Rarity of Uveal Melanoma Challenges Clinical Trial Enrollment

Richard D. Carvajal, MD

Richard D. Carvajal, MD

Uveal melanoma appears to be a relatively rare disease, which poses a major challenge to clinical trials evaluating newer and better treatment options for these patients. Despite a lack of patients to enroll in clinical trials, 2 particular agents seem promising in this setting compared with what may be considered the standard at this time, the combination of nivolumab (Opdivo) and ipilimumab (Yervoy).

IMCgp100 (tebentafusp), an immunotherapeutic agent,received a fast track designation for the treatment of patients with HLA-A*0201-positive metastatic uveal melanomawho were previously untreated, according to an announcement in April 2019. The agent demonstrated promising responses and survival in a small phase I study of this patient population and is now being evaluated further in registration clinical trials. 

The targeted therapy of IDE196, an inhibitor of PKC, has also demonstrated promising responses in patients with uveal melanoma. However, these trials were still small due to the rarity of this disease type and will be further evaluated in clinical trials.

In an interview withTargeted Oncology, Richard D. Carvajal, MD, director of Melanoma Service and Experimental Therapeutics Program at Columbia University Herbert Irving Comprehensive Cancer Center, discussed the challenges of conducting clinical trials for the treatment of patients with uveal melanoma, as well as the excitement surrounding 2 potential therapies in this space.

TARGETED ONCOLOGY: Could you provide an overview of the research surrounding uveal melanoma?

Carvajal:It has been an interesting time in the uveal melanoma field. Over the past decade or so, there has been an increased understanding of the biology of the disease, so this is leading to clinical trials and therapies that are at least providing a hint that we are helping our patients clinically.

TARGETED ONCOLOGY: What advances have been made?

Carvajal:The advances have been made on 2 fronts, including the targeted therapy front and immunotherapy front. For the first time in this field, we have 2 drugs in registration-intent clinical trials. The first is a targeted therapy called IDE196, and the other IMCgp100, which is a bispecific immunotherapy agent.

TARGETED ONCOLOGY: Could you discuss why these 2 particular advances are promising in this treatment landscape?

Carvajal:IDE196 is a PKC inhibitor. It hits both the conventional and novel forms of PKC. It had previously completed clinical trials when it was run by Novartis. If you look at the patients we treated at twice-daily dosing, which was a cohort of about 30 patients, the response rate was fairly modest in the teens. However, if you look at the number of patients who are doing well at a year or longer, about a quarter of the patients were still doing well, which is fairly remarkable for this disease. However, it is a small cohort of patients.

That drug is now in another clinical trial run by another company, IDEYA Biosciences, which is hoping to reproduce those findings or perhaps exceed those.

The other drug, IMCgp100, is a bispecific molecule targeting gp100 in HLA restricted fashion, and the other end binds to CD3. It brings the CD3 cells right into proximity of the tumor cells. In previously completed clinical trials, we have again seen modest response rates in the mid-teens, but what is interesting is when you look at the patients who do well at a year or so, over 70% of patients on the prior trials were alive at the 1-year time point. If you look against historical controls, this was much better.

Now, this drug is in registered clinical trials. The first of 2 trials has completed accrual, and that is just maturing. The second trial, which is a randomized trial of IMCgp100 against investigator’s choice should complete accrual this year.

TARGETED ONCOLOGY: What are the ongoing challenges in this space?

Carvajal:Trying to develop therapies for this disease is challenged by the same issues that other rare diseases have. We will see about 2,000 to 2,500 cases of this per year in the United States, so it is fairly tough to do big randomized trials. We don’t have a great [understanding] of the natural history of the disease, so we are often relying on single-institution experiences or [similar data] to figure out benchmarks for the clinical trials. It is still relatively studied, though. Thankfully, there are more and more underlying targets based on the biology that are being identified, and more and more we are able to get industry and biotech to invest in this disease. However, it is still a small population. It is a small market from the business perspective.

TARGETED ONCOLOGY: What do you hope oncologists take away from this?

Carvajal: