FDA Approves Tebentafusp-tebn for Unresectable or Metastatic Uveal Melanoma

FDA

The FDA has approved tebentafusp-tebn (Kimmtrak) for the treatment of HLA-A*02:01–positive adult patients with unresectable or metastatic uveal melanoma.¹

The regulatory decision is supported by data from the phase 3 IMCgp100-202 trial (NCT03070392), which showed that the agent resulted in a significant benefit in overall survival (OS) vs investigator's choice of treatment, when used in the frontline setting (HR, 0.51; 95% CI, 0.37-0.71; P < .0001).

The estimated median OS in the investigative arm was 21.7 months (95% CI, 18.6-28.6) vs 16.0 months (95% CI, 9.7-18.4) in the control arm. The estimated 1-year OS rates in the tebentafusp and investigator's choice arms were 73% (95% CI, 66%-79%) and 59% (95% CI, 48%-67%), respectively. The OS benefit with tebentafusp was generally noted across the prespecified subsets examined on the trial.

“Today’s approval of [tebentafusp] is a historic milestone and the culmination of years of dedication by the Immunocore team, patients, and our healthcare partners," Bahija Jallal, chief executive officer of Immunocore, stated in a press release. "Every year in the United States, hundreds of people are diagnosed with metastatic uveal melanoma who, until now, had no approved treatment options. [tebentafusp] is the first therapy to demonstrate a survival benefit to patients with this disease and we are focused on making [tebentafusp] available as quickly as possible."

The multicenter, randomized, phase 3 trial enrolled patients with local histologic or cytologic confirmation of metastatic uveal melanoma who were at least 18 years of age, have HLA-A*02:01 positivity, an ECOG performance status of 0 or 1, and at least 1 measurable lesion per RECIST v1.1 criteria.²

Patients could not have received prior systemic or liver-directed therapy for metastatic disease, nor could they have had symptomatic central nervous system metastases, active autoimmune disease for which they are receiving glucocorticoids, or have been receiving systemic immunosuppressive treatment.

A total of 378 participants were randomized 2:1 to receive tebentafusp (n = 252) or investigator's choice of treatment (n = 126), which could have included single-agent pembrolizumab (Keytruda; n = 103), ipilimumab (Yervoy; n = 16), or dacarbazine (n = 7).

Because intrapatient dose escalation of tebentafusp had been found to reduce toxicity, patients were given the drug intravenously (IV) at a dose of 20 μg on day 1, 30 μg on day 8, and 68 μg weekly thereafter. During the dose escalation, patients were monitored overnight after they received the treatment for the first 3 weeks.

Within the control group, IV pembrolizumab was given at a dose of 2 mg/kg of body weight to a maximum of 200 mg per dose or a fixed dose of 200 mg on day 1 of each 21-day treatment cycle. Those who received ipilimumab received it IV at a dose of 3 mg/kg on day 1 of each 21-day cycle for a maximum of 4 doses. IV dacarbazine was given at a dose of 1000 mg/m² of body surface area on day 1 of each 21-day cycle.

Patients were stratified based on their lactate dehydrogenase (LDH) status (higher than the upper limit of normal [ULN] range vs less than or equal to ULN).

With the exception of ipilimumab, treatment was given until radiographic progression, intolerable toxicity, investigator decision, or withdrawn consent.

The primary end point of the trial was OS, and secondary end points included disease control rate, objective response rate, and progression-free survival. All secondary end points were done via investigator assessment, and they were aware of the treatment assignment. Safety was also evaluated.

Among the randomized patients, 36% had a LDH level that was above the ULN, 5% had extrahepatic disease only, and the median time since their primary diagnosis was 2.8 years. No substantial difference between the groups was observed with regard to these variables.

The data cutoff date for the interim analysis of the trial was October 13, 2020, and the median duration of follow-up was 14.1 months.

Additional data showed that tebentafusp also significantly improved PFS vs investigator's choice of treatment in the intent-to-treat population. The 6-month PFS rates in the investigative and control arms were 31% and 19%, respectively (HR, 0.73; 95% CI, 0.58-0.94; P = .01).

Tebentafusp elicited an ORR of 9% (95% CI, 6%-13%) vs 5% (95% CI, 2%-10%) with investigator's choice of treatment. The median duration of response in the investigative arm was 9.9 months vs 9.7 months in the control arm. Moreover, the disease control rate proved to be higher with tebentafusp vs the control treatments, at 46% (95% CI, 39%-52%) vs 27% (95% CI, 20%-36%), respectively.

Findings from a landmark-based analysis revealed that tebtentafusp also improved survival over investigator's choice of treatment in those who experienced disease progression as their best response before day 100, at an estimated median OS of 15.3 months (95% CI, 12.0–not reached) vs 6.5 months (95% CI, 4.9-13.4), respectively (HR, 0.43; 95% CI, 0.27-0.68).

More patients who received tebentafusp experienced tumor regression that did not meet RECIST criteria for partial respones than those who received control treatment. In both arms, tumor regression was noted to be linked with longer OS.

The treatment-related adverse effects experienced with tebentafusp proved to be manageable and consistent with the proposed mechanism. The most common grade 3 or higher toxicities incluided rash (18%), pyrexia (4%), and pruritus (5%).

Among the 245 patients who received tebentafusp, grade 3 cytokine release syndrome (CRS) was experienced by less than 1% of patients and was found to be generally well managed. Notably, no grade 4 or 5 CRS effects were reported. However, a boxed warning is included for this toxicity, as it can potentially become serious or life threatening if not appropriately managed.

“Uveal melanoma is a devastating disease that has historically resulted in death within a year of metastasis for our patients,” said John Kirkwood, MD, director of the Melanoma Center at the UPMC Hillman Cancer Center, added in the press release. “The approval of tebentafusp-tebn represents a major paradigm shift in the treatment of metastatic uveal melanoma, and for the first time offers hope to those with this aggressive form of cancer.”

Immunocore Holdings Limited stated that they are ready to commercialize the product and anticipates making the agent commercially available in the United States within weeks.

In February 2021, the FDA granted a breakthrough therapy designation to tebentafusp for patients with unresectable or metastatic uveal melanoma.³ In August 2021, the FDA and the European Medicines Agency accepted applications seeking the approval of the agent for use in the treatment of adult patients with HLA-A*02:01–positive metastatic uveal melanoma.⁴

The United Kingdom's Medicines and Healthcare Regulatory Agency, Health Canada, and the Australian Government Department of Health Therapeutic Goods Administration have also accepted the submission of the company's marketing authorization application for tebentafusp.

References

1. Immunocore announces FDA approval of KIMMTRAK (tebentafusp-tebn) for the treatment of unresectable or metastatic uveal melanoma. News release. Immunocore Holdings Limited; January 26, 2022. Accessed January 26, 2022. https://yhoo.it/3r1C3fk
2. Nathan P, Hassel JC, Rutkowski P, et al. Overall survival benefit with tebentafusp in metastatic uveal melanoma. N Engl J Med. 2021;385(13):1196-1206. doi:10.1056/NEJMoa2103485
3. Immunocore's tebentafusp granted breakthrough therapy designation for unresectable or metastatic uveal melanoma from FDA. News release. Immunocore Holdings Limited; February 19, 2021. Accessed January 26, 2022. https://bit.ly/3ye8M1x
4. 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 January 26, 2022. https://bit.ly/3sHbVWx