Redefining management of uveal melanoma liver metastases: what oncologists need to know

Metastatic uveal melanoma may be a rare disease, but it poses a major clinical challenge, with limited systemic treatment options and a strong predilection for liver metastases. This expert commentary by consultant oncologist Dr Matthew Wheater examines the potential of liver-directed therapies, specifically melphalan-based percutaneous hepatic perfusion, and highlights key findings from the pivotal FOCUS trial that may alter the treatment approach for patients with liver-dominant disease.

Although rare, uveal melanoma is the most common primary intraocular malignancy in adults, with an incidence of approximately five cases per million per year.¹ Despite effective local control of the primary tumour, nearly 50% of patients develop metastatic disease, often years after initial diagnosis.²

Metastatic uveal melanoma (mUM) differs significantly from cutaneous melanoma in terms of its molecular profile, behaviour and treatment response. A striking feature of mUM is its propensity for hepatic metastasis, with up to 90% of metastatic cases involving the liver, either as the sole site or in combination with other sites.³

Despite advances in immunotherapy and targeted agents for cutaneous melanoma, these therapies have shown limited efficacy in mUM due to a lack of shared driver mutations such as BRAF and a relatively immunologically ‘cold’ tumour microenvironment.¹ The distinct biology of mUM requires equally distinct treatment strategies, particularly those that address the dominant hepatic involvement.

The unmet clinical need in mUM

Patients with mUM face a poor prognosis, particularly those with liver-dominant disease. The median overall survival (OS) after development of metastases is approximately 12 months, and this figure has remained largely unchanged over decades.⁴

In the absence of approved systemic therapies specifically for mUM, treatment has often relied on the use of drugs approved for cutaneous melanoma, such as immune checkpoint inhibitors. However, multiple studies have demonstrated limited clinical benefit from anti-PD-1 or anti-CTLA-4 therapy in this population, with response rates typically less than 5%.⁵

Chemotherapy, either as monotherapy or in combination, also lacks meaningful efficacy. Hepatic metastases are typically resistant to systemic therapy due to the liver’s unique immunosuppressive environment and the typically low mutational burden of uveal melanoma.⁶

Tebentafusp – a recently approved T-cell receptor-directed therapy for HLA-A\*02:01-positive patients with mUM – has shown benefit but has limited applicability due to the human leukocyte antigen restriction, which limits availability to around 40% of the population.

This agent is the first to show a significant impact on survival in mUM, but it has modest activity in patients with liver-dominant disease.⁷ This persistent unmet need highlights the importance of liver-directed approaches in mUM, particularly those that could achieve higher intrahepatic drug concentrations while minimising systemic exposure.

The case for liver-directed therapy in mUM

Given that over 90% of patients with mUM develop liver metastases, and often with the liver as the dominant or only site of disease, local hepatic therapies offer a rational and potentially impactful treatment approach.⁸

Percutaneous hepatic perfusion (PHP) with melphalan is one such approach that delivers high-dose chemotherapy directly to the liver via the hepatic artery, followed by extracorporeal haemofiltration to reduce systemic exposure. This method allows for significantly higher hepatic drug concentrations than can be achieved with systemic chemotherapy alone, offering the potential for enhanced anti-tumour activity with reduced systemic toxicity.⁹

The goal is to saturate the hepatic circulation with melphalan while protecting other organs, especially the bone marrow, from its toxic effects. By isolating the liver’s blood supply, PHP creates a pharmacologic advantage for liver-dominant disease.

Other liver-directed strategies – including transarterial chemoembolisation, radioembolisation and hepatic resection – have been explored, but PHP benefits from its repeatability and systemic-sparing pharmacokinetics.¹⁰ This makes it particularly well-suited for a disease like mUM where systemic therapy options are sparse and liver failure is the predominant cause of death.

Focus on the FOCUS trial

The FOCUS trial (NCT02678572) is a pivotal phase 3 study evaluating the efficacy and safety of melphalan/hepatic delivery system (melphalan/HDS) PHP in patients with liver-dominant mUM.

This randomised, controlled, multicentre trial enrolled patients who had progressed on, or were not candidates for, immune checkpoint inhibitors or other systemic therapies. Patients with liver-only or liver-dominant metastatic disease were included. Those with liver-dominant disease were defined as bone, subcutaneous, lung or lymph nodes amenable to resection or radiation with a defined treatment plan.

Patients were randomised to receive melphalan/HDS or the investigator’s choice of best alternative care, which included options such as transarterial chemoembolisation, pembrolizumab or dacarbazine.¹¹

The rationale behind FOCUS stemmed from prior phase 1/2 studies suggesting that melphalan/HDS PHP can achieve meaningful responses and disease control in mUM.

The FOCUS trial was initiated as a randomised study, however, relatively early into recruitment, it was apparent that significant numbers of patients were dropping out of the control arm at the point of randomisation. Following discussions with the US Food and Drug Administration, the trial protocol was amended to a single-arm study, utilising benchmark data from a systematic review of prior studies to inform the power analysis for the primary outcome.

Data have been published on both the primary analysis of the single-arm study and the results from the randomised section of the study.^11,12

Despite these hurdles, the FOCUS trial provides key evidence supporting the use of PHP in the subset of mUM patients with liver-dominant disease and limited extrahepatic spread.

Demonstrating promising efficacy and clinical activity

Results from the FOCUS study and earlier trials have demonstrated encouraging clinical activity for melphalan/HDS in mUM. In the FOCUS trial, melphalan/HDS was associated with an improved overall response rate of approximately 36% compared with 2% in the best alternative care arm.¹²

Median progression-free survival was also significantly extended to 9.0 months versus 3.1 months, respectively. Importantly, the disease control rate, which includes patients achieving partial response or stable disease, was over 70% in the treatment arm.

Although the study was not powered for OS, trends favoured PHP with a median survival of 20.5 months. Earlier phase studies have reported a median OS duration of 19 months in treated patients, notably higher than historical controls.¹³ These outcomes are particularly significant given the limited effectiveness of other systemic therapies.

The FOCUS trial results support melphalan/HDS as a meaningful treatment modality for patients with mUM, especially those with unresectable, liver-only or liver-dominant disease. Further research into predictive biomarkers and combination strategies may enhance patient selection and efficacy.

An acceptable safety profile

The safety profile of melphalan/HDS therapy reflects both the chemotherapeutic and procedural aspects of the treatment. The most commonly observed adverse events include haematologic toxicities such as thrombocytopaenia, neutropaenia and anaemia, which are consistent with melphalan’s known myelosuppressive effects.¹⁴ These are typically transient and manageable with supportive care, including primary growth factors and transfusions.

Non-haematologic toxicities include hypotension, nausea and transient elevations in liver enzymes. The procedure itself requires coordination of vascular access, general anaesthesia and extracorporeal filtration, all of which introduce procedural risks. Despite these complexities, melphalan/HDS has demonstrated an acceptable safety profile when performed at experienced centres with appropriate multidisciplinary support.

Serious adverse events occur in a minority of cases, with improved safety outcomes seen over time due to procedural refinements and greater operator experience.¹⁵ Importantly, the systemic toxicity profile is far milder than that observed with comparable doses of systemic chemotherapy. This balance between high intrahepatic drug exposure and reduced systemic toxicity is central to the rationale for melphalan/HDS and is a key advantage in the treatment of mUM.

Implications for clinical practice

Melphalan/HDS PHP offers a significant addition to the limited therapeutic armamentarium for mUM. Given the liver-centric nature of metastatic spread in this disease, PHP provides a rational and targeted approach, particularly in patients with limited or no extrahepatic involvement. With demonstrated clinical activity and a manageable safety profile, PHP has the potential to serve as a bridge to extended survival and improved quality of life in a historically hard-to-treat population.

In clinical practice, PHP should be considered for patients with unresectable, liver-dominant mUM, especially those who have failed or are ineligible for systemic options. Its integration into treatment pathways requires careful multidisciplinary planning and access to centres equipped to perform the procedure safely. Patient selection remains critical, as those with extensive extrahepatic disease or poor hepatic function may derive less benefit.

Furthermore, awareness and education about PHP among oncologists – particularly outside major referral centres – must improve to ensure equitable access to this promising therapy.

Shaping the future of liver-directed therapy for mUM

Looking ahead, several key research areas are likely to shape the future of liver-directed therapy in mUM. Combination strategies involving PHP and systemic agents – particularly immune checkpoint inhibitors, targeted therapies or investigational T-cell engagers – may enhance overall outcomes.¹⁶ Additionally, translational research aimed at identifying biomarkers of response to PHP could refine patient selection and maximise benefit.

Longitudinal studies and real-world data will be essential to understanding the durability of response, optimal sequencing with other therapies and quality-of-life outcomes. Further exploration of repeat treatment strategies and alternative dosing schedules may also enhance the clinical utility of PHP.

In conclusion, melphalan/HDS PHP represents a targeted and effective therapeutic option for patients with liver-dominant mUM. Its development addresses a significant unmet need in a rare and challenging malignancy. Continued clinical integration, coupled with robust research, will be key to fully realising its potential in improving outcomes for patients with mUM.

Author

Matthew Wheater BM FRCP PhD
Consultant oncologist, University Hospital Southampton NHS Foundation Trust

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