First-line tebentafusp may extend OS in HLA-A*02:01-positive metastatic uveal melanoma

15 May 2021 bởiRoshini Claire Anthony
First-line tebentafusp may extend OS in HLA-A*02:01-positive metastatic uveal melanoma

First-line treatment with the bispecific fusion protein tebentafusp demonstrated an overall survival (OS) benefit in patients with human leukocyte antigen (HLA)-A*02:01-positive metastatic uveal melanoma (mUM), according to a phase III, open-label trial presented at AACR 2021.

“Tebentafusp showed a highly significant and clinically meaningful improvement in OS as first-line treatment of mUM,” said Associate Professor Jessica Hassel from the University Hospital Heidelberg, Heidelberg, Germany. It is the first investigational therapy to show this benefit, she added.

Study participants were 378 previously untreated HLA-A*02:01+ individuals with mUM and ECOG performance status 0–1. They were randomized 2:1 to receive either tebentafusp (n=252; median age 64 years, 51 percent male) or investigator’s choice of either pembrolizumab (n=103), ipilimumab (n=15), or dacarbazine (n=7; median age 66 years, 49 percent male). Median time since diagnosis was 3.0 and 2.4 years in the tebentafusp and investigator’s treatment groups, respectively.

Patients were followed up for a median 14.1 months. The risk of death in the intention-to-treat population was almost halved among patients in the tebentafusp compared with investigator’s treatment group (median 21.7 vs 16.0 months; hazard ratio [HR], 0.51, 95 percent confidence interval, 0.37–0.71; p<0.0001). The estimated 1-year OS rate was 73.2 and 58.5 percent in the tebentafusp and investigator’s treatment groups, respectively. [AACR 2021, abstract CT002]

The OS benefit was apparent in multiple subgroups analysed including age, sex, region, and investigator’s treatment type.

At a median follow-up of 11.4 months, progression-free survival (PFS) was significantly improved with tebentafusp vs investigator’s treatment, though to a lesser extent than the OS benefit (median 3.3 vs 2.9 months; HRstratified, 0.73, 95 percent CI, 0.58–0.94; p=0.0139).

Overall response rate in the tebentafusp vs investigator’s treatment group was 9 percent vs 5 percent, with one tebentafusp recipient having a complete response vs none in the investigator’s treatment group, and 22 vs six having a partial response.

Disease control rate for ≥12 weeks was greater in the tebentafusp vs investigator’s treatment group (46 percent vs 27 percent). Thirty-seven and 22 percent, respectively, had stable disease, while 52 and 62 percent had progressive disease.

“Response and PFS were not as good as the OS benefit,” Hassel pointed out.

This led to a landmark OS analysis limited to patients with RECIST best response of progressive disease at 100 days which also showed an OS benefit with tebentafusp vs investigator’s choice (HR, 0.4).

Adverse events (AEs) were more common in tebentafusp vs investigator’s treatment recipients (99.6 percent vs 82 percent), as were grade 3–4 AEs (45 percent vs 17 percent). The AEs in the tebentafusp group were consistent with the proposed mechanism of action of the drug and were generally cytokine- or skin-mediated, with common any grade AEs including cytokine release syndrome, rash, pyrexia, and pruritus. There were no treatment-related deaths.

Most AEs occurred in the first few weeks and were generally manageable, and discontinuations were more common in the investigator’s treatment than tebentafusp group (4.5 percent vs 2 percent).

Twenty-nine percent of patients in the tebentafusp group and 9 percent in the investigator’s choice of treatment group remain on treatment, and 33 percent of each group are still being followed up for survival outcomes.

 

A new treatment?

“Even though uveal melanoma is rare overall, it is the most common eye cancer in adults, and represents approximately 3–5 percent of all melanomas,” said Hassel. “Prognosis for uveal melanoma is very poor with a median survival after metastasis of <1 year.”

“As there are currently no standard treatments for patients with mUM, tebentafusp has the potential to become a practice-changing therapy for patients with this disease,” she said.

Hassel noted that tebentafusp is only suitable for patients who are HLA-A*02:01+, though this HLA type is present in about 50 percent of Caucasians. “There still remains an unmet need for patients who do not have this particular surface protein,” she said.