Treatment with tebentafusp (IMCgp100), a novel bispecific T-cell receptor (TCR) fusion protein, extended survival in patients with metastatic uveal melanoma, according to the results from a recent phase 3 trial.
“Tebentafusp achieved a highly significant and clinically meaningful improvement in overall survival as first-line treatment of metastatic uveal melanoma. This is the first investigational therapy in a phase 3 trial to improve overall survival in uveal melanoma. The survival benefit was seen even in patients without a RECIST objective response,” said lead investigator Jessica Hassel, MD, Attending and Section Head, Dermato-Oncology, Dermatology Clinic, National Center for Tumor Diseases, Heidelberg University Hospital, Germany, during a presentation at the 2021 virtual American Association for Cancer Research annual meeting.
“Tebentafusp has the potential to be practice-changing, as it is the first therapy to demonstrate an overall survival benefit in metastatic uveal melanoma,” she said.
Tebentafusp recognizes 2 targets: gp100 (melanocytic protein present in melanoma cells) and a target on T-cells. The TCR binding domain recognizes a specific gp100 peptide present on human leukocyte antigen (HLA)-A*02:01, restricting the use of tebentafusp to patients with this HLA type.
Uveal melanoma accounts for up to 5% of melanomas. Although it is a rare malignancy overall, it is the most common eye cancer in adults. Approximately 50% of patients with uveal melanoma will develop liver metastasis; for these patients, 1-year overall survival (OS) is approximately 52%.
“There is no standard of care for this aggressive cancer once it becomes metastatic,” Dr Hassel noted.
The phase 3 IMCgp100-202 trial enrolled 378 patients with histologically or cytologically confirmed metastatic uveal melanoma who were HLA-A*02:01–positive, and had not received previous systemic therapy in the advanced setting or previous liver-directed therapy (except surgery). Any lactate dehydrogenase level was permitted. Patients were randomized in a 2:1 ratio to tebentafusp or investigator’s choice (IC) of either pembrolizumab (Keytruda), ipilimumab (Yervoy), or dacarbazine.
The co-primary end points in the trial were OS in patients randomized to tebentafusp versus IC in the intent-to-treat population and OS in patients randomized to tebentafusp with rash during week 1 versus IC. Key secondary end points included objective response rate and progression-free survival (PFS) per investigator assessment.
At 14-month follow-up, median OS was almost 22 months for tebentafusp versus 16 months for IC, representing a significant 49% reduction in the relative risk for death (P <.001). The 1-year survival rate was 73.2% for patients in the tebentafusp arm versus 57.5% for those in the IC arm.
The OS benefit of tebentafusp was observed in all subgroups, independent of age, sex, or geographic region.
In a subgroup analysis directly comparing the tebentafusp arm with the pembrolizumab arm, a similar magnitude of benefit was observed as in the overall trial (49% reduction in relative risk for death).
Although the difference in PFS between the 2 treatment arms was statistically significant, the magnitude of benefit was less robust than for OS.
Response rates did not explain the survival benefit. Objective response rate according to RECIST criteria was 9% in the tebentafusp arm versus 5% in the IC arm. However, the disease control rate at 12 weeks was notably higher with tebentafusp (46% vs 27%, respectively).
“Tebentafusp leads to an overall survival benefit even in patients not responding to treatment. The benefit is in slowing down progression, not achieving response. However, patients who have tumor shrinkage survive longer,” Dr Hassel said.
Treatment-related adverse events were reported in all patients (45% had severe grade treatment-related adverse events). Adverse reactions were mainly cytokine-mediated or skin-related; 2 patients developed severe cytokine release syndrome, but both continued therapy. The rate of treatment discontinuation was 2% in the tebentafusp arm versus 4% in the IC arm. No treatment-related deaths were reported.
“Most adverse events [with tebentafusp] occurred within the first cycles, and subsequently decreased in frequency and severity. Generally, the drug was then very well-tolerated,” said Dr Hassel. “That’s why tebentafusp is given in a dose-escalating fashion.”