Richard D. Carvajal, MD

Richard D. Carvajal, MD, director of experimental therapeutics and director of melanoma service at Columbia University Medical Center, discusses the mechanism of action and efficacy of tebentafusp-tebn (Kimmtrak) for patients with uveal melanoma.

Uveal melanoma is a rare disease with few effective treatment options. According to Carvajal, tebentafusp is a bispecific agent that binds to the GP-100 antigen and CD3-positive cells in patients who have human leucocyte antigen (HLA)-A*0201–positive disease, causing T cells to destroy cancer cells.

The phase 2 IMCgp100-202 trial (NCT03070392) randomized 378 previously untreated patients 2:1 to receive tebentafusp or investigator’s choice, which was most commonly pembrolizumab (Keytruda). The median OS for patients in the tebentafusp arm was 21.7 months (95% CI, 18.6-28.6) and 16.0 months (95% CI, 9.7-18.4) for the control arm. The rate of 1-year overall survival (OS) was 73% versus 59% in the control arm with a hazard ratio of 0.51 in the intent-to-treat population (95% CI, 0.37 to 0.71; 

Another phase 2 trial (NCT02570308) showed that tebentafusp also had clinical activity in previously treated patients with metastatic uveal melanoma. Based on the IMCgp100-202 trial, tebentafusp was approved by the FDA in January 2022 for patients with unresectable or metastatic uveal melanoma.

 Tebentafusp is a bispecific agent. [There are] 2 ends. One end is an optimized T-cell receptor, it binds very strongly to something called GP-100, a melanoma-associated antigen. It binds with very, very high affinity in an HLA-restricted fashion, which means that this drug is only going to work in the subset of patients who are HLA-A*0201 positive, [which] makes up about 40% to 50% of Caucasian [patients]. The other end binds to CD3-positive cells.

So 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 bring in, in a polyclonal fashion, the T cells in that area. And just by bringing the T-cell to the tumor cell in proximity, that’s enough to kill the cancer cell.

 And so there have been 2 trials now. One [was] a trial for patients who had been previously treated with something else for uveal melanoma, and then, really, the pivotal trial was a randomized trial. It randomized patients on a 2:1 ratio to either to tebentafusp or investigator’s choice. The majority of those patients got pembrolizumab [Keytruda].

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

Videos

Richard D. Carvajal, MD, discusses the mechanism of action and efficacy of tebentafusp-tebn for patients with uveal melanoma.


Tebentafusp Shows Significant OS Benefit in Advanced Uveal Melanoma

Richard D. Carvajal, MD, the director of Experimental Therapeutics and director of Melanoma Service at the Columbia University Medical Center, discusses 2 therapies in clinical trials registering patients with melanoma.

The first drug Carvajal talks about is called IDE196, and the other is called IMCgp100 or tebentafusp. IDE196 is a PKC inhibitor previously named LXS196, and it targets both a conventional and novel forms of PKC. In a previous clinical trial, a cohort of about 30 patients receiving this treatment on a twice daily schedule, the response rate was fairly modest; about a quarter of the patients were doing well after a year or more. He says this is fairly remarkable for this setting. IDE196 is now under evaluation in another clinical trial which will be trying to replicate or exceed these findings (NCT03947385).

IMCgp100 is a bispecific immunotherapy agent which targets TP100 in an HLA-restricted fashion; it also binds to CD3 and brings the CD3 cells in proximity with the tumor cells, according to Carvajal. The phase I trial investigating this drug recruited patients with HLA A2-positive malignant melanoma (NCT01211262). In previous trials, there has been a modest response rate, and over 70% of patients were alive at 1 year. He says compared to past control studies, this was much better.

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Richard D. Carvajal, MD, discusses 2 therapies in clinical trials registering patients with melanoma.

Early Trials in Melanoma Show Better Response After 1 Year

Richard D. Carvajal, MD, medical oncologist, Memorial Sloan-Kettering Cancer Center, describes the design of a phase II study of selumetinib versus temozolomide in gnaq/Gna11 mutant uveal melanoma.

It is challenging to conduct definitive trials in rare diseases, Carvajal says, and a lot of thought went into this trial's design. The trial design required the accrual of 80 patients and allowed 120 patients with the mutation. Over the course of three years, 98 patients were accrued across 15 sites.

The primary endpoint of the trial was progression-free survival (PFS). Final data showed that PFS doubled: 7 weeks with chemotherapy compared with 15.9 weeks with selumetinib (hazard ratio = 0.46).

There was also an increased response rate in patients treated with selumetinib, demonstrating biologic activity. Carvajal notes that about half of the patients treated with the drug experienced tumor shrinkage and 7 patients experienced major tumor shrinkage. In the context of the history of trials in this disease, response rates over 5% are very rare, Carvajal says.

This trial accrued 98 patients across 15 sites

PFS doubled with selumetinib vs chemotherapy

Selumetinib increased response rate, demonstrating biologic activity with the drug

Richard D. Carvajal, MD, describes the design of a phase II study of selumetinib versus temozolomide in gnaq/Gna11 mutant uveal melanoma.

The Design of a Trial Analyzing Selumetinib in Advanced Uveal Melanoma

Richard D. Carvajal, MD, medical oncologist, Memorial Sloan-Kettering Cancer Center, describes the use of selumetinib in patients with advanced uveal melanoma.

The trial exploring selumetinib was the first ever to find an agent that demonstrated efficacy for patients with advanced uveal melanoma. Even though trametinib (another MEK inhibitor) was recently approved, Carvajal says that clinical trials are still the most appropriate area for treatment with MEK inhibitors in uveal melanoma.

The trial exploring selumetinib was the first ever to find an agent that demonstrated efficacy for patients with advanced uveal melanoma

Clinical trials are still the most appropriate area for treatment with MEK inhibitors in this disease type

View all coverage from the 2013 ASCO Meeting

Richard D. Carvajal, MD | Authors

Articles

Tebentafusp Shows Significant OS Benefit in Advanced Uveal Melanoma

Early Trials in Melanoma Show Better Response After 1 Year

The Design of a Trial Analyzing Selumetinib in Advanced Uveal Melanoma

Using Selumetinib in Advanced Uveal Melanoma