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Clinical Trial
. 2022 Jun 10;40(17):1939-1948.
doi: 10.1200/JCO.21.01805. Epub 2022 Mar 7.

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

Affiliations
Clinical Trial

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

Richard D Carvajal et al. J Clin Oncol. .

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.

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Conflict of interest statement

Richard D. CarvajalConsulting or Advisory Role: Merck, Aura Biosciences, Castle Biosciences, Immunocore, PureTech, Sorrento Therapeutics, Chimeron Bio, Rgenix, InxMed, Pierre Fabre, TriSalus Life Sciences, Iovance Biotherapeutics, Oncosec, Regeneron, Genzyme, Amgen (Inst), Astellas Pharma (Inst), AstraZeneca (Inst), Bristol Myers Squibb/Medarex (Inst), Corvus Pharmaceuticals (Inst), Ideya (Inst), Mirati Therapeutics (Inst), Novartis (Inst), Pfizer (Inst), Plexxikon (Inst), Roche/Genentech (Inst)Speakers' Bureau: Bristol Myers Squibb/MedarexResearch Funding: Amgen (Inst), Astellas Pharma (Inst), AstraZeneca (Inst), Bayer (Inst), Bellicum Pharmaceuticals (Inst), Bristol Myers Squibb (Inst), Corvus Pharmaceuticals (Inst), Lilly (Inst), Immunocore (Inst), Incyte (Inst), Macrogenics (Inst), Merck (Inst), Mirati Therapeutics (Inst), Novartis (Inst), Pfizer (Inst), Plexxikon (Inst), Roche/Genentech (Inst), Array BioPharma (Inst), IDEAYA Biosciences (Inst), Regeneron (Inst) Paul NathanConsulting or Advisory Role: AstraZeneca, Bristol Myers Squibb, MSD, Immunocore, Pfizer, Pierre Fabre, Novartis, GlaxoSmithKline, Ipsen, 4SC, MerckSpeakers' Bureau: Bristol Myers Squibb, Novartis, MSD, MerckTravel, Accommodations, Expenses: Bristol Myers Squibb, MSD Joseph J. SaccoHonoraria: Immunocore, Pierre Fabre, NovartisConsulting or Advisory Role: Immunocore (Inst), Delcath Systems, MSD, BMS, ImmunocoreResearch Funding: AstraZeneca (Inst), Immunocore (Inst), Replimune (Inst), BMS (Inst)Travel, Accommodations, Expenses: BMS, MSD Marlana OrloffConsulting or Advisory Role: Immunocore, TriSalus Life Sciences, IDEAYA BiosciencesSpeakers' Bureau: Bristol Myers SquibbResearch Funding: Bristol Myers Squibb (Inst), Immunocore (Inst), Delcath Systems (Inst), Plexxikon (Inst), IDEAYA Biosciences (Inst), Linnaeus Therapeutics (Inst) Leonel F. Hernandez-AyaConsulting or Advisory Role: Massive Bio, Bristol Myers Squibb, Castle BiosciencesSpeakers' Bureau: Sanofi/RegeneronResearch Funding: Bristol Myers Squibb (Inst), Regeneron (Inst), Immunocore (Inst), Merck (Inst), Polynoma (Inst), Corvus Pharmaceuticals (Inst), Roche/Genentech (Inst), Merck Serono (Inst), Amgen (Inst), MedImmune (Inst), Takeda (Inst), Moderna Therapeutics (Inst), Foghorn Therapeutics (Inst)Travel, Accommodations, Expenses: Sanofi/Regeneron, Bristol Myers Squibb, Castle Biosciences Jason J. LukeStock and Other Ownership Interests: Actym Therapeutics, Mavu Pharmaceutical, Pyxis, Alphamab, Tempest Therapeutics, Kanaph Therapeutics, Onc.AI, Arch OncologyConsulting or Advisory Role: Bristol Myers Squibb, Merck, EMD Serono, Novartis, 7 Hills Pharma, Janssen, Reflexion Medical, Tempest Therapeutics, Alphamab, Spring Bank, AbbVie, Astellas Pharma, Bayer, Incyte, Mersana, Partner Therapeutics, Synlogic, Eisai, Werewolf Therapeutics, Ribon Therapeutics, Checkmate Pharmaceuticals, CStone Pharmaceuticals, Nektar, Regeneron, Rubius Therapeutics, Tesaro, Xilio Therapeutics, Xencor, Alnylam, Crown Bioscience, Flame Biosciences, Genentech, Kadmon, KSQ Therapeutics, Immunocore, Inzen Therapeutics, Pfizer, Silicon Therapeutics, TRex BioResearch Funding: Merck (Inst), Bristol Myers Squibb (Inst), Incyte (Inst), Corvus Pharmaceuticals (Inst), AbbVie (Inst), Macrogenics (Inst), Xencor (Inst), Array BioPharma, Agios, Astellas Pharma, EMD Serono, Immatics, Kadmon, Moderna Therapeutics, Nektar, Spring bank, Trishula Therapeutics, KAHR Medical, Fstar, Genmab, Ikena Oncology, Numab, Replimune, Rubius Therapeutics, Synlogic, Takeda, Tizona Therapeutics Inc, Trishula Therapeutics, BioNTech, Scholar RockPatents, Royalties, Other Intellectual Property: Serial #15/612,657 (Cancer Immunotherapy), Serial #PCT/US18/36052 (Microbiome Biomarkers for Anti–PD-1/PD-L1 Responsiveness: Diagnostic, Prognostic and Therapeutic Uses Thereof)Travel, Accommodations, Expenses: Bristol Myers Squibb, Array BioPharma, EMD Serono, Janssen, Merck, Novartis, Reflexion Medical, Mersana, Pyxis, Xilio Therapeutics Marcus O. ButlerHonoraria: Roche, Merck, Bristol Myers Squibb, NovartisConsulting or Advisory Role: Merck, Bristol Myers Squibb, Novartis, Immunovaccine, Immunocore, Adaptimmune, EMD Serono, GlaxoSmithKline, Genzyme, Sanofi, LaRoche Posay, Sun Pharma, Instil Bio, Iovance Biotherapeutics, PfizerResearch Funding: Merck, Takara BioExpert Testimony: Merck Sarah StanhopeEmployment: ImmunocoreStock and Other Ownership Interests: Immunocore Laura CollinsEmployment: ImmunocoreStock and Other Ownership Interests: Immunocore Cheryl McAlpineEmployment: Immunocore, Adaptimmune Chris HollandEmployment: ImmunocoreStock and Other Ownership Interests: Immunocore, Amgen, MacroGenicsPatents, Royalties, Other Intellectual Property: Coinvolvement in a patent for the compositions and methods for treating diffuse large B-cell lymphoma Shaad E. AbdullahEmployment: ImmunocoreStock and Other Ownership Interests: ImmunocorePatents, Royalties, Other Intellectual Property: AU2019270277A1—Treatment of Cancer, WO2020225552A1—Combination of monalizumab, durvalumab, chemotherapy, and bevacizumab or cetuximab for the treatment of colorectal cancer Takami SatoConsulting or Advisory Role: Immunocore, Castle BiosciencesResearch Funding: Immunocore (Inst), Verastem (Inst)Travel, Accommodations, Expenses: Castle BiosciencesNo other potential conflicts of interest were reported.

Figures

FIG 1.
FIG 1.
Dose escalation trial design. C1D1, cycle 1 day 1; C1D8, cycle 1 day 8; C1D15, cycle 1 day 15.
FIG 2.
FIG 2.
Occurrence and severity of AEs attenuate with repeated weekly dosing. Percentage of treated patients experiencing any grade or Gr 3+ of select treatment-related AEs occurring within 7 days of the first four doses (cycle 1), dose 8 (end cycle 2), and dose 12 (end cycle 3). Rash is a composite term for a list of skin toxicities of any grade (Data supplement). AE, adverse event; Gr, grade.
FIG 3.
FIG 3.
Clinical activity of tebentafusp. (A) Waterfall plot showing the best change in tumor size (n = 38). (B) Spider plot showing individual patients and the time frame (n = 40). For both (A) and (B), tumor size is measured as the sum of longest diameters of the target lesions according to RECISTv1.1 by investigator opinion. Best percent change in target lesion size is the maximum percent reduction from baseline or the minimum percent increase from baseline (in the absence of a reduction). Reference lines at 20%, –10%, and –30% mark target lesion response criteria for PD, MR, and PR, respectively. Only patients with baseline (A) or at least one evaluable postbaseline target lesion scans (A and B) are included. MR, minor response; PD, disease progression; PR, partial response; SD, stable disease.
FIG 4.
FIG 4.
OS for tebentafusp-treated metastatic uveal melanoma patients. (A) Kaplan-Meier plot of OS (N = 42). Events are deaths because of any cause. Patients not known to have died at the time of analysis are censored. Median (95% CI) is 25.5 (12.4 to 31.1) months. (B) Kaplan-Meier plot of OS by rash (any grade) within 7 days (N = 42). Hazard ratio (95% CI) for rash: 0.235 (0.101 to 0.544). Rash is a composite term for a list of skin toxicities of any grade (Data supplement). OS, overall survival.
FIG 5.
FIG 5.
Tebentafusp induced a pharmacodynamic response in multiple peripheral immune markers and increased CD3+, CD8+, or CD4+ cells in the TME. (A) Maximal postdose (log2) fold change, relative to baseline concentration, in response to first dose in serum markers (n = 41). (B) Temporal profile of post first and third dose fold-change response 12-24 hours following first dose (D1) versus third dose (D15); data points represent mean ± SEM, N = 42. (C) Temporal profile of blood lymphocytes post first and third dose expressed as a fold change from baseline. Data points represent mean ± SEM, n = 32. (D) Number of CD3+, CD8+, or CD4+ cells per mm2 tumor in paired pretreatment and on-treatment biopsies (taken cycle 1 day 16) from up to six patients; line per patient. (E) Representative immunohistochemistry images from patient 2 in (D) from pretreatment and on-treatment biopsies for CD3+ (total T cells), CD4+ (T cells and monocytes), and CD8+ cells (T cells and NK cell subset). HGF, hepatocyte growth factor; IFN, interferon; IL, interleukin; NK, natural killer; TME, tumor microenvironment; TNF, tumor necrosis factor.

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