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Nivolumab and Ipilimumab in the Treatment of Metastatic Uveal Melanoma: A Single-Center Experience

Nivolumab and Ipilimumab in the Treatment of Metastatic Uveal Melanoma: A Single-Center Experience Hindawi Case Reports in Oncological Medicine Volume 2019, Article ID 3560640, 8 pages https://doi.org/10.1155/2019/3560640 Case Series Nivolumab and Ipilimumab in the Treatment of Metastatic Uveal Melanoma: A Single-Center Experience 1 1 1 2 Vidhya Karivedu , Ihab Eldessouki , Ahmad Taftaf , Zheng Zhu , 3 4 Abouelmagd Makramalla , and Nagla Abdel Karim Department of Internal Medicine, Division of Hematology/Oncology, University of Cincinnati College of Medicine, Cincinnati, OH, USA Department of Biostatistics and Bioinformatics, Department of Environmental Health, College of Medicine, University of Cincinnati, Cincinnati, OH, USA Division of Vascular and Interventional Radiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA Department of Internal Medicine, Division of Hematology/Oncology, Medical College of Georgia-Augusta University, Augusta, GA, USA Correspondence should be addressed to Vidhya Karivedu; kariveva@ucmail.uc.edu Received 30 November 2018; Accepted 25 March 2019; Published 17 April 2019 Academic Editor: Jose I. Mayordomo Copyright © 2019 Vidhya Karivedu et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background. Metastatic uveal melanoma (MUM) is associated with a poor prognosis, with a median overall survival (OS) of 4–15 months. Despite new insights into the genetic and molecular background of MUM, satisfactory systemic treatment approaches are currently lacking. The study results of innovative treatment strategies are urgently needed. Patients and Methods. This was a retrospective case series of 8 patients with MUM managed at the University of Cincinnati between January 2015 and January 2018. The immune-related Response Evaluation Criteria in Solid Tumors (irRECIST) 1.1 criteria were used for patient evaluation, and magnetic resonance imaging was used for evaluation at treatment checkpoints. Objective. To assess the clinical outcome of patients with MUM treated with a combination of checkpoint inhibitors. Results. The series included eight patients, six men and two women, with MUM. Their median age at MUM diagnosis was 69 (range, 55–77) years. All patients were treated with ipilimumab and nivolumab combination along with transarterial chemoembolization (TACE), followed by nivolumab maintenance and monthly TACE procedures. The majority of patients had a partial response or stable disease. Two of the patients had partial response, while four others had stable disease. Two other patients experienced disease progression. Conclusion. We report the outcomes of eight patients with MUM treated with the combination of ipilimumab and nivolumab. We report the clinical outcome and toxicity associated with this treatment approach. Further studies are warranted to explore immunotherapy in MUM. These findings support the consideration of immunotherapy in MUM. 1. Introduction among Caucasians compared to that in other ethnic groups [3, 4]. Despite effective local therapies, there is a high poten- Uveal melanoma (UM) is the most common primary intra- tial for metastases even after a prolonged period of remission ocular malignancy in adults. It accounts for <5% of all mela- [4, 5]. While the cumulative five- and ten-year metastatic noma cases in the United States [1, 2]. UM can arise from rates reported by the Collaborative Ocular Melanoma Study melanocytes located along the uveal tract, which is the pig- (COMS) Group were 25% and 34%, respectively, up to 50% of patients develop metastatic disease [6, 7]. The predomi- mented layer composed of the iris and ciliary body anteriorly and choroid posteriorly. UM is a rare form of melanoma, nant target organ for metastases is the liver (89%). Metastases with an approximate incidence rate of 1,500 new cases diag- to the skin, bone, brain, and lungs have also been reported nosed each year in the US. There is a higher prevalence [8]. According to the TNM staging of metastatic disease in 2 Case Reports in Oncological Medicine cycles of treatment, imaging revealed the same number of uveal melanoma (MUM), M0 is defined as the absence of dis- tant metastasis, while M1a is a disease with distant metastasis hypodense lesions; the largest lesion measured 5 5×3 4 cm with the largest diameter of 3 cm or less, M1b is metastatic (Figure 1). In July 2016, treatment was stopped due to severe disease with the largest diameter of 3.1 to 8 cm, and M1c is autoimmune colitis as a side effect of the immunotherapy. metastatic disease with the largest diameter of 8 cm or more Later that year, in September 2016, the patient continued [9, 10]. Multiple therapeutic approaches for MUM have been nivolumab alone (240 mg every 2 weeks), which was also dis- studied but none has shown any impact on the overall sur- continued in February 2017 due to intolerance. Since then, vival (OS) [11]. Recent studies have shown that outcomes the patient had received transarterial chemoembolization of patient with MUM are dismal with median overall survival (TACE) for the hepatic lesions. In June 2017, the patient of 12 months from the time of metastasis diagnosis [12]. developed progressive disease, with an LDH of 317 U/L and ALP of 426 U/L. The patient was enrolled to hospice care There is no established standard of care for the systemic ther- apy of patients with MUM as they are usually excluded from and the patient expired within a month. large randomized trials; thus, the current treatment paradigm is based on the National Comprehensive Cancer Network 2.2. Case 2. A 69-year-old man was referred to an ocular (NCCN) guidelines [13]. Liver-directed therapies such as oncologist in 2014 due to visual changes in his left eye. He liver resection in a small subset of patients may induce remis- underwent enucleation in 2014 and histopathology showed sion in the setting of single-site metastases potentially T3aN0M0 choroidal melanoma. He underwent systemic prolonging OS, albeit with a high recurrence rate [7, 14]. staging and did not have metastatic disease at the time. Later UM is clinically and biologically distinct from cutaneous in April 2016, surveillance imaging showed multiple pulmo- melanoma. However, the systemic management of MUM is nary nodules (M1a), which were diagnosed as metastatic dis- adapted from that of cutaneous melanoma. Major improve- ease by right lung lower lobe wedge resection confirmed by ments have followed the introduction of BRAF/MEK inhibi- IHC (HMB-45 and MART-1), with an LDH of 191 U/L tors and immunotherapy in metastatic cutaneous melanoma. and ALP of 84 U/L. In July 2016, the patient started nivolu- Unlike cutaneous melanoma, several studies report lack of mab (1 mg/kg) and ipilimumab (3 mg/kg) administered BRAF kinase mutations, suggesting lack of benefit from every 3 weeks. Upon completion of four cycles, the treatment BRAF inhibitors in patients with advanced uveal melanoma was stopped due to autoimmune colitis as a side effect of [15–17]. Oncogenic mutations in G-protein subunits a immunotherapy. Imaging surveillance in September 2016 (GNAQ) and 11 (GNA11) have been described in 80% of showed progressive disease, with an LDH of 231 U/L and uveal melanomas [18]. ALP of 89 U/L, and the patient started treatment with nab- Small retrospective studies have reported low response paclitaxel and he continues to have stable disease with no rates to PD-1 inhibitor monotherapy for MUM. The combi- signs of disease progression for 18 months now. nation of nivolumab and ipilimumab has shown a survival benefit in patients with cutaneous melanoma at the expense 2.3. Case 3. A 77-year-old man was referred to an ocular of immune-related toxicities and has been approved for the oncologist in 2014 for visual changes in his right eye. He management of metastatic cutaneous melanoma [19–21]. was diagnosed with a choroidal melanoma by histopathology Patients with MUM were excluded from most of the clinical and IHC, treated with I-125 plaque brachytherapy. Surveil- trials; thus, the safety and efficacy of the currently studied lance imaging in March 2017 showed liver and pulmonary combinations remain unclear, especially the ocular toxicity lesions (M1a), with an LDH of 168 U/L and ALP of 54 U/L. of the combination in patients with MUM [22–24]. Ongoing A liver nodule biopsy confirmed the presence of MUM. trials are evaluating the combination of CTLA-4 and PD1 The patient completed selective internal radiation therapy blockade in MUM [25, 26]. (SIRT) to the liver metastases in March 2017. In March In this study, we report our experience in treating 2017, the patient also started treatment with nivolumab patients with MUM with the combination of ipilimumab (1 mg/kg) and ipilimumab (3 mg/kg) every 3 weeks for a and nivolumab. total of four cycles, followed by nivolumab maintenance (240 mg). The patient also underwent TACE simultaneously with immunotherapy every 5–6 weeks starting from May 2. Case Series 2017. Nivolumab was stopped in March 2018 due to throm- 2.1. Case 1. A 68-year-old man was initially diagnosed with bocytopenia, and the patient continued TACE every eight right primary choroidal melanoma by histopathology and weeks until September 2018 and later discontinued due to immunohistochemistry (IHC). He was treated with I-125 no tumor growth. Repeat imaging in February 2019 showed plaque brachytherapy in 2013. In April 2016, an abdominal stable disease. ultrasonography (US) revealed multiple scattered hypodense lesions throughout the liver; the largest lesion was within seg- 2.4. Case 4. A 76-year-old woman was referred to an ocular oncologist in 2014 for visual changes in her left eye and was ment 7 measuring 6 6× 5 1 cm (M1b). A US-guided liver biopsy confirmed a recurrence, with a lactic acid dehydroge- diagnosed with a ciliochoroidal melanoma by histopathol- ogy, treated with I-125 plaque brachytherapy. Surveillance nase (LDH) level of 220 U/L (110-270 U/L) and alkaline phosphatase (ALP) of 22 (7-52 U/L). In April 2016, the imaging in June 2017 showed multiple liver lesions with the patient started a combination of ipilimumab (3 mg/kg) and largest measuring 4 5×3 5 cm (M1b). A liver biopsy con- nivolumab (1 mg/kg) administered every 3 weeks. After three firmed MUM. The patient started therapy with nivolumab Case Reports in Oncological Medicine 3 (a) (b) Figure 1: (a) Pretreatment scans (MRI). Axial T2 WI (A) and postcontrast (Eovist) Axial T1 WI (B) showing a 7 cm mass in the right liver lobe (arrows) and multiple smaller lesions in both liver lobes. (b) Posttreatment scans (MRI). Axial T2 WI (A) and postcontrast (Eovist) Axial T1 WI (B) show the decrease in size of the largest mass in the right liver lobe (arrows). (a) (b) Figure 2: (a) Pretreatment scan (8/22/2016) (MRI). Axial T2 WI (A) and postcontrast (Eovist) Axial T1 WI (B) showing an 11 cm mass in the left liver lobe (arrows) and multiple smaller lesions in both liver lobes. (b) Ongoing treatment (5/2/2018) (MRI). Axial T2 WI (A) and postcontrast (Eovist) Axial T1 WI (B) show the decrease in size of the largest mass in the left liver lobe (arrows) now measuring 4.8 cm with no enhancement. There is a decrease in size and number of the multiple smaller lesions in both liver lobes. (1 mg/kg) and ipilimumab (3 mg/kg) every 3 weeks for four nivolumab/ipilimumab, he started maintenance nivolumab cycles, followed by maintenance nivolumab (240 mg) every (240 mg every 3 weeks) in January 2017. Repeat imaging two weeks simultaneously with TACE every 4 weeks. In showed continued response until August 2018. Imaging in October 2017, imaging showed stable liver lesions. Imaging September 2018 showed progression of disease; therapy surveillance in November 2017 showed the progression of switched to nab-paclitaxel. The patient currently has stable dis- the liver lesions, with an LDH of 466 U/L and ALP of 442 ease on nab-paclitaxel and TACE q8 weeks as of March 2019. U/L. Nivolumab was discontinued in November 2017, and the patient expired in January 2018. 2.6. Case 6. A 63-year-old man was initially referred to an ocular oncologist in February 2016 due to a visual change 2.5. Case 5. In 2014, a 65-year-old man was referred to an in his left eye. He was diagnosed with ciliochoroidal mela- noma by histopathology, T4bN0M0. He was treated with ocular oncologist for a visual change in his left eye and diagnosed with choroidal melanoma by histopathology enucleation of his left eye. In February 2017, surveillance and IHC, treated with enucleation, T1aN0M0. Surveillance imaging showed liver lesions, with the largest measuring imaging first showed hepatic lesions in January 2016. 2 2×2 1 cm in hepatic segment 7 (M1a) and an LDH of Active surveillance in August 2016 revealed that his liver 194 U/L, ALP of 94 U/L; biopsy confirmed metastatic lesions had increased in size and number with the largest melanoma. The patient started treatment with nivolumab lesion measuring 7 1×5 8 cm (M1b), with an LDH of (1 mg/kg) and ipilimumab (3 mg/kg) in May 2017. After 641 U/L and ALP of 111 U/L. Liver biopsy confirmed MUM. two doses of a combination of ipilimumab and nivolumab, The patient started therapy with nivolumab (1 mg/kg) he developed colitis, which was treated with prednisone. and ipilimumab (3 mg/kg) every 2 weeks simultaneously Repeated imaging in June 2017 showed a decrease in the size with TACE every 4 weeks in September 2016. A repeated of the metastatic hepatic lesion, from 2 2×2 1 to 1 7×1 5 abdominal magnetic resonance imaging (MRI) in November cm (Figure 3). The patient started nivolumab (240 mg every 2016 showed a marked decrease in the size and number of 2 weeks) in August 2017. In October 2017, imaging showed a metastatic liver lesions (Figure 2). After four cycles of mixed response, with stable lesions in segment 7 and new 4 Case Reports in Oncological Medicine (a) (b) Figure 3: (a) Pretreatment scans (MRI). Axial T2 WI (A, B) and postcontrast (Eovist) Axial T1 WI (C) show multiple metastatic lesions (arrows) in both liver lobes. (b) Posttreatment scans (MRI). Axial T2 WI (A, B) and postcontrast (Eovist) Axial T1 WI (C) show the decrease in size and number of multiple lesions (arrows) in both liver lobes. hepatic lesions in segment 8, with an LDH of 242 U/L, ALP of January 2018. Repeat imaging in February 2018 showed dis- 114 U/L. The patient continued nivolumab until disease pro- ease progression and the patient expired in April 2018. gression in April 2018, and the patient expired in June 2018. 3. Discussion 2.7. Case 7. A 73-year-old woman was referred to an ocular Median OS of MUM patients with M1a disease was 20 oncologist in June 2015 for visual changes in her right eye, months, while M1b disease was 10 months [10]. The current diagnosed with a primary choroidal melanoma by histopa- treatment for MUM is based on the recommendations for thology. She was treated with I-125 plaque brachytherapy metastatic cutaneous melanoma. Local interventions such in June 2015. Surveillance imaging showed hepatic lesions as chemoembolization further guide therapies for MUM. in September 2015, with LDH of 194 U/L, ALP of 73 U/L. One chemotherapeutic option, dacarbazine, has shown a The largest lesion measured 2 2×2 2cm (M1a). A liver limited response in MUM [27]. Other chemotherapeutic biopsy confirmed MUM. She started therapy with nab- regimens including temozolomide, cisplatin, treosulfan, paclitaxel and received three cycles simultaneously with fotemustine, and various combinations have been investi- TACE for left and right liver lobe metastases. In February gated in MUM with similar results [28–30]. 2016, imaging showed disease progression, with LDH of Several case series and small prospective studies have 519 U/L and ALP of 72 U/L. Therefore, the patient started evaluated immune checkpoint inhibitors in MUM [31–35]. therapy with ipilimumab (3 mg/kg) and nivolumab (1 Ipilimumab, an anti-CTLA4 agent, is an immune checkpoint mg/kg). After one cycle, she developed grade IV myalgia inhibitor that has shown response rates of 5–10% with ipi- and neuropathy requiring hospitalization and immunother- limumab in patients with MUM, with a median OS time apy was stopped. In May 2016, the patient was initiated on of 6.0–9.7 months [35–37]. Preliminary data from a phase pembrolizumab simultaneously with monthly TACE proce- II trial conducted by the Spanish Melanoma Group dure for liver metastases. However, she was hospitalized for (GEM), using front line ipilimumab 10 mg/kg IV every 3 pulmonary edema and autoimmune hepatitis. Imaging weeks for four doses followed by maintenance doses every repeated in September 2016 showed the progression of the 12 weeks until disease progression or acceptable toxicity in hepatic lesions. She was later enrolled to hospice care and treatment-naïve MUM patients, showed promising response expired in September 2016. rates at a median follow-up time of 5.5 months [38]. How- ever, the Dermatologic Cooperative Oncology Group 2.8. Case 8. A 55-year-old man was initially diagnosed with (DeCOG) conducted an open-label multicenter phase II trial primary choroidal melanoma of the left eye in October in treatment-naïve or pretreated MUM patients which 2016 by histopathology, treated with I-125 plaque brachy- reported a median progression-free survival (PFS) and OS therapy. Surveillance imaging in July 2017 showed numerous of only 2.8 and 6.8 months, respectively. Investigators also liver lesions, the largest measuring up to 1.6 cm (M1a), with determined that treatment-naïve patients did not have an an increase in his LDH level to 634 U/L, ALP 65 U/L. A liver improved 1- or 2-year survival compared to previously biopsy confirmed MUM. He started monthly TACE in treated patients [39]. August 2017. In September 2017, the patient started therapy The anti-PD1 agents nivolumab and pembrolizumab with ipilimumab (3 mg/kg) and nivolumab (1 mg/kg) every 3 have shown greater efficacy in cutaneous melanoma, with weeks. He finished his fourth cycle in November 2017. In an improved side effect profile compared to that of ipilimu- December 2017, an abdominal MRI showed a mixed mab. However, the activity of PD-1 inhibition in UM is not response, in which several lesions were stable while others yet well-described. One case series of 10 patients with had slightly increased in size, with LDH level of 267 U/L MUM treated with pembrolizumab reported one complete and ALP 256 U/L. The patient later continued maintenance response (CR), two partial response (PR), and one patient therapy with nivolumab (240 mg) every 2 weeks until with stable disease (SD) [40]. Another large multicenter case Case Reports in Oncological Medicine 5 Kaplan Meyer plot for overall survival series including 56 patients who received anti-PD1 (nivolu- mab, pembrolizumab) or anti-PDL1 (atezolizumab) agents 1.0 showed median OS and PFS of 7.6 months and 2.6 months, respectively [32]. Adverse events should be considered when 0.8 treating patients with immunotherapy since autoimmune side effects can affect therapy continuation or further man- agement in these patients. 0.6 While combination immunotherapy has achieved higher response rates in patients with metastatic cutaneous mela- noma compared to those for monotherapy, studies are ongo- 0.4 ing to evaluate combination therapy in MUM [25, 26]. Afzal et al. reported a case of MUM treated with the combination of nivolumab and ipilimumab for four cycles, followed by 0.2 maintenance therapy with nivolumab for two cycles in which the patient achieved a durable response and had continued to do well for 22 months since the start of combination therapy. 0.0 However, subsequent therapy was stopped due to the devel- 0 5 10 15 20 25 30 opment of autoimmune hepatitis [31]. Months The use of immune checkpoint inhibitors can lead to the development of adverse events and toxicities. The frequen- Figure 4: Median overall survival for the entire cohort. Median cies of immune-related adverse event (iRAE) effects are overall survival for this cohort was 14.2 months. higher for the combination of PD-1 and CTLA-4 agents compared to the frequencies for any of these therapies alone. small size of this study limits further analysis, but we were Toxicities are common in the GI tract, liver, and skin and the endocrine system. In a phase III trial (CheckMate 067), grade able to see a response, either in the form of SD or PR. 3 or 4 iRAEs occurred in 55% of the combination group vs. Although SD is not considered a response to the drug, it is 16% and 27%, respectively, for nivolumab and ipilimumab considered a disease control endpoint as it delays the time alone [19]. to progression. Patients in our study either had M1a or M1b disease. Five of eight patients had M1a disease, OS of Diarrhea and colitis are the most frequent iRAEs after ipilimumab either as monotherapy or in combination with these patients from metastatic disease diagnosis to date of PD1 inhibitors (33.1% and 44.1%, respectively). GI symp- death/date of last follow-up ranged 12, 14, 16, 23, and 24 toms usually appear 6 weeks after treatment initiation. months. The rest of the patients had M1b disease, OS of Treatment-related adverse event of any grade leading to their these patients ranged 7, 15, and 30 months. While previ- ous studies stated that LDH level, CRP level, eosinophil discontinuation happened in 36.4% and 14.8% in the combi- nation arm and ipilimumab group, respectively, with the count, and Eastern Cooperative Oncology Group (ECOG) most common being diarrhea and colitis. In our study, four performance status can be used as prognostic factors for out of eight patients experienced autoimmune colitis (50%) UM [41, 42], these data could not be assessed in our study. with the combination. Adverse events were generally manage- TACE depends on the concept of embolization compo- nents that can interrupt blood supply to the tumor and thus able with established guidelines, including the use of steroids for grade 3or 4adverse events. Thesafety profile of ipilimumab cause ischemic necrosis and decrease in size. This may lead to and nivolumab combination in our study was similar to that controlled growth or even regression of the tumor [43]. observed in cutaneous melanoma receiving combination. TACE was offered to six of the eight patients included in Our retrospective study assessed patients with MUM our study and was well-tolerated. treated with immunotherapy combination within a single institute (summarized in Table 1). During the study period, 4. Conclusion no available open and feasible clinical trials were available to this group of patients. After obtaining written informed MUM is associated with a poor prognosis with no current consent, immunotherapy was administered on a compas- standard of care. There is an urgent need for new strategies sionate use basis since no other appropriate medical thera- for patients with MUM as no therapy has succeeded in pies were available; no other ethical approvals were needed. improving the OS. Given the development of molecular pro- In our series, patients were treated with the combination of filing techniques and the availability of additional immuno- ipilimumab and nivolumab plus TACE followed by mainte- therapeutic agents, chemotherapeutic agents, and target nance nivolumab along with monthly TACE procedures. therapies, dedicated management strategies and guidelines The majority of patients had initial PR or SD. Out of the eight should be feasible. Immunotherapy in MUM remains an area patients, two achieved PR, while four others had SD. Two of active exploration. While checkpoint inhibition with anti- other patients had progression of disease (POD). Median PD-1 and anti-CTLA-4 therapy has drastically changed the OS (from the date of immunotherapy initiation to the date treatment approach to cutaneous melanoma, its efficacy in of death/date of last follow-up) by Kaplan-Meier methodol- MUM is still being evaluated. Our study reported durable ogy for the eight patients was 14 months (Figure 4). The responses in MUM patients treated with anti-PD-1/anti- Survival probability 6 Case Reports in Oncological Medicine Table 1: Summary of cases. Primary tumor diagnosis Diagnosis of metastatic Response to Case # Age/sex Genomic findings MUM treatment Side effects (year), treatment uveal melanoma (MUM), site immunotherapy Ipilimumab 3 mg/kg and nivolumab April 2016, liver 1 mg/kg for three cycles, followed by Autoimmune 1 68, M 2013, brachytherapy No genetic alterations Stable disease metastases nivolumab 240 mg × 2 weeks + monthly colitis TACE until February 2017 June 2016, pulmonary Ipilimumab 3 mg/kg plus nivolumab Autoimmune Progression of 2 69, M 2014, enucleation GNAQ Q209P +ve metastases 1 mg/kg every 3 weeks for four cycles colitis disease Ipilimumab 3 mg/kg plus nivolumab March 2017, liver and GNA11 Q209L +ve, 1 mg/kg every 3 weeks for four cycles 3 77, M 2014, enucleation None Stable disease followed by nivolumab 240 mg every pulmonary metastases BAP +ve, MGMT +ve 2 weeks plus monthly TACE Ipilimumab 3 mg/kg plus nivolumab Stable August June 2017, liver 1 mg/kg every 3 weeks for four cycles 4 76, F 2014, brachytherapy GNA11 Q209L +ve None 2017, POD metastases followed by nivolumab 240 mg every November 2017 two weeks until November 2017 GNAQ Q209P +ve, Ipilimumab 3 mg/kg plus nivolumab August 2016, liver MYC +ve, BAP +ve, 1 mg/kg every 3 weeks followed by 5 65, M 2014, enucleation None Partial response metastases DNMT3A +ve, low nivolumab 240 mg every 2 weeks mutational burden plus TACE from January 2017 Ipilimumab 3 mg/kg plus nivolumab 1 mg/kg initiated in May 2017 for Autoimmune February 2017, liver 6 63, M 2016, enucleation NA two cycles, followed by nivolumab colitis with Partial response metastases 240 mg every 3 weeks plus TACE combination from August 2017 TACE plus Abraxane for three cycles followed by ipilimumab 3 mg/kg plus Autoimmune September 2015, No genetic alterations, nivolumab 1 mg/kg for one cycle in Progression of 7 73, F 2015, brachytherapy colitis with liver metastases c-KIT +ve February 2017, pembrolizumab disease combination 200 mg every 3 weeks from May 2017 to September 2017 Monthly TACE from August 2017, ipilimumab 3 mg/kg plus nivolumab June 2017, liver 8 55, M 2016, brachytherapy NA 1 mg/kg every 3 weeks for four cycles None Stable disease metastases followed by nivolumab 240 mg every 2 weeks from December 2017 Case Reports in Oncological Medicine 7 [8] M. Diener-West, S. M. Reynolds, D. J. Agugliaro et al., “Devel- CTLA-4 therapy; thus, this approach may be a viable option opment of metastatic disease after enrollment in the COMS for these patients. Patients who receive combination immu- trials for treatment of choroidal melanoma: Collaborative notherapy should also be carefully monitored for iRAEs. Ocular Melanoma Study Group Report No. 26,” Archives of The major limitations of this study include its retrospective Ophthalmology, vol. 123, no. 12, pp. 1639–1643, 2005. nature as some of the data could not be retrieved. There is [9] S. B. Edge and C. C. Compton, “The American Joint Commit- an urgent need for specifically approved systemic and local tee on Cancer: the 7th edition of the AJCC cancer staging man- treatment options for patients with MUM. 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Nivolumab and Ipilimumab in the Treatment of Metastatic Uveal Melanoma: A Single-Center Experience

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Hindawi Publishing Corporation
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Copyright © 2019 Vidhya Karivedu et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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10.1155/2019/3560640
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Abstract

Hindawi Case Reports in Oncological Medicine Volume 2019, Article ID 3560640, 8 pages https://doi.org/10.1155/2019/3560640 Case Series Nivolumab and Ipilimumab in the Treatment of Metastatic Uveal Melanoma: A Single-Center Experience 1 1 1 2 Vidhya Karivedu , Ihab Eldessouki , Ahmad Taftaf , Zheng Zhu , 3 4 Abouelmagd Makramalla , and Nagla Abdel Karim Department of Internal Medicine, Division of Hematology/Oncology, University of Cincinnati College of Medicine, Cincinnati, OH, USA Department of Biostatistics and Bioinformatics, Department of Environmental Health, College of Medicine, University of Cincinnati, Cincinnati, OH, USA Division of Vascular and Interventional Radiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA Department of Internal Medicine, Division of Hematology/Oncology, Medical College of Georgia-Augusta University, Augusta, GA, USA Correspondence should be addressed to Vidhya Karivedu; kariveva@ucmail.uc.edu Received 30 November 2018; Accepted 25 March 2019; Published 17 April 2019 Academic Editor: Jose I. Mayordomo Copyright © 2019 Vidhya Karivedu et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background. Metastatic uveal melanoma (MUM) is associated with a poor prognosis, with a median overall survival (OS) of 4–15 months. Despite new insights into the genetic and molecular background of MUM, satisfactory systemic treatment approaches are currently lacking. The study results of innovative treatment strategies are urgently needed. Patients and Methods. This was a retrospective case series of 8 patients with MUM managed at the University of Cincinnati between January 2015 and January 2018. The immune-related Response Evaluation Criteria in Solid Tumors (irRECIST) 1.1 criteria were used for patient evaluation, and magnetic resonance imaging was used for evaluation at treatment checkpoints. Objective. To assess the clinical outcome of patients with MUM treated with a combination of checkpoint inhibitors. Results. The series included eight patients, six men and two women, with MUM. Their median age at MUM diagnosis was 69 (range, 55–77) years. All patients were treated with ipilimumab and nivolumab combination along with transarterial chemoembolization (TACE), followed by nivolumab maintenance and monthly TACE procedures. The majority of patients had a partial response or stable disease. Two of the patients had partial response, while four others had stable disease. Two other patients experienced disease progression. Conclusion. We report the outcomes of eight patients with MUM treated with the combination of ipilimumab and nivolumab. We report the clinical outcome and toxicity associated with this treatment approach. Further studies are warranted to explore immunotherapy in MUM. These findings support the consideration of immunotherapy in MUM. 1. Introduction among Caucasians compared to that in other ethnic groups [3, 4]. Despite effective local therapies, there is a high poten- Uveal melanoma (UM) is the most common primary intra- tial for metastases even after a prolonged period of remission ocular malignancy in adults. It accounts for <5% of all mela- [4, 5]. While the cumulative five- and ten-year metastatic noma cases in the United States [1, 2]. UM can arise from rates reported by the Collaborative Ocular Melanoma Study melanocytes located along the uveal tract, which is the pig- (COMS) Group were 25% and 34%, respectively, up to 50% of patients develop metastatic disease [6, 7]. The predomi- mented layer composed of the iris and ciliary body anteriorly and choroid posteriorly. UM is a rare form of melanoma, nant target organ for metastases is the liver (89%). Metastases with an approximate incidence rate of 1,500 new cases diag- to the skin, bone, brain, and lungs have also been reported nosed each year in the US. There is a higher prevalence [8]. According to the TNM staging of metastatic disease in 2 Case Reports in Oncological Medicine cycles of treatment, imaging revealed the same number of uveal melanoma (MUM), M0 is defined as the absence of dis- tant metastasis, while M1a is a disease with distant metastasis hypodense lesions; the largest lesion measured 5 5×3 4 cm with the largest diameter of 3 cm or less, M1b is metastatic (Figure 1). In July 2016, treatment was stopped due to severe disease with the largest diameter of 3.1 to 8 cm, and M1c is autoimmune colitis as a side effect of the immunotherapy. metastatic disease with the largest diameter of 8 cm or more Later that year, in September 2016, the patient continued [9, 10]. Multiple therapeutic approaches for MUM have been nivolumab alone (240 mg every 2 weeks), which was also dis- studied but none has shown any impact on the overall sur- continued in February 2017 due to intolerance. Since then, vival (OS) [11]. Recent studies have shown that outcomes the patient had received transarterial chemoembolization of patient with MUM are dismal with median overall survival (TACE) for the hepatic lesions. In June 2017, the patient of 12 months from the time of metastasis diagnosis [12]. developed progressive disease, with an LDH of 317 U/L and ALP of 426 U/L. The patient was enrolled to hospice care There is no established standard of care for the systemic ther- apy of patients with MUM as they are usually excluded from and the patient expired within a month. large randomized trials; thus, the current treatment paradigm is based on the National Comprehensive Cancer Network 2.2. Case 2. A 69-year-old man was referred to an ocular (NCCN) guidelines [13]. Liver-directed therapies such as oncologist in 2014 due to visual changes in his left eye. He liver resection in a small subset of patients may induce remis- underwent enucleation in 2014 and histopathology showed sion in the setting of single-site metastases potentially T3aN0M0 choroidal melanoma. He underwent systemic prolonging OS, albeit with a high recurrence rate [7, 14]. staging and did not have metastatic disease at the time. Later UM is clinically and biologically distinct from cutaneous in April 2016, surveillance imaging showed multiple pulmo- melanoma. However, the systemic management of MUM is nary nodules (M1a), which were diagnosed as metastatic dis- adapted from that of cutaneous melanoma. Major improve- ease by right lung lower lobe wedge resection confirmed by ments have followed the introduction of BRAF/MEK inhibi- IHC (HMB-45 and MART-1), with an LDH of 191 U/L tors and immunotherapy in metastatic cutaneous melanoma. and ALP of 84 U/L. In July 2016, the patient started nivolu- Unlike cutaneous melanoma, several studies report lack of mab (1 mg/kg) and ipilimumab (3 mg/kg) administered BRAF kinase mutations, suggesting lack of benefit from every 3 weeks. Upon completion of four cycles, the treatment BRAF inhibitors in patients with advanced uveal melanoma was stopped due to autoimmune colitis as a side effect of [15–17]. Oncogenic mutations in G-protein subunits a immunotherapy. Imaging surveillance in September 2016 (GNAQ) and 11 (GNA11) have been described in 80% of showed progressive disease, with an LDH of 231 U/L and uveal melanomas [18]. ALP of 89 U/L, and the patient started treatment with nab- Small retrospective studies have reported low response paclitaxel and he continues to have stable disease with no rates to PD-1 inhibitor monotherapy for MUM. The combi- signs of disease progression for 18 months now. nation of nivolumab and ipilimumab has shown a survival benefit in patients with cutaneous melanoma at the expense 2.3. Case 3. A 77-year-old man was referred to an ocular of immune-related toxicities and has been approved for the oncologist in 2014 for visual changes in his right eye. He management of metastatic cutaneous melanoma [19–21]. was diagnosed with a choroidal melanoma by histopathology Patients with MUM were excluded from most of the clinical and IHC, treated with I-125 plaque brachytherapy. Surveil- trials; thus, the safety and efficacy of the currently studied lance imaging in March 2017 showed liver and pulmonary combinations remain unclear, especially the ocular toxicity lesions (M1a), with an LDH of 168 U/L and ALP of 54 U/L. of the combination in patients with MUM [22–24]. Ongoing A liver nodule biopsy confirmed the presence of MUM. trials are evaluating the combination of CTLA-4 and PD1 The patient completed selective internal radiation therapy blockade in MUM [25, 26]. (SIRT) to the liver metastases in March 2017. In March In this study, we report our experience in treating 2017, the patient also started treatment with nivolumab patients with MUM with the combination of ipilimumab (1 mg/kg) and ipilimumab (3 mg/kg) every 3 weeks for a and nivolumab. total of four cycles, followed by nivolumab maintenance (240 mg). The patient also underwent TACE simultaneously with immunotherapy every 5–6 weeks starting from May 2. Case Series 2017. Nivolumab was stopped in March 2018 due to throm- 2.1. Case 1. A 68-year-old man was initially diagnosed with bocytopenia, and the patient continued TACE every eight right primary choroidal melanoma by histopathology and weeks until September 2018 and later discontinued due to immunohistochemistry (IHC). He was treated with I-125 no tumor growth. Repeat imaging in February 2019 showed plaque brachytherapy in 2013. In April 2016, an abdominal stable disease. ultrasonography (US) revealed multiple scattered hypodense lesions throughout the liver; the largest lesion was within seg- 2.4. Case 4. A 76-year-old woman was referred to an ocular oncologist in 2014 for visual changes in her left eye and was ment 7 measuring 6 6× 5 1 cm (M1b). A US-guided liver biopsy confirmed a recurrence, with a lactic acid dehydroge- diagnosed with a ciliochoroidal melanoma by histopathol- ogy, treated with I-125 plaque brachytherapy. Surveillance nase (LDH) level of 220 U/L (110-270 U/L) and alkaline phosphatase (ALP) of 22 (7-52 U/L). In April 2016, the imaging in June 2017 showed multiple liver lesions with the patient started a combination of ipilimumab (3 mg/kg) and largest measuring 4 5×3 5 cm (M1b). A liver biopsy con- nivolumab (1 mg/kg) administered every 3 weeks. After three firmed MUM. The patient started therapy with nivolumab Case Reports in Oncological Medicine 3 (a) (b) Figure 1: (a) Pretreatment scans (MRI). Axial T2 WI (A) and postcontrast (Eovist) Axial T1 WI (B) showing a 7 cm mass in the right liver lobe (arrows) and multiple smaller lesions in both liver lobes. (b) Posttreatment scans (MRI). Axial T2 WI (A) and postcontrast (Eovist) Axial T1 WI (B) show the decrease in size of the largest mass in the right liver lobe (arrows). (a) (b) Figure 2: (a) Pretreatment scan (8/22/2016) (MRI). Axial T2 WI (A) and postcontrast (Eovist) Axial T1 WI (B) showing an 11 cm mass in the left liver lobe (arrows) and multiple smaller lesions in both liver lobes. (b) Ongoing treatment (5/2/2018) (MRI). Axial T2 WI (A) and postcontrast (Eovist) Axial T1 WI (B) show the decrease in size of the largest mass in the left liver lobe (arrows) now measuring 4.8 cm with no enhancement. There is a decrease in size and number of the multiple smaller lesions in both liver lobes. (1 mg/kg) and ipilimumab (3 mg/kg) every 3 weeks for four nivolumab/ipilimumab, he started maintenance nivolumab cycles, followed by maintenance nivolumab (240 mg) every (240 mg every 3 weeks) in January 2017. Repeat imaging two weeks simultaneously with TACE every 4 weeks. In showed continued response until August 2018. Imaging in October 2017, imaging showed stable liver lesions. Imaging September 2018 showed progression of disease; therapy surveillance in November 2017 showed the progression of switched to nab-paclitaxel. The patient currently has stable dis- the liver lesions, with an LDH of 466 U/L and ALP of 442 ease on nab-paclitaxel and TACE q8 weeks as of March 2019. U/L. Nivolumab was discontinued in November 2017, and the patient expired in January 2018. 2.6. Case 6. A 63-year-old man was initially referred to an ocular oncologist in February 2016 due to a visual change 2.5. Case 5. In 2014, a 65-year-old man was referred to an in his left eye. He was diagnosed with ciliochoroidal mela- noma by histopathology, T4bN0M0. He was treated with ocular oncologist for a visual change in his left eye and diagnosed with choroidal melanoma by histopathology enucleation of his left eye. In February 2017, surveillance and IHC, treated with enucleation, T1aN0M0. Surveillance imaging showed liver lesions, with the largest measuring imaging first showed hepatic lesions in January 2016. 2 2×2 1 cm in hepatic segment 7 (M1a) and an LDH of Active surveillance in August 2016 revealed that his liver 194 U/L, ALP of 94 U/L; biopsy confirmed metastatic lesions had increased in size and number with the largest melanoma. The patient started treatment with nivolumab lesion measuring 7 1×5 8 cm (M1b), with an LDH of (1 mg/kg) and ipilimumab (3 mg/kg) in May 2017. After 641 U/L and ALP of 111 U/L. Liver biopsy confirmed MUM. two doses of a combination of ipilimumab and nivolumab, The patient started therapy with nivolumab (1 mg/kg) he developed colitis, which was treated with prednisone. and ipilimumab (3 mg/kg) every 2 weeks simultaneously Repeated imaging in June 2017 showed a decrease in the size with TACE every 4 weeks in September 2016. A repeated of the metastatic hepatic lesion, from 2 2×2 1 to 1 7×1 5 abdominal magnetic resonance imaging (MRI) in November cm (Figure 3). The patient started nivolumab (240 mg every 2016 showed a marked decrease in the size and number of 2 weeks) in August 2017. In October 2017, imaging showed a metastatic liver lesions (Figure 2). After four cycles of mixed response, with stable lesions in segment 7 and new 4 Case Reports in Oncological Medicine (a) (b) Figure 3: (a) Pretreatment scans (MRI). Axial T2 WI (A, B) and postcontrast (Eovist) Axial T1 WI (C) show multiple metastatic lesions (arrows) in both liver lobes. (b) Posttreatment scans (MRI). Axial T2 WI (A, B) and postcontrast (Eovist) Axial T1 WI (C) show the decrease in size and number of multiple lesions (arrows) in both liver lobes. hepatic lesions in segment 8, with an LDH of 242 U/L, ALP of January 2018. Repeat imaging in February 2018 showed dis- 114 U/L. The patient continued nivolumab until disease pro- ease progression and the patient expired in April 2018. gression in April 2018, and the patient expired in June 2018. 3. Discussion 2.7. Case 7. A 73-year-old woman was referred to an ocular Median OS of MUM patients with M1a disease was 20 oncologist in June 2015 for visual changes in her right eye, months, while M1b disease was 10 months [10]. The current diagnosed with a primary choroidal melanoma by histopa- treatment for MUM is based on the recommendations for thology. She was treated with I-125 plaque brachytherapy metastatic cutaneous melanoma. Local interventions such in June 2015. Surveillance imaging showed hepatic lesions as chemoembolization further guide therapies for MUM. in September 2015, with LDH of 194 U/L, ALP of 73 U/L. One chemotherapeutic option, dacarbazine, has shown a The largest lesion measured 2 2×2 2cm (M1a). A liver limited response in MUM [27]. Other chemotherapeutic biopsy confirmed MUM. She started therapy with nab- regimens including temozolomide, cisplatin, treosulfan, paclitaxel and received three cycles simultaneously with fotemustine, and various combinations have been investi- TACE for left and right liver lobe metastases. In February gated in MUM with similar results [28–30]. 2016, imaging showed disease progression, with LDH of Several case series and small prospective studies have 519 U/L and ALP of 72 U/L. Therefore, the patient started evaluated immune checkpoint inhibitors in MUM [31–35]. therapy with ipilimumab (3 mg/kg) and nivolumab (1 Ipilimumab, an anti-CTLA4 agent, is an immune checkpoint mg/kg). After one cycle, she developed grade IV myalgia inhibitor that has shown response rates of 5–10% with ipi- and neuropathy requiring hospitalization and immunother- limumab in patients with MUM, with a median OS time apy was stopped. In May 2016, the patient was initiated on of 6.0–9.7 months [35–37]. Preliminary data from a phase pembrolizumab simultaneously with monthly TACE proce- II trial conducted by the Spanish Melanoma Group dure for liver metastases. However, she was hospitalized for (GEM), using front line ipilimumab 10 mg/kg IV every 3 pulmonary edema and autoimmune hepatitis. Imaging weeks for four doses followed by maintenance doses every repeated in September 2016 showed the progression of the 12 weeks until disease progression or acceptable toxicity in hepatic lesions. She was later enrolled to hospice care and treatment-naïve MUM patients, showed promising response expired in September 2016. rates at a median follow-up time of 5.5 months [38]. How- ever, the Dermatologic Cooperative Oncology Group 2.8. Case 8. A 55-year-old man was initially diagnosed with (DeCOG) conducted an open-label multicenter phase II trial primary choroidal melanoma of the left eye in October in treatment-naïve or pretreated MUM patients which 2016 by histopathology, treated with I-125 plaque brachy- reported a median progression-free survival (PFS) and OS therapy. Surveillance imaging in July 2017 showed numerous of only 2.8 and 6.8 months, respectively. Investigators also liver lesions, the largest measuring up to 1.6 cm (M1a), with determined that treatment-naïve patients did not have an an increase in his LDH level to 634 U/L, ALP 65 U/L. A liver improved 1- or 2-year survival compared to previously biopsy confirmed MUM. He started monthly TACE in treated patients [39]. August 2017. In September 2017, the patient started therapy The anti-PD1 agents nivolumab and pembrolizumab with ipilimumab (3 mg/kg) and nivolumab (1 mg/kg) every 3 have shown greater efficacy in cutaneous melanoma, with weeks. He finished his fourth cycle in November 2017. In an improved side effect profile compared to that of ipilimu- December 2017, an abdominal MRI showed a mixed mab. However, the activity of PD-1 inhibition in UM is not response, in which several lesions were stable while others yet well-described. One case series of 10 patients with had slightly increased in size, with LDH level of 267 U/L MUM treated with pembrolizumab reported one complete and ALP 256 U/L. The patient later continued maintenance response (CR), two partial response (PR), and one patient therapy with nivolumab (240 mg) every 2 weeks until with stable disease (SD) [40]. Another large multicenter case Case Reports in Oncological Medicine 5 Kaplan Meyer plot for overall survival series including 56 patients who received anti-PD1 (nivolu- mab, pembrolizumab) or anti-PDL1 (atezolizumab) agents 1.0 showed median OS and PFS of 7.6 months and 2.6 months, respectively [32]. Adverse events should be considered when 0.8 treating patients with immunotherapy since autoimmune side effects can affect therapy continuation or further man- agement in these patients. 0.6 While combination immunotherapy has achieved higher response rates in patients with metastatic cutaneous mela- noma compared to those for monotherapy, studies are ongo- 0.4 ing to evaluate combination therapy in MUM [25, 26]. Afzal et al. reported a case of MUM treated with the combination of nivolumab and ipilimumab for four cycles, followed by 0.2 maintenance therapy with nivolumab for two cycles in which the patient achieved a durable response and had continued to do well for 22 months since the start of combination therapy. 0.0 However, subsequent therapy was stopped due to the devel- 0 5 10 15 20 25 30 opment of autoimmune hepatitis [31]. Months The use of immune checkpoint inhibitors can lead to the development of adverse events and toxicities. The frequen- Figure 4: Median overall survival for the entire cohort. Median cies of immune-related adverse event (iRAE) effects are overall survival for this cohort was 14.2 months. higher for the combination of PD-1 and CTLA-4 agents compared to the frequencies for any of these therapies alone. small size of this study limits further analysis, but we were Toxicities are common in the GI tract, liver, and skin and the endocrine system. In a phase III trial (CheckMate 067), grade able to see a response, either in the form of SD or PR. 3 or 4 iRAEs occurred in 55% of the combination group vs. Although SD is not considered a response to the drug, it is 16% and 27%, respectively, for nivolumab and ipilimumab considered a disease control endpoint as it delays the time alone [19]. to progression. Patients in our study either had M1a or M1b disease. Five of eight patients had M1a disease, OS of Diarrhea and colitis are the most frequent iRAEs after ipilimumab either as monotherapy or in combination with these patients from metastatic disease diagnosis to date of PD1 inhibitors (33.1% and 44.1%, respectively). GI symp- death/date of last follow-up ranged 12, 14, 16, 23, and 24 toms usually appear 6 weeks after treatment initiation. months. The rest of the patients had M1b disease, OS of Treatment-related adverse event of any grade leading to their these patients ranged 7, 15, and 30 months. While previ- ous studies stated that LDH level, CRP level, eosinophil discontinuation happened in 36.4% and 14.8% in the combi- nation arm and ipilimumab group, respectively, with the count, and Eastern Cooperative Oncology Group (ECOG) most common being diarrhea and colitis. In our study, four performance status can be used as prognostic factors for out of eight patients experienced autoimmune colitis (50%) UM [41, 42], these data could not be assessed in our study. with the combination. Adverse events were generally manage- TACE depends on the concept of embolization compo- nents that can interrupt blood supply to the tumor and thus able with established guidelines, including the use of steroids for grade 3or 4adverse events. Thesafety profile of ipilimumab cause ischemic necrosis and decrease in size. This may lead to and nivolumab combination in our study was similar to that controlled growth or even regression of the tumor [43]. observed in cutaneous melanoma receiving combination. TACE was offered to six of the eight patients included in Our retrospective study assessed patients with MUM our study and was well-tolerated. treated with immunotherapy combination within a single institute (summarized in Table 1). During the study period, 4. Conclusion no available open and feasible clinical trials were available to this group of patients. After obtaining written informed MUM is associated with a poor prognosis with no current consent, immunotherapy was administered on a compas- standard of care. There is an urgent need for new strategies sionate use basis since no other appropriate medical thera- for patients with MUM as no therapy has succeeded in pies were available; no other ethical approvals were needed. improving the OS. Given the development of molecular pro- In our series, patients were treated with the combination of filing techniques and the availability of additional immuno- ipilimumab and nivolumab plus TACE followed by mainte- therapeutic agents, chemotherapeutic agents, and target nance nivolumab along with monthly TACE procedures. therapies, dedicated management strategies and guidelines The majority of patients had initial PR or SD. Out of the eight should be feasible. Immunotherapy in MUM remains an area patients, two achieved PR, while four others had SD. Two of active exploration. While checkpoint inhibition with anti- other patients had progression of disease (POD). Median PD-1 and anti-CTLA-4 therapy has drastically changed the OS (from the date of immunotherapy initiation to the date treatment approach to cutaneous melanoma, its efficacy in of death/date of last follow-up) by Kaplan-Meier methodol- MUM is still being evaluated. Our study reported durable ogy for the eight patients was 14 months (Figure 4). The responses in MUM patients treated with anti-PD-1/anti- Survival probability 6 Case Reports in Oncological Medicine Table 1: Summary of cases. Primary tumor diagnosis Diagnosis of metastatic Response to Case # Age/sex Genomic findings MUM treatment Side effects (year), treatment uveal melanoma (MUM), site immunotherapy Ipilimumab 3 mg/kg and nivolumab April 2016, liver 1 mg/kg for three cycles, followed by Autoimmune 1 68, M 2013, brachytherapy No genetic alterations Stable disease metastases nivolumab 240 mg × 2 weeks + monthly colitis TACE until February 2017 June 2016, pulmonary Ipilimumab 3 mg/kg plus nivolumab Autoimmune Progression of 2 69, M 2014, enucleation GNAQ Q209P +ve metastases 1 mg/kg every 3 weeks for four cycles colitis disease Ipilimumab 3 mg/kg plus nivolumab March 2017, liver and GNA11 Q209L +ve, 1 mg/kg every 3 weeks for four cycles 3 77, M 2014, enucleation None Stable disease followed by nivolumab 240 mg every pulmonary metastases BAP +ve, MGMT +ve 2 weeks plus monthly TACE Ipilimumab 3 mg/kg plus nivolumab Stable August June 2017, liver 1 mg/kg every 3 weeks for four cycles 4 76, F 2014, brachytherapy GNA11 Q209L +ve None 2017, POD metastases followed by nivolumab 240 mg every November 2017 two weeks until November 2017 GNAQ Q209P +ve, Ipilimumab 3 mg/kg plus nivolumab August 2016, liver MYC +ve, BAP +ve, 1 mg/kg every 3 weeks followed by 5 65, M 2014, enucleation None Partial response metastases DNMT3A +ve, low nivolumab 240 mg every 2 weeks mutational burden plus TACE from January 2017 Ipilimumab 3 mg/kg plus nivolumab 1 mg/kg initiated in May 2017 for Autoimmune February 2017, liver 6 63, M 2016, enucleation NA two cycles, followed by nivolumab colitis with Partial response metastases 240 mg every 3 weeks plus TACE combination from August 2017 TACE plus Abraxane for three cycles followed by ipilimumab 3 mg/kg plus Autoimmune September 2015, No genetic alterations, nivolumab 1 mg/kg for one cycle in Progression of 7 73, F 2015, brachytherapy colitis with liver metastases c-KIT +ve February 2017, pembrolizumab disease combination 200 mg every 3 weeks from May 2017 to September 2017 Monthly TACE from August 2017, ipilimumab 3 mg/kg plus nivolumab June 2017, liver 8 55, M 2016, brachytherapy NA 1 mg/kg every 3 weeks for four cycles None Stable disease metastases followed by nivolumab 240 mg every 2 weeks from December 2017 Case Reports in Oncological Medicine 7 [8] M. 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