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Practice-Changing Results in Metastatic Uveal Melanoma

— Bispecific T cell-engaging tebentafusp reduces survival hazard by 50%

MedpageToday

A novel bispecific protein significantly improved overall survival (OS) in metastatic uveal melanoma as compared with investigator's choice of treatment, including checkpoint inhibitors, a randomized trial showed.

Patients treated with tebentafusp had a median OS of 21.7 months versus 16.0 months for the control group. The benefit was consistent across all prespecified subgroups.

Grade 3/4 treatment-related adverse events (TRAEs) occurred infrequently, including a 1% incidence of severe cytokine release syndrome (CRS), reported Jessica C. Hassel, MD, of University Hospital Heidelberg in Germany, at the American Association for Cancer Research (AACR) virtual meeting.

"Tebentafusp showed a highly significant and clinically meaningful improvement in overall survival as first-line treatment of metastatic uveal melanoma," she said. "It is the first investigational therapy in a phase III trial to improve overall survival in metastatic uveal melanoma, and this overall survival benefit was seen even in patients without RECIST objective response."

"We found a predictable and manageable adverse event profile which was consistent with the mechanism of action of tebentafusp, plus a low rate of related discontinuation and no treatment-related deaths," she stated. "Therefore, tebentafusp has the potential to be practice changing in uveal melanoma. It is the first TCR (T-cell receptor) therapeutic to demonstrate an overall survival benefit."

The trial produced several firsts that made a case for practice-changing potential, said AACR President Antoni Ribas, MD, PhD, of the University of California Los Angeles.

"It's the first-ever clinical trial improving overall survival in patients with uveal melanoma," Ribas said during an AACR press briefing. "It's the first TCR therapeutic that has been successfully developed, and it's the first therapeutic targeting melanocytes to show an improvement in a randomized trial. It's a practice-changing study, and we ought to be able to use this in practice."

A rare malignancy associated with low tumor mutational burden, uveal melanoma has not had standard of care in the metastatic setting, and metastatic disease has a poor prognosis, including 12-month survival of about 50%, said Hassel. Malignant cells frequently express the melanocytic protein gp100. Tebentafusp comprises a soluble TCR fused to an anti-CD3 antibody that binds and activates T cells independent of TCR specificity and redirects T cells to gp100-expressing cells.

Hassel reported the primary findings from a phase III randomized trial involving patients with untreated metastatic uveal melanoma. Eligible patients who were HLA-A*0201-positive were randomized 2:1 to tebentafusp or investigator's choice of pembrolizumab (Keytruda), ipilimumab (Yervoy), or dacarbazine. The primary endpoint was OS in all randomized patients. Secondary endpoints included investigator-assessed objective response rate (ORR) and progression-free survival (PFS).

Data analysis included 348 patients. After a median follow-up of 14.1 months, the 5.7-month absolute difference in OS translated into a 49% reduction in the survival hazard in favor of tebentafusp (95% CI 0.37-0.71, P<0.0001). The 1-year OS was 73.2% in the tebentafusp arm and 58.5% in the control group.

The most common cytokine-mediated TRAEs in tebentafusp-treated patients were CRS (89%), pyrexia (76%), chills (47%), nausea (43%), fatigue (41%), vomiting (26%) and headache (22%). Skin-related TRAEs included rash (83%), pruritus (69%), dry skin (29%), and erythema (23%). The most frequently reported grade 3/4 TRAEs were rash (18%) and pruritus (5%). No other grade 3/4 TRAEs occurred in more than 4% of patients.

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    Charles Bankhead is senior editor for oncology and also covers urology, dermatology, and ophthalmology. He joined ľֱ in 2007.

Disclosures

The study was supported by Immunocore.

Hassel disclosed relevant relationships with Pierre Fabre, Sanofi, Sun Pharma, Merck, Immunocore, Bristol Myers Squibb, Novartis, Roche, Novartis, BioNTech, Regeneron, Genentech, 4SC, Philogen, Pfizer, and Almirall.

Primary Source

American Association for Cancer Researech

Hassel J, et al "Phase III randomized trial comparing tebentafusp with investigator's choice in first-line uveal melanoma" AACR 2021; Abstract CT002.