Phase I Study of Safety, Tolerability, and Efficacy of Tebentafusp Using a Step-Up Dosing Regimen and Expansion in Patients With Metastatic Uveal Melanoma.

Abstract

PURPOSE:

This phase I study aimed to define the recommended phase II dose (RP2D) of tebentafusp, a first-in-class T-cell receptor/anti-CD3 bispecific protein, using a three-week step-up dosing regimen, and to assess its safety, pharmacokinetics, pharmacodynamics, and preliminary clinical activity in patients with metastatic uveal melanoma (mUM).

METHODS:

In this open-label, international, phase I/II study, HLA-A*02 or HLA-A*02:01+ patients with mUM received tebentafusp 20 μg once in week 1 and 30 μg once in week 2. Dose escalation (starting at 54 μg) began at week 3 in a standard 3 + 3 design to define RP2D. Expansion-phase patients were treated at the RP2D (20-30-68 μg). Blood and tumor samples were collected for pharmacokinetics/pharmacodynamics assessment, and treatment efficacy was evaluated for all patients with baseline efficacy data as of December 2017.

RESULTS:

Between March 2016 and December 2017, 42 eligible patients who failed a median of two previous treatments were enrolled: 19 in the dose escalation cohort and 23 in an initial dose expansion cohort. Of the dose levels investigated, 68 μg was identified as the RP2D. Most frequent treatment-emergent adverse events regardless of attribution were pyrexia (91%), rash (83%), pruritus (83%), nausea (74%), fatigue (71%), and chills (69%). Toxicity attenuated following the first three doses. The overall response rate was 11.9% (95% CI, 4.0 to 25.6). With a median follow-up of 32.4 months, median overall survival was 25.5 months (range, 0.89-31.1 months) and 1-year overall survival rate was 67%. Treatment was associated with increased tumor T-cell infiltration and transient increases in serum inflammatory mediators.

CONCLUSION:

Using a step-up dosing regimen of tebentafusp allowed a 36% increase in the RP2D compared with weekly fixed dosing, with a manageable side-effect profile and a signal of efficacy in mUM.

• Authors: Richard D Carvajal, Paul Nathan, Joseph J Sacco, Marlana Orloff, Leonel F Hernandez-Aya, Jessica Yang, Jason J Luke, Marcus O Butler, Sarah Stanhope, Laura Collins, Cheryl McAlpine, Chris Holland, Shaad E Abdullah, Takami Sato
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 40 Issue 17 Pg. 1939-1948 (06 10 2022) ISSN: 1527-7755 [Electronic] United States
• PMID: 35254876 (Publication Type: Clinical Trial, Phase I, Clinical Trial, Phase II, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• HLA-A Antigens
• Immunoconjugates
• Receptors, Antigen, T-Cell
• Recombinant Fusion Proteins
• tebentafusp

Topics

• HLA-A Antigens (therapeutic use)
• Humans
• Immunoconjugates (therapeutic use)
• Melanoma (pathology)
• Neoplasms, Second Primary (drug therapy)
• Receptors, Antigen, T-Cell (therapeutic use)
• Recombinant Fusion Proteins
• Uveal Neoplasms (drug therapy)