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• Uveal melanoma is the most common intraocular tumor in adults worldwide. • One patient out of two recurs at a distance with the development of metastases, mainly in the liver. • There are various emerging options for the treatment of hepatic oligoprogression, including percutaneous infusion of chemotherapy when partial hepatectomy is not available. • Metastatic cancer has a poor prognosis, with a survival rate of about 10% at 2 years. • Tebentafusp, a bispecific protein that recruits and activates polyclonal T cells, is a new hope for metastatic patients, as it is the first drug to demonstrate a significant increase in overall survival. Uveal melanoma (UM), also known as choroidal melanoma, is the leading adult intraocular tumor worldwide, affecting mainly Caucasian populations. The last decade has seen an improvement in the outcome of these tumors at the localized stage, in favor of conservative treatment of the eye, notably with new radioactive treatment techniques. Despite optimal management, half of the patients will become metastatic, with liver involvement in 90% of cases. The prognosis is pejorative and considers clinical, tumor anatomy, histological and molecular parameters. This review provides a broad overview of the different therapeutic options for the management of localized or metastatic UM disease, with recently updated data. Despite the known limited efficacy of chemotherapy and immune checkpoint inhibitors (ICI), we discuss the first results of combined immunotherapies, the arrival of a new first-in-class immunomodulatory treatment Tebentafusp, in HLA-A*02:01 patients, avenues of research into targeted anti-tyrosine kinase therapies, and the growing use of ctDNA to guide treatment prescription. [ABSTRACT FROM AUTHOR]

Purpose: Subcutaneous recombinant interleukin-2 (rIL-2) and recombinant interferon alfa-2a (rIFNalpha-2a) have been used extensively in the treatment of metastatic renal cancer. Most results, coming from noncontrolled phase II trials, showed inconsistent rates of response. More recently, the addition of fluorouracil (FU) was proposed to improve the efficacy of these regimens.Patients and Methods: The role of a subcutaneous combination of rIL-2 and rIFNalpha-2a with or without FU was investigated. Patients were randomly assigned to receive a combination of rIL-2 and rIFNalpha-2a at weeks 1, 3, 5, and 7 or the same combination together with a continuous infusion of FU at weeks 1 and 5. The major end points of this multicenter, randomized trial were progression-free survival, response rate, and toxicity. Overall survival was a secondary end point. Tumor responses were reviewed by an independent committee. Analysis of the results was performed on an intention-to-treat basis.Results: One hundred thirty-one patients were enrolled. There was no difference in toxicity between the arms, and no toxic death was observed. One partial response was observed in arm A and five in arm B. Progression-free survival did not differ between the arms, and rates at 1 year were 12% and 15% in arms A and B, respectively. No statistically significant differences were detected in any end point.Conclusion: The subcutaneous combination of rIL-2 and rIFNalpha-2a with or without FU does not benefit patients with metastatic renal carcinoma. Neither of these regimens can be recommended as standard treatment. The results of the subcutaneous cytokine regimen seem disappointing.: CommentaryThe treatment of metastatic renal cancer remains a particularly difficult problem given the resistance of this disease to most treatment options. The use of cytokines, particularly IL-2 and interferon, has produced small numbers of responders with durable complete responses occurring in a very small percentage of patients. Of the chemotherapeutic agents studied in the past, the fluorouracils have demonstrated the most consistent, albeit uncommon, activity. It was therefore natural that the combination of IL-2, interferon, and 5-FU (the FUNIL regimen) would be widely tested. Recently we have seen a number of manuscripts describing the efficacy of these agents in combination in the management of relatively large numbers of patients with metastatic renal cancer. Various dosing regimens have also been used. In the phase II trial reported by Allen et al. (Br J Cancer 2000;83:980–5), 55 patients treated using the Atzpodien regimen resulted in a 31% response rate with 3 patients (5.5%) achieving a complete response. Toxicity was significant with 12 patients unable to complete one cycle of treatment and 36% experiencing grade 3-4 toxicity. These response rates, however, were not reproduced in the trials of Elias et al. (Cancer 2000;89:597–603) or Dutcher et al. (Clin Cancer Res 2000;6:3442–50) where response rates of approximately 18% were seen in patients in whom response could be determined. Interestingly, approximately 5% of evaluable patients in these latter two studies also achieved a complete response, in agreement with the work of Allen and associates. In a randomized comparison of subcutaneous IL-2 and interferon alpha-2a with or without continuous infusion 5-FU, Ne´grier et al. (J Clin Oncol 2000;18:4009–15) could not demonstrate an advantage of the addition of 5-FU in a study of 131 patients. Progression–free survival in the two arms was 12% and 15%, respectively.So, what are the take-home messages from these manuscripts? Firstly, the FUNIL regimen is toxic but toxicity is manageable in most patients. A significant percentage of patients, however, may not be able to complete one cycle of therapy, suggesting that this regimen is best suited for fit patients with good performance status. It appears that the regimen can achieve a complete response rate of about 5% and that these responses are durable. Is this regimen better than high dose IL-2 alone? Probably not, although these studies do not directly address this question. Finally, the FUNIL regimen is probably not of sufficient efficacy to be considered standard therapy for metastatic renal cancer.Robert Flanigan, M.D. [Copyright &y& Elsevier]

Treatment with tivozanib, a highly selective and potent vascular endothelial growth factor receptor tyrosine kinase inhibitor, has demonstrated single-agent efficacy in advanced renal cell carcinoma (RCC) along with minimal off-target toxicities and a favorable adverse event (AE) profile. We report final results from TiNivo, a phase Ib/II study of tivozanib combined with nivolumab. In phase Ib, patients with metastatic RCC received tivozanib 1.0 mg once daily (QD) for 21 days followed by 7 days off treatment (n = 3) or tivozanib 1.5 mg QD (n = 3) plus nivolumab 240 mg every 2 weeks. The maximum tolerated dose was determined to be tivozanib 1.5 mg, and 22 additional patients were enrolled at the maximum tolerated dose for phase II. Primary end points included safety and tolerability, with secondary end points of objective response rate, disease control rate, and progression-free survival. In total, 25 patients were treated with tivozanib 1.5 mg QD [12 (48%) treatment-naïve; 13 (52%) previously treated]. Treatment-related grade 3/4 AEs were reported in 20 patients (80%); 4 patients (17%) experienced AEs that led to dose reduction, and 8 (32%) discontinued due to AEs. The objective response rate was 56% (including one complete response) and disease control rate was 96%, with a median time to best response of 7.9 weeks. Twenty patients (80%) had tumor shrinkage. With a median follow-up of 19.0 months (range, 12.6–22.8), median progression-free survival was 18.9 months (95% confidence interval 16.4–not reached) in all patients and was similar in treatment-naïve and previously treated patients. Tivozanib plus nivolumab combination therapy showed a generally tolerable AE profile and promising antitumor efficacy. These results support further development of tivozanib combined with nivolumab as a treatment option in patients with treatment-naïve or previously treated metastatic RCC. NCT03136627. [ABSTRACT FROM AUTHOR]

The success of targeted therapies, including inhibitors of the vascular endothelial growth factor pathway or the mammalian target of rapamycin, in the treatment of metastatic renal cell carcinoma led to interest in testing their efficacy in the adjuvant setting. Results from the first trials are now available, with other studies due to report imminently. This review provides an overview of adjuvant targeted therapy in renal cell carcinoma, including interpretation of currently available conflicting data and future direction of research. We discuss the key differences between the completed targeted therapy adjuvant trials, and highlight the importance of accurately identifying patients who are likely to benefit from adjuvant treatment. We also consider reasons why blinded independent radiology review and treatment dose may prove critical for adjuvant treatment success. The implications of using disease-free survival as a surrogate end point for overall survival from the patient perspective and measurement of health benefit have recently been brought into focus and are discussed. Finally, we discuss how the ongoing adjuvant trials with targeted therapies and checkpoint inhibitors may improve our understanding and ability to prevent tumor recurrence after nephrectomy in the future. [ABSTRACT FROM AUTHOR]

Despite an improved antitumor efficacy as noticed by an enhanced response rate and an improved progression-free survival, the hepatic intra-arterial fotemustine did not increase the overall survival of uveal melanoma patients with liver metastases only. We propose to consider intrahepatic treatment as an experimental approach.Background In uveal melanoma (UM) with metastatic disease limited to the liver, the effect of an intrahepatic treatment on survival is unknown. We investigated prospectively the efficacy and toxicity of hepatic intra-arterial (HIA) versus systemic (IV) fotemustine in patients with liver metastases from UM. Patients and methods Patients were randomly assigned to receive either IV or HIA fotemustine at 100 mg/m2 on days 1, 8, 15 (and 22 in HIA arm only) as induction, and after a 5-week rest period every 3 weeks as maintenance. Primary end point was overall survival (OS). Response rate (RR), progression-free survival (PFS) and safety were secondary end points. Results Accrual was stopped after randomization of 171 patients based on the results of a futility OS analysis. A total of 155 patients died and 16 were still alive [median follow-up 1.6 years (range 0.25–6 years)]. HIA did not improve OS (median 14.6 months) when compared with the IV arm (median 13.8 months), hazard ratio (HR) 1.09; 95% confidence interval (CI) 0.79–1.50, log-rank P = 0.59. However, there was a significant benefit on PFS for HIA compared with IV with a median of 4.5 versus 3.5 months, respectively (HR 0.62; 95% CI 0.45–0.84, log-rank P = 0.002). The 1-year PFS rate was 24% in the HIA arm versus 8% in the IV arm. An improved RR was seen in the HIA (10.5%) compared with IV treatment (2.4%). In the IV arm, the most frequent grade ≥3 toxicity was thrombocytopenia (42.1%) and neutropenia (62.6%), compared with 21.2% and 28.7% in the HIA arm. The main grade ≥3 toxicity related to HIA was catheter complications (12%) and liver toxicity (4.5%) apart from two toxic deaths. Conclusion HIA treatment with fotemustine did not translate into an improved OS compared with IV treatment, despite better RR and PFS. Intrahepatic treatment should still be considered as experimental. EudraCT number and ClinicalTrials.gov identifier 2004-002245-12 and NCT00110123. [ABSTRACT FROM PUBLISHER]

Background: The European Advanced Renal Cell Carcinoma Sorafenib (EU-ARCCS) expanded-access study provided sorafenib to advanced renal cell carcinoma (RCC) patients in whom previous systemic therapy had failed. The study assessed the safety and use of sorafenib for the treatment of advanced RCC in a large community-based patient population across 11 countries in Europe.Patients and methods: EU-ARCCS was a single-arm, open-label trial of sorafenib in advanced RCC patients. End points included safety, time to progression, progression-free survival (PFS), and disease control rate (DCR). Subgroup analyses included age, Eastern Cooperative Oncology Group performance status, histology, prior therapy, and number and sites of metastases.Results: About 1159 advanced RCC patients were enrolled. Most patients (94%) experienced drug-related adverse events (AEs) of any grade, with the most common grade ≥3 AEs including hand–foot skin reaction (13%), diarrhea (7%), fatigue (7%), hypertension (6%), and rash/desquamation (5%). The incidence of AEs in the subgroups was similar to that in the overall population. Median PFS was 6.6 months; DCR at ≥8 and ≥12 weeks was 85% and 78%, respectively.Conclusions: The sorafenib safety profile in European community-based practice settings was similar to that reported in clinical trials. The heterogeneous advanced RCC patient population in EU-ARCCS permitted assessment of sorafenib in important subpopulations of advanced RCC patients. [ABSTRACT FROM AUTHOR]