Dr. Alexander Shoushtari Discusses Five-Year Kimmtrak Data and the Future of TCR Therapy in Metastatic Uveal Melanoma

In an interview with BioPharm International^©, melanoma oncologist and cellular therapist Dr. Alexander Shoushtari of Memorial Sloan Kettering Cancer Center discussed what the latest data mean for patient care, the growing importance of circulating tumor DNA monitoring, and how Kimmtrak is reshaping expectations for immunotherapy in metastatic uveal melanoma.

What stands out most to you about the five-year survival data from the Kimmtrak trial?

I think the most important thing is that with mature follow-up—which in oncology, five years for this disease is a very meaningful time point—we’re still seeing a consistent survival benefit with tebentafusp compared with what was previously available.

The exact numbers are not a reason for everyone to retire and say the job is done. Unfortunately, many patients still die from this disease. But the benefit has clearly been maintained over time, and at this point, the data are unlikely to change significantly.

What’s important is that clinicians can now tell patients there is realistic hope to live five years or longer with the tools we currently have available. Historically, metastatic uveal melanoma carried an almost universally grim outlook. Once the disease spread, particularly to the liver, there was often a sense that nothing meaningful could be done.

I’ve had patients tell me their physicians didn’t even strongly recommend surveillance for recurrence because there was a belief that knowing earlier would not change the outcome. I think this trial strongly pushes back against that kind of thinking.

There is something you can do about it. You can tell a patient in the clinic that there’s realistic hope to live five years and more with the tools we have available in our hands.

How significant is this trial from a broader oncology perspective?

It’s significant for several reasons. First, this is the longest prospective Phase 3 randomized trial to report five-year overall survival data in metastatic uveal melanoma. It’s also the longest follow-up reported for a T-cell engager in a solid tumor.

In oncology, we’ve seen situations where early survival advantages disappear over time. Sometimes later disease progression or treatment effects erase the initial benefit. What’s reassuring here is that we are not seeing that happen.

This trial confirms that the survival improvement seen earlier at one year and three years continues to hold up with longer follow-up.

For me, that cements tebentafusp as the preferred treatment option for patients with the HLA-A*02:01 allele, assuming they are otherwise appropriate candidates for therapy.

The trial showed durable benefit even among higher-risk patients. What does that suggest about the broader potential of TCR therapies in solid tumors?

I think it reinforces the idea that precision matters in immunotherapy. For many years, uveal melanoma was often described as a cancer where immunotherapy “doesn’t work.” It was frequently contrasted with cutaneous melanoma, where checkpoint inhibitors transformed outcomes.

What this study shows is that immunotherapy is not one-size-fits-all. Different immune-based tools work differently depending on the biology of the disease and the targets available.

With tebentafusp, you have a therapy specifically designed to engage T cells against GP100-expressing tumor cells in a selected patient population. That level of precision matters.

I think what this trial has really shown is that you have to get more precise as a scientist, and you have to be more aware as a physician that different tools now exist to manipulate the body’s immune system to fight cancer.

The data also showed a consistent trend favoring tebentafusp across multiple patient subgroups, including those with elevated LDH or other high-risk features. While subgroup analyses are never definitive on their own, seeing that consistency strengthens confidence in recommending the therapy for a broad range of eligible patients.

One of the more surprising findings involved patients who appeared to benefit despite initial disease progression. How should clinicians interpret that?

This is one of the most interesting and counterintuitive aspects of the trial.

Traditionally, when you perform a scan after starting treatment and see tumors enlarging, that’s considered bad news. In melanoma and most cancers, imaging has historically been the gold standard for determining whether treatment is working.

Checkpoint inhibitors introduced the concept of pseudo-progression, where tumors can initially appear larger before stabilizing or shrinking. We don’t see that very often, but it happens enough that clinicians are aware of it.

With tebentafusp, there may be something similar happening, but potentially through somewhat different mechanisms.

Among patients whose first scans showed progressive disease, some still appeared to derive benefit if treatment was continued. When investigators compared outcomes between patients continuing tebentafusp and those continuing checkpoint inhibitors despite progression, the tebentafusp group still showed a substantially lower risk of death.

That tells us there may be more happening biologically than simply “bigger tumors equal treatment failure.”

Sometimes tumors may enlarge because of immune-cell infiltration or inflammatory activity—a kind of immune “tug of war” occurring inside the tumor microenvironment.

The challenge now is figuring out which patients are experiencing meaningful immune-related changes and which patients truly have progressing disease.

ctDNA emerged as an important biomarker in the study. How could that influence future treatment decisions?

Circulating tumor DNA, or ctDNA, is becoming increasingly important because it may help us better understand whether treatment is actually benefiting a patient when imaging alone is unclear.

The study showed that patients whose ctDNA levels dropped significantly—or became undetectable—often experienced better outcomes, even in some cases where scans initially looked worse.

That’s potentially very valuable clinically.

If you have a little bit of growth on your scan, but the patient feels well, circulating tumor DNA measurements can be helpful.

We still need more data, and not every oncologist interprets ctDNA the same way yet. The trial was not specifically designed to definitively prove ctDNA is superior to imaging. But the findings strongly suggest it can provide important additional information.

Right now, many clinicians are beginning to think about ctDNA as part of a broader decision-making process that includes imaging, physical examination, symptoms, and overall clinical status.

In diseases like metastatic uveal melanoma, where treatment options remain limited, those additional layers of information can be especially important.

What does this mean for the future of metastatic uveal melanoma research?

Philosophically, I think this trial helps remove some of the pessimism that historically surrounded this disease.

Ten or fifteen years ago, many people believed immunotherapy simply would not work in uveal melanoma. There was a real sense of therapeutic nihilism because checkpoint inhibitors did not deliver the same kind of dramatic responses seen in cutaneous melanoma.

This trial changes that conversation.

It shows that if you identify the right target and develop the right immune-based approach, you can absolutely generate meaningful and durable benefit in this disease.

There was this kind of depression and gloom that I think this drug has really helped partially lift.

That matters not only for patients, but also for researchers, clinicians, and drug developers working in the space.

When a therapy demonstrates durable survival benefit, it creates momentum. It encourages additional research, combination strategies, biomarker development, and next-generation immunotherapy approaches.

It also reinforces the idea that rare cancers deserve innovative clinical investigation rather than being dismissed because prior approaches were unsuccessful.

Looking ahead, how do you see these findings shaping the standard of care?

I think these five-year data solidify tebentafusp as the standard first-line treatment for HLA-A*02:01-positive metastatic uveal melanoma patients whenever appropriate.

The longer follow-up is important because it confirms the benefit is durable and not simply an early statistical effect that disappears over time.

But beyond standard of care, I think the study also broadens how we think about immunotherapy in solid tumors more generally.

It reminds us that immune-based therapies are becoming increasingly sophisticated. We’re moving beyond simplistic ideas of “hot” versus “cold” tumors and learning that precision targeting, immune engagement strategies, biomarkers, and disease biology all matter enormously.

For patients with metastatic uveal melanoma, perhaps the most important takeaway is that survival expectations are beginning to change.

For a disease that historically offered very little hope, that’s an important step forward.