Tebentafusp Shows Significant OS Benefit in Advanced Uveal Melanoma

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; P < .001).

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.

TRANSCRIPTION:

0:08 | 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.

1:00 | 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.