Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer that has a poor prognosis in patients with advanced disease.,Avelumab [anti-programmed death-ligand 1 (PD-L1)] became the first approved treatment for patients with metastatic MCC (mMCC), based on efficacy and safety data observed in the JAVELIN Merkel 200 trial.,We report long-term overall survival (OS) data after >5 years of follow-up from the cohort of patients with mMCC whose disease had progressed after one or more prior lines of chemotherapy.,In Part A of the single-arm, open-label, phase II JAVELIN Merkel 200 trial, patients with mMCC that had progressed following one or more prior lines of chemotherapy received avelumab 10 mg/kg by intravenous infusion every 2 weeks until confirmed disease progression, unacceptable toxicity, or withdrawal.,In this analysis, long-term OS was analyzed.,In total, 88 patients were treated with avelumab.,At data cut-off (25 September 2020), median follow-up was 65.1 months (range 60.8-74.1 months).,One patient (1.1%) remained on treatment, and an additional patient (1.1%) had reinitiated avelumab after previously discontinuing treatment.,Median OS was 12.6 months [95% confidence interval (CI) 7.5-17.1 months], with a 5-year OS rate of 26% (95% CI 17% to 36%).,In patients with PD-L1+ versus PD-L1− tumors, median OS was 12.9 months (95% CI 8.7-29.6 months) versus 7.3 months (95% CI 3.4-14.0 months), and the 5-year OS rate was 28% (95% CI 17% to 40%) versus 19% (95% CI 5% to 40%), respectively (HR 0.67; 95% CI 0.36-1.25).,Avelumab monotherapy resulted in meaningful long-term OS in patients with mMCC whose disease had progressed following chemotherapy.,These results further support the role of avelumab as a standard of care for patients with mMCC.,•Avelumab led to meaningful long-term OS in patients with previously treated mMCC.,•After >5 years of follow-up, median OS was 12.6 months and the 5-year OS rate was 26%.,•Longer OS was observed in patients with PD-L1+ versus PD-L1- tumors.,•The survival benefit with avelumab greatly exceeds that seen in retrospective analyses of second-line or later chemotherapy.,•These results further support the role of avelumab as a standard of care for patients with mMCC.,Avelumab led to meaningful long-term OS in patients with previously treated mMCC.,After >5 years of follow-up, median OS was 12.6 months and the 5-year OS rate was 26%.,Longer OS was observed in patients with PD-L1+ versus PD-L1- tumors.,The survival benefit with avelumab greatly exceeds that seen in retrospective analyses of second-line or later chemotherapy.,These results further support the role of avelumab as a standard of care for patients with mMCC.
The vascular endothelial growth factor receptor‐1 (VEGFR‐1) is a tyrosine kinase receptor frequently expressed in melanoma.,Its activation by VEGF‐A or placental growth factor (PlGF) promotes tumour cell survival, migration and invasiveness.,Moreover, VEGFR‐1 stimulation contributes to pathological angiogenesis and induces recruitment of tumour‐associated macrophages.,Since melanoma acquired resistance to BRAF inhibitors (BRAFi) has been associated with activation of pro‐angiogenic pathways, we have investigated VEGFR‐1 involvement in vemurafenib resistance.,Results indicate that human melanoma cells rendered resistant to vemurafenib secrete greater amounts of VEGF‐A and express higher VEGFR‐1 levels compared with their BRAFi‐sensitive counterparts.,Transient VEGFR‐1 silencing in susceptible melanoma cells delays resistance development, whereas in resistant cells it increases sensitivity to the BRAFi.,Consistently, enforced VEGFR‐1 expression, by stable gene transfection in receptor‐negative melanoma cells, markedly reduces sensitivity to vemurafenib.,Moreover, melanoma cells expressing VEGFR‐1 are more invasive than VEGFR‐1 deficient cells and receptor blockade by a specific monoclonal antibody (D16F7 mAb) reduces extracellular matrix invasion triggered by VEGF‐A and PlGF.,These data suggest that VEGFR‐1 up‐regulation might contribute to melanoma progression and spreading after acquisition of a drug‐resistant phenotype.,Thus, VEGFR‐1 inhibition with D16F7 mAb might be a suitable adjunct therapy for VEGFR‐1 positive tumours with acquired resistance to vemurafenib.