Patrick Terheyden

9031 Background: Ipilimumab is a recently approved immunotherapy that has shown an overall survival benefit in previously treated and treatment-naïve patients with metastatic melanoma in two phase III trials. However, results of registrational trials might not address all questions regarding safety and efficacy of ipilimumab in advanced melanoma patients seen in daily routine. We performed a multicenter, phase II clinical trial of ipilimumab in patients with different subtypes of metastatic melanoma. Methods: Pretreated patients with unresectable stage III or stage IV with cutaneous, mucosal, ocular or unknown primary melanoma (MUP) were included into this study (CA184-137; supported by BMS). Treatment-naïve patients with metastatic ocular melanoma were eligible, too. Four cycles ipilimumab should be administered at a dose of 3 mg/kg 3 weeks apart. Tumor assessments according to RECIST 1.1 version were conducted at baseline, weeks 12, 24, 36 and 48. Adverse events (AEs), including immune-related AEs were graded according to National Cancer Institute Common Toxicity Criteria v.4.0. Primary endpoint was the overall survival (OS) rate at 12 months. Results: Between May 2011 to December 2013, 156 patients were enrolled in 25 German centers and received at least one dose of ipilimumab, including 83 cutaneous, 7 mucosal, 53 ocular melanomas and 13 MUP. After a median follow-up of 7 months (range 0.1-26.4), 12-month OS rates were 37% for cutaneous, 14% for mucosal, and 22% for ocular melanomas and 27% for MUP. The median OS from the first dose of ipilimumab was 6.9 months (95% CI 5.7-8.1). The overall response rates among 104 evaluable patients were 16% for cutaneous, 17% for mucosal, 9% for ocular melanomas and 11% for MUP. There were one patient with complete response (1%), 13 patients with partial response (13%), and 23 patients with stable disease (22%). Treatment-related AEs were observed in 106 patients (68%), including 39 grade 3-4 events (25%). There was a drug-related death due to pancytopenia. Conclusions: Ipilimumab is a treatment option for patients with cutaneous, ocular, mucosal and unknown primary melanoma with manageable toxicity. Clinical trial information: NCT01355120.

The combination of the antiangiogenic antibody bevacizumab with standard chemotherapy has improved the prognosis in patients with metastastic colorectal cancer and other advanced cancers. The role of combined anti-VEGF and chemotherapy in metastastic melanoma is just starting to be elucidated. We tested this notion in three patients with advanced and therapy-refractory melanoma. Interestingly, two patients achieved objective regressions after three courses of therapy; the third patient, albeit progressing demonstrated a pronounced liquid necrosis in bulky lymphnode metastasis. Further studies are warranted to scrutinise these impressive therapeutic effects on the combination of bevacizumab and chemotherapy in melanoma.

To scrutinize published data from small mono-centric studies and case reports which implicated high response rates and promising survival times for a combination therapy consisting of epifocal dinitrochlorobenzene (DNCB) and dacarbazine (DTIC) for metastasized melanoma. This therapy merges the effects of an allergic contact dermatitis elicited at the site of a cutaneous metastasis, and systemic chemotherapy. We performed a retrospective survey with nine German centers and evaluated 72 patients treated from 1993 to 2005. The objective response rate in stage III melanoma (n = 39) was 62%. In contrast, only 9% objective responses were observed in 33 stage IV patients. Interestingly, more than half of patients with objective remissions remained progression-free for more than 1 year irrespective of the stage of disease. Epifocal DNCB combined with DTIC is effective in patients with regionally metastasized melanoma not amenable to surgery or isolated limb perfusion, whereas in stage IV disease in spite of few durable remissions the addition of DNCB does not improve the therapeutic efficacy of DTIC.

Genes of the Raf family encode kinases that are regulated by Ras and mediate cellular responses to growth signals. Recently, it was shown that activating mutations of BRaf are found with high frequency in human melanomas. The Ras family member most often mutated in melanoma is NRas. The constitutive activation of the Ras/Raf signaling pathway suggests an impact on the clinical course of the tumor. To address this notion, we analyzed tumor DNA from 114 primary cutaneous melanomas and of 86 metastatic lesions obtained from 174 patients for mutations in BRaf (exons 15 and 11) and NRas (exons 1 and 2) by direct sequencing of PCR products and correlated these results with the clinical course. In 57.5% of the tumors either BRaf or NRas were mutated with a higher incidence in metastatic (66.3%) than in primary lesions (50.9%). Although the majority of BRaf mutations affected codon 599, almost 15% of mutations at this position were different from the well-described exchange from valine to glutamic acid. These mutations (V599R and V599K) also displayed increased kinase and transforming activity. Surprisingly, the additional BRaf variants D593V, G465R and G465E showed a complete loss of activity in the in vitro kinase assay; however, cells overexpressing these mutants displayed increased Erk phosphorylation. The correlation of mutational status and clinical course revealed that the presence of BRaf/NRas mutations in primary tumors did not negatively impact progression free or overall survival. In contrast, however, for metastatic lesions the presence of BRAF/NRAS mutations was associated with a significantly poorer prognosis, i.e. a shortened survival. We demonstrate a high – albeit lower than initially anticipated – frequency of activating BRaf mutations in melanoma in the largest series of directly analyzed tumors reported to date. Notably, the clinical course of patients harboring activating BRaf mutations in metastatic melanoma was significantly affected by the presence of a constitutive BRaf activation in these.