Emergence of Tebentafusp Underscores the Need for Additional Advancements in Uveal Melanoma

When the FDA approved tebentafusp-tebn (Kimmtrak) for the treatment of patients with HLA-A*02:01–positive unresectable or metastatic uveal melanoma in January 2022, it underscored 2 things about the treatment space in the disease, according to Richard D. Carvajal, MD. He said testing patients for HLA status is vital, and more studies are needed to develop therapies for patients who are not eligible to receive tebentafusp.

“In uveal melanoma, HLA typing is critical. We must know if tebentafusp is an option [for individual patients],” said Carvajal, who presented on new treatments in uveal melanoma at the 40th Annual CFS®. “Clinical trials are still high priority. Although the median overall survival [OS] for uveal melanoma is now over 20 months, we are still losing patients. We must prioritize these clinical trials.”

In an interview with OncLive^® following his presentation, Carvajal discussed the implications of the FDA approval of tebentafusp in uveal melanoma, the possibility of exploring tebentafusp in other HLA subtypes, and other areas of intriguing research in uveal melanoma. Carvajal is the director of Experimental Therapeutics and director of the Melanoma Service at Columbia University Medical Center in New York, New York.

OncLive^®: Could you describe the current treatment landscape for uveal melanoma?

Carvajal: It has been an incredibly exciting time for the field of uveal melanoma. For the first time ever, we have an FDA-approved drug that meaningfully improves OS for patients with metastatic disease [with] tebentafusp approved in January [2022].

Tebentafusp has been a major leap forward and a major advance. However, there is certainly still work to do. There are several novel systemic therapies that are in development that can continue to impact the outcome for our patients positively.

What are some of the prognostic factors that differentiate uveal melanoma from cutaneous melanoma?

Uveal melanoma is very distinct, both biologically and clinically. If you look at the genomics, it is well known that cutaneous melanoma has a very high mutation burden. Cutaneous melanoma is amongst the highest [burden] of all tumors. Uveal melanoma is on the opposite end of the spectrum, [with] one of the lowest mutation burdens. When looking at the expression of things such as PD-L1, it’s generally low for uveal melanoma.

The clinical behavior of uveal melanoma is different, in that it is extremely hepatotropic. When uveal melanoma spreads, it tends to like to go to the liver, which is very hard to treat across all tumor types. We have a disease that is biologically aggressive, likes to metastasize, likes the immunosuppressive environment of the liver, and our current therapies—certainly before tebentafusp—don't work for the vast majority of patients.

What has the FDA approval of tebentafusp meant for the treatment of patients with HLA-A*02:01–positive metastatic uveal melanoma?

When we got the data, it brought tears to my eyes. Patients are absolutely thrilled. Tebentafusp reduced the risk of death by [49% vs investigator’s choice of therapy in the phase 3 IMCgp100-202 trial (NCT03070392)], which is a huge deal.

However, there are issues. For one, tebentafusp is HLA restricted. This is a therapy that can meaningfully help people, but only if they're HLA-A*02:01 positive. That means that for about 50% of our patients, [tebentafusp] is not an option.

Two, there was a meaningful improvement in OS without a very high response rate or improvement in progression-free survival. OS is the most meaningful end point, but there are patients who have a large burden of disease, rapidly progressing disease, where you need a response. We need better therapies for that subset of patients.

Are there any other specific unmet needs in uveal melanoma that you hope to see addressed in future trials?

Now that we have an effective therapy in the metastatic setting, just like with other disease settings and agents, we have to move earlier in disease states. We need to move [tebentafusp] into the adjuvant setting, and that is high priority.

A second priority would be to make sure that we’re able to use therapies like this for other HLA subtypes. Tebentafusp is a therapy where we have to expand its availability by HLA type and move earlier in the disease stage.

Are there any other intriguing clinical trials ongoing in uveal melanoma?

There are a number of trials being done now in the systemic and regional settings, many of which I am extremely excited about.

One specific agent is a drug called darovasertib [IDE196], which is a PKC inhibitor. We have a fairly large dataset and experience with this drug, either alone or in combination for patients with uveal melanoma.

[In data from a phase 2 trial (NCT03947385)], we saw darovasertib in combination with crizotinib [Xalkori] had an [overall] response rate [of 31% in patients with metastatic uveal melanoma treated in any line]. If you look at the waterfall plot, almost all patients have some degree of tumor shrinkage, even if patients don't meet that partial response definition. [The ORR] was striking. The disease control rate and progression-free survival seem good, which is interesting.

I also spoke a bit about data on percutaneous hepatic perfusion and intrahepatic perfusion. These regional therapies, where we’re delivering a chemotherapy or other treatments directly to the liver, [that] have high response rates. In the patients where there is rapidly progressing disease and we need a quick response, various regional therapies make a lot of sense, [so] further work in that space is important.