Dr McKean on the Importance of Risk Stratification After Treatment of the Primary Tumor in Uveal Melanoma

"The fact that we could finally break through and find an effective treatment and something that improved overall survival [in metastatic uveal melanoma]—that's ultimately what we're always shooting for in oncology. How can we help our patients live longer?"

Meredith McKean, MD, MPH, director of the Melanoma and Skin Cancer Research Program at Sarah Cannon Research Institute, discussed how the distinct biology of uveal melanoma shapes surveillance and prognostication, as well as the overall survival benefit seen with the bispecific tebentafusp-tebn (Kimmtrak) in patients with HLA-A*02:01–positive metastatic disease and where the agent is headed next.

Although uveal and cutaneous melanoma share a cell of origin, where the disease arises dramatically changes treatment, McKean explained. Cutaneous melanoma typically carries a high tumor mutational burden driven by UV damage, along with driver mutations in the RAS-RAF-MEK-ERK pathway. Uveal melanoma, by contrast, harbors few mutations, with key alterations usually in GNAQ or GNA11 and high-risk mutations in BAP1, she said.

Uveal melanoma most often recurs in the liver, which makes careful hepatic monitoring with triple-phase CT or MRI with gadoxetate disodium (Eovist) central to surveillance, according to McKean. Metastases can still develop in the bone, lungs, lymph nodes, and peritoneum, though at a much lower incidence, she added. At primary treatment, a biopsy of as few as approximately 20 cells can undergo gene expression profiling, sequencing, or chromosomal analysis to stratify patients into low-, intermediate-, or high-risk groups for recurrence, which informs counseling, imaging surveillance, and adjuvant trial selection, she noted.

McKean described tebentafusp, though limited to HLA-A*02:01–positive patients, as a major advance. In the phase 3 IMCgp100-202 trial (NCT03070392; n = 378), the 1-year overall survival (OS) rate was 73% with tebentafusp vs 59% with investigator's choice of therapy (HR, 0.51; 95% CI, 0.37-0.71; P < .001).

Ongoing studies are moving the agent earlier, including a phase 2 neoadjuvant study (NCT06414590) and the phase 3 adjuvant ATOM trial (NCT06246149), to test whether it could help prevent metastatic disease, McKean said. Still, response rates with tebentafusp remain lower than desired, and because many patients have small liver tumors, shrinkage on imaging is hard to appreciate; data suggest circulating tumor DNA may be an easier measure of response, she explained. How to combine tebentafusp with other liver-directed or systemic therapies will be a big area of exploration, McKean concluded.