Liver-directed Therapy Offers Effective Treatment for Rare Metastatic Uveal Melanoma
Key Findings
- Uveal melanoma that metastasizes to the liver is extremely difficult to treat, resulting in a poor prognosis with historical median survival of 10-12 months
- A new program offers access to a complex procedure that isolates the liver to administer high-dose chemotherapy while avoiding systemic exposure
- The FDA-approved protocol enables the administration of multiple rounds of chemotherapy to optimize both treatment response and patient outcomes
Massachusetts General Hospital is among the few sites in the country offering access to a recently approved method for treating an extremely rare and deadly form of cancer — metastatic uveal melanoma. Proximity to one of the nation's preeminent ophthalmology groups at Mass Eye and Ear, is benefiting both the new program and the high volume of patients it's focused on helping.
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"We're excited to make this treatment available to patients historically limited in their therapeutic options," says Eric Wehrenberg-Klee, MD, an interventional radiologist at Mass General. "As the only center in New England offering this procedure, we're eager to provide patients throughout the region with an effective therapy for a rare and devastating cancer."
Unmasking a Rare and Aggressive Malignancy
Despite an estimated incidence of only five cases per million annually, uveal melanoma (UM) is the most common eye cancer in adults, accounting for up to 90% of ocular malignancies. Local therapies are effective in 95% of primary disease. However, approximately 50% of patients develop metastases, sometimes years after treatment.
The primary features that distinguish UM from other melanomas are the mutations that drive the malignancies. The mutational profile of UM is distinct from cutaneous melanomas. And despite its rarity, UM is further divided into four distinct genomic subtypes with different behaviors
Although the precise mechanism remains unknown, the liver is the site of metastasis in up to 90% of cases of metastatic UM (mUM).
Liver metastases can present in different patterns but often present as diffuse infiltrated cancer cells throughout the liver, which typically excludes resection as a therapeutic option.
"This type of aggressive, widespread infiltration is unique among metastatic cancers targeting the liver," says Dr. Wehrenberg-Klee.
The result is a malignancy that's extremely difficult to treat and with death typically occurring 1-3 years after metastatic diagnosis.
Finding and Hitting an Evasive Target
UM is poorly responsive to checkpoint inhibitor therapies that have been so successful in cutaneous melanoma. The combination of nivolumab and ipilimumab showed only an 18% response rate in a phase II study. More success has recently been seen with the bi-specific T-cell engager therapy tebentafusp. This therapy is limited to a subset of patients with the correct HLA subtype and has only a 9% response rate but improved overall survival relative to best-alternative care. Based on the results of a phase III trial, tebentafusp became the first approved therapy for metastatic UM.
Because of the limited systemic therapy options, and the high rate of metastasis to the liver, liver-directed therapy plays a particularly important role in the treatment of UM patients.
Liver-directed therapies for liver malignancies include those that deliver treatment directly to a tumor through its blood supply via the hepatic artery. These techniques rely on guiding a catheter into the tumor vasculature for therapy delivery. In mUM these routes can include:
- Transarterial radioembolization (TARE): Tiny beads carrying a radioactive isotope (yttrium-90) lodge in tumor vasculature and slowly release radiation.
- Transarterial chemoembolization (TACE): High concentrations of chemotherapy are directed to the tumor, followed by infusion of an agent to block blood flow.
Each method focuses its respective mechanism on the tumor while largely excluding healthy tissue. However, mUM liver metastases are often characterized by diffuse infiltration, forming small tumor niches throughout the liver with poor arterial supply. Although embolization approaches can be quite efficacious against mUM, their inability to access all of the cancer is compounded by limitations in how often they can be used. For TARE, Dr. Wehrenberg-Klee notes that safety guidelines often restrict it to a one-time treatment due to concerns of exposing the liver to too much radiation.
Eliminating Places for Cancer to Hide
In 2023, the FDA approved the first and only liver-directed therapy targeting mUM following results from a phase 3 trial (FOCUS). The method (percutaneous hepatic perfusion; PHP) involves isolating and redirecting the blood supply to and from the liver to allow its saturation with a high dose of chemotherapy (melphalan). High dose chemotherapy is delivered percutaneously via the hepatic artery. The chemotherapy is then removed by passing blood from the liver through a filtration unit, after which normal circulation is restored.
Dr. Wehrenberg-Klee emphasizes the need for specialized anesthesiologists, perfusionists, and interventional radiologists to perform this procedure. The highly trained anesthesiology team is led by Raphael Vazquez, MD. The steps of the procedure include:
- Inserting balloon catheters to block venous blood flow out of the liver
- Establishing a venous-venous bypass circuit attached to the filtration unit
- Positioning an arterial infusion line in the hepatic artery
- Delivering chemotherapy to the liver (approximately 30 minutes)
- Flushing the drug from the liver via filtration (an additional 30 minutes)
- Restoring normal blood flow through the liver
"By isolating the liver, we're able to deliver chemotherapy and allow it to diffuse throughout the entire organ while minimizing systemic contamination," he explains. Importantly, the protocol supports up to six treatments every six to eight weeks. "The ability to administer multiple rounds of therapy is a major benefit in terms of maximizing duration of treatment response."
According to results from the FOCUS trial, treatment responses to PHP relative to the best alternative care (BAC) included:
- A threefold higher objective response rate (ORR; evidence of tumor response to therapy) and progression-free survival (PFS) rate
- A complete response to treatment in 8% of patients (vs. none in the BAC group)
- Overall response rate of 36.3%, disease control rate of 73.6%, progression free survival of 9.0 months, and overall survival of 20 months.
A phase II trial (CHOPIN) currently underway involves a protocol combining PHP with immunotherapy. That trial builds upon previous results, of a small Phase I study reporting an ORR of 85.7%, a disease control rate of 100%. At time of reporting the median PFS was 22.4 mo with all patients still alive. "PHP currently provides patients with an effective treatment option," Dr. Wehrenberg-Klee says. "It's exciting to think that they may soon have access to something with even greater efficacy."
The Right Time and Place
Dr. Wehrenberg-Klee says that starting a program focused on offering a highly complex procedure for a rare type of cancer presents several unique challenges. However, he adds that doing so at Mass General removes a lot of the obstacles.
"This procedure requires specialists that aren't always available all in one place," he explains. These include anesthesiologists and perfusionists with relevant transplant and cancer surgery experience, as well as pharmacists well-versed in chemotherapy administration and side effects. We’ve also been fortunate to have support for post-procedure care from teams led by Dr. Casey Luckhurst, Dr. Ryan Horvath, and Dr. Ken Tanabe. "All of these folks were excited about the opportunity and immediately became committed to making the program work for our patients"
Dr. Wehrenberg-Klee adds that working with the Ocular Melanoma Eye Tumor Program, as well as Kamaneh Montazeri, MD, medical oncologist at the Mass General Cancer Center, and Ryan Sullivan, MD, director of the Center for Melanoma, strengthened relationships that translated into support for the program. However, the ultimate motivating factor was helping patients with a rare disease and few options.
"I quickly became invested in the patients and the impact that I believed liver-directed therapy could deliver," he says. Proximity to Mass Eye and Ear offers access to high patient volumes, which translates to both increased technical proficiency and improved outcomes. "Although the uveal melanoma community is small, we're fortunate to be in a position allowing us to provide a lifesaving treatment to a lot of patients."