Chen RD Et Al., 2022 (Nihms-1894235)

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Expert Rev Anticancer Ther. Author manuscript; available in PMC 2023 May 15.
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Published in final edited form as:

Expert Rev Anticancer Ther. 2022 October ; 22(10): 1017–1027. doi:10.1080/14737140.2022.2124971.
Tebentafusp for the treatment of HLA-A*02:01–positive adult

patients with unresectable or metastatic uveal melanoma
Lanyi Nora Chen,
Richard D. Carvajal*
Columbia University Medical Center, 161 Fort Washington Avenue, New York, NY 10032
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Abstract
Introduction: Metastatic uveal melanoma is associated with poor prognosis and few treatment
options. Tebentafusp recently became the first FDA-approved agent for metastatic uveal
melanoma.
Areas covered: In this review, we describe the mechanism of action of tebentafusp as well
as preclinical data showing high tumor specificity of the drug. We also review promising early
phase trials in which tebentafusp demonstrated activity in metastatic uveal melanoma patients
with an acceptable toxicity profile that included cytokine-mediated, dermatologic-related, and
liver-related adverse events. Finally, we summarize findings from a pivotal phase III randomized
trial in which tebentafusp demonstrated significant improvement in overall survival in comparison
with investigator choice therapy.
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Expert opinion: Tebentafusp has transformed the treatment paradigm for metastatic uveal
melanoma and should be the preferred frontline agent for most HLA-A*0201 positive patients.
However, patients with rapidly progressing disease or high tumor benefit may not derive the same
benefit. Areas of future study should focus on its role in the adjuvant setting as well as strategies to
improve efficacy of tebentafusp in the metastatic setting.
Keywords
gp100; Immune-mobilizing monoclonal T cell receptor against cancer; Immunotherapy;
Tebentafusp; Uveal Melanoma
1. INTRODUCTION
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Although uveal melanoma (UM) is a rare disease with an incidence of 5.1 per million
in the US, it comprises 85% of cases of primary ocular malignancies[1]. Local therapies,
*
Corresponding author: [email protected].
Declaration of interest
RD Carvajal has received consultancy fees from; Alkermes, Bristol-Myers Squibb, Castle Biosciences, Eisai, Ideaya, Immunocore,
InxMed, Iovance, Merck, Novartis, Oncosec, Pierre Fabre, PureTech Health, Regeneron, Sanofi Genzyme, Sorrento Therapeutics,
Trisalus. RD Carvajal has served omn the clinical and scientific advisory boards of; Aura Biosciences, Chimeron, Rgenix and
has received research funding to Columbia University from; Amgen, Astellis, AstraZeneca, Bristol-Myers Squibb, Corvus, Ideaya,
Immunocore, Iovance, Merck, Mirati, Novartis, Pfizer, Plexxikon, Regeneron and Roche/Genentech.
The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or
financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Chen and Carvajal Page 2
which include enucleation and globe-sparing approaches such as brachytherapy and proton
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beam therapy, effectively manage the primary tumor in over 95% of cases[2]. However,
up to 50% of patients will develop metastatic disease, most commonly to the liver, lung,
bone, and skin. The risk can be even higher based on certain clinical, cytogenetic, and
molecular features [3,4] . The American Joint Committee on Cancer (AJCC) Tumor-Node-
Metastasis (TNM) system, which uses tumor size, ciliary body involvement, and extraocular
extension to categorize patients by stage, predicts increased risk of metastasis in higher
stage disease[5]. Five-year metastasis-free survival is estimated as 97% for stage I disease
and 25% for stage IIIC disease[6]. Combining AJCC tumor classification with cytogenetics
analysis improves prognostication[7]. The Cancer Genome Atlas (TCGA) Project classifies
UM into class A, B, C, or D based on the presence or absence of chromosome 3 monosomy
and chromosome 8q gain[8,9]. Class A patients, which show disomy 3 and 8, have the best
prognosis while those with Class B, C, or D disease have increased risk of metastasis[8-10].
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DecisionDx-UM, which is a 15-gene expression panel, uses next-generation sequencing to

classify tumors as class 1 or class 2. Five-year risk of metastatic disease for class 2 tumors is
over 70%[11].
For patients who develop metastatic uveal melanoma, prognosis is poor and median
survival is estimated at 12 months[12-16]. A meta-analysis of 29 trials for metastatic
uveal melanoma between 2000 and 2016 identified a 1-year overall survival (OS) of 43%
regardless of prior treatment[16]. For some patients with oligometastatic liver disease,
surgical resection and other regional approaches such as intra-arterial chemotherapy,
hepatic artery chemoembolization, immunoembolization,radioembolization, isolated hepatic
perfusion, and percutaneous hepatic perfusion can improve disease control, though careful
patient selection is critical and survival benefit is largely unclear[17-24] Until recently,
advances in systemic treatments have not been shown to meaningfully improve survival[13].
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Chemotherapeutic agents such as dacarbazine, temozolomide, and cisplatin have not

demonstrated significant clinical activity[25]. Unlike its cutaneous counterpart, metastatic
uveal melanoma is also largely refractory to immune checkpoint inhibitors. Single-agent
checkpoint inhibitors have had disappointing clinical trial results. In one phase II trial,
single-agent ipilimumab led to a 1-year OS of 22%, which was the primary endpoint; it did
not lead to any partial or complete responses, and median OS was 6.8 months[26]. A phase
II trial of single-agent tremelimumab, which had a primary endpoint of progression-free
survival (PFS) at 6 months, led to a 9.1% 6-month PFS rate, no responses, and an OS of 12.8
months[27]. A retrospective review of patients treated with PD-1 or PD-L1 blockade yielded
an objective response rate (ORR) of 3.6% and median OS of 7.6 months[28].
Dual checkpoint blockade has had modest success. In the phase II PROSPER trial, which
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had a primary endpoint of ORR, the combination of nivolumab and ipilimumab led to
an ORR of 18%, a median OS of 19.1 months, and one-year OS rate of 56%[29]. The
phase II GEM-1402 trial had a primary endpoint of 12-month OS, which was 52% with
nivolumab and ipilimumab[30]. ORR was 11.5% and median OS was 12.7 months[30].
While these outcomes were more promising than those of single agent immunotherapy
trials, they are still comparable to historical survival data for patients who are treated for
metastatic disease[15]. They also remain considerably worse when compared to outcomes
of checkpoint inhibitor therapy for cutaneous melanoma[31,32]. Uveal melanoma has a
low tumor mutation burden, relatively low PD-L1 expression, and tends to metastasize to
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an immunosuppressive liver environment, which may explain its relative insensitivity to

checkpoint blockade[33-35].
Targeted therapies have also had little success in treating metastatic uveal melanoma.
Selumetinib, a mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK)
inhibitor, was compared to chemotherapy in a randomized phase II trial with a primary
endpoint of PFS. Median PFS was significantly higher with selumetinib compared to
chemotherapy (15.9 weeks vs. 7 weeks, p<0.001) but the magnitude of clinical benefit was
small. Selumetinib led to an ORR of 14%, and median OS was not significantly different
compared to chemotherapy (11.8 months vs. 9.1 months, p=0.09)[36]. In a subsequent phase
III trial (SUMIT), selumetinib plus dacarbazine was compared to placebo plus dacarbazine
and the primary endpoint was PFS. Median PFS was 2.8 months (selumetinib plus
dacarbazine) vs. 1.8 months (dacarbazine alone), which was not a significant improvement
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(p=0.32). The ORR was 3% with selumetinib plus dacarbazine, and OS was not significantly
improved (HR 0.75, p=0.40)[37]. The randomized phase II SelPAC trial, which compared
selumetinib plus dacarbazine to dacarbazine alone, met its primary endpoint of PFS, but
the PFS improvement was modest (4.8 months vs. 3.4 months, p=0.02). ORR, a secondary
endpoint, was 14% (selumetinib plus dacarbazine) and 4% (dacarbazine). Median OS,
another secondary endpoint, was not significantly different between the treatment and
control arms (9 months vs. 10 months, p=0.469)[38].
Until recently, there were no FDA-approved treatments for metastatic uveal melanoma. Due
to disappointing results seen with chemotherapy, immunotherapy, and targeted therapies,
there continues to be a significant unmet need for patients with this disease.
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2. TEBENTAFUSP: DRUG INTRODUCTION

2.1 Mechanism of action and pre-clinical data
Tebentafusp (IMCgp100) is a first-in-class immune-mobilizing monoclonal T cell receptor
against cancer (ImmTAC). ImmTAC molecules are bispecific agents that are engineered
to include a high-affinity monoclonal T cell receptor (mTCR) that recognizes a specific
peptide-HLA complex, fused to an anti-CD3 single-chain antibody fragment (scFv) that
engages T cells (Figure 1)[39]. These molecules have been shown to successfully activate
and redirect cytotoxic T cells to kill tumor cells and induce a polyclonal response[40,41].
Tebentafusp consists of a mTCR that recognizes glycoprotein 100 (gp100), a peptide

presented by HLA-A*0201 that is highly expressed on uveal melanoma cells[42]. Preclinical
studies demonstrated that IMCgp100 has a very high binding affinity for HLA-A-gp100,
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with a KD of 15pM and an EC50 less than 100pM[40]. It has relatively weak binding to
CD3 (with a KD in the nM range), which allows for highly specific tumor cell binding
followed by activation and redirection of polyclonal CD8+ and CD4+ T cells to elicit
cytotoxic activity against melanoma cells[41]. Beyond T cell cytotoxic activity, IMCgp100
also induces T cells to release broad range of cytokines and chemokines including IL-6,
IL-2, and TNF-a, further enhancing its potential anti-cancer immune activity[41]. IMCgp100
activity in T-cell activation was observed at a concentration of 1pM, with maximal response
seen at 1nM and off-target effects seen only at concentrations much higher than 1nM,
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indicating high tumor antigen specificity and a wide therapeutic window[43]. In vitro
activity of IMCgp100 correlated with levels of gp100-HLA-A*02 expression[43].
2.2 Drug Metabolism

Tebentafusp has an estimated half-life of 6-8 hours with a distribution that is primarily
limited to the central blood volume (Vss approximately 6-7 L)[44]. It is expected to be
catabolized into small peptides and amino acids[45].
3. EARLY PHASE CLINICAL TRIALS

3.1 First-in-man phase I/II trial
Encouraging preclinical data formed the basis for a multicenter, first-in-man phase I/II trial
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of tebentafusp in metastatic or unresectable melanoma (NCT01211262, Table 1) [46]. This

trial included 84 HLA-A*0201 positive patients who mostly had cutaneous (n=61) and uveal
(n=19) melanoma and who were treated with a median of 1 prior line of therapy. Weekly
(arm 1, n=66) and daily (arm 2, n=18) dosing were explored at a range of doses [arm 1:
5-900 ng/kg dose escalation; arm 2: once daily x 4 days every 3 weeks using 10 to 50mcg
per dose]. Hypotension was observed as the dose-limiting toxicity for patients who received
900 ng/kg, so the maximum tolerated weekly dose was 600 ng/kg (or 50 mcg flat dose).
The recommended phase II dose for weekly dosing was set at 50 mcg. ORR by RECIST
criteria was 8.7% (all partial responses), while 55% of patients had stable disease [46]. Of
the patients who received 600 ng/kg or greater (n=26), response rate was higher at 15%,
suggesting a dose-response relationship [47-49]. Three uveal melanoma patients achieved a
partial response, for an ORR of 16.7% amongst patients with this disease. Median duration
of response was 10.5 months, and median survival was 33.4 months. One-year OS rate
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was 65% (95% CI, 48-78%) and was similar between patients with uveal melanoma and
cutaneous melanoma [46].
Tebentafusp was well-tolerated, and toxicities were mostly cytokine-mediated or

dermatologic (Table 2). Cytokine release syndrome (CRS), considered to be an on-target,
on-tumor toxicity, was seen in 60% of patients, though cases were generally mild and no
grade ≥3 cases were reported [46]. Dermatologic toxicities, which are considered on-target,
off-tumor, manifested as rash (68%) and pruritis (70%). Common grade ≥3 treatment-related
adverse events (TRAEs) were rash (26%) and lymphopenia (13%), which was thought to
be an on-target effect specific to melanocytic gp100 and peripheral T-cell redirection. Eight
percent of patients experienced grade ≥3 hypotension [46]. Toxicities were usually reversible
within 24 hours, and most were limited to the first two weeks of treatment.
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Analysis of post-treatment patient serum samples revealed increased levels of IFN-inducible

chemokines CXCL10, CXCL11, IL2, IL6, and IL10, with CXCL10 showing the greatest
increase [46]. Induction of serum cytokines appeared to be transient and reached maximal
levels 8-24 hours after the dose before returning to baseline. CXCL10, however, remained
elevated compared to baseline. Increases in serum CXCL10 and CXCL11 were associated
with longer overall survival [46]. Post-treatment tumor biopsies exhibited increased
intratumoral CD3+, CD4+, and CD8 T-cells, further confirming the drug’s mechanistic role
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in T-cell redirection and immune activation [46]. A two-fold increase in PD-L1 expression
was in seen in five of nine post-treatment tumor biopsies [46].
3.2 Phase I/II Trial with step-up dosing regimen

Given the dose-response relationship and dose-limiting hypotension/CRS seen early on in
the treatment course in the first-in-man trial, a second phase I trial (Table 1) was conducted
in an effort to increase the maximum tolerated dose by using a three-week step-up dosing
regimen [44]. Nineteen HLA-A*0201 positive patients with advanced uveal melanoma were
included in the initial dose expansion cohort. These patients were heavily pretreated and had
a median of 4 lines of prior therapy[44,50]. Each patient received 20 mcg of tebentafusp on
C1D1, 30 mcg on C1D8, then an escalated dose on C1D15 and thereafter (ranging from 54
mcg to 73 mcg). Each cycle consisted of 4 weeks. Dose-limiting transaminase elevation was
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observed in 2 of 4 patients treated at the 73 mcg dose, which was deemed not tolerable [44].
The observed transaminase elevations resolved within 1 week without requiring steroids,
and all patients were able to tolerate restarting the drug at a reduced dose. None of the six
patients treated with 68 mcg experienced a dose-limiting toxicity, so 68 mcg was established
as the recommended phase II dose [44]. Notably, the step-up dosing regimen permitted
a 36% increase in dose compared with what was tolerable using a flat dosing regimen.
Twenty-three patients were included in the subsequent expansion cohort and were treated
with 68 mcg on C1D15 and thereafter.
The median number of cycles completed were 7.5 (dose escalation group) and 6 (dose
expansion group). ORR was 11.9% (confirmed partial response was observed in 5 patients),
and 55% of patients achieved any degree of tumor size reduction. Median OS was 25.5
months, and one-year OS rate was 67% [44], representing a significant improvement over
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historical survival estimates of 12 months for median OS and around 50% for 1-year OS
rate[16].
Common adverse events included pyrexia (90%) pruritis (71%), nausea (74%), and
fatigue (71%); 71% of patients experienced a grade ≥3 adverse event, which included
hypophosphatemia (14%), hypotension (12%), abdominal pain (12%), fatigue (10%), and
AST elevation (10%) [44]. Thirty-eight (90%) patients experienced CRS, and most (90%)
cases were grade 1 or 2 (Table 2). CRS was mostly reversible with IV fluids and in some
cases required a short course of corticosteroids. Acute transaminase elevation was seen
in 9 (21%) patients, usually early in the treatment course in the setting of CRS, whereas
chronic LFT elevations were associated with disease progression. Skin toxicities included
rash (83%), pruritis (83%), dry skin (64%), and were grade 1 or 2 in 67% of cases. Patients
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were treated with antihistamines and topical steroids. TRAE’s became less frequent and less
severe with repeated dosing[44]. A post-hoc analysis of the 24 patients who experienced
rash of any grade within 7 days of the first dose showed that these patients had longer
survival compared to patients who did not have rash (HR 0.23, 95% CI 0.10 to 0.54).
One-year OS rate was 83% among patients who experienced rash (95% CI, 68 to 98) vs.
44% among patients who did not have rash (95% CI, 21 to 67).
To assess the pharmacodynamic response to tebentafusp, serum cytokine profiles were

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assessed pre-treatment and at 8 hours and 12-24 hours after the first and third doses [44].
The greatest increases relative to baseline were seen for CXCL10, CXCL11, IL-2, IL-6,
IL-10, and interferon (IFN)y, with most (60-95%) patients showing a greater than 10-fold
increase. Most rises in serum markers were transient, but CXCL10 and CXCL11 levels
remained elevated relative to baseline. Changes in serum biomarkers were not associated
with longer OS. Below median (<6 fold) increases in IL-10, however, was associated
with greater tumor shrinkage, consistent with the immunosuppressive role of IL-10 [44].
Six patients had pre-treatment and during-treatment tumor biopsies available. On-treatment
biopsy samples had a higher concentration of CD3+ T cells and an increase in CD4+ and
CD8+ immune cells compared to baseline biopsy samples [44].
A subsequent phase II trial treated a total of 127 HLA-A*0201 positive patients, including
23 patients from the previously described phase I expansion cohort, with the recommended
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phase II dosing regimen (Table 1) [51]. All patients had received at least 1 prior therapy for
metastatic disease, and 58% had elevated LDH. Most (70%) patients had an ECOG score of
0. Patients were treated with weekly IV tebentafusp (20 mcg on C1D1, 30 mcg on C1D8,
68 mcg on C1D15 and thereafter). The primary endpoint was ORR, and secondary endpoints
included safety, OS, and PFS. At a median follow-up of 19.6 months, ORR was low at
5%, with 6 patients achieving a partial response by RECIST criteria. Median duration of
response was 8.7 months (95% CI: 5.6-24.5). Although ORR was low, 44% of patients had
a reduction in target lesions. Median PFS was 2.8 months (95% CI: 2-3.6), median OS was
16.8 months (95% CI, 12.9-21.3), and the 12-month OS rate was 62% (95% CI: 53-70%).
Common TRAEs included cutaneous and cytokine-mediated events, consistent with

predicted on-target effects (Table 2) [51]. They included pruritis (67%), pyrexia (80%),
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chills (64%), and grade ≥3 AEs included maculopapular rash (13%), hypotension (8%), and
increased AST (6%). TRAEs were manageable; they also occurred less frequently and were
less severe after the third dose. Patients who developed rash within a week of starting the
drug (64% of patients) had better survival outcomes, with median survival of 22.5 months
compared to 10.3 months among patients who did not develop rash [51].
Despite promising overall survival, there was a low rate of overall response by RECIST
criteria, indicating that radiographic assessment may underestimate survival benefit [51].
Circulating tumor DNA (ctDNA) levels, which are associated with treatment response in
other disease settings, were measured at baseline and at weeks 5 and 9 on treatment using
a custom panel of mutations commonly found in uveal melanoma from Natera Inc. [52].
In data presented at ESMO in 2021, 116 patients had evaluable ctDNA at baseline, and 99
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patients had evaluable ctDNA at baseline and at week 9. Baseline ctDNA levels correlated
significantly with tumor size [52]. At week 9, 70% of patients had any ctDNA reduction
and 14% of patients achieved ctDNA clearance. ctDNA reduction was associated with
greater mean tumor shrinkage, less tumor growth, and was significantly associated with
better overall survival (p<0.0001). Among patients with a best radiographic response of
progressive disease, those with a ≥ 0.5 log reduction in ctDNA by week 9 had improved
OS compared to those with < 0.5 log ctDNA reduction. Among the patients who achieved
complete ctDNA clearance, most had either stable (57%) or progressive (29%) disease on
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imaging, and 100% were alive at 1 year [52].
4. RANDOMIZED PHASE III TRIAL

An open-label randomized phase III trial was conducted to evaluate the efficacy of
tebentafusp in patients with previously untreated metastatic uveal melanoma[53]. 378 HLA-
A*0201-positive patients were randomized in a 2:1 ratio to receive first-line tebentafusp or
investigator choice of therapy (single-agent pembrolizumab, ipilimumab, or dacarbazine).
The single-agent control arm was used because the trial was designed before data
from the dual checkpoint blockade trials (GEM-1402 and PROSPER) were known and
because of concerns for toxicity with dual checkpoint blockade[29,30]. Patients were
stratified according to LDH. Inclusion criteria included HLA-A*0201 positivity, lack of
prior systemic or liver-directed treatment, ECOG of 0 or 1, and measurable disease by
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RECIST 1.1 criteria. Exclusion criteria included CNS metastases, treatment with steroids
for autoimmune disease, or receipt or other systemic immunosuppressive treatment. The
primary endpoint of the study was OS in both the intention-to-treat population and in the
prespecified population of patients who developed a rash of any grade within 1 week after
treatment initiation. Secondary endpoints included disease control, ORR, and PFS.
Patients who were randomized to receive tebentafusp were dosed 20 mcg IV on C1D1,
30 mcg IV on C1D8, and 68 mcg IV on C1D15 and weekly thereafter. Among patients
randomized to the investigator’s choice control group, 82% (n=103) were assigned to
receive pembrolizumab, 13% (n=16) were assigned to receive ipilimumab, and 6% (n=7)
were assigned to receive dacarbazine [53]. Crossover was not initially permitted, but after
the first interim analysis identified a survival benefit, patients in the control group were
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permitted to cross over to receive tebentafusp.
Baseline clinical characteristics were well-balanced between the two groups. Median patient
age was 64 years in the tebentafusp group and 66 years in the control group. Thirty six
percent of patients in the study had elevated LDH, 73% had an ECOG of 0, 44% had both
hepatic and extrahepatic metastases, and median time since initial diagnosis was 2.8 years.
The first planned interim analysis was performed after a median follow-up time of 14.1
months, at which time 150 deaths had occurred in the intention-to-treat population [53].
OS rate at 1 year was 73% (tebentafusp group) compared to 59% (control group) in the
intention-to-treat population. Median OS was 21.7 months (tebentafusp) compared to 16.0
months (investigator’s choice therapy). The hazard ratio (HR) for death was 0.51 (95% CI,
0.37-0.71), which was statistically significant (p<0.001). In subgroup analyses, the overall
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survival benefit with tebentafusp was mostly consistent, though there appeared to be less
benefit with tebentafusp compared to patients treated with ipilimumab and among patients
with either ECOG 1 performance status or larger metastatic lesions (M1b or M1c disease).
Six-month PFS was 31% (tebentafusp) compared to 19% (control), for a HR of 0.73 (95%
CI 0.58-0.94) that was significant (p=0.01). ORR was only 9% (95% CI, 6-13) in the
tebentafusp group and 5% (95% CI, 2-10) in the control group. Forty-six percent (95% CI,
39-52) of patients who received tebentafusp had disease control (complete response, partial
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response, or stable disease for 12+ weeks) compared to 27% (95% CI, 20 to 36) in the
control group.
While the OS benefit of tebentafusp was both clinically and statistically significant, the PFS
benefit was relatively low despite being statistically significant. The rate of radiographic
tumor response with tebentafusp was also low at 9%; while numerically higher than
the control group, it was not statistically significant. Among patients with radiographic
disease progression, those who received tebentafusp still had longer survival than those
in the control arm, suggesting a benefit with tebentafusp even in the absence of a
radiographic response. This disconnect between radiographic response assessment and OS,
seen previously in the early phase trials, is consistent with an immunological pattern of
clinical response. A similar pattern of response, for instance, was observed with ipilimumab
when compared with a gp100 vaccine for patients with metastatic melanoma. While single-
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agent ipilimumab led to a relatively low ORR of 10.9%, it significantly improved median
OS (10.1 months vs. 6.4 months, HR 0.66, p=0.003)[54].
As in early phase trials, two major types of treatment-related adverse events were
observed in the tebentafusp arm (Table 2): cytokine-mediated, including pyrexia (76%),
hypotension (38%), and chills (47%), and skin-related, including rash (83%), pruritis
(69%), and erythema (23%). There were more grade 3-4 TRAEs seen in the tebentafusp
group (44%) than in the control group (17%). Liver-related toxicities were thought to be
mostly due to disease progression rather than a drug-related effect. The rate of treatment
discontinuation due to treatment-related adverse events was low in both groups (2% in the
tebentafusp group, 5% in the control group). No treatment-related deaths were seen in either
group. Most adverse events observed in the tebentafusp arm occurred during the first 4
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weeks of treatment, and the incidence and severity decreased with each subsequent dose.
Hospitalization was uncommonly required to administer the fourth dose and beyond.
Cytokine release syndrome was observed in 89% of patients in the tebentafusp group, but
99% of those patients had at most grade 1-2 symptoms and symptoms mostly occurred
within hours of administering the first three doses. Most patients who experienced CRS
were treated with a combination of antipyretics and intravenous fluids; although some
required systemic glucocorticoids, escalation to tocilizumab and pressors for hypotension
was uncommon. Skin toxicities and were usually manageable with acetaminophen,
diphenhydramine, and topical steroids.
Based on phase II data suggesting a relationship between appearance of rash and increased
survival when treated with tebentafusp, a prespecified OS analysis was performed for the
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149 patients treated with tebentafusp who developed rash within a week. These patients
had a significantly longer median OS compared to the control group [27.4 months (95%
CI, 20.2 to not reached) vs. 16.0 months (95% CI, 9.7-18.4)], p<0.001. However, rash was
not a significant independent predictor of OS benefit with tebentafusp in a multivariate Cox
model.
The authors concluded that first-line treatment with tebentafusp significantly prolonged
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overall survival compared to investigator’s choice of treatment with either pembrolizumab,

ipilimumab, or dacarbazine. The one-year OS rate of 73% seen with tebentafusp was higher
than one year survival rates previously reported with dual checkpoint blockade[29,30] and
in meta-analyses of patients treated for metastatic disease[15]. Median OS of the control
arm also outperformed historical controls, which further highlights the benefit seen with
tebentafusp.
5. POST-MARKETING SURVEILLANCE
The most common adverse events seen with tebentafusp across clinical trials and in clinical
practice can be grouped into dermatologic, cytokine release syndrome-related, and liver-
related toxicities (Table 2). These toxicities have overlap with the safety profile of other
immunotherapies. Table 3 compares the characteristics of ImmTAC molecules to other
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immunotherapy drug classes that activate and/or engage T cells.
6. REGULATORY AFFAIRS
On January 25, 2022, tebentafusp received FDA approval for treatment for HLA-A*02:01-
positive adult patients with unresectable or metastatic uveal melanoma and is now available
for use in the US[55]. The European Commission approved tebentafusp on April 4, 2022 for
the treatment of unresectable or metastatic uveal melanoma. With this, tebentafusp became
the first TCR therapy to be approved in the EU and has received market authorization in
all EU member states[56]. As of the time of this publication, there has not been regulatory
approval of tebentafusp in Australia, Asia, or Africa.
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7. CONCLUSION
Uveal melanoma is a rare cancer with a high risk of metastasis and few effective systemic
treatment options. Tebentafusp is a first-in-class ImmTAC; it is a bispecific gp100-HLA-
A*02:01-directed T-cell receptor and CD3 T-cell engager that elicits a polyclonal T-cell
response against uveal melanoma cells. Preclinical studies of IMCgp100 showed highly
specific tumor antigen binding and suggested a wide therapeutic window. Early phase
trials of tebentafusp demonstrated a dose-response relationship as well as feasibility and
tolerability of an escalating dose regimen. Pharmacodynamic assays demonstrated an
increase in serum cytokines after tebentafusp dosing, and evaluation of tumor biopsy
samples while on treatment showed increased concentration of T-cells. A phase III trial
compared tebentafusp to investigator choice single-agent therapy and found significant
PFS and OS benefit. The pattern of clinical response was variable, as some patients
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with radiographic evidence of progression still had a survival benefit with tebentafusp.
Tebentafusp is well-tolerated, with low rates of treatment discontinuation and mostly on-
target side effects that can be grouped into dermatologic and cytokine-mediated events.
These adverse events usually occur early on in the treatment course and can be effectively
managed. The liver-related toxicities observed were thought to mostly be in the setting
of disease progression. Based on the promising results of the phase III trial, tebentafusp
became the first FDA-approved treatment for metastatic uveal melanoma.
8. EXPERT OPINION
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Tebentafusp has changed the landscape of treatment for metastatic uveal melanoma and
should be considered for all HLA-A*0201-positive patients. While there was a clear
survival benefit with first-line tebentafusp over single agent ipilimumab, pembrolizumab,
or dacarbazine, there have been no head-to-head comparisons between tebentafusp and dual
checkpoint blockade, which has been commonly used over single agent therapy for this
patient population. It is unlikely that another randomized trial will be performed. However,
given the proven overall survival benefit and acceptable toxicity profile of tebentafusp
that was demonstrated in a large, international, randomized clinical trial, it should be the
preferred agent for metastatic disease in most HLA-A*0201 positive patients.
In subgroup analyses of overall survival in the phase III trial, the benefit of tebentafusp was
less clear when compared to ipilimumab alone and when looking at patients with ECOG 1
Author Manuscript
or higher tumor burden (M1b or M1c disease) [53]. Although the hazard ratio for overall
survival suggested less benefit for tebentafusp when compared to the ipilimumab subgroup
(HR 0.89, CI 0.38-2.31), patients who received ipilimumab (n=40) made up only a minority
(15%) of the comparator group, which impairs the reliability of this subgroup comparison.
Given the disappointing historical outcomes seen with single-agent checkpoint inhibition,
including a phase II trial of ipilimumab in which 1-year OS was 22% and median OS
was 6.8 months [57], we believe that the available data collectively support a benefit of
tebentafusp over single-agent ipilimumab.
The hazard ratio for overall survival in the subgroup of patients with ECOG 1 also suggested
less benefit with tebentafusp (HR 0.72, 95% CI 0.39-1.36). Although tebentafusp was
well-tolerated, this supports performance status as a general prognostic marker and may also
Author Manuscript
reflect the difficulty of effectively administering a weekly systemic treatment in patients

with worse performance status. Subgroup analyses are by no means conclusive, and while
we would continue to offer tebentafusp to patients with ECOG 1, performance status
should be a consideration in practice when discussing an individual patient’s’ candidacy
for tebentafusp.
The subgroup analysis of patients with larger metastatic lesions (AJCC M1b or M1c disease)
compared to smaller metastatic lesions (AJCC M1a disease) suggests that tebentafusp may
not be as beneficial for patients with high tumor burden and that patients with early
metastatic disease may derive the most survival benefit. Furthermore, since ORR was low
at 9% in the phase III trial and prior early-phase data showed a median time to response
of 7.4 months [44], tebentafusp may not be the best upfront agent for patients with rapidly
progressive disease. These data highlight that for some patients who do not have the time
Author Manuscript
to wait for a response on tebentafusp, other therapies are needed. Liver-directed therapies
such as chemoembolization have shown benefit in some patients with bulky liver disease
[58-60], but the benefit of sequencing liver-directed therapies with tebentafusp has not yet
been studied.
Another major limitation of tebentafusp is its exclusive binding in the context of HLA-
A*0201, a subtype that is expressed in approximately 50% of Caucasians [61,62]. This
restriction highlights an unmet therapeutic need among patients with other HLA subtypes,
Author Manuscript
as there are no FDA-approved treatments to date that apply specifically to this population.
IMMTacs targeting gp100 in the context of other relatively common HLA subtypes such as
HLA-A*0101 and HLA-A*0301[62,63] would be of utility.
Several questions remain unanswered. For instance, the optimal duration of treatment on
tebentafusp is unknown. The median duration of treatment in the phase I trial was 6-7.5
cycles[44] and in the phase II trial was 5.5 months, with 17% of patients remaining
on treatment at the time of data cutoff[51]. In all trials, toxicities were generally mild,
predictable, and easily managed. Rates of drug discontinuation from toxicity were low, and
most adverse events took place early in the treatment course. Until there are further data to
suggest otherwise, it may be a reasonable approach to continue tebentafusp until confirmed
radiologic progression, as is done with other immunotherapies.
Author Manuscript
As with other immunotherapies, the optimal method to evaluate treatment response on

tebentafusp is unclear. In both the early phase and phase III trials, there was a discordance
between survival benefit and radiographic response using RECIST 1.1 criteria, highlighting
the shortcomings of traditional measures of response as well as the need for other clinical
and laboratory markers of anti-tumor activity. Although development of rash within one
week correlated with improved survival in the phase III trial, it was not a significant
independent predictor of survival in a multivariable analysis[53]. In phase I trials, below-
median increase in IL-10 was associated with greater tumor shrinkage[44] and induction
of serum CXCL10 and CXCL11 were associated improved survival[46]. Incidence of CRS
after the first dose of tebentafusp also appeared to be associated with greater reduction
in tumor size in the first-in-man trial[46,64]. Similar data have not yet been reported
from the phase III trial. Reduction in circulating tumor DNA (ctDNA) is a promising
Author Manuscript
surrogate for clinical benefit. In the phase II trial, baseline ctDNA level was associated
with tumor burden, and reduction of ctDNA with tebentafusp by week 9 of treatment was
associated with improved OS even among patients who had radiographic evidence of disease
progression[51,52]. Expanded ctDNA testing will be necessary to better characterize its role
as an indicator of treatment benefit.
Objectives of ongoing and future trials include identifying the optimal sequence of treatment
between tebentafusp and checkpoint blockade, as well as the benefit of combining the two
modalities. NCT02535078 is an ongoing phase 1b/2 study of combination tebentafusp with
durvalumab and/or tremelimumab in metastatic cutaneous melanoma that is refractory to
prior PD-1 inhibitors. Within uveal melanoma, phase I data showed that tebentafusp led to
an increase in tumor PD-L1 expression[46], suggesting a potential benefit of administering
Author Manuscript
immunotherapy after tebentafusp. Thirty-five percent of patients who received tebentafusp in

the phase III trial subsequently received a PD-1 inhibitor[53]; subgroup analysis of patients
by subsequent systemic therapy received may be informative.
Six percent of patients in the phase III tebentafusp arm underwent subsequent liver-directed
local therapy. While regional therapies have shown benefit in carefully selected patients with
oligometastatic liver disease, prospective data is largely limited to single-institution trials.
It is still unclear whether they will have an increasing role as concurrent or subsequent
therapies for patients treated with tebentafusp, but as discussed above, they may provide
Author Manuscript
benefit as upfront treatment prior to tebentafusp for patients with bulky disease. The safety
and efficacy of tebentafusp in combination or in sequence with liver-directed therapies is an
important area of future investigation. Given the survival benefit achieved with tebentafusp
in advanced disease as well as the association of benefit with lower overall disease burden,
the evaluation of tebentafusp in the adjuvant setting after definitive therapy of primary
disease is also of high priority.
Finally, in addition to gp100, other therapeutic targets in metastatic uveal melanoma have
emerged and are being studied. PRAME (preferentially expressed antigen in melanoma) is
highly expressed in Class 1 uveal melanomas and is an independent biomarker for increased
metastatic risk[65]. Immunocore recently developed IMC-F106C, an ImmTAC with a T-cell
receptor that targets PRAME, which is being studied in an ongoing Phase 1 and 2 study for
HLA-A*0201-positive patients with PRAME-positive tumors.
Author Manuscript
While there are some limitations to its use, tebentafusp is an exciting new drug for
metastatic uveal melanoma. The unsettled questions that remain, including proper disease
response monitoring and benefit in other treatment settings, should be subjects of future
investigation.
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recognition and management. Blood [Internet]. 2016;127:3321–3330. Available from: 10.1182/
blood-2016-04-703751. [PubMed: 27207799]
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Article highlights
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• Uveal melanoma is a rare disease with effective therapies for local disease
but with a high risk of metastasis that is influenced by disease stage, tumor
cytogenetics, and tumor gene expression.
• There are few treatment options for metastatic uveal melanoma, as

chemotherapy, immune checkpoint inhibitors, and targeted therapies have had
disappointing results.
• Tebentafusp is a first-in-class immune-mobilizing monoclonal T cell receptor

against cancer (ImmTAC) that has a high binding affinity for the melanoma-
associated antigen gp100 presented by HLA-A*0201 and relatively low
binding affinity for CD3.
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• In preclinical studies, tebentafusp was shown to have high tumor antigen

specificity and a wide therapeutic window.
• In phase I and II trials, treatment with tebentafusp using a dose escalation

regimen was feasible with an acceptable toxicity profile and showed activity
in patients with metastatic uveal melanoma.
• In a randomized phase III trial, first-line tebentafusp showed superior PFS and
OS compared to single-agent chemotherapy or immune checkpoint inhibitor.
• In 2022, tebentafusp became the first FDA- and EMA- approved agent for
metastatic uveal melanoma.
• In most cases, tebentafusp should be the preferred front-line agent for the
treatment of metastatic uveal melanoma. However, it is limited to patients
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with HLA-A2*0201 positivity and may not be the preferred upfront agent in
patients with rapidly progressing disease or high tumor burden.
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Figure 1.
A) ImmTAC molecules are bispecific molecules that include an antigen-binding T-cell
receptor (TCR) and an anti-CD3 domain. B) The antigen-binding TCR recognizes a specific
peptide-HLA complex on the target tumor cell, while the anti-CD3 fragment binds to CD3
on circulating T cells, thus redirecting and activating T cells for tumor cell killing
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Table 1.
Summary of Clinical Trials

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Trial Phase Study Interventions Study Size References

NCT01211262 I/II IMCgp100 weekly IV fixed dosing (Arm 1) vs. IMCgp100 N = 84 [46]
daily IV dosing (Arm 2)
NCT02570308 I/II Three-week step-up dosing regimen with 20 mcg for week 1, N = 42 (Phase I) [44,51]
30 mcg for week 2, then dose escalation for week 3, with 68 N = 127 (Phase II)
mcg as the identified R2PD for week 3
NCT03070392 III Tebentafusp (20 mcg D1, 30 mcg D8, 68 mcg thereafter) vs. N = 378; Tebentafusp (N = 252) [53]
Investigator’s choice systemic therapy vs. Placebo (N = 126)
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Table 2.
Summary of Adverse Events for Patients who received Tebentafusp on Clinical Trial
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Trial Phase Any Grade Grade ≥3 Adverse Events n References

Adverse Events n (%)
(%)
I/II Dermatologic Rash: 57 (68) Rash: 22 (26) [46]
Pruritis: 59 (70) Pruritis: 1(1)
Skin exfoliation: 24 (29) Skin exfoliation: 0 (0)
NCT01211262 Dry skin: 23 (27) Erythema: 19 (23) Dry skin: 0 (0)
N=84 Erythema: 0 (0)
Cytokine CRS: 50 (60) CRS: 0 (0)

Release Other CRS-related: 8 (10) Other CRS-related: 8 (10)
Syndrome
I Dermatologic Rash 13 (31) Rash 2 (4.8) [44]
Rash generalized: 9 (21.4) Rash generalized: 1 (2.4)
Pruritis: 30 (71.4) Pruritis: 2 (4.8)
Skin exfoliation: 5 (11.9) Skin exfoliation: 0 (0)
Dry skin: 27 (64.3) Dry skin: 0 (0)
Erythema: 17 (40.5) Erythema: 2 (4.8)
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Pigment Change: 18 (42.8) Pigment Change: 0 (0)
NCT02570308 Cytokine CRS: 38 (90) CRS: 1 (2%)

N=42 Release CRS requiring tocilizumab: 0 (0)
Syndrome CRS requiring supplemental oxygen:
1 (2)
Hepatic Toxicity AST increased: 8 (19) AST increased: 4 (9.5)

Alkaline phosphatase increased: 8 (19) Alkaline phosphatase increased: 2
Hepatic pain: 7 (16.7) (4.8)
Hyperbilirubinemia: 6 (14.3) Hepatic pain: 0 (0)
Hyperbilirubinemia: 2 (4.8)
II Dermatologic Rash: 81 (64) Rash: 16 (13) [51]

Pruritis: 85 (67)
NCT02570308 Cytokine CRS: 109 (86) CRS: 5 (4)

N=127 Release
Syndrome
Hepatic Toxicity Not reported AST increased: 6 (5)
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III Dermatologic Rash: 203 (83) Rash: 45 (18) [53]

Pruritis: 169 (69) Pruritis: 11 (4)
Dry skin: 72 (29) Dry skin: 0 (0)
Erythema: 56 (23) Erythema: 0 (0)
NCT03070392 Cytokine CRS: 217 (89) CRS: 2 (1)

N=252 Release
Syndrome
Hepatic Toxicity AST increased: 47 (19) AST increased: 11 (4)
ALT increased: 43 (18) ALT increased: 7 (3)
Hyperbilirubinemia: 21 (9) Hyperbilirubinemia: 5 (2)
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Table 3.
Comparison of Immune-mobilizing monoclonal T-cell receptors (IMMTac) with other Immunotherapies that
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Engage and/or Activate T cells
Drug Drug Design Advantages Disadvantages Notable Adverse References

Class Examples and Events
(FDA- Mechanism
approved) of
Action
Immune- Tebentafusp Bispecific Very high Restricted to a • Cytokine-release [66]
mobilizing molecule TCR affinity specific HLA syndrome,
monoclonal consisting of a for tumor- subtype usually low-grade
T-cell monoclonal T- specific target
receptor cell receptor antigen (HLA- • Other cytokine-
(IMMTac) (which peptide mediated events
recognizes a complex)
• Skin toxicity (on-
specific HLA-
target off-tumor
peptide High
effect of
complex) fused specificity for
Tebentafusp)
to an anti-CD3 target antigen
antibody.
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Results in Access to a
recruitment of broad range of
polyclona1 T tumor targets:
cells to tumor Can be
cells designed to
target both
intracellular
and
extracellular
antigens
presented by
HLA
Bispecific Blinatumomab Bispecific Not MHC- Fewer potential • Cytokine-release [66]

T-cell antibody that specific, so tumor targets syndrome
Engager consists of two can be used compared to
separate regardless of IMMTac • Cytopenias
single-chain HLA subtype platform: Does
• Neurotoxicity
variable not target
regions, one High intracellular
that recognizes specificity for tumor antigens
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a tumor- target antigen

associated
antigen (ex. Targets cell
CD19) and surface
another that antigens
recognizes the
Fc region of
the CD3
receptor on T
cells. Acts as a
linker between
T cells and a
specific target
antigen on
tumor cell
Immune Nivolumab Monoclonal Broad Causes • Fatigue [67]

Checkpoint Ipilimumab antibody that spectrum of indiscriminate T
Inhibitor Pembrolizumab targets PD-1, activity with cell activation • Immune-
PD-L1, or indications that can lead to mediated
CTLA-4 in across immune-related toxicities: Skin
rash, Diarrhea/
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order to block multiple tumor organ toxicities

T cell types, mainly Colitis,
inhibitory solid tumors Anti-tumor Endocrine
interactions effect relies on toxicities
and allow for Durable tumor (hypophysitis,
anti-tumor T responses infiltration of T- thyroiditis,
cell activity observed cells adrenal
insufficiency),
Pneumonitis,
Drug Drug Design Advantages Disadvantages Notable Adverse References

Class Examples and Events
(FDA- Mechanism
Author Manuscript
approved) of
Action
Hepatic toxicities
(commonly
asymptomatic
AST/ALT
elevations)
Chimeric Abecma Autologous T- Growing Complex • Cytokine-release [68,69]

Antigen (idecabtagene cells undergo application production syndrome,
Receptor vicleucel) ex vivo genetic across process for ex including high-
(CAR)-T Breyanzi engineering to hematologic vivo genetic grade events
Cell (lisocabtagen e express a malignancies modification and requiring
Therapy maraleucel) chimeric T cell expansion tocilizumab and
Kymriah antigen “Living drug” intensive care
(tisagenlecleucel) receptor that with both Requires
Tecartus includes an immediate and prolonged • Neurologic
(brexucabtagene extracellular long-term anti- inpatient toxicities
autoleucel) tumor-targeted tumor activity monitoring after
• Hypersensitivity
Yescarta antibody autologous T
reactions
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(axicabtagene fragment and cell infusion

ciloleucel) intracellular T- • Cytopenias
cell activating High rate of
domains. adverse events, • Prolonged
Engineered some life- hypogammaglo
cells are threatening bulinemia
infused and
target tumor Little activity in
cells. solid tumors
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Author Manuscript

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Tebentafusp for the treatment of HLA-A*02:01–positive adult

DecisionDx-UM, which is a 15-gene expression panel, uses next-generation sequencing to

Chemotherapeutic agents such as dacarbazine, temozolomide, and cisplatin have not

an immunosuppressive liver environment, which may explain its relative insensitivity to

2. TEBENTAFUSP: DRUG INTRODUCTION

Tebentafusp consists of a mTCR that recognizes glycoprotein 100 (gp100), a peptide

2.2 Drug Metabolism

3. EARLY PHASE CLINICAL TRIALS

of tebentafusp in metastatic or unresectable melanoma (NCT01211262, Table 1) [46]. This

Tebentafusp was well-tolerated, and toxicities were mostly cytokine-mediated or

Analysis of post-treatment patient serum samples revealed increased levels of IFN-inducible

3.2 Phase I/II Trial with step-up dosing regimen

To assess the pharmacodynamic response to tebentafusp, serum cytokine profiles were

Common TRAEs included cutaneous and cytokine-mediated events, consistent with

imaging, and 100% were alive at 1 year [52].

4. RANDOMIZED PHASE III TRIAL

permitted to cross over to receive tebentafusp.

overall survival compared to investigator’s choice of treatment with either pembrolizumab,

immunotherapy drug classes that activate and/or engage T cells.

reflect the difficulty of effectively administering a weekly systemic treatment in patients

As with other immunotherapies, the optimal method to evaluate treatment response on

immunotherapy after tebentafusp. Thirty-five percent of patients who received tebentafusp in

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PLoS One [Internet]. 2018;13:e0205491. Available from: 10.1371/journal.pone.0205491.

(mUM). Ann Oncol. 2020;31:S1441–S1451. *Phase II trial of tebentafusp in metastatic uveal

Cancer Discov. 2013;3:388–398. [PubMed: 23550147]

• There are few treatment options for metastatic uveal melanoma, as

• Tebentafusp is a first-in-class immune-mobilizing monoclonal T cell receptor

• In preclinical studies, tebentafusp was shown to have high tumor antigen

• In phase I and II trials, treatment with tebentafusp using a dose escalation

Summary of Clinical Trials

Trial Phase Study Interventions Study Size References

Trial Phase Any Grade Grade ≥3 Adverse Events n References

Cytokine CRS: 50 (60) CRS: 0 (0)

Pigment Change: 18 (42.8) Pigment Change: 0 (0)

NCT02570308 Cytokine CRS: 38 (90) CRS: 1 (2%)

Hepatic Toxicity AST increased: 8 (19) AST increased: 4 (9.5)

II Dermatologic Rash: 81 (64) Rash: 16 (13) [51]

NCT02570308 Cytokine CRS: 109 (86) CRS: 5 (4)

III Dermatologic Rash: 203 (83) Rash: 45 (18) [53]

NCT03070392 Cytokine CRS: 217 (89) CRS: 2 (1)

Engage and/or Activate T cells

Drug Drug Design Advantages Disadvantages Notable Adverse References

Bispecific Blinatumomab Bispecific Not MHC- Fewer potential • Cytokine-release [66]

a tumor- target antigen

Immune Nivolumab Monoclonal Broad Causes • Fatigue [67]

order to block multiple tumor organ toxicities

Drug Drug Design Advantages Disadvantages Notable Adverse References

Chimeric Abecma Autologous T- Growing Complex • Cytokine-release [68,69]