NEW YORK – SkylineDx has scaled up efforts to drive adoption of its Merlin test in recent months after several new studies showcased its ability to predict which patients with cutaneous melanoma are at risk of metastasis and which can safely forgo sentinel lymph node biopsy surgery.
The Merlin test, also called CP-GEP, combines clinicopathologic variables with gene-expression profiling via qPCR to stratify patients with cutaneous melanoma as high risk or low risk of nodal metastasis. Currently, international guidelines recommend sentinel lymph node biopsy to assess this risk for patients with tumors 0.8 mm in thickness or greater or those with tumors less than 0.8 mm that also have ulceration, or that have risk factors such as young age, lymphovascular invasion, or positive margins on biopsy. Sentinel lymph node biopsy is used to determine not only the stage of melanoma for a patient but also the patient's eligibility for adjuvant therapy. According to National Comprehensive Cancer Network and European Society of Medical Oncology guidelines, certain patients at risk of metastasis may receive radiation and systemic therapy including PD-L1 inhibitors or, for those with BRAF-mutated tumors, BRAF and MEK inhibitors.
About 75 percent to 85 percent of patients who undergo sentinel lymph node biopsy have no nodal metastasis in the sentinel node, the first node to which cancer is likely to spread from the primary tumor. Up to 11 percent of patients who undergo biopsy experience postoperative complications, and most will need to visit their doctor multiple times over several weeks. SkylineDx and Mayo Clinic developed the Merlin test to help physicians determine if some melanoma patients can avoid the risks of surgery and identify others who are at high risk and need further intervention.
Merlin is a noninvasive in vitro diagnostic test that measures RNA expression of eight target genes involved in tumor development — MLANA, GDF15, CXCL8, LOXL4, TGFBR1, ITGB3, PLAT, and SERPINE2 — plus two housekeeping genes. The gene-expression signals are combined with two clinical and pathology variables, the age of the patient, and thickness of the lesion in an algorithm designed to predict the outcome of a sentinel lymph node biopsy. Based on these parameters, the algorithm classifies the patient as low risk or high risk for nodal metastasis.
SkylineDx partnered with the Belgian firm Biocartis in 2021 to commercialize the test in Europe on Biocartis' Idylla PCR-based diagnostics platform. Rotterdam, Netherlands-based SkylineDx obtained a CE-IVD mark for Merlin in 2022 and secured Medicare coverage that same year for it in the US. Merlin is now commercially available in the US and Europe as a laboratory-developed test and in Europe as an Idylla in vitro diagnostic. Quest Diagnostics has also launched its own version of the Merlin CP-GEP model as a laboratory-developed test in the US under the brand name MelaNodal Predict.
Skyline CEO Dharminder Chahal hopes that results from Merlin will help melanoma patients discuss options with their doctors. "Knowing your personal risk assessment is important for patients," he said. "The doctor can discuss the test result and categorize the patient in the appropriate surgical action categories listed in evidence-based cancer treatment guidelines."
Results of several new studies have now provided further validation of Merlin's clinical utility. At the 21st International Congress of the Society for Melanoma Research earlier this month in New Orleans, SkylineDx researchers presented results from MERLIN_001, a large, prospective, multicenter study involving more than 1,600 patients with stage T1 to stage T3 melanoma that underwent sentinel lymph node biopsy. According to Dharminder, this is the "largest prospective trial of a genomic assay yet conducted in melanoma."
The study showed the test had a negative predictive value of 92.9 percent. Among the 37 percent of patients that Merlin classified as low risk, 7.1 percent, or about 40 patients, had a positive sentinel lymph node indicating metastasis. For those classified as high risk, 23.8 percent had a positive sentinel lymph node. Based on the test's performance, study investigators concluded the results could inform conversations with patients about surgical options, allowing more precise and individualized care.
In another study presented last weekend at the Australasian Melanoma Conference in Sydney, researchers from the Melanoma Institute Australia analyzed data from independent validation studies of the Merlin model conducted between 2020 and 2024 and found the test had a 93 percent sensitivity and a negative predictive value of 95 percent. The investigators noted that it performed particularly well in patients with stage pT2 melanoma, which are 1.01 mm to 2.0 mm in thickness, significantly reducing unnecessary biopsy procedures. They also found that patients with pT3 and pT4 melanomas were less likely to benefit from the model, since very few of those patients would benefit from skipping sentinel lymph node biopsy. In patients with melanomas 1.0 mm or less in thickness, heterogeneity in the data prevented the researchers from drawing any reliable conclusions, and the study authors called for further research.
But a third recent study presented at the Society for Melanoma Research congress earlier this month addressed that population. Researchers from the Mayo Clinic and other academic centers evaluated the ability of the Merlin test to stratify T1a melanoma patients for potential sentinel lymph node biopsies, including patients without ulcerations or high-risk features. Stage T1a melanomas are less than 0.8 mm thick and do not have ulcerations.
Typically, these patients would not undergo a sentinel lymph node biopsy because their risk of metastasis is very low, and for most, that's the right choice. But according to Alexander Meves, a dermatologist at the Mayo Clinic and one of the inventors of the Merlin test, a small percentage of those low-risk T1a melanoma patients do go on to develop metastasis.
"Taking out the lymph nodes does two things," Meves said. "It gives you diagnostic information as to how aggressive [the tumor is]. But it also offers a therapeutic procedure." If there are metastatic cancer cells in the lymph node, removing it can prevent recurrence. On the other hand, if the same patient forgoes lymph node surgery, and develops a recurrence of cancer in the node, it will require a more complex and risky surgery to remove the cancer.
In a retrospective analysis, Meves and his colleagues studied 153 T1a melanoma patients from 11 centers diagnosed between 2007 and 2021 who underwent sentinel lymph node biopsy at the discretion of the treating surgeon. Meves noted that a large number of centers had to be involved to find enough patients for the study since these patients don't normally have this surgery.
Five patients in the cohort, or 3.3 percent, had a positive result from their sentinel lymph node biopsy. The Merlin model classified 134 patients as low risk, and only 1.5 percent of the low-risk group had a positive node. Another 19 patients, or 12 percent, were classified as high risk by the Merlin test, and the lymph node positivity rate for that group was 15.8 percent. The resulting negative predictive value of the test was 98.5 percent.
Bolstered by all this data, SkylineDx is pushing ahead with plans to increase uptake of its test. In the US, SkylineDx is commercializing the Merlin test with Tempus under an agreement signed in 2023. And it is collaborating with diagnostic service providers around the world to increase market access globally. Over the course of the year, Chahal said SkylineDx has built a focused sales and marketing team to support the product, while Tempus has assembled a dermatology team to commercialize the Merlin test.
Skyline will also continue validating the test across melanoma stages, as well as in T1a melanoma patients where the company said Merlin offers a new standard of care with the potential to improve outcomes. The advantage of the test for this patient group, Meves said, is that if there's a concern with a T1a melanoma patient who would not normally qualify for sentinel lymph node biopsy under current guidelines, there's an option to investigate further.
"The intent is to help prevent undertreatment in seemingly low-risk, early-stage melanoma patients who are actually at risk for nodal metastasis," he said, adding that those patients can then receive a sentinel lymph node biopsy and may even be eligible for adjuvant treatment, even if they don't have traditional clinical risk factors.