis with particular interest in ICI and the comparison of single- and dual-agent ICIs for the treatment of metastatic uveal melanoma. Despite receiving tebentafusp approval for HLA-A*02:01-positive patients with uveal melanoma, the ICI regimen continues to remain an important choice for the treatment of this disease. Based on the data of 1,414 cases from the 41 cohorts, the pooled ORR, DCR, and OS were 5.6%, 32.5%, and 11.2 months, respectively. Compared to monotherapy, ICI combination therapy (PD-1 + CTLA-4, nivolumab/pembrolizumab plus ipilimumab) significantly improved these outcomes. Our results inform the expected treatment-related outcomes and suggest a future need for randomized trials regarding the dual ICI strategy for metastatic uveal melanoma.
Data availability
The data supporting the findings of this study are available from the corresponding author upon reasonable request.
References
Pandiani, C., Béranger, G. E., Leclerc, J., Ballotti, R. & Bertolotto, C. Focus on cutaneous and uveal melanoma specificities. Genes Dev. 31, 724–743. https://doi.org/10.1101/gad.296962.117 (2017).
Orloff, M. Clinical trials in metastatic uveal melanoma: Immunotherapy. Ocul. Oncol. Pathol. 7, 168–176. https://doi.org/10.1159/000513336 (2021).
Rantala, E. S., Hernberg, M. M., Piperno-Neumann, S., Grossniklaus, H. E. & Kivelä, T. T. Metastatic uveal melanoma: The final frontier. Prog. Retin. Eye Res. 90, 101041. https://doi.org/10.1016/j.preteyeres.2022.101041 (2022).
Damato, B. E., Dukes, J., Goodall, H. & Carvajal, R. D. Tebentafusp: T cell redirection for the treatment of metastatic uveal melanoma. Cancers https://doi.org/10.3390/cancers11070971 (2019).
Rantala, E. S., Hernberg, M. & Kivela, T. T. Overall survival after treatment for metastatic uveal melanoma: A systematic review and meta-analysis. Melanoma Res. 29, 561–568. https://doi.org/10.1097/CMR.0000000000000575 (2019).
Wessely, A. et al. The Role of Immune Checkpoint Blockade in Uveal Melanoma. Int. J. Mol. Sci. https://doi.org/10.3390/ijms21030879 (2020).
Hodi, F. S. et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363, 711–723. https://doi.org/10.1056/NEJMoa1003466 (2010).
Cohen, Y. et al. Lack of BRAF mutation in primary uveal melanoma. Investig. Ophthalmol. Vis. Sci. 44, 2876–2878. https://doi.org/10.1167/iovs.02-1329 (2003).
Edmunds, S. C. et al. Absence of BRAF gene mutations in uveal melanomas in contrast to cutaneous melanomas. Br. J. Cancer 88, 1403–1405. https://doi.org/10.1038/sj.bjc.6600919 (2003).
Rimoldi, D. et al. Lack of BRAF mutations in uveal melanoma. Cancer Res. 63, 5712–5715 (2003).
Nathan, P. et al. Overall survival benefit with tebentafusp in metastatic uveal melanoma. N. Engl. J. Med. 385, 1196–1206. https://doi.org/10.1056/NEJMoa2103485 (2021).
Motzer, R. J. et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N. Engl. J. Med. 378, 1277–1290. https://doi.org/10.1056/NEJMoa1712126 (2018).
Hellmann, M. D. et al. Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. N. Engl. J. Med. 378, 2093–2104. https://doi.org/10.1056/NEJMoa1801946 (2018).
Janjigian, Y. Y. et al. CheckMate-032 study: Efficacy and safety of nivolumab and nivolumab plus ipilimumab in patients with metastatic esophagogastric cancer. J. Clin. Oncol. 36, 2836–2844. https://doi.org/10.1200/jco.2017.76.6212 (2018).
Overman, M. J. et al. Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer. J. Clin. Oncol. 36, 773–779. https://doi.org/10.1200/jco.2017.76.9901 (2018).
Baas, P. et al. First-line nivolumab plus ipilimumab in unresectable malignant pleural mesothelioma (CheckMate 743): A multicentre, randomised, open-label, phase 3 trial. Lancet 397, 375–386. https://doi.org/10.1016/s0140-6736(20)32714-8 (2021).
Fukumoto, T. & Horita, N. Single or dual immune checkpoint inhibitor as adjuvant therapy in advanced melanoma. Eur. J. Cancer 147, 140–141. https://doi.org/10.1016/j.ejca.2021.01.031 (2021).
Eisenhauer, E. A. et al. New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur. J. cancer 45, 228–247. https://doi.org/10.1016/j.ejca.2008.10.026 (2009).
Stang, A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur. J. Epidemiol. 25, 603–605. https://doi.org/10.1007/s10654-010-9491-z (2010).
Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, Welch VA. Cochrane Handbook for Systematic Reviews of Interventions version 6.3 http://handbook.cochrane.org/front_page.htm (Accessed February 2022) (2022).
Wilson, E. B. Probable inference, the law of succession, and statistical inference. J. Am. Stat. Assoc. 22, 209–212. https://doi.org/10.1080/01621459.1927.10502953 (1927).
Zang, J., Xiang, C. & He, J. Synthesis of median survival time in meta-analysis. Epidemiology 24, 337–338. https://doi.org/10.1097/EDE.0b013e318282a66c (2013).
Higgins, J. P., Thompson, S. G., Deeks, J. J. & Altman, D. G. Measuring inconsistency in meta-analyses. BMJ 327, 557–560. https://doi.org/10.1136/bmj.327.7414.557 (2003).
Ahmad, S. S. et al. Ipilimumab in the real world: The UK expanded access programme experience in previously treated advanced melanoma patients. Melanoma Res. 25, 432–442. https://doi.org/10.1097/cmr.0000000000000185 (2015).
Alexander, M., Mellor, J. D., McArthur, G. & Kee, D. Ipilimumab in pretreated patients with unresectable or metastatic cutaneous, uveal and mucosal melanoma. Med. J. Aust. 201, 49–53. https://doi.org/10.5694/mja13.10448 (2014).
Algazi, A. P. et al. Clinical outcomes in metastatic uveal melanoma treated with PD-1 and PD-L1 antibodies. Cancer 122, 3344–3353. https://doi.org/10.1002/cncr.30258 (2016).
Bender, C., Enk, A., Gutzmer, R. & Hassel, J. C. Anti-PD-1 antibodies in metastatic uveal melanoma: A treatment option?. Cancer Med. 6, 1581–1586. https://doi.org/10.1002/cam4.887 (2017).
Bol, K. F. et al. Real-world impact of immune checkpoint inhibitors in metastatic uveal melanoma. Cancers https://doi.org/10.3390/cancers11101489 (2019).
Danielli, R. et al. Ipilimumab in pretreated patients with metastatic uveal melanoma: Safety and clinical efficacy. Cancer Immunol. Immunother. 61, 41–48. https://doi.org/10.1007/s00262-011-1089-0 (2012).
Heppt, M. V. et al. Prognostic factors and outcomes in metastatic uveal melanoma treated with programmed cell death-1 or combined PD-1/cytotoxic T-lymphocyte antigen-4 inhibition. Eur. J. Cancer 82, 56–65. https://doi.org/10.1016/j.ejca.2017.05.038 (2017).
Jansen, Y. J. L., Seremet, T. & Neyns, B. Pembrolizumab for the treatment of uveal melanoma: A case series. Rare tumors 12, 2036361320971983. https://doi.org/10.1177/2036361320971983 (2020).
Johnson, D. B. et al. Response to Anti-PD-1 in uveal melanoma without high-volume liver metastasis. J. Natl. Compr. Cancer Netw. 17, 114–117. https://doi.org/10.6004/jnccn.2018.7070 (2019).
Joshua, A. M. et al. A phase 2 study of tremelimumab in patients with advanced uveal melanoma. Melanoma Res. 25, 342–347. https://doi.org/10.1097/cmr.0000000000000175 (2015).
Karydis, I. et al. Clinical activity and safety of pembrolizumab in ipilimumab pre-treated patients with uveal melanoma. Oncoimmunology 5, e1143997. https://doi.org/10.1080/2162402x.2016.1143997 (2016).
Keilholz, U. et al. Avelumab in patients with previously treated metastatic melanoma: Phase 1b results from the JAVELIN solid tumor trial. J. Immunother. Cancer 7, 12. https://doi.org/10.1186/s40425-018-0459-y (2019).
Kelderman, S. et al. Ipilimumab in pretreated metastastic uveal melanoma patients. results of the dutch working group on immunotherapy of oncology (WIN-O). Acta Oncologica 52, 1786–1788. https://doi.org/10.3109/0284186x.2013.786839 (2013).
Kelly, D. et al. Development of a metastatic uveal melanoma prognostic score (MUMPS) for use in patients receiving immune checkpoint inhibitors. Cancers https://doi.org/10.3390/cancers13143640 (2021).
Khattak, M. A., Fisher, R., Hughes, P., Gore, M. & Larkin, J. Ipilimumab activity in advanced uveal melanoma. Melanoma Res. 23, 79–81. https://doi.org/10.1097/CMR.0b013e32835b554f (2013).
Kirchberger, M. C., Moreira, A., Erdmann, M., Schuler, G. & Heinzerling, L. Real world experience in low-dose ipilimumab in combination with PD-1 blockade in advanced melanoma patients. Oncotarget 9, 28903–28909. https://doi.org/10.18632/oncotarget.25627 (2018).
Klemen, N. D. et al. Survival after checkpoint inhibitors for metastatic acral, mucosal and uveal melanoma. J. Immunother. Cancer https://doi.org/10.1136/jitc-2019-000341 (2020).
Koch, E. A. T. et al. Immune checkpoint blockade for metastatic uveal melanoma: Re-induction following resistance or toxicity. Cancers https://doi.org/10.3390/cancers14030518 (2022).
van der Kooij, M. K. et al. Anti-PD1 treatment in metastatic uveal melanoma in the Netherlands. Acta Oncol. 56, 101–103. https://doi.org/10.1080/0284186x.2016.1260773 (2017).
Kottschade, L. A. et al. The use of pembrolizumab for the treatment of metastatic uveal melanoma. Melanoma Res. 26, 300–303. https://doi.org/10.1097/cmr.0000000000000242 (2016).
Luke, J. J. et al. Clinical activity of ipilimumab for metastatic uveal melanoma: A retrospective review of the dana-farber cancer institute, massachusetts general hospital, memorial sloan-kettering cancer center, and university hospital of lausanne experience. Cancer 119, 3687–3695. https://doi.org/10.1002/cncr.28282 (2013).
Maio, M. et al. Efficacy and safety of ipilimumab in patients with pre-treated, uveal melanoma. Ann.Oncol. 24, 2911–2915. https://doi.org/10.1093/annonc/mdt376 (2013).
Mignard, C. et al. Efficacy of immunotherapy in patients with metastatic mucosal or uveal melanoma. J. Oncol. 2018, 1908065. https://doi.org/10.1155/2018/1908065 (2018).
Moser, J. C. et al. The Mayo Clinic experience with the use of kinase inhibitors, ipilimumab, bevacizumab, and local therapies in the treatment of metastatic uveal melanoma. Melanoma Res. 25, 59–63. https://doi.org/10.1097/cmr.0000000000000125 (2015).
Najjar, Y. G. et al. Ipilimumab plus nivolumab for patients with metastatic uveal melanoma: A multicenter, retrospective study. J. Immunother. Cancer https://doi.org/10.1136/jitc-2019-000331 (2020).
Namikawa, K. et al. Nivolumab for patients with metastatic uveal melanoma previously untreated with ipilimumab: A single-institution retrospective study. Melanoma Res. 30, 76–84. https://doi.org/10.1097/cmr.0000000000000617 (2020).
Nathan, P. et al. Safety and efficacy of nivolumab in patients with rare melanoma subtypes who progressed on or after ipilimumab treatment: A single-arm, open-label, phase II study (CheckMate 172). Eur. J. Cancer 119, 168–178. https://doi.org/10.1016/j.ejca.2019.07.010 (2019).
Pelster, M. S. et al. Nivolumab and ipilimumab in metastatic uveal melanoma: Results from a single-arm phase II study. J. Clin. Oncol. 39, 599–607. https://doi.org/10.1200/jco.20.00605 (2021).
Piulats, J. M. et al. Nivolumab plus ipilimumab for treatment-naïve metastatic uveal melanoma: An open-label, multicenter, phase II trial by the spanish multidisciplinary melanoma group (GEM-1402). J. Clin. Oncol. 39, 586–598. https://doi.org/10.1200/jco.20.00550 (2021).
Rossi, E. et al. Pembrolizumab as first-line treatment for metastatic uveal melanoma. Cancer Immunol. Immunother. 68, 1179–1185. https://doi.org/10.1007/s00262-019-02352-6 (2019).
Sander, M. S. et al. Evaluation of the modified immune prognostic index to prognosticate outcomes in metastatic uveal melanoma patients treated with immune checkpoint inhibitors. Cancer Med. 10, 2618–2626. https://doi.org/10.1002/cam4.3784 (2021).
Tacar, S. Y. et al. Nivolumab for metastatic uveal melanoma: A multicenter, retrospective study. Melanoma Res. 31, 449–455. https://doi.org/10.1097/cmr.0000000000000744 (2021).
Wiater, K. et al. Efficacy and safety of ipilimumab therapy in patients with metastatic melanoma: A retrospective multicenter analysis. Contemp. oncol. 17, 257–262. https://doi.org/10.5114/wo.2013.35785 (2013).
Xu, L. T. et al. Uveal melanoma metastatic to the liver: Treatment trends and outcomes. Ocul. oncol. Pathol. 5, 323–332. https://doi.org/10.1159/000495113 (2019).
Turkish Oncology Group study. Arzu Yaşar, H. et al. Prognostic factors for survival in patients with mucosal and ocular melanoma treated with ipilimumab. J. Oncol. Pharm. Pract. 26, 267–272. https://doi.org/10.1177/1078155219840796 (2020).
Zimmer, L. et al. Phase II DeCOG-study of ipilimumab in pretreated and treatment-naïve patients with metastatic uveal melanoma. PloS ONE 10, e0118564. https://doi.org/10.1371/journal.pone.0118564 (2015).
Pradeep, J., Win, T. T., Aye, S. N. & Sreeramareddy, C. T. Efficacy and safety of immune checkpoint inhibitors for advanced malignant melanoma: A meta-analysis on monotherapy vs combination therapy. J. Cancer 13, 3091–3102. https://doi.org/10.7150/jca.72210 (2022).
Zhu, Y. et al. The efficacy and safety of combined ipilimumab and nivolumab versus ipilimumab in patients with Stage III/IV unresectable melanoma: A systematic review and meta-analysis. J. Cancer Res. Ther. 17, 1679–1688. https://doi.org/10.4103/jcrt.jcrt_1669_21 (2021).
Petzold, A. et al. Is tebentafusp superior to combined immune checkpoint blockade and other systemic treatments in metastatic uveal melanoma? A comparative efficacy analysis with population adjustment. Cancer Ttreat. Rev. 115, 102543. https://doi.org/10.1016/j.ctrv.2023.102543 (2023).
Khair, D. O. et al. Combining immune checkpoint inhibitors: established and emerging targets and strategies to improve outcomes in melanoma. Front. Immunol. 10, 453. https://doi.org/10.3389/fimmu.2019.00453 (2019).
Matsumoto, H. et al. Adverse events induced by durvalumab and tremelimumab combination regimens: A systematic review and meta-analysis. Ther. Adv. Med. Oncol. 15, 17588359231198452. https://doi.org/10.1177/17588359231198453 (2023).
Somekawa, K. et al. Adverse events induced by nivolumab and ipilimumab combination regimens. Ther. Adv. Med. Oncol. https://doi.org/10.1177/17588359211058393 (2022).
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The authors thank Dr. Yoshitake Yamada and Kiyomi Abe for their valuable assistance.
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K.Y., M.T., N.H., T.F., N.M. were responsible for the conception or design of the work. K.Y., M.T., N.H., T.F. were responsible for the acquisition, analysis, or interpretation of data. K.Y., M.T., N.H. drafted the manuscript. All authors revised the manuscript for important intellectual content. All authors approved the manuscript for submission.
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Yamada, K., Takeuchi, M., Fukumoto, T. et al. Immune checkpoint inhibitors for metastatic uveal melanoma: a meta-analysis. Sci Rep 14, 7887 (2024). https://doi.org/10.1038/s41598-024-55675-5
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DOI: https://doi.org/10.1038/s41598-024-55675-5
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