Tebentafusp Represents a Potential Frontline Therapy for Patients with Uveal Melanoma

Richard D. Carvajal, MD

In findings from a recent phase 3 clinical trial (NCT03070392), the novel bispecific fusion protein tebentafusp (IMCgp100) showed statistically significant improvements in overall survival for patients with uveal melanoma, according to Richard D. Carvajal, MD.

Carvajal added that the treatment paradigm for patients with uveal and other rare, non-cutaneous melanomas has remained stagnant. However, he said the PDUFA date for tebentafusp is February, and the drug’s approval could provide a big benefit in an area where there have been few effective, FDA-approved therapies.

“We're anticipating approval hopefully very soon,” Carvajal said. “Once that's approved, this should be the standard frontline therapy for either untreated or previously treated patients who are HLA-A0201 positive.”

In an interview with OncLive®, Carvajal, the coleader of Precision Oncology and Systems Biology Program, director of Experimental Therapeutics, and director of Melanoma Service at Columbia University Medical Center, discussed the need for additional treatment options in patients with rare melanomas, the promise of tebentafusp, and ongoing trials in the pipeline for this patient population.

OncLive®: What is some of the progress that has been made in the treatment of rare melanomas?

Carvajal: Although there’s been dramatic progress in our ability to treat and cure cutaneous melanoma, our management of uncommon subsets of melanoma has just lagged. When we think of melanoma, it’s a skin cancer, and that’s true for most cases, but there are rarer types of melanomas that arise from non-cutaneous sites. These are things like mucosal melanomas, melanomas that arise from the mouth, the sinuses, the rectal area, [or] the vaginal area. Another extra cutaneous melanoma is something called uveal melanoma, which arises from lanocytes in the eye, and a lot of people don't know these things exist.

If you look back over the past couple of decades, there have been several approvals of checkpoint inhibitors and targeted therapies for melanoma, but they've really been tested and proven in skin melanoma. When you look at the efficacy of [nivolumab (Opdivo) and ipilimumab (Yervoy)] in cutaneous melanoma, our median survival is 72 months. It was not that 20 years ago.

Unfortunately, outcomes for mucosal melanoma and uveal melanoma have really lagged. For mucosal melanoma, the median survivals that we're seeing now are certainly under 2 years, even with aggressive immunotherapy or targeted therapies. For uveal melanoma, historically, it's been a median survival of about a year, despite what we've been able to do for cutaneous disease.

Have there been any trials in the space pivotal in moving the needle forward?

It’s crazy to think it’s 2021 and we’ve diseases that we see for which there’s no effective therapy, no FDA-approved therapy. That’s the case for where we are now with uveal melanoma. And that’s despite the conduct of several trials of chemotherapy, regional therapies, [and] targeted therapies. But we do have an agent for uveal [melanoma] that will be approved soon, and that’s a drug called tebentafusp.

This is the one practice-changing finding that is important to be shared more broadly. Tebentafusp is a bispecific agent. [There are] 2 ends. One end is an optimized T-cell receptor that binds very strongly to GP-100, a melanoma-associated antigen. It binds with very high affinity in an HLA-restricted fashion, meaning that this drug is only going to work in the subset of patients who are HLA-A0201 positive, which makes up about 40-50% of Caucasians. The other end binds to CD3-positive cells.

What you can think of this drug doing, it hones and binds very tightly to the tumor cell—in this case, uveal melanoma—and then [in a polyclonal fashion], brings in the T-cells in that area. Just by bringing the T-cell to the tumor cell in proximity, that’s enough to kill the cancer cell.

There have been 2 trials now. One was a trial for patients who had been previously treated with something else for uveal melanoma, but the pivotal trial was the [phase 3] randomized trial [NCT03070392]. It randomized patients on a 2:1 ratio to either to tebentafusp or investigator’s choice. Most patients got pembrolizumab [Keytruda].

That randomized trial showed a significant improvement in overall survival. The median was almost 22 months for patients treated with tebentafusp vs around 16 months for those treated with the investigator choice. The hazard ratio for survival [was] highly statistically significant, [representing a] 49% reduction in the risk of death. Absolutely groundbreaking.

The PDUFA date for [tebentafusp] is February, so we're anticipating approval hopefully very soon. Once that's approved, this should be the standard frontline therapy for either untreated or previously treated patients who are A0201 positive.

What is the current state of care for patients when sequencing drugs?

In uveal melanoma, there is no currently available, approved, effective therapy. Even looking at the [National Comprehensive Cancer Network] (NCCN) guidelines now, frontline therapy is a clinical trial. The NCCN guidelines will also list checkpoint blockade, chemotherapy, or targeted therapy with a MEK inhibitor.

Chemotherapy and single-agent therapy with a MEK inhibitor, it does not work that much [in this patient population]. Although it is listed, and sometimes we’ll do it, but we lower that in terms of priority.

Outside of the clinical trial, many of us do checkpoint blockade. What we’ve learned from several series and single-arm trials is that with single-agent checkpoint blockade, either with CTLA-4 or PD-1/PD-L1, response rates are generally in the single digits with no meaningful signal of [progression free survival] (PFS)or [overall survival] (OS) benefit.

For combination checkpoint blockade, we have a couple of nice retrospective series in 2 single-arm prospective studies that all show consistently that the response rates are at least in the teens. Median overall survival is all over a year, so 15, 16 months or so. In my practice, if I’m going to treat outside of a clinical trial with systemic therapy, I turn to [nivolumab and ipilimumab].

The other thing to note for these patients is the recurrence is very commonly a hepatotropic disease. Recurrence typically happens in the liver. That’s where the predominance of the metastatic disease frequently is. Because of that, we can also consider doing regional therapies, so therapies directly into the liver. That’s things like radioembolization, gland embolization, hepatic infusion of chemotherapy. All of those are also reasonable options and should be considered.

What does the future of this patient population look like?

When all of us saw the phase 3 results from the tebentafusp trial, we were just [excited]. This is a patient population that had nothing before, and the future is looking bright. There are definitely gaps. Now we’ve got an effective drug, the question will be how we make it work better.

We are going to be looking at various combination strategies. Is there a role for this drug in the adjuvant setting? That’s something that must be explored. Then there’s still that patient population that is either ineligible for [tebentafusp] because they have the wrong HLA type, or for whom [tebentafusp] doesn’t work or stops working.