2 Clarke Drive
Suite 100
Cranbury, NJ 08512
© 2025 MJH Life Sciences™ and OncLive - Clinical Oncology News, Cancer Expert Insights. All rights reserved.
Marlana Orloff, MD, discusses data for the combination of darovasertib and crizotinib in metastatic uveal melanoma.
Although the uveal melanoma treatment paradigm has expanded in recent years, a need remains to develop novel treatment approaches applicable to the overall population, according to Marlana Orloff, MD.
“We are still looking for a systemic therapy that can be offered to everyone, regardless of HLA status. [This is] what we need,” Orloff said.
One such novel systemic approach using the combination of the PKC inhibitor darovasertib and crizotinib (Xalkori) is being investigated in the phase 1/2 OptimUM-01 trial (NCT03947385). Findings from the trial presented at the 2025 Society for Melanoma Research Congress demonstrated that patients with metastatic uveal melanoma treated with the combination in the first-line setting (n = 41) achieved a median overall survival (OS) of 21.1 months (95% CI, 12.5-27.1).1,2 At a median follow-up of 25 months, the combination also generated a median progression-free survival of 7.0 months (95% CI, 3.8-7.7). Patients also experienced an overall response rate (ORR) of 34.1% (95% CI, 20.1%-50.6%) and a disease control rate of 90.2% (95% CI, 76.9%-97.3%).
In an interview with OncLive®, Orloff detailed current challenges associated with the management of metastatic uveal melanoma, the rationale for investigating the combination of darovasertib and crizotinib in the frontline setting for this patient population, and the implications of the data from OptimUM-01.
Orloff is an assistant professor and the Alexander & Johnston Family Endowed Clinical Director in Uveal Melanoma at Thomas Jefferson University in Philadelphia, Pennsylvania.
Orloff: Over just the last few years, fortunately, there have been a lot of new options for patients with metastatic uveal melanoma. The one unfortunate thing is our first FDA-approved systemic therapy—tebentafusp [Kimmtrak]—is restricted [to patients with HLA-A*02:01–positive disease]. To have a drug that finally shows some activity in the disease [is good], but it's only really an option for probably less than half the population. A huge unmet need [remains] for all the patients who are not eligible for tebentafusp.
We had our second FDA-approved therapy specifically for uveal melanoma, that being percutaneous hepatic perfusion [Hepzato], which is a liver-directed therapy. However, there are also restrictions and boundaries to that treatment. [Patients need to have] liver-only or liver-dominant [disease], but it can't be too much liver tumor—it has to be less than 50%. Patients have to be fit enough for the treatment, and they need to be able to get to a center that does the treatment. Again, we have another therapy, but it's not necessarily a therapy for everyone, and it only treats the liver. It doesn't really do anything for tumors outside the liver.
There are other therapy options, [including] other liver-directed therapies that maybe aren't officially FDA approved for uveal melanoma, but we use them anyway, things like immuno-embolization, chemoembolization, Y-90, and then other immunotherapies, such as ibulumab [Yervoy] and nivolumab [Opdivo].
For being a rare disease, we actually know quite a bit about uveal melanoma molecularly and the genetics of it. It turns out that there's a hallmark mutation that drives most uveal melanomas, and that's the driver mutation in GNAQ and GNA11. Depending on what you read, [these mutations] are present in approximately 80% to 90% of all uveal melanomas. There can be other mutations, but GNAQ and GNA11 are the main mutations that drive uveal melanoma. This is at the very top of the MAPK cell-signaling pathway, and this pathway is not unique to uveal melanoma. In cutaneous melanoma, BRAF [mutations are] tucked in there, and we know that targeting these driver mutations in cancer with inhibitors can impact disease, cause tumor shrinkage, and improve patient outcomes. So
Ideally, we would have a GNAQ and GN11 inhibitor, but that's tricky. There has not been a safe and efficacious GNAQ/GNA11 inhibitor that we can use in uveal melanoma. Therefore, a lot of the efforts have now been looking at targeting things downstream from [GNAQ/GNA11], such as MEK. There have been other attempts to block other things in the pathway, and there have actually been other attempts to block PKC. PKC is a bit downstream from GNAQ and GNA11. However, it turns out darovasertib seems to be safer and more effective than previous [PKC inhibitors].
Darovasertib is a PKC inhibitor. We had actually been testing it as a single agent for quite a while before combining it with crizotinib, and when we used it alone, there were some patients who had some nice benefit. [It was] mostly stable disease, but durable stable disease. Anytime you start trying to target things in the MAPK pathway, there's always this thought of, 'What if I block 2 things or 3 things?' It turns out, when you start blocking more than 2 things, you see lots of adverse effects. Therefore, if you are going to try to start blocking 2 things, you need to try to understand makes sense as the best partner.
Early on in this trial, darovasertib was being combined with either crizotinib, and we tried to combine it with binimetinib [Mektovi], which is a MEK inhibitor that's approved in cutaneous melanoma. It turned out—and there were some preclinical data that showed this—that there is secondary up-regulation of MET [with the use of darovasertib], so coming in with a drug that could potentially inhibit that, like crizotinib, makes sense.
For a long time, and even still now, certainly when patients are first diagnosed, they'll go on the internet and search [for uveal melanoma]. Historically, and honestly, what still sometimes sits on the internet, is a historic OS of a few months once patients are diagnosed with metastatic uveal melanoma, specifically to the liver. Up until the more modern treatment approaches, such as liver-directed therapy, being used, and certainly patients getting MRIs to detect smaller tumors, a median OS of less than 6 months was probably what it was [previously]. In the more modern era, with patients getting MRIs every 3 months after their eye is diagnosed, us picking up small tumors, and patients getting access to a variety of different treatments—albeit, not all of them extremely effective—I would say median OS has been improving, despite what the internet continues to say.
However, looking at the trials that got tebentafusp approved or other liver-directed therapies, a median OS of about 2 years should be our new benchmark. The median OS here is [was 22.1 months], and [pushing beyond 2 years] is definitely our goal right now. Hopefully we can go beyond that [2-year mark], and it may be [darovasertib] that takes us out that far. Then you could [potentially] sequence it with another treatment that might get a patient another 12 or 24 months, and so on.
When we're looking at drugs for uveal melanoma, the thing that we've been lacking— certainly with systemic therapy—is ORR. We will see patients where we need shrinkage of tumor. it's one thing if we can stabilize some patients for a while, but if they have bulky tumor or decent tumor burden, we are looking for an overall response. I used to say that when we were really lacking effective therapies in uveal melanoma, stable disease was the goal. We have another number of treatments now under our belt where we can get stable disease, and we got greedy. Now we want overall response. I want to be able to shrink tumors in patients, and what we're starting to see with this drug combination is a response rate.
We used to see ORRs in the single digits, certainly with systemic therapy. Even with tebentafusp, where we know there is an OS benefit, ORR is in the single digits to, very low double digits, depending on what trials and what real-world evidence you look at. [With darovasertib plus criztonib], we're seeing ORRs that are triple [the ORRs of other approaches], which is impressive for a drug that is not HLA restricted. This drug is potentially for everyone, regardless of whether tumors are inside or outside the liver.
Anytime you start with therapies targeting that MAPK pathway, we think of AEs like nausea, vomiting, and diarrhea. This drug combination has a bit more of a unique AE profile of swelling and edema, which may be related to hypoalbuminemia, so this needs to be managed a bit differently. If we look at other drugs in the space right now that are being used in uveal melanoma, tebentafusp and immune checkpoint inhibitors have their own AE profile, and then liver-directed therapy has its own AE profile, [With darovasertib plus criztonib], we have our first taste of a drug in the space that's more of your typical cancer treatment with general cancer treatment–related toxicities, including nausea, vomiting, diarrhea. For providers who treat a lot of uveal melanoma, these aren't necessarily AEs that we've had to deal with in our patients with uveal melanoma per se, but these AEs are certainly not unique because we see this with other targeted therapies and chemotherapies. Nothing unexpected [occurred regarding safety], but these AEs are going to be something that we're going to need to have to manage in these patients because it's a pill that they take every day.
There is an ongoing randomized [phase 2/3] trial [NCT05987332] looking at the combination of darovasertib and crizotinib vs [immunotherapy] in patients who are HLA-A*02:01–negative, and if that trial is positive, then we will have another systemic therapy option for our patients. There are a number of patients who've been who are HLA-A*02:01–positive who also received this treatment, not necessarily on that phase 3 trial, but in other cohorts of the previous trial. There is potential that we'll get approval in both HLA types, and we would have another systemic therapy that would be an option for all patients. That's potentially where this is headed. We'll have to see how it does in that [phase 3] trial.
It's exciting for patients because just over the last number of years, there has been a lot more interest in the [uveal melanoma] space with a lot more drugs under development. With every drug that kind of crosses the finish line, it just paves the way for us to keep doing better.
Related Content:
