Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Clinical Trial
. 2024 Jun 6;12(6):e009028.
doi: 10.1136/jitc-2024-009028.

Long-term survival follow-up for tebentafusp in previously treated metastatic uveal melanoma

Joseph J Sacco  1   2 , Richard D Carvajal  3   4 , Marcus O Butler  5   6 , Alexander N Shoushtari  7 , Jessica C Hassel  8 , Alexandra Ikeguchi  9   10 , Leonel Hernandez-Aya  11 , Paul Nathan  12   13 , Omid Hamid  14 , Josep M Piulats  15   16 , Matthew Rioth  17 , Douglas B Johnson  18 , Jason J Luke  19 , Enrique Espinosa  20 , Serge Leyvraz  21 , Laura Collins  22 , Chris Holland  23 , Takami Sato  24   25
Affiliations
Clinical Trial

Long-term survival follow-up for tebentafusp in previously treated metastatic uveal melanoma

Joseph J Sacco et al. J Immunother Cancer. .

Abstract

Background: Tebentafusp, a bispecific (gp100×CD3) ImmTAC, significantly improved overall survival (OS) outcomes for HLA-A*02:01+ adult patients with untreated metastatic uveal melanoma (mUM) and showed promising survival in previously treated mUM with 1-year OS of 62% in the primary analysis of study IMCgp100-102. Here we report long-term outcomes from this phase 1/2 study in pretreated mUM.

Patients and methods: Patients with previously treated mUM received tebentafusp weekly intravenous at 20 µg dose 1, 30 µg dose 2 and either 54, 64, 68, or 73 µg (phase 1) or 68 µg (phase 2) dose 3+. The primary objective was overall response rate. Secondary objectives included OS and safety. OS was estimated by Kaplan-Meier methods. Association between OS and baseline covariates, on-treatment Response Evaluation Criteria in Solid Tumors (RECIST) response, baseline tumor biopsy and circulating-tumor DNA (ctDNA) changes were assessed.

Results: 146 patients were treated with tebentafusp: 19 in phase 1 and 127 in phase 2. With a median follow-up duration of 48.5 months, the median OS was 17.4 months (95% CI, 13.1 to 22.8), and the 1-year, 2-year, 3-year and 4-year OS rates were 62%, 40%, 23% and 14%, respectively. Improved survival was associated with lower ctDNA baseline levels and greater ctDNA reductions by week 9 on-treatment, with 100% 1-year, 73% 2-year and 45% 3-year OS rates for patients with ctDNA clearance. Baseline gp100 expression was not associated with survival, despite more RECIST responses among patients with higher expression. No new safety signals were reported with long-term dosing.

Conclusions: This study represents the longest follow-up of a Tcell receptor bispecific to date and confirms the durable survival benefits achieved with tebentafusp in previously treated mUM with good tolerability long-term. A role for ctDNA reduction as an early indicator of clinical benefit was again suggested for patients treated with tebentafusp.

Keywords: T cell receptor - TCR; bispecific T cell engager - BiTE; circulating tumor DNA - ctDNA; immunotherapy; solid tumor.

PubMed Disclaimer

Conflict of interest statement

Competing interests: JJS discloses PI on clinical trial: Amgen, AstraZeneca, Bristol-Myers Squibb, Delcath Systems, Merck, Replimune, Transgene; Research Grant/Contract: AstraZeneca, Bristol-Myers Squibb, Immunocore; Consultant/Advisory Board: Bristol-Myers Squibb, Delcath Systems, Immunocore, Merck; Congress attendance: Bristol-Myers Squibb, Merck. RDC discloses Consultant: Aura Biosciences, Castle Biosciences, Chimeron, Immunocore, InxMed, Iovance, Merck, Oncosec, Pierre Fabre Pharmaceuticals Inc., PureTech Health, Regeneron Pharmaceuticals, Rgenix, Sanofi Genzyme, Sorrento Therapeutics, TriSalus; Stock Option: Aura Biosciences, Chimeron, Rgenix. MOB discloses Consultant/Advisory Board: Adaptimmune, Bristol-Myers Squibb Canada, GlaxoSmithKline, Immunocore, Instil Bio, Iovance Biotherapeutics, Merck, Novartis, Pfizer, Sanofi Pasteur Inc., Sun Pharma, IDEAYA Bio, Medison, Regeneron and Iovance.; Safety Review Committee: GlaxoSmithKline, Adaptimmune; Research Funding: Merck, Takara Bio, Novartis. ANS discloses Grant/Contract: Bristol-Myers Squibb, Immunocore, Novartis, Targovax, Pfizer, Alkermes, Checkmate Pharmaceuticals, Foghorn Therapeutics, Linnaeus Therapeutics, Prelude Therapeutics, Iovance Biotherapeutics, Bristol-Myers Squibb, Immunocore, Novartis, Pfizer, Polaris, Xcovery. JCH discloses Speaker: Amgen, Bristol-Myers Squibb, GSK, Immunocore, Merck Sharp and Dohme, Novartis Pharma, Pierre Fabre, Sanofi-Aventis U.S. LLC; Sunpharma; Research grant/contract: Bristol-Myers Squibb, Sanofi, Sunpharma; Consultant/Advisory Board: Bristol-Myers Squibb, GSK, Immunocore, Merck Sharp and Dohme, Novartis Pharma, Pierre Fabre Pharmaceuticals Inc., Philogen, Onkowissen, Sanofi-Aventis U.S. LLC, Sun Pharmaeutical Industries Inc. AI discloses Research Funding to Institution: Dynavax, GSK/Sarah Cannon, Immunocore, Merck, Neon Therapeutics/Sarah Cannon, Checkmate Pharmaceuticals. LH-A discloses Advisory/Consulting: BMS, Castle Bioscience; Research Funding to Institution: BMS, AstraZeneca, Merck, Amgen, Roche, Regeneron, Novartis, Immunocore, Merck-EMD, Corvus, Polynoma, Genentech, Foghorn. PN discloses Data and Safety Monitoring: 4SC, Achilles; Consultant/Advisory Board: 4SC, Bristol-Myers Squibb, Immunocore, Merck, Merck Sharp and Dohme, Novartis, Pfizer; Research Grant/Contract: Immunocore. OH discloses Contract: Aduro biotech, Akeso biotech, Amgen Inc., Beigene Ltd, Bioatla, Bristol-Myers Squibb, Genentech USA, Inc., GlaxoSmithKline, Idera Pharmaceuticals, Immunocore, Incyte Corporation, Janssen Global Services, LLC, Merck, Next Cure Inc., Novartis, Pfizer, Regeneron Pharmaceuticals Inc., Sanofi, Seattle Genetics, Tempus, Zelluna Immunotherapy; Contracted Research for Institution: Aduro biotech, Akeso biotech, Amgen Inc., Arcus Biosciences, Bioatla, Bristol-Myers Squibb, CytomX Therapeutics, Exelixis Inc., Genentech, GlaxoSmithKline, Idera Pharmaceuticals, Immunocore, Incyte Corporation, Iovance Biotherapeutics, Merck, Merck Serono, Moderna, NextCure Inc., Novartis, Pfizer, Regeneron Pharmaceuticals, Sanofi Genzyme, Seattle Genetics, Torque Pharma, Zelluna Immunotherapy; Speakers Bureau: Bristol-Myers Squibb, Novartis, Pfizer. MR discloses employment and stock ownership in Syapse Inc. DBJ discloses Advisory Boards/Consultant: Bristol-Myers Squibb, Catalyst Biopharma, Iovance, Jansen, Mallinckrodt, Merck, Mosaic ImmunoEngineering, Novartis, Oncosec, Pfizer, Targovax, and Teiko; Research Funding: Bristol-Myers Squibb, Incyte. JJL discloses DSMB: AbbVie, Agenus, Amgen, Immutep, Evaxion; Scientific Advisory Board: (no stock) 7 Hills, Affivant, Bright Peak, Exo, Fstar, Inzen, RefleXion, Xilio (stock) Actym, Alphamab Oncology, Arch Oncology, Duke Street Bio, Kanaph, Mavu, NeoTx, Onc.AI, OncoNano, physIQ, Pyxis, Saros, STipe, Tempest; Consultancy with compensation: AbbVie, Agenus, Alnylam, Atomwise, Bayer, Bristol-Myers Squibb, Castle, Checkmate, Codiak, Crown, Cugene, Curadev, Day One, Eisai, EMD Serono, Endeavor, Flame, G1 Therapeutics, Genentech, Gilead, Glenmark, HotSpot, Kadmon, KSQ, Janssen, Ikena, Inzen, Immatics, Immunocore, Incyte, Instil, IO Biotech, Macrogenics, Merck, Mersana, Nektar, Novartis, Partner, Pfizer, Pioneering Medicines, PsiOxus, Regeneron, Replimmune, Ribon, Roivant, Servier, STINGthera, Synlogic, Synthekine; Research Support: (all to institution for clinical trials unless noted) AbbVie, Astellas, AstraZeneca, Bristol-Myers Squibb, Corvus, Day One, EMD Serono, Fstar, Genmab, Ikena, Immatics, Incyte, Kadmon, KAHR, Macrogenics, Merck, Moderna, Nektar, Next Cure, Numab, Palleon, Pfizer, Replimmune, Rubius, Servier, Scholar Rock, Synlogic, Takeda, Trishula, Tizona, Xencor; Patents: (both provisional) Serial #15/612,657 (Cancer Immunotherapy), PCT/US18/36052 (Microbiome Biomarkers for Anti-PD-1/PD-L1 Responsiveness: Diagnostic, Prognostic and Therapeutic Uses Thereof). EE discloses Advisory Boards/Consultant: Immunocore. SL discloses Consulting: Bayer, Immunocore; Expenses: Bayer. LC discloses Employment and Stock: Immunocore. CH discloses Stock: Amgen Inc., Macrogenics; Employment: Immunocore. TS discloses advisory/consulting: Immunocore, Castle Biosciences; research funding to institution (clinical trials): Immunocore, Verastem, IDEAYA, TriSalus, and BMS.

Figures

Figure 1
Figure 1
Overall survival and duration of treatment for tebentafusp-treated patients (N=146). The median duration of treatment beyond progression was 2.8 months (range: <1–34 months; n=97).
Figure 2
Figure 2
Kaplan-Meier plots of overall survival with 95% Hall-Wellner bands for (A) all patients treated (N=146) and (B) patients enrolled in the phase 2 cohort (n=127). Events were defined as deaths due to any cause. Patients not known to have died at the time of analysis were censored. The median overall survival for all patients was 17.4 (95% CI, 13.1 to 22.8) months with 1-year, 2-year, 3-year, and 4-year overall survival rates of 62% (95% CI, 54% to 70%), 40% (95% CI, 32% to 48%), 23% (95% CI, 17% to 30%), and 14% (95% CI, 9% to 21%).
Figure 3
Figure 3
Survival prognosis according to patient baseline characteristics. Forest plot showing the results of the multivariate analysis of the factors associated with overall survival (N=146). ALC, absolute lymphocyte count; ALP, alkaline phosphatase; BL, baseline; CPI, checkpoint inhibitor; Dx, diagnosis; ECOG, Eastern Cooperative Oncology Group; F, female; LDH, lactate dehydrogenase; ULN, upper limit of normal.
Figure 4
Figure 4
Circulating-tumor DNA (ctDNA) levels at baseline and on-treatment were associated with overall survival. (A) The level of ctDNA at baseline was plotted for patients with overall survival <1 year (n=45), 1 to <2 years (n=29), 2 to <3 years (n=25) and >3 years (n=18). ND, not detected. (B) The percentage of patients alive at 1 year (orange), 2 years (green) and 3 years (blue) was plotted for all ctDNA evaluable patients (left panel) and those with a best response of progressive disease (PD; right panel) based on their per cent reduction in ctDNA by week 9 on-treatment.
Figure 5
Figure 5
Select treatment-related adverse events (TRAEs) over time with tebentafusp treatment. The percentage of patients experiencing Grade 1–2 (light bars) and Grade 3–4 (dark bars) rash (blue), fever (magenta), hypotension (green) and elevations in liver function tests (yellow) are plotted in 3-month intervals during the course of treatment. Inset includes the percentage of patients experiencing these select TRAEs in the first 3 months of treatment. The number of patients at risk are denoted for each time interval. Rash and liver function tests are composite terms for a list of related adverse events of any grade (online supplemental table 5).
See this image and copyright information in PMC

References

    1. Barker CA, Salama AK. New NCCN guidelines for Uveal Melanoma and treatment of recurrent or progressive distant metastatic Melanoma. J Natl Compr Canc Netw 2018;16:646–50. 10.6004/jnccn.2018.0042 - DOI - PubMed
    1. Diener-West M, Reynolds SM, Agugliaro DJ, et al. . Development of metastatic disease after enrollment in the COMS trials for treatment of Choroidal Melanoma: collaborative ocular Melanoma study group report No.26. Arch Ophthalmol-Chic 2005;123:1639–43. 10.1001/archopht.123.12.1639 - DOI - PubMed
    1. Khoja L, Atenafu EG, Suciu S, et al. . Meta-analysis in metastatic Uveal Melanoma to determine progression free and overall survival benchmarks: an international rare cancers initiative (IRCI) ocular Melanoma study. Ann Oncol 2019;30:1370–80. 10.1093/annonc/mdz176 - DOI - PubMed
    1. Rantala ES, Hernberg M, Kivelä TT. Overall survival after treatment for metastatic Uveal Melanoma: A systematic review and meta-analysis. Melanoma Res 2019;29:561–8. 10.1097/CMR.0000000000000575 - DOI - PMC - PubMed
    1. Carvajal RD, Butler MO, Shoushtari AN, et al. . Clinical and molecular response to Tebentafusp in previously treated patients with metastatic Uveal Melanoma: a phase 2 trial. Nat Med 2022;28:2364–73. 10.1038/s41591-022-02015-7 - DOI - PMC - PubMed

Publication types

Substances

Supplementary concepts