Three-Year Overall Survival with Tebentafusp in Metastatic Uveal Melanoma

Abstract

Background: Tebentafusp, a T-cell receptor-bispecific molecule that targets glycoprotein 100 and CD3, is approved for adult patients who are positive for HLA-A*02:01 and have unresectable or metastatic uveal melanoma. The primary analysis in the present phase 3 trial supported a long-term survival benefit associated with the drug.

Methods: We report the 3-year efficacy and safety results from our open-label, phase 3 trial in which HLA-A*02:01-positive patients with previously untreated metastatic uveal melanoma were randomly assigned in a 2:1 ratio to receive tebentafusp (tebentafusp group) or the investigator's choice of therapy with pembrolizumab, ipilimumab, or dacarbazine (control group), with randomization stratified according to the lactate dehydrogenase level. The primary end point was overall survival.

Results: At a minimum follow-up of 36 months, median overall survival was 21.6 months in the tebentafusp group and 16.9 months in the control group (hazard ratio for death, 0.68; 95% confidence interval, 0.54 to 0.87). The estimated percentage of patients surviving at 3 years was 27% in the tebentafusp group and 18% in the control group. The most common treatment-related adverse events of any grade in the tebentafusp group were rash (83%), pyrexia (76%), pruritus (70%), and hypotension (38%). Most tebentafusp-related adverse events occurred early during treatment, and no new adverse events were observed with long-term administration. The percentage of patients who discontinued treatment because of adverse events continued to be low in both treatment groups (2% in the tebentafusp group and 5% in the control group). No treatment-related deaths occurred.

Conclusions: This 3-year analysis supported a continued long-term benefit of tebentafusp for overall survival among adult HLA-A*02:01-positive patients with previously untreated metastatic uveal melanoma. (Funded by Immunocore; IMCgp100-202 ClinicalTrials.gov number, NCT03070392; EudraCT number, 2015-003153-18.).

Figure 1.. Kaplan–Meier Estimates of Overall Survival and Progression-free Survival in the Intention-to-Treat Population.

Patients in the control group received the investigator’s choice of single-agent therapy with pembrolizumab, ipilimumab, or dacarbazine. Tick marks indicate censored data.

Figure 2.. Kaplan–Meier Estimates of Postlandmark Overall Survival among Patients with Best Overall Response of Disease Progression.

Shown is overall survival after the landmark (day 100 after randomization) among the patients with a best overall response of progressive disease before the landmark, with progressive disease defined according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. Tick marks indicate censored data.

Figure 3.. Dynamics of Circulating Tumor DNA and Association with Overall Survival in Patients Treated with Tebentafusp.

Panel A shows a waterfall plot of percent changes in the circulating tumor DNA (ctDNA) level at week 9 during treatment in all 123 tebentafusp-treated patients with evaluable data. Panel B shows Kaplan–Meier estimates of overall survival from week 9 among tebentafusp-treated patients who had ctDNA clearance as compared with those who did not have ctDNA clearance at week 9. Panel C shows K aplan–Meier estimates of overall survival from week 9 among tebentafusp-treated patients who had a reduction of at least 50% in the ctDNA level as compared with those who had a reduction of less than 50%, no change, or an increase at week 9. Tick marks in Panels B and C indicate censored data.

Figure 4.. Long-term Frequency and Severity of Selected Treatment-Related Adverse Events with Tebentafusp.

The numbers of patients at risk for each time interval are indicated. Rash, hypotension, and liver-function tests (i.e., elevated liver-function values) are composite terms for a list of related adverse events of any grade (Table S11).