FDA and EMA Accept Tebentafusp Applications for Metastatic Uveal Melanoma

The FDA and the European Medicines Agency have accepted applications seeking the approval of tebentafusp for use in the treatment of adult patients with HLA-A*02:01–positive metastatic uveal melanoma.

The FDA and the European Medicines Agency (EMA) have accepted applications seeking the approval of tebentafusp (IMCgp100) for use in the treatment of adult patients with HLA-A*02:01–positive metastatic uveal melanoma.1

In the United States, the regulatory agency has granted priority review to the biologics license application for the agent. The FDA is expected to decide on the BLA by February 23, 2022, under the Prescription Drug User Fee Act.

In Europe, the EMA’s Committee for Medicinal Products for Human Use accepted the marketing authorization application (MAA) for tebentafusp and has also granted a request for accelerated assessment of the application. Although the review period of a MAA can take up to 210 days, the accelerated assessment reduces the timeframe to 150 days.

Both applications are supported by findings from the phase 3 IMCgp100-202 trial (NCT03070392), in which single-agent tebentafusp resulted in a statistically significant improvement in overall survival (OS) over investigator’s choice of either pembrolizumab (Keytruda), ipilimumab (Yervoy), or dacarbazine (hazard ratio [HR], 0.51; 95% CI, 0.37-0.71; P < .0001).

At a median follow-up of 14.1 months, the median OS reported with tebentafusp was 21.7 months (95% CI, 18.6-23.6) vs 16.0 months (95% CI, 9.7-19.4) with investigator’s choice of treatment. The OS rate at 1 year was 73.2% in the investigative arm and 58.5% in the control arm.2

“There is an urgent need for an approved treatment for metastatic uveal melanoma, an aggressive form of cancer for which there are very limited treatment options,” Bahija Jallal, chief executive officer of Immunocore Holding Plc, stated in a press release. “We are excited to work with the FDA and EMA to bring tebentafusp to patients as quickly as possible.”

Uveal melanoma is a rare disease with a low mutational burden and a poor prognosis. About 50% of patients with this disease will develop metastases in the liver and only few patients will benefit from treatment with immunotherapeutics. Notably, no standard-of-care options are available for those with metastatic disease. The 1-year OS rate observed in patients with this disease in frontline trials has been approximately 50%.

Tebentafusp is a bispecific protein that is made up of a soluble T-cell receptor that is fused to an anti-CD3 immune-effector domain. The agent is designed to target the melanocytic protein gp100, which is often expressed in patients with uveal melanoma.

The phase 3 IMCgp100-202 trial enrolled a total of 378 previously untreated patients with uveal melanoma. Patients needed to be at least 18 years of age, have histologically or cytologically confirmed disease, HLA A*0201 positivity according to central assay, and an ECOG performance status of up to 1.3 Patients could enroll regardless of lactate dehydrogenase level (LDH). If patients had prior systemic treatment in the advanced setting or they received liver-directed therapy other than surgery, they were excluded.

The co-primary end points of the trial included OS in those randomized to receive tebentafusp compared with investigator’s choice of treatment in the ITT population and OS in those randomized to tebentafusp with rash during week 1 vs investigator’s choice of treatment. Secondary end points comprised objective response rate and investigator-assessed progression-free survival.

Additional data from the trial previously reported during the AACR Annual Meeting 2021 showed that the HR between the investigative and control arms in those with an LDH at the upper limit of normal (ULN) or below was 0.35 (95% CI, 0.21-0.60) compared with 0.70 (95% CI, 0.46-1.09) in those with a LDH that was higher than the ULN.3

Regarding safety, 99.6% of patients reported any-grade adverse effects (AEs), with 45% of patients experiencing effects that were grade 3 or 4 in severity. With tebentafusp, the most common any-grade cytokine-mediated AEs included cytokine release syndrome (89%), pyrexia (76%), chills (47%), nausea (43%), fatigue (41%), and hypotension (38%).

Among those who experienced grade 3/4 cytokine-mediated toxicities, 4% reported pyrexia, 3% had fatigue, and 3% reported hypotension.

Moreover, 83% of participants experienced rash with tebentafusp and 69% experienced pruritus. Other toxicities reported with the agent included dry skin (29%) and erythema (23%). Grade 3/4 rash was reported in 18% of patients and 5% of patients experienced grade 3/4 pruritus.

Most of the toxicities occurred within the first few weeks of treatment. These effects were noted to decrease in frequency and severity over time. No treatment-related deaths were reported per investigator assessment.

Previously, in February 2021, tebentafusp was granted a breakthrough therapy designation from the FDA as a potential therapeutic option for adult patients with HLA-A*02:01–positive, unresectable or metastatic uveal melanoma.4 The decision was supported by earlier data from IMCgp100-202.


  1. Immunocore announces the US Food and Drug Administration and European Medicines Agency accept biologics license application and marketing authorization application for tebentafusp in metastatic uveal melanoma. News release. Immunocore Holdings Limited. August 24, 2021. Accessed August 24, 2021. https://bit.ly/3sHbVWx
  2. Safety and efficacy of IMCgp100 versus investigator choice in advanced uveal melanoma. ClinicalTrials.gov. Updated February 25, 2021. Accessed April 9, 2021. https://clinicaltrials.gov/ct2/show/NCT03070392
  3. Piperno-Neumann S, Hassel JC, Rutkowski P, et al. Phase 3 randomized trial compared tebentafusp with investigator’s choice in first line metastatic uveal melanoma. Cancer Res. 2021;81(13). doi:10.1158/1538-7445.AM2021-CT002
  4. Immunocore’s tebentafusp granted breakthrough therapy designation for unresectable or metastatic uveal melanoma from FDA. News release. Immunocore Holdings Limited. February 19, 2021. Accessed August 24, 2021. https://bit.ly/3ye8M1x