Revolutionizing Uveal Melanoma Treatment: SCANDIUM-II Trial Combines Chemotherapy and Immunotherapy for Promising Results 

By Alice Bradbury, PhD 

Uveal melanoma is the most common ocular cancer in adults. Despite effective treatment of the primary tumor, around half of all patients with uveal melanoma will develop metastases, typically to the liver (1). In these patients the prognosis is poor and very few patients survive >5 years (1, 2), indicating the need for novel therapeutic strategies.  

Isolated hepatic perfusion (IHP) is a regional treatment where the liver is isolated from the systemic circulation to allow delivery of a high concentration of a chemotherapeutic agent with minimal systemic exposure and is used to treat some liver cancers or liver metastases. A recent clinical trial (SCANDIUM-II; NCT04463368) published in ESMO Open found that IHP with the chemotherapeutic melphalan in combination with immunotherapies, ipilimumab and nivolumab, was efficacious in the treatment of patients with liver-dominant metastases of uveal melanoma, but was associated with severe adverse events (3).   

The trial was led by Roger Olofsson Bagge, MD, PhD, recipient of the 2021 AACR-OMF Career Development Award, in honor of Robert C. Allen, MD. Now a full professor at the University of Gothenburg in Sweden, he highlighted the importance of securing funding for clinical trials, explaining, “Running clinical trials and translational research is extremely expensive and often requires combined funding from numerous sources. The AACR grant helped fund vital parts of the SCANDIUM-II clinical trial and was instrumental in helping to secure additional funding.” 

The SCANDIUM-II trial was an expansion of the phase III SCANDIUM trial (NCT01785316), also led by Dr. Olofsson Bagge, which found that IHP with melphalan achieved a superior overall response rate and progression free survival (PFS) compared to best alternative care in treatment-naïve patients with isolated liver metastases of uveal melanoma (4). With growing evidence that some chemotherapeutic agents trigger cell death associated with inflammatory signaling and activation of immunity (5), Dr. Olofsson Bagge hypothesized that beyond providing a direct antitumoral effect, IHP with melphalan may activate the immune system through these immunological mechanisms, which could be potentiated by combining the treatment with immune checkpoint inhibitors. 

Testing this hypothesis, Dr. Olofsson Bagge and his colleagues enrolled 18 patients with histologically or cytologically confirmed liver metastases from uveal melanoma across six sites in Sweden. Patients were randomly assigned in a 1:1 ratio to either a post-operative or pre-operative arm. In the post-operative arm, nine patients received IHP followed by four cycles of ipilimumab/nivolumab every three weeks. In the pre-operative arm, nine patients received one pre-operative cycle of ipilimumab/nivolumab before IHP, followed by three cycles. Both arms then received nivolumab monotherapy every four weeks for up to one year. Eight patients in the post-operative arm and seven patients in the pre-operative arm received IHP as per the protocol. In both arms of the study, patients received a median of 3 cycles (range 1-4) of ipilimumab/nivolumab, and three out of nine patients in each group received all four cycles.  

To determine the incidence and severity of adverse and serious adverse events, the study team registered adverse events from the first treatment dose until 100 days after the last treatment or 30 days after the last treatment if the participant started a new anti-cancer treatment, whichever occurred first. They recorded at least one grade 3 of 4 adverse event in eight out of the eight patients in the post-operative arm, and in five out of the seven patients in the pre-operative arm who received IHP. Among patients who received at least one cycle of ipilimumab/nivolumab, they recorded grade 3 or higher immune-related adverse events in three patients in the post-operative arm and in eight patients in the pre-operative arm. Furthermore, an increased number of immune-related adverse events were recorded overall in the pre-operative arm.  

In addition to safety, response was measured in seven out of nine patients in the post-operative arm, and nine out of nine patients in the pre-operative arm. The investigators carried out clinical and radiological evaluations every 3 months for up to 2 years by either CT or MRI of the liver, with additional CT imaging of the thorax. The response was graded according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) criteria (6), compared to baseline evaluation. They found that the post-operative approach demonstrated better efficacy in terms of objective response rate (ORR), defined as the percentage of patients with a best overall response of complete response or partial response, and progression free survival (PFS), defined as the time from randomization to documented progression at any site, or death from any cause according to RECIST 1.1 criteria.  

Dr. Olofsson said, “In this AACR funded phase Ib trial (the SCANDIUM-II trial), we explored how advanced locoregional treatment can be combined with modern immunotherapy for patients with uveal melanoma liver metastases.” Explaining the main findings of the trial, he said, “Giving immunotherapy before isolated hepatic perfusion was more toxic and did not convey any obvious efficacy benefit compared to giving the immunotherapy afterwards. This finding has been instrumental for the design of a follow-up trial, the SCANDIUM-III trial, where percutaneous hepatic perfusion will be combined with immunotherapy.” 

He went on to say, “Receiving an AACR grant helped the trial and has been very important for my career. Receiving a prestigious international grant, such as this AACR grant, provides credibility that has helped me to secure long-term additional grant funding in Europe.” 

References: 

1. Diener-West M, et al. Development of metastatic disease after enrollment in the COMS trials for treatment of choroidal melanoma: Collaborative Ocular Melanoma Study Group Report No. 26. Arch Ophthalmol. 2005;123(12):1639-1643. 

2. Khoja L, et al. Meta-analysis in metastatic uveal melanoma to determine progression free and overall survival benchmarks: an international rare cancers initiative (IRCI) ocular melanoma study. Ann Oncol. 2019;30(8):1370-1380. 

3. Olofsson Bagge R, et al. A phase Ib randomized multicenter trial of isolated hepatic perfusion in combination with ipilimumab and nivolumab for uveal melanoma metastases (SCANDIUM II trial). ESMO Open. 2024 Jul;9(7):103623. 

4. Olofsson Bagge R, et al. Isolated hepatic perfusion with melphalan for patients with isolated uveal melanoma liver metastases: a multicenter, randomized, open-label, phase III trial (the SCANDIUM trial). J Clin Oncol. 2023;41(16):3042-3050. 

5. Tesniere A, et al. Molecular characteristics of immunogenic cancer cell death. Cell Death Differ. 2008;15(1):3-12. 

6. Eisenhauer EA, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-247.