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Immune checkpoint blockade for unresectable or metastatic uveal melanoma: A systematic review
Accepted Manuscript Systematic or Meta-analysis Studies Immune checkpoint blockade for unresectable or metastatic uveal melanoma: a systematic review Markus V. Heppt, Theresa Steeb, J. Gabriel Schlager, Stefanie Rosumeck, Corinna Dressler, Thomas Ruzicka, Alexander Nast, Carola Berking PII: DOI: Reference:
S0305-7372(17)30132-9 http://dx.doi.org/10.1016/j.ctrv.2017.08.009 YCTRV 1667
To appear in:
Cancer Treatment Reviews Cancer Treatment Reviews
Received Date: Revised Date: Accepted Date:
4 July 2017 18 August 2017 19 August 2017
Please cite this article as: Heppt, M.V., Steeb, T., Gabriel Schlager, J., Rosumeck, S., Dressler, C., Ruzicka, T., Nast, A., Berking, C., Immune checkpoint blockade for unresectable or metastatic uveal melanoma: a systematic review, Cancer Treatment Reviews Cancer Treatment Reviews (2017), doi: http://dx.doi.org/10.1016/j.ctrv. 2017.08.009
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Immune checkpoint blockade for unresectable or metastatic uveal melanoma: a systematic review
Markus V. Heppt1, Theresa Steeb1, J. Gabriel Schlager1, Stefanie Rosumeck2, Corinna Dressler2, Thomas Ruzicka1, Alexander Nast2, Carola Berking1,*
1
Department of Dermatology and Allergy, University Hospital, LMU Munich, Frauenlobstr. 9-
11, 80337 Munich, Germany 2
Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin,
Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Dermatology, Division of Evidence – Based Medicine, Charitéplatz 1, 10117 Berlin, Germany * Correspondence should be addressed to Carola Berking Department of Dermatology and Allergy University Hospital, LMU Munich Frauenlobstr. 9-11 80337 Munich Germany Phone:
0049-89-4400-0
Fax:
0049-89-4400-56226
Email:
[email protected]
Word counts:
249 (abstract) 3653 (body)
Figure(s):
1
Tables:
3 (regular), 3 (supplementary)
1
Title: Immune checkpoint blockade for unresectable or metastatic uveal melanoma: a systematic review
2
Abstract
Background: The use of immune checkpoint blockade (ICB) for uveal melanoma (UM) is little established. The aim of this review was to provide a comprehensive overview on the efficacy, safety, and tolerability of ICB in patients with UM. Methods: We performed a systematic literature research covering MEDLINE, Embase and CENTRAL. Abstracts of pertinent conferences and trial registers were handsearched for relevant studies. Results: Out of 1,327 records initially identified, 12 eligible studies were included in the qualitative synthesis. They comprised 7 expanded access or named patient programs (n=162), 4 phase II trials (n=171), and 1 phase Ib trial (sample size unknown), while no randomized controlled trial was found. Ipilimumab monotherapy was assessed at 3 mg/kg in 5 trials (n=186) with a response rate of 0-5%. Two reports investigated ipilimumab at 10 mg/kg (n=45) with radiological responses observed in 0-6.5%. The median progression-free survival (PFS) was below 3 months and the median overall survival was 5.2-9.8 months for ipilimumab monotherapy. Severe immune-related adverse events occurred at a frequency comparable to cutaneous melanoma (6-36%). Two studies investigated pembrolizumab (2 mg/kg) and nivolumab (3 mg/kg) with overall response rates of 30% and 6%, respectively. Data on combined ipilimumab and programmed cell death protein 1 inhibition were available from one expanded access program, but no response was observed with a median PFS of 2.9 months. Conclusions: UM is little responsive to ipilimumab regardless of dosage schemes. Sound randomized clinical trials are needed to evaluate the efficacy of combined ICB in patients with UM.
Key words: uveal melanoma; CTLA-4; ipilimumab; immune checkpoint blockade; pembrolizumab; nivolumab
3
Introduction Uveal melanoma (UM) is an ocular malignancy which originates from melanocytes residing in the choroid layer of the eye. With an incidence of 4-7 cases per million in Europe, it is much rarer than cutaneous melanoma [1]. Several risk factors for the development of UM have been identified in observational studies, including the presence of choroidal or cutaneous nevi, fair skin, light eye color, and exposure to ultraviolet radiation [2]. Despite these similarities in risk factors, UM is clinically and biologically distinct from cutaneous melanoma. Genetic alterations frequently affect the guanine nucleotide binding proteins Q polypeptide (GNAQ) and α11 (GNA11), whereas activating mutations of the v-Raf murine sarcoma viral oncogene homolog (BRAF) and neuroblastoma rat sarcoma viral oncogene homolog (NRAS), which are commonly detected in cutaneous melanoma, are rarely found [3, 4]. Further somatic mutations of UM involve the BRCA1-associated protein (BAP1) on chromosome 3. Patients with a selective loss of this chromosome as observed in monosomy 3 are at high risk for developing hepatic metastases. The reasons for this selective liver-homing behavior are widely unknown. Clinically, a variety of local liverdirected, destructive treatment approaches have been described, but most of them failed to demonstrate a clear survival benefit in metastatic disease [5]. Therapeutic options of local disease are radiation therapy such as brachytherapy, external beam radiotherapy, particle radiation, photon-based radiation or surgical approaches like local resection and enucleation of the affected eye. Although these measures are highly effective to achieve local tumor control, up to 50% of all patients develop distant metastases, most commonly localized to liver and lungs. In case of unresectable or metastatic disease, patients should receive systemic treatment. Improved understanding on the molecular pathways which drive disease progression like the mitogen-activated protein kinase (MAPK) pathway, G protein-coupled receptor or HIPPO signaling offers new therapeutic strategies. However, once metastases are present, the disease course is often aggressive and the prognosis remains dismal. In this stage, therapy has largely been adopted from cutaneous melanoma where immune checkpoint blockade (ICB) with PD-1 inhibitors and ipilimumab has shown strong survival benefits in recent years [6-8]. Yet, patients with UM have been widely excluded from most of the pivotal trials. The high efficacy of ICB may fall short of expectations in UM, because it is by far less immunogenic, evident by a low burden of somatic mutations and little expression of neoantigens by the tumors [9-11]. However, a systematic literature assessment to summarize the efficacy of ICB in metastatic UM has not been performed to date. Considering the high treatment-related costs and development of severe, potentially lethal immune-related toxicity, treating advanced UM with ICB should be evidenced-based instead 4
of being driven by mere extrapolation and analogy to the results achieved in cutaneous melanoma. Here, we performed a systematic review to provide a comprehensive and up-todate overview on the efficacy, safety, and tolerability of ICB in patients with UM.
5
Methods Protocol and registration The protocol for this review was defined a priori and registered online in the PROSPERO international
prospective
register
of
systematic
reviews
on
21
February
2017
(http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42017057344) with an amendment on 29 May 2017. The register ID was PROSPERO 2017:CRD42017057344. This review was conducted and reported according to the PRISMA guidelines [12]. Eligibility criteria We aimed to investigate patients with unresectable or metastatic UM who have been treated with ICB. Agents of ICB included anti-CTLA-4-blocking antibodies (e.g. ipilimumab, tremelimumab), anti-PD-1-blocking antibodies (e.g. pembrolizumab, nivolumab), anti-PD-L1blocking antibodies (e.g. avelumab, atezolizumab), or any combination of these substances. We included randomized controlled trials (RCTs), and clinically controlled trials (CCT), noncontrolled prospective trials, and prospective observational studies with a sample size of n>10 as well as protocol-driven expanded access and named patient programs since UM is an orphan condition and we expected to find few RCTs. Retrospective studies, narrative reviews and case reports or series were excluded. Language restrictions were records published in English or German. Additionally, studies involving patients with systemic or surgical treatment for UM other than ICB during the study period were excluded. In RCTs and controlled observational studies, placebo, chemotherapy or one of the above-mentioned interventions served as control. Search strategy and data sources We searched the electronic databases MEDLINE via PubMed (from 1968), Embase Ovid and the CENTRAL Ovid (from 1980) to identify all relevant records until 5 May 2017. The search strategy for MEDLINE can be found in table 1. The remaining search strategies and queries are listed in supplementary table 1. Additional sources were published conference abstracts retrieved by handsearch for “uveal melanoma” or “ocular melanoma” from the American Society of Clinical Oncology (ASCO), the Society of Melanoma Research (SMR), the European Society of Medical Oncology (ESMO) and the European Association of Dermato-Oncology (EADO) annual meetings from 2014 to 2017. Furthermore, we searched the following trial registers for the same keywords: ISRCTN registry (www.controlled-trials.com); US National Institutes of Health Ongoing Trials Register
(www.clinicaltrials.gov);
Australian
New
Zealand
Clinical
Trials
Registry
(www.anzctr.org.au); World Health Organization International Clinical Trials Registry Platform (www.who.int/trialsearch/); EU Clinical Trials Register (https://www.clinicaltrialsregister.eu/) 6
(last search: 21 February 2017). For ongoing trials and completed trials without data publication, principal investigators or trial sponsors were contacted to obtain preliminary or unpublished data. Besides, reference lists of included records were screened for additional studies. Study selection Two authors (JGS, TS) independently screened titles and abstracts for eligibility that were identified in the electronic database searches. Conference abstracts and trial registers were handsearched and assessed for eligibility by one author (MVH and JGS, respectively). For those records that were considered relevant according to title and abstract screening, full text articles were obtained and inclusion and exclusion criteria were applied. Whenever discrepancies arose, a third author (CB, MVH) was consulted as arbiter for resolution. Outcomes The primary outcomes were (i) radiologic overall response rate (ORR) determined by the sum of complete response (CR) and partial response (PR), (ii) median progression-free survival (PFS), (iii) median overall survival (OS), and (iv) the one-year survival rate (KaplanMeier estimator). Secondary outcomes were (i) the development of severe adverse events, defined as grade 3 or higher according to the Common Terminology Criteria for Adverse Events (CTCAE) v4.03 published by the National Institutes of Health in 2010, and (ii) treatment-related quality of life, assessed with any validated instrument. Data collection, synthesis and management Information for each included study regarding study design, baseline characteristics, intervention, dosage, and risk of bias/ methodological quality as well as on the primary and secondary outcomes were collected and summarized. Data were extracted to an internally piloted data extraction spreadsheet using Microsoft Excel 2010. If no information regarding the outcomes was clearly reported, outcomes were visually extracted from Kaplan-Meier curves whenever applicable and feasible. The baseline characteristics and the outcomes of interest of each study were qualitatively described within the text. Assessment of methodological quality Three different tools to assess the methodological quality and the risk of bias of the included studies were selected: (i) Cochrane risk of bias tool for the evaluation of RCTs [13]; (ii) Risk Of Bias In Non-randomized Studies of Interventions (ROBINS-I) tool for non-randomized studies [14]; (iii) quality assessment tool for before-after (pre-post) studies with no control group as described by the National Heart, Lung, and Blood Institute (NHLBI) for uncontrolled before-after
studies
(available
from
https://www.nhlbi.nih.gov/health-pro/guidelines/in-
develop/cardiovascular-risk-reduction/tools/before-after). 7
Two authors (MVH, TS) independently assessed the risk of bias or the methodological quality of each included study applying the appropriate tool. The individual methodological quality for each record was assessed qualitatively and extracted on a standardized tool. Whenever discrepancies arose, a third author (CB) was consulted as arbiter for resolution. If at least 10 RCTs reported a specific comparison, we intended to assess publication bias by creating a funnel plot.
8
Results Our initial literature search identified 1,327 references (last updated 14 August 2017). After removing duplicates, 965 citations remained. Following title and abstract screening, 920 studies were not considered relevant since they did not meet our inclusion criteria and were consequently excluded. Hence, 45 records underwent full text review (Figure 1). Of these 45 items, 8 additional duplicates were identified [15-21]. Fifteen studies did not meet the inclusion criteria, mostly because they had a retrospective uncontrolled design [2229] or did not provide data on UM subgroups [30-34]. One narrative review [35] and a study with unclear inclusion criteria [36] were excluded as well (table 2). Six ongoing studies were identified which are currently in different stages (table S2). Furthermore, 4 completed registered trials were detected, but no published data was found and the investigators either did not reply or did not consent to preliminary data publication in this review after we had contacted them (table S3). Finally, 12 records met our eligibility criteria and were included in the qualitative synthesis. They comprised data from 7 expanded access programs (EAP) or named patient programs (NPP) (n=162 patients), 4 phase II trials (n=171 patients), and 1 phase Ib trial (sample size unknown). The number of patients with UM per study ranged from 6 to 83 patients with an average of 18 patients. Results were available for ipilimumab (n=8), tremelimumab (n=1), pembrolizumab (n=1), nivolumab (n=1), and combined ipilimumab with nivolumab or pembrolizumab (n=1). None of the included studies reported the secondary outcome healthor treatment-related quality of life. Furthermore, no RCT was found. Anti-CTLA-4-blocking antibodies Ipilimumab Blank et al. investigated a combination of ipilimumab with radiofrequency ablation (RFA) in a phase Ib/II trial (SECIRA-UM trial). Results of the phase Ib part were published as conference abstract [37] Patients with at least two liver metastases from UM were included. Four doses of ipilimumab were assessed (0.3 mg/kg, 3 mg/kg, 10 mg/kg) with infusions applied every three weeks (Q3W). RFA was combined with ipilimumab at a dose up to 10 mg/kg. One patient (17%) developed a grade 3 immune-related colitis. PR was observed in 1 case (17%) in the 10 mg/kg cohort. PFS and OS were not reported and the overall sample sizes of the cohorts remained elusive [37]. Ipilimumab was assessed at a dose of 3 mg/kg (body weight) in 5 further studies with a total of 186 patients [38-40, 34, 41]. Jung et al. published data of 106 melanoma patients treated within a Korean EAP. Ten UM patients were treated in this setting, but the subgroup was poorly characterized and most primary and secondary outcomes of this review were not 9
reported. The median PFS was graphically estimated as 2.8 months based on the published time-to-event analyses. Median OS appeared not to have been reached by the population [41]. Kelderman et al. analyzed 22 patients treated in a Dutch EAP (WIN-O). Ipilimumab was applied for up to 4 cycles (Q3W). No CR was observed, 1 patient showed a PR (4.5%). The median PFS and OS were 2.9 (95% CI 2.3-5.3) and 5.2 (95%CI 4.9-9.6) months, respectively. After 1 year, 27% of all treated patients were still alive, as visually estimated and extracted from the published Kaplan-Meier curve. In 3 patients (13.6%), predominantly immune-related adverse events (AEs) graded as ≥3 were detected [38]. Maio et al. investigated ipilimumab 3 mg/kg (4 cycles, Q3W) in 82 pre-treated patients with advanced UM. Patients with initial immune-related disease control were eligible for re-induction with ipilimumab at the same dosage and schedule. PR was observed in 4 patients, revealing an ORR of 5%. The median OS and PFS amounted to 6.0 (95% CI 4.3-7.7) and 3.6 (95% CI 2.8-4.4) months, respectively. The 1-year OS rate was 31% and severe AEs were observed in 5 patients (6%) [39]. Shaw et al. reported data from an EAP in the United Kingdom for patients with mucosal, acral and ocular melanoma. Eighteen patients with UM were treated with ipilimumab 3 mg/kg Q3W for up to 4 cycles. The median PFS was 14.5 weeks (range 664); the median OS was not indicated in the conference abstract. Likewise, other outcomes such as ORR or AE rates were not clearly reported for the UM subgroup [40]. Zimmer et al. undertook a multicenter open-label phase II trial to assess the safety and efficacy of ipilimumab 3 mg/kg (4 cycles, Q3W) in distinct melanoma subtypes. A total of 53 patients received at least one cycle of treatment. No radiologic response was observed in any case. The median OS was 6.8 months (95% CI 3.7-8.1) and the median PFS 2.8 months (95% CI 2.5-2.9). The 1-year OS rate was 22%. Treatment-related grade 3-4 events occurred in 19 patients (36%) [42]. Ipilimumab was assessed at a dose of 10 mg/kg (body weight) in 2 more studies with a total of 45 patients [43, 44]. Danielli et al. performed a subgroup analysis of UM patients treated within the Italian ipilimumab-ocular melanoma EAP (I-OMEAP). Thirteen patients received ipilimumab 10 mg/kg (4 cycles, Q3W). No objective response was observed. Median OS was 36 weeks, PFS was not reported. Severe immune-related AEs occurred in 3 patients (23%) [44]. Piulats et al. presented data from a phase II trial in 32 treatment-naïve patients from Spain (GEM1 trial). The treatment consisted of 4 cycles ipilimumab 10 mg/kg Q3W (induction), followed by one application every 12 weeks (Q12W) as maintenance. The median OS was 9.8 months, whereas PFS was not reported. PR was observed in 6.5% (95% CI 0.79-21.42), the rate of severe AEs was reported as 10% (n=10) [43]. Tremelimumab
10
Joshua et al. performed a multicenter phase II trial on the CTLA-4-blocking antibody tremelimumab (CP-675206). Patients received 15 mg/kg tremelimumab every 90 days for up to 4 cycles (n=11). No patient achieved a CR or PR. The median PFS was 2.9 months (95% CI 2.8-3.0). The median OS was 12.8 months, yet with high variation (95% CI 3.8-19.7), and the 1-year OS was 55% (graphically estimated). The rate of AEs ≥grade 3 was not clearly stated. Due to the poor PFS and the lack of a radiologic response, the trial was stopped for futility at the first interim stage [45]. Anti-PD1- and anti-PD-L1-blocking antibodies Kottschade et al. investigated a sample of 10 patients with metastatic UM who were treated with pembrolizumab in an EAP. Pembrolizumab was given at a dose of 2 mg/kg Q3W until disease progression or development of unacceptable toxicity for up to 2 years. One patient had a CR (10%) and 2 had a PR (20%), resulting in an ORR of 30%. However, the PFS was only 18 weeks (range 3.14-49.3) and data on OS were not reported. Severe AEs were observed in 1 patient (10%) [46]. The phase II trial CheckMate 172 evaluated the safety and efficacy of nivolumab monotherapy (3 mg/kg, Q2W) in 75 UM patients who progressed after anti-CTLA-4 therapy. After a minimum follow-up of 1 year, 2 patients in the UM subgroup had a PR (ORR 6%, 95% CI 1-20) and 15 patients showed disease stabilization (44%). The median OS was 11 months (95% CI 7-15) and the OS rate at 1 year 47% (95% CI 34-59). Data on PFS or severe AEs were not specifically reported for the UM subgroup [47]. Studies investigating other PD-1 or PD-L1 inhibitors which met the inclusion criteria of this review were not identified. Combined CTLA-4 and PD-1 blockade Shoushtari et al. provided data on the combination of ipilimumab with nivolumab or pembrolizumab from an EAP. In total, 64 patients with metastatic melanoma were enrolled and treated in this program with nivolumab (1 mg/kg) and ipilimumab (3 mg/kg) administered every 3 weeks for 1-4 doses, followed by maintenance treatment with nivolumab (3 mg/kg) every two weeks or pembrolizumab (2 mg/kg) every three weeks. Six patients with UM were included. The median PFS was 2.8 months (95% CI 1.2-4.6 months) and the ORR was 0% (95% CI 0-51%) in the UM subgroup. OS and rates of severe AEs were not specifically reported for the subgroup [48]. Assessment of methodological quality Since we only included uncontrolled before-after studies and EAPs, we used the NHLBI tool to assess the methodological quality. Nine studies were rated as fair [37, 44, 45, 41, 38, 46, 39, 47, 48], 2 records as poor [40, 43], and 1 trial as good [42] (table 3).
11
Discussion In this systematic review, we identified 12 eligible studies which were used to provide an upto-date overview on the efficacy, safety and tolerability of ICB in patients with advanced UM. The majority of studies investigated ipilimumab at 3 mg/kg or 10 mg/kg, whereas only 3 records met our inclusion criteria for PD-1 inhibitor monotherapy or combined CTLA-4 and PD-1 blockade. No RCTs or CCTs were identified in our search, underlining that there is currently only little evidence for the use of ICB in UM, most likely because it is an orphan condition. The response to ICB in the included trials was low. The ORR for ipilimumab monotherapy at a dose of 3 mg/kg ranged from 0-5% and at a dose of 10 mg/kg from 0-6.5%. In line with these results, the median PFS was below 3 and the median OS poor in most records. Treatment with tremelimumab, another CTLA-4-blocking antibody, did not achieve any response in a phase II trial. These data suggest that UM is generally little susceptible to CTLA-4 blockade, regardless of distinct antibody types or dosage schemes. Moreover, immune-related AEs occurred at a frequency comparable to the reported ones for cutaneous melanoma. One study even described serious AEs in 36% of treated patients [34]. These data indicate that CTLA-4 blockade lacks efficacy but maintains toxicity in metastatic UM and do not support the application of CTLA-4 blockade as monotherapy in daily practice. We identified only 2 trials on PD-1 inhibitor monotherapy, namely pembrolizumab at 2 mg/kg Q3W and nivolumab at 3 mg/kg Q2W. Even though radiological responses were observed in 30% with pembrolizumab, the study had a small sample size (n=10) and is at risk to overestimate the treatment effect [46]. Furthermore, this relatively high ORR reported by Kottschade et al. stands in contrast to 6% revealed in the CheckMate 172 trial [47] and several other retrospective reports investigating PD-1 inhibitor monotherapy that were identified by our literature search, but excluded from the qualitative synthesis due to their retrospective and uncontrolled design. Algazi et al. investigated a large cohort of patients (n=58) treated with PD-1 or PD-L1 inhibitors with a response of 3.6% [22]. Similar results were obtained by Kelderman et al. and Karydis et al. in retrospective evaluations of pembrolizumab and nivolumab in smaller cohorts [26, 27]. Only one report was identified investigating ipilimumab combined with PD-1 inhibition within an EAP. No radiological response was observed and the PFS was poor (2.9 months) [48]. However, only 6 patients with UM were investigated and the conclusions drawn from this small sample should be interpreted with caution. The results from these studies suggest that the efficacy of ICB is lower in UM compared to cutaneous or mucosal melanoma, yet future RCTs are warranted to give more reliable estimates.
12
In this context, it remains to be determined if adding a loco-regional treatment may enhance the systemic response to ICB. Several studies have suggested an abscopal response of cutaneous melanoma when systemic ICB was combined with a destructive peripheral treatment modality [49-51]. We identified one phase Ib study which investigated RFA for liver metastasis with different dosages of ipilimumab [37]. However, the information available from this conference abstract was limited and survival data were not reported. It is remarkable that quality of life was not reported in any study. Our review suggests that ICB in UM maintains the toxicity profile observed in cutaneous melanoma despite lower efficacy. Thus, the treatment- and health-related quality of life may be particularly unfavorable in this disease because treatment-related AEs do significantly affect patients’ quality of life. This outcome is becoming increasingly more important in oncology and should be respected in future trials investigating ICB, particularly in patients with UM [52, 53]. We are aware that our review has several limitations. Our review only identified before-after studies and EAPs. This may be explained by the fact that UM is an orphan disease. Besides, conference abstracts often report incomplete or preliminary data. Nevertheless, patients with advanced UM have a high unmet need and systemic therapy options are limited and not evidence-based. Here, we conducted a systematic and comprehensive literature research and presented in our review a body of highest possible evidence available regarding the treatment of ICB in patients with advanced UM. Even though a number of narrative reviews and expert statements have been published on this topic, an unbiased systematic review and qualitative data synthesis following a predefined and published protocol has not yet been conducted to the best of our knowledge [54-57, 35, 58]. The databases MEDLINE, CENTRAL and Embase were searched. However, handsearching of the trial registers and conference abstracts for this review was conducted by one author only. Records in English and German were respected and other languages were not considered. Although we closely followed the PRISMA guidelines, we cannot fully exclude selection bias in our review. Furthermore, we did not assess and cannot exclude the existence of publication bias. When evaluating the methodological quality for the 12 included records, only 1 study was rated as “good”, whereas 9 were considered “fair” and 2 “poor” according to the NHLBI assessment tool. Although the tool is less established and less distinctive than others [13, 14], the results of the bias assessment should be kept in mind when interpreting our results. As we are aware of the importance of assessing the methodological quality and the risk of bias in a review, we still decided to conduct a bias assessment despite the fact that we did not include any RCT or controlled observational study [14, 13].
13
Taken together, our results do not support the use of ipilimumab monotherapy for the treatment of advanced UM. The current application of combined ipilimumab and PD-1 inhibition is not yet evidence-based. However, the results of several ongoing trials have to be awaited to give a reliable estimate on the efficacy of combined ICB. Future efforts should be undertaken to conduct multicenter RCTs in order to provide results of highest possible evidence for this orphan albeit important condition. Acknowledgements None. Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Conflicts of interest CB has received speaker’s and advisor’s honoraria by Amgen, AstraZeneca, BMS, MSD, Novartis, Pierre Fabre, and Roche. MVH received speaker’s honoraria from Roche, Novartis, BMS, MSD and travel support from BMS. All remaining authors have declared no conflicts of interest. Author contributions MVH, JGS, CD, SR, AN, and CB designed the study. MVH, TS, JGS, and SR performed the literature search. MVH, TS, and JGS extracted data from full texts and conducted the risk of bias assessments. MVH, TS, TR, and CB wrote the manuscript.
14
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Piulats JM, De La Cruz-Merino L, Curiel Garcia MT, Berrocal A, Alonso-Carrión L, Espinosa M et al. Phase II multicenter, single arm, open label study of nivolumab (NIVO) in combination with ipilimumab (IPI) as first line in adult patients (pts) with metastatic uveal melanoma (MUM): GEM1402 NCT02626962. J Clin Oncol 2017;35.
[22]
Algazi AP, Tsai KK, Soushtari AN, Munhoz RR, Eroglu Z, Piulats JM et al. Clinical outcomes in metastatic uveal melanoma treated with PD-1 and PD-L1 antibodies. Cancer Immunol Immunother 2016;122:3344-53.
[23]
Itchins M, Ascierto PA, Menzies AM, Oatley M, Lo S, Douraghi-Zadeh D et al. A multireferral centre retrospective cohort analysis on the experience in treatment of metastatic uveal melanoma and utilization of sequential liver-directed treatment and immunotherapy. Melanoma Res 2017;27:243-50.
16
[24]
Piperno-Neumann S, Servois V, Mariani P, Cassoux N, Barnhill R, Rodrigues JM. Activity of anti-PDI drugs in uveal melanoma patients. J Clin Oncol 2016;34.
[25]
Tian L, Ding F, Sander C, Rose A, Pruckner C, Wilson M et al. PD-1 blockade to treat mucosal and uveal melanoma: The University of Pittsburghh experience. J Clin Oncol 2016;34.
[26]
van der Kooij MK, Joosse A, Speetjens FM, Hospers GAP, Bisschop C, de Groot JWB et al. Anti-PD1 treatment in metastatic uveal melanoma in the Netherlands. Acta Oncol 2017;56:101-3.
[27]
Karydis I, Chan PY, Wheater M, Arriola E, Szlosarek PW, Ottensmeier CH. Clinical activity and safety of Pembrolizumab in Ipilimumab pre-treated patients with uveal melanoma. Oncoimmunology 2016;5:e1143997.
[28]
Luke JJ, Callahan MK, Postow MA, Romano E, Ramaiya N, Bluth M et al. Clinical activity of ipilimumab for metastatic uveal melanoma: a retrospective review of the Dana-Farber Cancer Institute, Massachusetts General Hospital, Memorial SloanKettering Cancer Center, and University Hospital of Lausanne experience. Cancer 2013;119:3687-95.
[29]
McKean MA, Haydu LE, Ma J, Bassett RL, Hwu W, Patel SP et al. Prognostic factors for overall survival (OS) in metastatic melanoma (MM) patients (pts) treated with immune checkpoint inhibitors: A single institution study of 696 pts. J Clin Oncol 2017;35.
[30]
Cesas A, Cesiene J, Poskiene A. A single center experience in heavily pretreated melanoma patients in an ipilimumab expanded access programme at the klaipeda university hospital (lithuania). J Dtsch Dermatol Ges 2013;11.
[31]
Di Giacomo AM, Danielli R, Calabro L, Bertocci E, Nannicini C, Giannarelli D et al. Ipilimumab experience in heavily pretreated patients with melanoma in an expanded access program at the University Hospital of Siena (Italy). Cancer Immunol Immunother 2011;60:467-77.
[32]
Naing A, Papadopoulos KP, Infante JR, Wong DJL, Autio KA, Ott PA et al. Clinical activity and safety of pegylated human IL-10 (AM0010) in combination with anti-PD1. J Clin Oncol 2016;34.
[33]
Schmerling R, Herchenhorn D, Rinck JA, De Camargo VP, Camargo J, Serrano SV et al. Ipilimumab for stage unresectable III/IV melanoma: Brazilian experience in an expanded access program. J Clin Oncol 2014;32.
[34]
Zimmer L, Eigentler T, Vaubel J, Mohr P, Jradi Z, Kiecker F et al. Open-label, multicenter, single-arm phase II study (DeCOG-Trial) to further evaluate the efficacy and safety of ipilimumab in patients with cutaneous melanoma and rare subgroups. J Clin Oncol 2014;32. 17
[35]
Breazzano MP, Milam RW, Batson SA, Johnson DB, Daniels AB. Immunotherapy for uveal melanoma. Int Ophthalmol Clin 2017;57:29-39.
[36]
Shapira-Frommer R, Stephen F, Ben-Ami E, Hamburger T, Markel G, Ospovat I et al. Ipilimumab for advanced, refractory melanoma: A report of the Israeli cohort of expanded access program. J Clin Oncol 2013;31.
[37]
Blank C, Geukes Foppen M, Prevoo W, Meier M, Van Thienen H, Kvistborg P et al. Combined radiofrequency ablation (RFA) and ipilimumab (IPI) in uveal melanoma: Phase 1b results from the SECIRA-UM trial. Eur J Cancer 2015;51:S109-S10.
[38]
Kelderman S, van der Kooij MK, van den Eertwegh AJ, Soetekouw PM, Jansen RL, van den Brom RR et al. Ipilimumab in pretreated metastastic uveal melanoma patients. Results of the Dutch Working group on Immunotherapy of Oncology (WINO). Acta Oncol 2013;52:1786-8.
[39]
Maio M, Chairion Sileni V, Pilla L, Nicoletti SVL, Di Guardo L, Queirolo P et al. Efficacy and safety of ipilimumab in patients with pretreated, ocular melanoma: Experience from Italian clinics participating in the European expanded access programme (EAP). Ann Oncol 2012;23:ix369-ix70.
[40]
Shaw H, Larkin J, Corrie P, Ellis S, Nobes J, Marshall E et al. Ipilimumab for advanced melanoma in an expanded access programme (EAP): Ocular, mucosal and acral subtype UK experience. Ann Oncol 2012;23:374.
[41]
Jung M, Lee J, Kim TM, Lee DH, Kang JH, Oh SY et al. Ipilimumab Real-World Efficacy and Safety in Korean Melanoma Patients from the Korean Named-Patient Program Cohort. Cancer Res Treat 2017;49:44-53.
[42]
Zimmer L, Vaubel J, Mohr P, Hauschild A, Utikal J, Simon J et al. Phase II DeCOGstudy of ipilimumab in pretreated and treatment-naive patients with metastatic uveal melanoma. PLoS One 2015;10.
[43]
Piulats JM, Ochoa-De-Olza M, Lopez-Martin JA, Codes M, Berrocal A, Martin-Algarra S. Phase II study evaluating Ipilimumab monotherapy in the first-line treatment of adult patients with metastatic uveal melanoma (MUM): The GEM1 trial. Pigment Cell Melanoma Res 2014;27:1219.
[44]
Danielli R, Ridolfi R, Chiarion-Sileni V, Queirolo P, Testori A, Plummer R et al. Ipilimumab in pretreated patients with metastatic uveal melanoma: safety and clinical efficacy. Cancer Immunol Immunother 2012;61:41-8.
[45]
Joshua AM, Monzon JG, Mihalcioiu C, Hogg D, Smylie M, Cheng T. A phase 2 study of tremelimumab in patients with advanced uveal melanoma. Melanoma Res 2015;25:342-7.
18
[46]
Kottschade LA, McWilliams RR, Markovic SN, Block MS, Villasboas Bisneto J, Pham AQ et al. The use of pembrolizumab for the treatment of metastatic uveal melanoma. Melanoma Res 2016;26:300-3.
[47]
Schadendorf D, Ascierto PA, Haanen JB, Espinosa E, Demidov LV, Garbe C et al. Efficacy and safety of nivolumab (NIVO) in patients with advanced melanoma (MEL) and poor prognostic factors who progressed on or after ipilimumab (IPI): Results from a phase II study (CheckMate 172). J Clin Oncol 2017;35.
[48]
Shoushtari A, Navld-Azarbaljanl P, Friedman CF, Panageas K, Postow MA, Callahan MK et al. Efficacy of nivolumab and ipilimumab (Nivo + Ipi) combination in melanoma patients (pts) treated at a single institution on an expanded-access program (EAP). J Clin Oncol 2016;34.
[49]
Heppt MV, Eigentler TK, Kahler KC, Herbst RA, Goppner D, Gambichler T et al. Immune checkpoint blockade with concurrent electrochemotherapy in advanced melanoma: a retrospective multicenter analysis. Cancer Immunol Immunother 2016;65:951-9.
[50]
Grimaldi AM, Simeone E, Giannarelli D, Muto P, Falivene S, Borzillo V et al. Abscopal effects of radiotherapy on advanced melanoma patients who progressed after ipilimumab immunotherapy. Oncoimmunology 2014;3:e28780.
[51]
Theurich S, Rothschild SI, Hoffmann M, Fabri M, Sommer A, Garcia-Marquez M et al. Local Tumor Treatment in Combination with Systemic Ipilimumab Immunotherapy Prolongs Overall Survival in Patients with Advanced Malignant Melanoma. Cancer Immunol Res 2016;4:744-54.
[52]
Atkinson TM, Hay JL, Shoushtari A, Li Y, Paucar DJ, Smith SC et al. Relationship between physician-adjudicated adverse events and patient-reported health-related quality of life in a phase II clinical trial (NCT01143402) of patients with metastatic uveal melanoma. J Cancer Res Clin Oncol 2017;143:439-45.
[53]
Coens C, Suciu S, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD et al. Healthrelated quality of life with adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): secondary outcomes of a multinational, randomised, double-blind, phase 3 trial. Lancet Oncol 2017;18:393403.
[54]
Komatsubara KM, Carvajal RD. Immunotherapy for the Treatment of Uveal Melanoma: Current Status and Emerging Therapies. Curr Oncol Rep 2017;19:45.
[55]
Komatsubara KM, Carvajal RD. Adopting a new stance on immunotherapy for uveal melanoma. Lancet Oncol 2017;18:702-4.
[56]
Oliva M, Rullan AJ, Piulats JM. Uveal melanoma as a target for immune-therapy. Ann Transl Med 2016;4:172. 19
[57]
Chattopadhyay C, Kim DW, Gombos DS, Oba J, Qin Y, Williams MD et al. Uveal melanoma: From diagnosis to treatment and the science in between. Cancer 2016;122:2299-312.
[58]
Luke JJ, Triozzi PL, McKenna KC, Van Meir EG, Gershenwald JE, Bastian BC et al. Biology of advanced uveal melanoma and next steps for clinical therapeutics. Pigment Cell Melanoma Res 2015;28:135-47.
20
Figure 1: Flowchart of the literature search according to the PRISMA guidelines.
Records identified through database searching
MEDLINE (n=463) CENTRAL (n=29) EMBASE via Ovid (n=729)
Conference abstracts
Identification
(n=12)
(n=94)
Records identified (n=1327)
Screening
Trial register
Duplicates removed (n=362)
Records after duplicates removed (n=965)
Records screened (n=965)
Records excluded based on abstracts and titles (n=920)
Eligibility
Records (n=33) excluded for the following reasons:
Records assessed for eligibility (n=45)
Included
Records included in qualitative synthesis (n=12)
Duplicates (n=8) Ongoing studies (n=6) Completed trial register-study, but no published data available (n=4) Other reasons (n=15)
21
Table 1: Search query in Medline/PubMed. Key search terms: Choroid, iris, ocular, uvea Melanoma, neoplasms CTLA-4, cytotoxic T-lymphocyte-associated protein-4, immune checkpoint, ipilimumab, Keytruda, nivolumab, Opdivo, pembrolizumab, PD-1, PD-L1, programmed cell death protein, tremelimumab, Yervoy MeSH terms: uveal neoplasms, antibodies Combination operators: (("uveal neoplasms"[MeSH Terms]) OR (uveal melanoma*[Title/Abstract]) OR (uveal neoplasm*[Title/Abstract]) OR (choroid* AND melanoma*[Title/Abstract]) OR (choroid* AND neoplasm*[Title/Abstract]) OR (iris melanoma*[Title/Abstract]) OR (iris neoplasm*[Title/Abstract]) OR (ocular melanoma*[Title/Abstract]) OR (ocular neoplasm*[Title/Abstract])) AND ((ipilimumab[Title/Abstract]) OR (yervoy[Title/Abstract]) OR (pembrolizumab[Title/Abstract]) OR (keytruda[Title/Abstract]) OR (nivolumab[Title/Abstract]) OR (opdivo[Title/Abstract]) OR (PD1[Title/abstract]) OR (PD-1[Title/Abstract]) OR (PDL1[Title/Abstract]) OR (PDCD1[Title/Abstract]) OR (programmed cell death protein[Title/Abstract]) OR (CTLA-4[Title]) OR (CTLA4[Title]) OR (cytotoxic T-lymphocyteassociated[Title/Abstract]) OR ("antibodies"[MeSH Terms]) OR (immune*[Title/Abstract]))
22
Table 2: Records assessed for eligibility but excluded from the qualitative synthesis (n=15). First author and year
Record type
Population
Intervention
Control
Reported efficacy outcomes
Reason for exclusion
pembrolizumab Algazi 2016 [22]
n=58 (UM only) journal article
ORR nivolumab
uncontrolled
multicenter
retrospective design OS
atezolizumab Breazzano 2017 [35]
journal article
n.a.
n.a.
n.a.
ipilimumab
uncontrolled (EAP)
n.a.
narrative review
ORR
no data available for UM subgroup
n=21 (total) Cesas 2013 [30]
conference abstract
n=3 (UM)
PFS single center n=27 (total)
Di Giacomo 2011 [31]
DCR journal article
n=3 (UM)
ipilimumab
uncontrolled (EAP) OS
no data available for UM subgroup
single center ipilimumab Itchins 2017 [23]
ORR
n=37 (UM only) journal article
pembrolizumab
uncontrolled
PFS
retrospective design
single center nivolumab N=25 (UM only)
Karydis 2016 [27]
journal article
Luke 2013 [28]
journal article
OS uncontrolled
PFS
(EAP)
OS
pembrolizumab multicenter
retrospective design
n=39 (UM only)
ORR ipilimumab
uncontrolled
multicenter
retrospective design OS
ipilimumab McKean 2017 [29]
n=696 (total) conference abstract
nivolumab
uncontrolled
OS
retrospective design
n=22 (UM) pembrolizumab
23
n=19 Naing 2016 [32]
PipernoNeumann 2016 [24]
conference abstract
number of patients with UM not reported
pegylated IL-10 with pembrolizumab
uncontrolled ORR (phase I)
no data available for UM subgroup
ORR pembrolizumab conference abstract
n=21 (UM only)
uncontrolled
PFS
retrospective design
nivolumab OS n=450 (total)
Schmerling 2014 [33]
PFS conference abstract
8.4% with UM
ipilimumab
uncontrolled (EAP) OS
no data available for UM subgroup
multicenter ShapiraFrommer 2013 [36]
n=183 conference abstract
ORR
not clear if UM patients included
ipilimumab
n=17 (total)
nivolumab
n=9 (UM)
pembrolizumab
uncontrolled (EAP) OS
inclusion of UM patients not clear
ORR Tian 2016 [25]
conference abstract
uncontrolled
PFS
retrospective design
OS ORR van der Kooij 2017 [26]
n=17 (UM only)
nivolumab
multicenter
pembrolizumab
journal article
uncontrolled
PFS
retrospective design
OS ORR Zimmer 2014 [34]
n=156 (total) journal article
uncontrolled ipilimumab
n=53 (UM)
PFS (phase II)
data for ocular melanoma not reported
OS
Abbreviations: ORR = overall response rate; DCR = disease control rate; PFS = progression-free survival; OS = overall survival; UM = patients with uveal melanoma; n.a. = not applicable; EAP = expanded access program; IL = interleukin. 24
25
Table 3: Studies included in the qualitative data synthesis (n=12). Study characteristics Author
Primary outcomes
Secondary outcomes
Bias assessment
Design
Sample size
Intervention
Dosage [mg/kg]
ORR
PR
CR
PFS (median)
OS (median)
1-year OS
AEs > grade 3
QoL
Open-label, 3armed, phase Ib trial
n.r.
RFA + Ipilimumab
10
n.r.
1 (17%)
n.r.
n.r.
n.r.
n.r.
1 (17%)
n.r.
fair
Danielli 2012
EAP
13
Ipilimumab
10
0
0
0
n.r.
36 wks. (range 2-172+ wks)
n.r.
3 (23%)
n.r.
fair
Joshua 2015
Observational, prospective, open-label, multicenter phase II study
11
Tremelimuma b
15
0
0
0
2,9 mo. (95% CI 2.8-3.0)
12.8 mo. (95% CI 3.8-19.7)
0.55
not clearly reported
n.r.
fair
Jung 2017
NPP
10
Ipilimumab
3
n.r.
n.r.
n.r.
2.8 mo.
not reached
not determinable
not clearly reported
n.r.
fair
Keldermann 2013
EAP
22
Ipilimumab
3
n.r.
1 (4.5%)
0
2.9 mo. (95% CI: 2.3-5.3)
5.2 mo. (95%CI: 4.9-9.6)
27%
3 (13.6%)
n.r.
fair
Kottschade 2016
EAP
10
Pembrolizuma b
2
3 (30%)
2 (20%)
1 (10%)
18 wks. (range 3.14-49.3)
n.r.
n.r.
1 (10%)
n.r.
fair
Maio 2012
EAP
83
Ipilimumab
3
4 (5%)
4 (5%)
0
3.6 mo. (95% CI 2.8–4.4)
6.0 mo (95% CI 4.3-7.7)
26 (31%)
5 (6%)
n.r.
fair
Piulats 2014
Observational, prospective, open-label, single arm phase II trial
32
Ipilimumab
10
n.r.
2 (6.45%) (95% CI 0.7921.42)
n.r.
n.r.
9.8 mo.
n.r.
10 (31%)
n.r.
poor
Schadendorf 2017
Single-arm, open-label, multicenter, phase II trial
75
Nivolumab
3
2/34 (5.8%) at 12 wks.
2 (5.8%)
0
n.r.
11 mo. (95% CI 7-15)
47% (95% CI 3459)
Not clearly reported for UM subgroup
n.r.
fair
Shaw 2012
EAP
18
Ipilimumab
3
n.r.
n.r.
n.r.
14.5 wks. (range: 6-64)
n.r.
n.r.
not clearly reported
n.r.
poor
Shoushtari 2016
EAP
6
Nivolumab, Ipilumamb
1 and 3, resp.
0/5 (95%C I: 0-
n.r.
n.r.
2.9 mo. (95% CI 2.3-5.3)
n.r.
n.r.
n.r.
n.r.
fair
Blank 2015
26
51%)
Zimmer 2015
Observational, prospective, open-label, uncontrolled, multicenter phase II
53
Ipilimumab
3
0
0
0
2.8 mo. (95% CI 2.5–2.9)
6.8 mo. (95% CI 3.7-8.1)
22% (95% CI 12– 35)
19 (36%)
n.r.
good
Abbreviations: EAP = expanded access program; NPP = named patient program; ORR = overall response rate; PR = partial response; CR = complete response; PFS = progression-free survival; OS = overall survival; n.r. = not reported; AE = adverse events; QoL = Quality of Life, CI = confidence interval, mo. = months, wks. = weeks, resp. = respectively.
27
Highlights
Metastatic uveal melanoma (UM) is an orphan disease of high unmet need
The current use of immune checkpoint blockade in UM is not evidence-based
A systematic review on immune checkpoint blockade for UM was performed
CTLA-4 blockade lacks efficacy but maintains toxicity in metastatic UM
28
S0305-7372(17)30132-9 http://dx.doi.org/10.1016/j.ctrv.2017.08.009 YCTRV 1667
To appear in:
Cancer Treatment Reviews Cancer Treatment Reviews
Received Date: Revised Date: Accepted Date:
4 July 2017 18 August 2017 19 August 2017
Please cite this article as: Heppt, M.V., Steeb, T., Gabriel Schlager, J., Rosumeck, S., Dressler, C., Ruzicka, T., Nast, A., Berking, C., Immune checkpoint blockade for unresectable or metastatic uveal melanoma: a systematic review, Cancer Treatment Reviews Cancer Treatment Reviews (2017), doi: http://dx.doi.org/10.1016/j.ctrv. 2017.08.009
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Immune checkpoint blockade for unresectable or metastatic uveal melanoma: a systematic review
Markus V. Heppt1, Theresa Steeb1, J. Gabriel Schlager1, Stefanie Rosumeck2, Corinna Dressler2, Thomas Ruzicka1, Alexander Nast2, Carola Berking1,*
1
Department of Dermatology and Allergy, University Hospital, LMU Munich, Frauenlobstr. 9-
11, 80337 Munich, Germany 2
Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin,
Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Dermatology, Division of Evidence – Based Medicine, Charitéplatz 1, 10117 Berlin, Germany * Correspondence should be addressed to Carola Berking Department of Dermatology and Allergy University Hospital, LMU Munich Frauenlobstr. 9-11 80337 Munich Germany Phone:
0049-89-4400-0
Fax:
0049-89-4400-56226
Email:
[email protected]
Word counts:
249 (abstract) 3653 (body)
Figure(s):
1
Tables:
3 (regular), 3 (supplementary)
1
Title: Immune checkpoint blockade for unresectable or metastatic uveal melanoma: a systematic review
2
Abstract
Background: The use of immune checkpoint blockade (ICB) for uveal melanoma (UM) is little established. The aim of this review was to provide a comprehensive overview on the efficacy, safety, and tolerability of ICB in patients with UM. Methods: We performed a systematic literature research covering MEDLINE, Embase and CENTRAL. Abstracts of pertinent conferences and trial registers were handsearched for relevant studies. Results: Out of 1,327 records initially identified, 12 eligible studies were included in the qualitative synthesis. They comprised 7 expanded access or named patient programs (n=162), 4 phase II trials (n=171), and 1 phase Ib trial (sample size unknown), while no randomized controlled trial was found. Ipilimumab monotherapy was assessed at 3 mg/kg in 5 trials (n=186) with a response rate of 0-5%. Two reports investigated ipilimumab at 10 mg/kg (n=45) with radiological responses observed in 0-6.5%. The median progression-free survival (PFS) was below 3 months and the median overall survival was 5.2-9.8 months for ipilimumab monotherapy. Severe immune-related adverse events occurred at a frequency comparable to cutaneous melanoma (6-36%). Two studies investigated pembrolizumab (2 mg/kg) and nivolumab (3 mg/kg) with overall response rates of 30% and 6%, respectively. Data on combined ipilimumab and programmed cell death protein 1 inhibition were available from one expanded access program, but no response was observed with a median PFS of 2.9 months. Conclusions: UM is little responsive to ipilimumab regardless of dosage schemes. Sound randomized clinical trials are needed to evaluate the efficacy of combined ICB in patients with UM.
Key words: uveal melanoma; CTLA-4; ipilimumab; immune checkpoint blockade; pembrolizumab; nivolumab
3
Introduction Uveal melanoma (UM) is an ocular malignancy which originates from melanocytes residing in the choroid layer of the eye. With an incidence of 4-7 cases per million in Europe, it is much rarer than cutaneous melanoma [1]. Several risk factors for the development of UM have been identified in observational studies, including the presence of choroidal or cutaneous nevi, fair skin, light eye color, and exposure to ultraviolet radiation [2]. Despite these similarities in risk factors, UM is clinically and biologically distinct from cutaneous melanoma. Genetic alterations frequently affect the guanine nucleotide binding proteins Q polypeptide (GNAQ) and α11 (GNA11), whereas activating mutations of the v-Raf murine sarcoma viral oncogene homolog (BRAF) and neuroblastoma rat sarcoma viral oncogene homolog (NRAS), which are commonly detected in cutaneous melanoma, are rarely found [3, 4]. Further somatic mutations of UM involve the BRCA1-associated protein (BAP1) on chromosome 3. Patients with a selective loss of this chromosome as observed in monosomy 3 are at high risk for developing hepatic metastases. The reasons for this selective liver-homing behavior are widely unknown. Clinically, a variety of local liverdirected, destructive treatment approaches have been described, but most of them failed to demonstrate a clear survival benefit in metastatic disease [5]. Therapeutic options of local disease are radiation therapy such as brachytherapy, external beam radiotherapy, particle radiation, photon-based radiation or surgical approaches like local resection and enucleation of the affected eye. Although these measures are highly effective to achieve local tumor control, up to 50% of all patients develop distant metastases, most commonly localized to liver and lungs. In case of unresectable or metastatic disease, patients should receive systemic treatment. Improved understanding on the molecular pathways which drive disease progression like the mitogen-activated protein kinase (MAPK) pathway, G protein-coupled receptor or HIPPO signaling offers new therapeutic strategies. However, once metastases are present, the disease course is often aggressive and the prognosis remains dismal. In this stage, therapy has largely been adopted from cutaneous melanoma where immune checkpoint blockade (ICB) with PD-1 inhibitors and ipilimumab has shown strong survival benefits in recent years [6-8]. Yet, patients with UM have been widely excluded from most of the pivotal trials. The high efficacy of ICB may fall short of expectations in UM, because it is by far less immunogenic, evident by a low burden of somatic mutations and little expression of neoantigens by the tumors [9-11]. However, a systematic literature assessment to summarize the efficacy of ICB in metastatic UM has not been performed to date. Considering the high treatment-related costs and development of severe, potentially lethal immune-related toxicity, treating advanced UM with ICB should be evidenced-based instead 4
of being driven by mere extrapolation and analogy to the results achieved in cutaneous melanoma. Here, we performed a systematic review to provide a comprehensive and up-todate overview on the efficacy, safety, and tolerability of ICB in patients with UM.
5
Methods Protocol and registration The protocol for this review was defined a priori and registered online in the PROSPERO international
prospective
register
of
systematic
reviews
on
21
February
2017
(http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42017057344) with an amendment on 29 May 2017. The register ID was PROSPERO 2017:CRD42017057344. This review was conducted and reported according to the PRISMA guidelines [12]. Eligibility criteria We aimed to investigate patients with unresectable or metastatic UM who have been treated with ICB. Agents of ICB included anti-CTLA-4-blocking antibodies (e.g. ipilimumab, tremelimumab), anti-PD-1-blocking antibodies (e.g. pembrolizumab, nivolumab), anti-PD-L1blocking antibodies (e.g. avelumab, atezolizumab), or any combination of these substances. We included randomized controlled trials (RCTs), and clinically controlled trials (CCT), noncontrolled prospective trials, and prospective observational studies with a sample size of n>10 as well as protocol-driven expanded access and named patient programs since UM is an orphan condition and we expected to find few RCTs. Retrospective studies, narrative reviews and case reports or series were excluded. Language restrictions were records published in English or German. Additionally, studies involving patients with systemic or surgical treatment for UM other than ICB during the study period were excluded. In RCTs and controlled observational studies, placebo, chemotherapy or one of the above-mentioned interventions served as control. Search strategy and data sources We searched the electronic databases MEDLINE via PubMed (from 1968), Embase Ovid and the CENTRAL Ovid (from 1980) to identify all relevant records until 5 May 2017. The search strategy for MEDLINE can be found in table 1. The remaining search strategies and queries are listed in supplementary table 1. Additional sources were published conference abstracts retrieved by handsearch for “uveal melanoma” or “ocular melanoma” from the American Society of Clinical Oncology (ASCO), the Society of Melanoma Research (SMR), the European Society of Medical Oncology (ESMO) and the European Association of Dermato-Oncology (EADO) annual meetings from 2014 to 2017. Furthermore, we searched the following trial registers for the same keywords: ISRCTN registry (www.controlled-trials.com); US National Institutes of Health Ongoing Trials Register
(www.clinicaltrials.gov);
Australian
New
Zealand
Clinical
Trials
Registry
(www.anzctr.org.au); World Health Organization International Clinical Trials Registry Platform (www.who.int/trialsearch/); EU Clinical Trials Register (https://www.clinicaltrialsregister.eu/) 6
(last search: 21 February 2017). For ongoing trials and completed trials without data publication, principal investigators or trial sponsors were contacted to obtain preliminary or unpublished data. Besides, reference lists of included records were screened for additional studies. Study selection Two authors (JGS, TS) independently screened titles and abstracts for eligibility that were identified in the electronic database searches. Conference abstracts and trial registers were handsearched and assessed for eligibility by one author (MVH and JGS, respectively). For those records that were considered relevant according to title and abstract screening, full text articles were obtained and inclusion and exclusion criteria were applied. Whenever discrepancies arose, a third author (CB, MVH) was consulted as arbiter for resolution. Outcomes The primary outcomes were (i) radiologic overall response rate (ORR) determined by the sum of complete response (CR) and partial response (PR), (ii) median progression-free survival (PFS), (iii) median overall survival (OS), and (iv) the one-year survival rate (KaplanMeier estimator). Secondary outcomes were (i) the development of severe adverse events, defined as grade 3 or higher according to the Common Terminology Criteria for Adverse Events (CTCAE) v4.03 published by the National Institutes of Health in 2010, and (ii) treatment-related quality of life, assessed with any validated instrument. Data collection, synthesis and management Information for each included study regarding study design, baseline characteristics, intervention, dosage, and risk of bias/ methodological quality as well as on the primary and secondary outcomes were collected and summarized. Data were extracted to an internally piloted data extraction spreadsheet using Microsoft Excel 2010. If no information regarding the outcomes was clearly reported, outcomes were visually extracted from Kaplan-Meier curves whenever applicable and feasible. The baseline characteristics and the outcomes of interest of each study were qualitatively described within the text. Assessment of methodological quality Three different tools to assess the methodological quality and the risk of bias of the included studies were selected: (i) Cochrane risk of bias tool for the evaluation of RCTs [13]; (ii) Risk Of Bias In Non-randomized Studies of Interventions (ROBINS-I) tool for non-randomized studies [14]; (iii) quality assessment tool for before-after (pre-post) studies with no control group as described by the National Heart, Lung, and Blood Institute (NHLBI) for uncontrolled before-after
studies
(available
from
https://www.nhlbi.nih.gov/health-pro/guidelines/in-
develop/cardiovascular-risk-reduction/tools/before-after). 7
Two authors (MVH, TS) independently assessed the risk of bias or the methodological quality of each included study applying the appropriate tool. The individual methodological quality for each record was assessed qualitatively and extracted on a standardized tool. Whenever discrepancies arose, a third author (CB) was consulted as arbiter for resolution. If at least 10 RCTs reported a specific comparison, we intended to assess publication bias by creating a funnel plot.
8
Results Our initial literature search identified 1,327 references (last updated 14 August 2017). After removing duplicates, 965 citations remained. Following title and abstract screening, 920 studies were not considered relevant since they did not meet our inclusion criteria and were consequently excluded. Hence, 45 records underwent full text review (Figure 1). Of these 45 items, 8 additional duplicates were identified [15-21]. Fifteen studies did not meet the inclusion criteria, mostly because they had a retrospective uncontrolled design [2229] or did not provide data on UM subgroups [30-34]. One narrative review [35] and a study with unclear inclusion criteria [36] were excluded as well (table 2). Six ongoing studies were identified which are currently in different stages (table S2). Furthermore, 4 completed registered trials were detected, but no published data was found and the investigators either did not reply or did not consent to preliminary data publication in this review after we had contacted them (table S3). Finally, 12 records met our eligibility criteria and were included in the qualitative synthesis. They comprised data from 7 expanded access programs (EAP) or named patient programs (NPP) (n=162 patients), 4 phase II trials (n=171 patients), and 1 phase Ib trial (sample size unknown). The number of patients with UM per study ranged from 6 to 83 patients with an average of 18 patients. Results were available for ipilimumab (n=8), tremelimumab (n=1), pembrolizumab (n=1), nivolumab (n=1), and combined ipilimumab with nivolumab or pembrolizumab (n=1). None of the included studies reported the secondary outcome healthor treatment-related quality of life. Furthermore, no RCT was found. Anti-CTLA-4-blocking antibodies Ipilimumab Blank et al. investigated a combination of ipilimumab with radiofrequency ablation (RFA) in a phase Ib/II trial (SECIRA-UM trial). Results of the phase Ib part were published as conference abstract [37] Patients with at least two liver metastases from UM were included. Four doses of ipilimumab were assessed (0.3 mg/kg, 3 mg/kg, 10 mg/kg) with infusions applied every three weeks (Q3W). RFA was combined with ipilimumab at a dose up to 10 mg/kg. One patient (17%) developed a grade 3 immune-related colitis. PR was observed in 1 case (17%) in the 10 mg/kg cohort. PFS and OS were not reported and the overall sample sizes of the cohorts remained elusive [37]. Ipilimumab was assessed at a dose of 3 mg/kg (body weight) in 5 further studies with a total of 186 patients [38-40, 34, 41]. Jung et al. published data of 106 melanoma patients treated within a Korean EAP. Ten UM patients were treated in this setting, but the subgroup was poorly characterized and most primary and secondary outcomes of this review were not 9
reported. The median PFS was graphically estimated as 2.8 months based on the published time-to-event analyses. Median OS appeared not to have been reached by the population [41]. Kelderman et al. analyzed 22 patients treated in a Dutch EAP (WIN-O). Ipilimumab was applied for up to 4 cycles (Q3W). No CR was observed, 1 patient showed a PR (4.5%). The median PFS and OS were 2.9 (95% CI 2.3-5.3) and 5.2 (95%CI 4.9-9.6) months, respectively. After 1 year, 27% of all treated patients were still alive, as visually estimated and extracted from the published Kaplan-Meier curve. In 3 patients (13.6%), predominantly immune-related adverse events (AEs) graded as ≥3 were detected [38]. Maio et al. investigated ipilimumab 3 mg/kg (4 cycles, Q3W) in 82 pre-treated patients with advanced UM. Patients with initial immune-related disease control were eligible for re-induction with ipilimumab at the same dosage and schedule. PR was observed in 4 patients, revealing an ORR of 5%. The median OS and PFS amounted to 6.0 (95% CI 4.3-7.7) and 3.6 (95% CI 2.8-4.4) months, respectively. The 1-year OS rate was 31% and severe AEs were observed in 5 patients (6%) [39]. Shaw et al. reported data from an EAP in the United Kingdom for patients with mucosal, acral and ocular melanoma. Eighteen patients with UM were treated with ipilimumab 3 mg/kg Q3W for up to 4 cycles. The median PFS was 14.5 weeks (range 664); the median OS was not indicated in the conference abstract. Likewise, other outcomes such as ORR or AE rates were not clearly reported for the UM subgroup [40]. Zimmer et al. undertook a multicenter open-label phase II trial to assess the safety and efficacy of ipilimumab 3 mg/kg (4 cycles, Q3W) in distinct melanoma subtypes. A total of 53 patients received at least one cycle of treatment. No radiologic response was observed in any case. The median OS was 6.8 months (95% CI 3.7-8.1) and the median PFS 2.8 months (95% CI 2.5-2.9). The 1-year OS rate was 22%. Treatment-related grade 3-4 events occurred in 19 patients (36%) [42]. Ipilimumab was assessed at a dose of 10 mg/kg (body weight) in 2 more studies with a total of 45 patients [43, 44]. Danielli et al. performed a subgroup analysis of UM patients treated within the Italian ipilimumab-ocular melanoma EAP (I-OMEAP). Thirteen patients received ipilimumab 10 mg/kg (4 cycles, Q3W). No objective response was observed. Median OS was 36 weeks, PFS was not reported. Severe immune-related AEs occurred in 3 patients (23%) [44]. Piulats et al. presented data from a phase II trial in 32 treatment-naïve patients from Spain (GEM1 trial). The treatment consisted of 4 cycles ipilimumab 10 mg/kg Q3W (induction), followed by one application every 12 weeks (Q12W) as maintenance. The median OS was 9.8 months, whereas PFS was not reported. PR was observed in 6.5% (95% CI 0.79-21.42), the rate of severe AEs was reported as 10% (n=10) [43]. Tremelimumab
10
Joshua et al. performed a multicenter phase II trial on the CTLA-4-blocking antibody tremelimumab (CP-675206). Patients received 15 mg/kg tremelimumab every 90 days for up to 4 cycles (n=11). No patient achieved a CR or PR. The median PFS was 2.9 months (95% CI 2.8-3.0). The median OS was 12.8 months, yet with high variation (95% CI 3.8-19.7), and the 1-year OS was 55% (graphically estimated). The rate of AEs ≥grade 3 was not clearly stated. Due to the poor PFS and the lack of a radiologic response, the trial was stopped for futility at the first interim stage [45]. Anti-PD1- and anti-PD-L1-blocking antibodies Kottschade et al. investigated a sample of 10 patients with metastatic UM who were treated with pembrolizumab in an EAP. Pembrolizumab was given at a dose of 2 mg/kg Q3W until disease progression or development of unacceptable toxicity for up to 2 years. One patient had a CR (10%) and 2 had a PR (20%), resulting in an ORR of 30%. However, the PFS was only 18 weeks (range 3.14-49.3) and data on OS were not reported. Severe AEs were observed in 1 patient (10%) [46]. The phase II trial CheckMate 172 evaluated the safety and efficacy of nivolumab monotherapy (3 mg/kg, Q2W) in 75 UM patients who progressed after anti-CTLA-4 therapy. After a minimum follow-up of 1 year, 2 patients in the UM subgroup had a PR (ORR 6%, 95% CI 1-20) and 15 patients showed disease stabilization (44%). The median OS was 11 months (95% CI 7-15) and the OS rate at 1 year 47% (95% CI 34-59). Data on PFS or severe AEs were not specifically reported for the UM subgroup [47]. Studies investigating other PD-1 or PD-L1 inhibitors which met the inclusion criteria of this review were not identified. Combined CTLA-4 and PD-1 blockade Shoushtari et al. provided data on the combination of ipilimumab with nivolumab or pembrolizumab from an EAP. In total, 64 patients with metastatic melanoma were enrolled and treated in this program with nivolumab (1 mg/kg) and ipilimumab (3 mg/kg) administered every 3 weeks for 1-4 doses, followed by maintenance treatment with nivolumab (3 mg/kg) every two weeks or pembrolizumab (2 mg/kg) every three weeks. Six patients with UM were included. The median PFS was 2.8 months (95% CI 1.2-4.6 months) and the ORR was 0% (95% CI 0-51%) in the UM subgroup. OS and rates of severe AEs were not specifically reported for the subgroup [48]. Assessment of methodological quality Since we only included uncontrolled before-after studies and EAPs, we used the NHLBI tool to assess the methodological quality. Nine studies were rated as fair [37, 44, 45, 41, 38, 46, 39, 47, 48], 2 records as poor [40, 43], and 1 trial as good [42] (table 3).
11
Discussion In this systematic review, we identified 12 eligible studies which were used to provide an upto-date overview on the efficacy, safety and tolerability of ICB in patients with advanced UM. The majority of studies investigated ipilimumab at 3 mg/kg or 10 mg/kg, whereas only 3 records met our inclusion criteria for PD-1 inhibitor monotherapy or combined CTLA-4 and PD-1 blockade. No RCTs or CCTs were identified in our search, underlining that there is currently only little evidence for the use of ICB in UM, most likely because it is an orphan condition. The response to ICB in the included trials was low. The ORR for ipilimumab monotherapy at a dose of 3 mg/kg ranged from 0-5% and at a dose of 10 mg/kg from 0-6.5%. In line with these results, the median PFS was below 3 and the median OS poor in most records. Treatment with tremelimumab, another CTLA-4-blocking antibody, did not achieve any response in a phase II trial. These data suggest that UM is generally little susceptible to CTLA-4 blockade, regardless of distinct antibody types or dosage schemes. Moreover, immune-related AEs occurred at a frequency comparable to the reported ones for cutaneous melanoma. One study even described serious AEs in 36% of treated patients [34]. These data indicate that CTLA-4 blockade lacks efficacy but maintains toxicity in metastatic UM and do not support the application of CTLA-4 blockade as monotherapy in daily practice. We identified only 2 trials on PD-1 inhibitor monotherapy, namely pembrolizumab at 2 mg/kg Q3W and nivolumab at 3 mg/kg Q2W. Even though radiological responses were observed in 30% with pembrolizumab, the study had a small sample size (n=10) and is at risk to overestimate the treatment effect [46]. Furthermore, this relatively high ORR reported by Kottschade et al. stands in contrast to 6% revealed in the CheckMate 172 trial [47] and several other retrospective reports investigating PD-1 inhibitor monotherapy that were identified by our literature search, but excluded from the qualitative synthesis due to their retrospective and uncontrolled design. Algazi et al. investigated a large cohort of patients (n=58) treated with PD-1 or PD-L1 inhibitors with a response of 3.6% [22]. Similar results were obtained by Kelderman et al. and Karydis et al. in retrospective evaluations of pembrolizumab and nivolumab in smaller cohorts [26, 27]. Only one report was identified investigating ipilimumab combined with PD-1 inhibition within an EAP. No radiological response was observed and the PFS was poor (2.9 months) [48]. However, only 6 patients with UM were investigated and the conclusions drawn from this small sample should be interpreted with caution. The results from these studies suggest that the efficacy of ICB is lower in UM compared to cutaneous or mucosal melanoma, yet future RCTs are warranted to give more reliable estimates.
12
In this context, it remains to be determined if adding a loco-regional treatment may enhance the systemic response to ICB. Several studies have suggested an abscopal response of cutaneous melanoma when systemic ICB was combined with a destructive peripheral treatment modality [49-51]. We identified one phase Ib study which investigated RFA for liver metastasis with different dosages of ipilimumab [37]. However, the information available from this conference abstract was limited and survival data were not reported. It is remarkable that quality of life was not reported in any study. Our review suggests that ICB in UM maintains the toxicity profile observed in cutaneous melanoma despite lower efficacy. Thus, the treatment- and health-related quality of life may be particularly unfavorable in this disease because treatment-related AEs do significantly affect patients’ quality of life. This outcome is becoming increasingly more important in oncology and should be respected in future trials investigating ICB, particularly in patients with UM [52, 53]. We are aware that our review has several limitations. Our review only identified before-after studies and EAPs. This may be explained by the fact that UM is an orphan disease. Besides, conference abstracts often report incomplete or preliminary data. Nevertheless, patients with advanced UM have a high unmet need and systemic therapy options are limited and not evidence-based. Here, we conducted a systematic and comprehensive literature research and presented in our review a body of highest possible evidence available regarding the treatment of ICB in patients with advanced UM. Even though a number of narrative reviews and expert statements have been published on this topic, an unbiased systematic review and qualitative data synthesis following a predefined and published protocol has not yet been conducted to the best of our knowledge [54-57, 35, 58]. The databases MEDLINE, CENTRAL and Embase were searched. However, handsearching of the trial registers and conference abstracts for this review was conducted by one author only. Records in English and German were respected and other languages were not considered. Although we closely followed the PRISMA guidelines, we cannot fully exclude selection bias in our review. Furthermore, we did not assess and cannot exclude the existence of publication bias. When evaluating the methodological quality for the 12 included records, only 1 study was rated as “good”, whereas 9 were considered “fair” and 2 “poor” according to the NHLBI assessment tool. Although the tool is less established and less distinctive than others [13, 14], the results of the bias assessment should be kept in mind when interpreting our results. As we are aware of the importance of assessing the methodological quality and the risk of bias in a review, we still decided to conduct a bias assessment despite the fact that we did not include any RCT or controlled observational study [14, 13].
13
Taken together, our results do not support the use of ipilimumab monotherapy for the treatment of advanced UM. The current application of combined ipilimumab and PD-1 inhibition is not yet evidence-based. However, the results of several ongoing trials have to be awaited to give a reliable estimate on the efficacy of combined ICB. Future efforts should be undertaken to conduct multicenter RCTs in order to provide results of highest possible evidence for this orphan albeit important condition. Acknowledgements None. Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Conflicts of interest CB has received speaker’s and advisor’s honoraria by Amgen, AstraZeneca, BMS, MSD, Novartis, Pierre Fabre, and Roche. MVH received speaker’s honoraria from Roche, Novartis, BMS, MSD and travel support from BMS. All remaining authors have declared no conflicts of interest. Author contributions MVH, JGS, CD, SR, AN, and CB designed the study. MVH, TS, JGS, and SR performed the literature search. MVH, TS, and JGS extracted data from full texts and conducted the risk of bias assessments. MVH, TS, TR, and CB wrote the manuscript.
14
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Atkinson TM, Hay JL, Shoushtari A, Li Y, Paucar DJ, Smith SC et al. Relationship between physician-adjudicated adverse events and patient-reported health-related quality of life in a phase II clinical trial (NCT01143402) of patients with metastatic uveal melanoma. J Cancer Res Clin Oncol 2017;143:439-45.
[53]
Coens C, Suciu S, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD et al. Healthrelated quality of life with adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): secondary outcomes of a multinational, randomised, double-blind, phase 3 trial. Lancet Oncol 2017;18:393403.
[54]
Komatsubara KM, Carvajal RD. Immunotherapy for the Treatment of Uveal Melanoma: Current Status and Emerging Therapies. Curr Oncol Rep 2017;19:45.
[55]
Komatsubara KM, Carvajal RD. Adopting a new stance on immunotherapy for uveal melanoma. Lancet Oncol 2017;18:702-4.
[56]
Oliva M, Rullan AJ, Piulats JM. Uveal melanoma as a target for immune-therapy. Ann Transl Med 2016;4:172. 19
[57]
Chattopadhyay C, Kim DW, Gombos DS, Oba J, Qin Y, Williams MD et al. Uveal melanoma: From diagnosis to treatment and the science in between. Cancer 2016;122:2299-312.
[58]
Luke JJ, Triozzi PL, McKenna KC, Van Meir EG, Gershenwald JE, Bastian BC et al. Biology of advanced uveal melanoma and next steps for clinical therapeutics. Pigment Cell Melanoma Res 2015;28:135-47.
20
Figure 1: Flowchart of the literature search according to the PRISMA guidelines.
Records identified through database searching
MEDLINE (n=463) CENTRAL (n=29) EMBASE via Ovid (n=729)
Conference abstracts
Identification
(n=12)
(n=94)
Records identified (n=1327)
Screening
Trial register
Duplicates removed (n=362)
Records after duplicates removed (n=965)
Records screened (n=965)
Records excluded based on abstracts and titles (n=920)
Eligibility
Records (n=33) excluded for the following reasons:
Records assessed for eligibility (n=45)
Included
Records included in qualitative synthesis (n=12)
Duplicates (n=8) Ongoing studies (n=6) Completed trial register-study, but no published data available (n=4) Other reasons (n=15)
21
Table 1: Search query in Medline/PubMed. Key search terms: Choroid, iris, ocular, uvea Melanoma, neoplasms CTLA-4, cytotoxic T-lymphocyte-associated protein-4, immune checkpoint, ipilimumab, Keytruda, nivolumab, Opdivo, pembrolizumab, PD-1, PD-L1, programmed cell death protein, tremelimumab, Yervoy MeSH terms: uveal neoplasms, antibodies Combination operators: (("uveal neoplasms"[MeSH Terms]) OR (uveal melanoma*[Title/Abstract]) OR (uveal neoplasm*[Title/Abstract]) OR (choroid* AND melanoma*[Title/Abstract]) OR (choroid* AND neoplasm*[Title/Abstract]) OR (iris melanoma*[Title/Abstract]) OR (iris neoplasm*[Title/Abstract]) OR (ocular melanoma*[Title/Abstract]) OR (ocular neoplasm*[Title/Abstract])) AND ((ipilimumab[Title/Abstract]) OR (yervoy[Title/Abstract]) OR (pembrolizumab[Title/Abstract]) OR (keytruda[Title/Abstract]) OR (nivolumab[Title/Abstract]) OR (opdivo[Title/Abstract]) OR (PD1[Title/abstract]) OR (PD-1[Title/Abstract]) OR (PDL1[Title/Abstract]) OR (PDCD1[Title/Abstract]) OR (programmed cell death protein[Title/Abstract]) OR (CTLA-4[Title]) OR (CTLA4[Title]) OR (cytotoxic T-lymphocyteassociated[Title/Abstract]) OR ("antibodies"[MeSH Terms]) OR (immune*[Title/Abstract]))
22
Table 2: Records assessed for eligibility but excluded from the qualitative synthesis (n=15). First author and year
Record type
Population
Intervention
Control
Reported efficacy outcomes
Reason for exclusion
pembrolizumab Algazi 2016 [22]
n=58 (UM only) journal article
ORR nivolumab
uncontrolled
multicenter
retrospective design OS
atezolizumab Breazzano 2017 [35]
journal article
n.a.
n.a.
n.a.
ipilimumab
uncontrolled (EAP)
n.a.
narrative review
ORR
no data available for UM subgroup
n=21 (total) Cesas 2013 [30]
conference abstract
n=3 (UM)
PFS single center n=27 (total)
Di Giacomo 2011 [31]
DCR journal article
n=3 (UM)
ipilimumab
uncontrolled (EAP) OS
no data available for UM subgroup
single center ipilimumab Itchins 2017 [23]
ORR
n=37 (UM only) journal article
pembrolizumab
uncontrolled
PFS
retrospective design
single center nivolumab N=25 (UM only)
Karydis 2016 [27]
journal article
Luke 2013 [28]
journal article
OS uncontrolled
PFS
(EAP)
OS
pembrolizumab multicenter
retrospective design
n=39 (UM only)
ORR ipilimumab
uncontrolled
multicenter
retrospective design OS
ipilimumab McKean 2017 [29]
n=696 (total) conference abstract
nivolumab
uncontrolled
OS
retrospective design
n=22 (UM) pembrolizumab
23
n=19 Naing 2016 [32]
PipernoNeumann 2016 [24]
conference abstract
number of patients with UM not reported
pegylated IL-10 with pembrolizumab
uncontrolled ORR (phase I)
no data available for UM subgroup
ORR pembrolizumab conference abstract
n=21 (UM only)
uncontrolled
PFS
retrospective design
nivolumab OS n=450 (total)
Schmerling 2014 [33]
PFS conference abstract
8.4% with UM
ipilimumab
uncontrolled (EAP) OS
no data available for UM subgroup
multicenter ShapiraFrommer 2013 [36]
n=183 conference abstract
ORR
not clear if UM patients included
ipilimumab
n=17 (total)
nivolumab
n=9 (UM)
pembrolizumab
uncontrolled (EAP) OS
inclusion of UM patients not clear
ORR Tian 2016 [25]
conference abstract
uncontrolled
PFS
retrospective design
OS ORR van der Kooij 2017 [26]
n=17 (UM only)
nivolumab
multicenter
pembrolizumab
journal article
uncontrolled
PFS
retrospective design
OS ORR Zimmer 2014 [34]
n=156 (total) journal article
uncontrolled ipilimumab
n=53 (UM)
PFS (phase II)
data for ocular melanoma not reported
OS
Abbreviations: ORR = overall response rate; DCR = disease control rate; PFS = progression-free survival; OS = overall survival; UM = patients with uveal melanoma; n.a. = not applicable; EAP = expanded access program; IL = interleukin. 24
25
Table 3: Studies included in the qualitative data synthesis (n=12). Study characteristics Author
Primary outcomes
Secondary outcomes
Bias assessment
Design
Sample size
Intervention
Dosage [mg/kg]
ORR
PR
CR
PFS (median)
OS (median)
1-year OS
AEs > grade 3
QoL
Open-label, 3armed, phase Ib trial
n.r.
RFA + Ipilimumab
10
n.r.
1 (17%)
n.r.
n.r.
n.r.
n.r.
1 (17%)
n.r.
fair
Danielli 2012
EAP
13
Ipilimumab
10
0
0
0
n.r.
36 wks. (range 2-172+ wks)
n.r.
3 (23%)
n.r.
fair
Joshua 2015
Observational, prospective, open-label, multicenter phase II study
11
Tremelimuma b
15
0
0
0
2,9 mo. (95% CI 2.8-3.0)
12.8 mo. (95% CI 3.8-19.7)
0.55
not clearly reported
n.r.
fair
Jung 2017
NPP
10
Ipilimumab
3
n.r.
n.r.
n.r.
2.8 mo.
not reached
not determinable
not clearly reported
n.r.
fair
Keldermann 2013
EAP
22
Ipilimumab
3
n.r.
1 (4.5%)
0
2.9 mo. (95% CI: 2.3-5.3)
5.2 mo. (95%CI: 4.9-9.6)
27%
3 (13.6%)
n.r.
fair
Kottschade 2016
EAP
10
Pembrolizuma b
2
3 (30%)
2 (20%)
1 (10%)
18 wks. (range 3.14-49.3)
n.r.
n.r.
1 (10%)
n.r.
fair
Maio 2012
EAP
83
Ipilimumab
3
4 (5%)
4 (5%)
0
3.6 mo. (95% CI 2.8–4.4)
6.0 mo (95% CI 4.3-7.7)
26 (31%)
5 (6%)
n.r.
fair
Piulats 2014
Observational, prospective, open-label, single arm phase II trial
32
Ipilimumab
10
n.r.
2 (6.45%) (95% CI 0.7921.42)
n.r.
n.r.
9.8 mo.
n.r.
10 (31%)
n.r.
poor
Schadendorf 2017
Single-arm, open-label, multicenter, phase II trial
75
Nivolumab
3
2/34 (5.8%) at 12 wks.
2 (5.8%)
0
n.r.
11 mo. (95% CI 7-15)
47% (95% CI 3459)
Not clearly reported for UM subgroup
n.r.
fair
Shaw 2012
EAP
18
Ipilimumab
3
n.r.
n.r.
n.r.
14.5 wks. (range: 6-64)
n.r.
n.r.
not clearly reported
n.r.
poor
Shoushtari 2016
EAP
6
Nivolumab, Ipilumamb
1 and 3, resp.
0/5 (95%C I: 0-
n.r.
n.r.
2.9 mo. (95% CI 2.3-5.3)
n.r.
n.r.
n.r.
n.r.
fair
Blank 2015
26
51%)
Zimmer 2015
Observational, prospective, open-label, uncontrolled, multicenter phase II
53
Ipilimumab
3
0
0
0
2.8 mo. (95% CI 2.5–2.9)
6.8 mo. (95% CI 3.7-8.1)
22% (95% CI 12– 35)
19 (36%)
n.r.
good
Abbreviations: EAP = expanded access program; NPP = named patient program; ORR = overall response rate; PR = partial response; CR = complete response; PFS = progression-free survival; OS = overall survival; n.r. = not reported; AE = adverse events; QoL = Quality of Life, CI = confidence interval, mo. = months, wks. = weeks, resp. = respectively.
27
Highlights
Metastatic uveal melanoma (UM) is an orphan disease of high unmet need
The current use of immune checkpoint blockade in UM is not evidence-based
A systematic review on immune checkpoint blockade for UM was performed
CTLA-4 blockade lacks efficacy but maintains toxicity in metastatic UM
28