Real-World Outcomes of Novel Treatments in Patients with Advanced Melanoma in The Netherlands
B LeenemanM FrankenAnouk JochemsM SchouwenburgMaureen J.B. AartsAlexander C.J. van AkkooiF van den BerkmortelA van den EertweghGerard GroenewegenJoris R. de GrootJohn B.A.G. HaanenGeke A.P. HospersH.W. KapiteijnRutger H.T. KoornstraWim H.J. KruitMarieke W.J. LouwmanDjura PiersmaR. van RijnA ten TijeGerard VreugdenhilMichel W.J.M. WoutersM van ZeijlJ van der HoevenC Uyl - de Groot
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Background. Checkpoint inhibitors are effective in the treatment of several types of cancer, either being used separately or in combination. Ipilimumab pioneered the treatment of metastatic melanoma, and nowadays, it has been used more frequently in combination with anti-PD-1. Since the development of anti-PD1 for melanoma, rechallenge with ipilimumab has not been considered, although its use was considered in early trials. Cases. In this study, we analyzed 22 patients with metastatic melanoma who had benefited from the first treatment with ipilimumab, but eventually had progressive disease. They received ipilimumab at the same dose as the first treatment. Most of the patients received the second course after six months or more from the first treatment with ipilimumab. The median progression-free survival (mPFS) of the treatment with ipilimumab was 8.9 months, and the median progression-free survival of the second course was 6.3 months. Conclusion. There are limited data on rechallenge with ipilimumab addressing progression-free survival (PFS). In our analysis, twenty-two patients treated with a second course of ipilimumab were analyzed and most of them had a significant benefit. Despite the current alternatives for salvage therapies, rechallenging with ipilimumab might be an alternative to be considered in patients who had initial benefit.
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CTLA-4
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Stage IV metastatic melanoma patients historically have a poor prognosis with 5-10% 5-year survival. Ipilimumab, a monoclonal antibody against cytotoxic T-lymphocyte antigen 4 (CTLA4), is one of the first treatments to provide beneficial durable responses in advanced melanoma. However, less than 25% of those treated benefit, treatment is expensive, and side effects can be fatal. Since soluble (s) CTLA4 may mediate inhibitory effects previously ascribed to the membrane-bound isoform (mCTLA4), we hypothesized patients benefiting from ipilimumab have higher serum levels of sCTLA4. We found that higher sCTLA4 levels correlated both with response and improved survival in patients treated with ipilimumab in a small patient cohort (patients with (n=9) and without (n=5) clinical benefit). sCTLA4 levels were statistically higher in ipilimumab-treated patients with response to ipilimumab. In contrast, sCTLA4 levels did not correlate with survival in patients who did not receive ipilimumab (n=11). These preliminary observations provide a previously unrecognized link between serum sCTLA-4 levels and response to ipilimumab as well as to improved survival in ipilimumab-treated melanoma patients and a potential mechanism by which ipilimumab functions.
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Metastatic melanoma has been historically associated with a poor prognosis; however, the therapeutic landscape has experimented and impressive change in the last years due to rapid advances in the immunotherapy field. The first immunotherapy treatment for metastatic melanoma was ipilimumab (anti-CTLA-4), which showed a significant improvement of overall survival compared to chemotherapy. However, in 2015 anti-PD-1 pembrolizumab shown an improved overall survival, progression-free survival and response rate compared to ipilimumab with either a better toxicity profile. Moreover, other immunotherapy combinations and target therapies, such as BRAF and MEK inhibitors combinations, have shown better outcomes than ipilimumab. Thus, ipilimumab seems to have no role in frontline metastatic melanoma treatment and even their role in second line is being less frequent due to clinical efficacy of those other treatments. Actually, the role of ipilimumab in second line after anti-PD-1 progression is not clear although there is clinical evidence for its use. Here, we report two cases of treatment response with ipilimumab in second line setting after receiving anti-PD-1 combination. So that, ipilimumab may have a role after progression to an anti-PD-1 treatment.
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Targeted therapy and immunotherapy in metastatic melanoma have led to a marked improvement in patients' survival and their quality of life. Although there are data on anti-programmed-death-receptor-1 (anti-PD1) after ipilimumab, only few data are available on ipilimumab following anti-PD1 as the first-line treatment. The aim of our study was to evaluate tolerance and survival of patients treated with ipilimumab as the second-line immunotherapy among metastatic melanoma patients following anti-PD1 treatment. Retrospective and descriptive epidemiological studies were carried out at the Dermatology Department of the University Hospital of Lille. We describe a case series of patients treated with ipilimumab after anti-PD1 failure for metastatic melanomas. For each patient, we assessed disease extension since ipilimumab introduction using RECIST 1.1. The time between ipilimumab introduction and other systemic treatment and overall survival (between ipilimumab introduction and last patient visit) was assessed. The effect of ipilimumab after anti-PD1 treatment was evaluated in eight patients. Four patients responded to ipilimumab: three showed a complete response and one showed a partial response. For these patients, the time period between the first ipilimumab injection and another systemic treatment ranged from 209 to 391 days and the overall survival ranged from 314 to 581 days. One patient showed grade 3 chorioretinitis, an unusual toxicity with ipilimumab or anti-PD1 to our knowledge. We have described the efficacy of ipilimumab following anti-PD1 in metastatic melanoma in eight patients. Several comparative studies are still in progress, and their results will be important to develop an optimal therapeutic strategy for our patients.
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The impact on survival of a second primary melanoma (SPM) is unclear. We used our melanoma center's database to examine clinicopathologic risk factors and outcomes of stage 0 to IV cutaneous melanoma in patients with one versus two primaries. Among 12,325 patients with primary melanoma, 969 (7.86%) developed SPM. SPMs were significantly thinner than autologous primary melanomas (P = 0.01), and 451 SPM patients had better overall and melanoma-specific survival than 451 prognostically matched non-SPM patients (P < 0.0001 and 0.0001, respectively) at a median follow-up of 142.37 months. Patients with cutaneous melanoma are at high risk for development of SPM, but the development of SPM does not seem to impair survival.
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Ipilimumab, a monoclonal CTLA-4 antibody, was the first drug improving overall survival in patients with metastatic melanoma. However, there are still unanswered questions concerning therapeutic regimes, e.g. if maintenance therapy is needed to achieve long-term response. We present three patients with metastatic melanoma who received ipilimumab after progression under chemotherapy. In all of these patients ipilimumab led to a long-term tumor control of at least 32 months. Interestingly, all of them developed severe autoimmune toxicity and ipilimumab treatment was discontinued after 1 respectively 2 cycles. The present cases demonstrate that a long-term response to ipilimumab can be achieved without maintenance therapy.
Maintenance therapy
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