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Purpose: To assess the clinical and biological activity of the association of bevacizumab and fotemustine as first-line treatment in advanced melanoma patients.Experimental Design: Previously untreated, metastatic melanoma patients (n = 20) received bevacizumab (at 15 mg/kg every 3 weeks) and fotemustine (100 mg/m2 by intravenous administration on days 1, 8, and 15, repeated after 4 weeks) in a multicenter, single-arm, open-label, phase II study. Primary endpoint was the best overall response rate; other endpoints were toxicity, time to progression (TTP), and overall survival (OS). Serum cytokines, angiogenesis, and lymphangiogenesis factors were monitored by multiplex arrays and by in vitro angiogenesis assays. Effects of fotemustine on melanoma cells, in vitro, on vascular endothelial growth factor (VEGF)-C release and apoptosis were assessed by ELISA and flow cytometry, respectively.Results: One complete response, 2 partial responses (PR), and 10 patients with stable disease were observed. TTP and OS were 8.3 and 20.5 months, respectively. Fourteen patients experienced adverse events of toxicity grade 3–4. Serum VEGF-A levels in evaluated patients (n = 15) and overall serum proangiogenic activity were significantly inhibited. A significant reduction in VEGF-C levels was found in several post-versus pretherapy serum samples. In vitro, fotemustine inhibited VEGF-C release by melanoma cells without inducing significant cell death. Serum levels of interleukin (IL)-10 and IL-12p70 showed the highest levels in sera of PR patients, compared with patients with stable or progressive disease whereas IL-23 showed the opposite pattern.Conclusions: The combination of bevacizumab plus fotemustine has clinical activity in advanced melanoma and promotes systemic modulation of angiogenesis and lymphangiogenesis factors. Clin Cancer Res; 16(23); 5862–72. ©2010 AACR.

Supplementary Figures S1-S3 and Supplementary Table S1.

Melanoma immunotherapy based on immune checkpoint blockade, by targeting of CTLA-4 or PD-1, has markedly improved the treatment of advanced disease, as shown by several recent trials. Monotherapy with CTLA-4-specific antibody (Ipilimumab) prolongs overall survival, while PD-1-specific antibodies (Nivolumab and Lambrolizumab) induce durable tumor regression in a large fraction of patients. Moreover, a recent trial based on combination checkpoint blockade (Ipilimumab plus Nivolumab) has shown an objective response rate of 53%, with tumor reduction of 80% in responding patients, without escalation of toxic effects. In spite of these highly relevant results, clinical benefit by immunotherapy targeting CTLA-4 or PD-1 remains limited to a fraction of patients. This points to the existence of immune escape mechanisms, which, in some tumors, may prevent effective elimination of neoplastic cells, in spite of the reactivated T cell immunity. This hypothesis was tested in a melanoma patient, treated with Ipilimumab, and that we recently reported (J. Clin. Oncol. 29:e783-8, 2011) to have a strong T cell infiltrate and evidence of T cell maturation/activation only in a regressing right adrenal metastasis, but not in the progressing controlateral lesion. To this end, we carried out DASL whole genome gene expression analysis and extensive immunohistochemistry (IHC) on paraffin-embedded neoplastic tissues. The results indicated that, in comparison to the progressing metastasis, the regressing lesion had a distinct gene expression profile characterized by enhanced expression of several genes involved in T cell differentiation to cytolytic effector stage. Most importantly, the regressing lesion retained expression of HLA molecules on neoplastic cells. In contrast, the progressing lesion showed almost complete loss of HLA class I and Class II molecules by the tumor, as documented by IHC. Taken together, these results suggest that lack/loss of expression of HLA molecules, by tumor cells, may represent a highly effective tumor resistance mechanism to immune checkpoint blockade. Moreover, pre-therapy IHC on tumor samples may allow to test whether HLA antigen expression/loss is a predictive marker for response/resistance to therapy targeting CTLA-4 or PD-1. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A89. Citation Format: Andrea Anichini, Filippo G. de Braud, Roberta Montarini, Ilaria Bersani, Gabrina Tragni, Loris de Cecco, Silvana Canevari, Lorenza Di Guardo, Lorenzo Pilla, Michele Del Vecchio. Loss of HLA molecules as melanoma resistance mechanism in immune checkpoint blockade therapy. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A89.