MADRID — The significant survival benefit with the bispecific T-cell receptor therapy tebentafusp (Kimmtrak) held up at 3 years for selected patients with previously untreated metastatic uveal melanoma, updated results of a phase III trial demonstrated.
In HLA-A*02:01-positive patients, landmark analyses showed improved overall survival (OS) at 1, 2, and 3 years with tebentafusp versus investigator’s choice of single-agent therapy, most commonly a PD-1 inhibitor:
- 1 year: 72% vs 60%, respectively
- 2 years: 45% vs 30%
- 3 years: 27% vs 18%
Tebentafusp induced greater disease control — including durable responses and tumor shrinkage — along with a high rate of circulating tumor DNA (ctDNA) reduction, and “there were no new safety signals,” reported Sophie Piperno-Neumann, MD, of Institut Curie in Paris, at the European Society for Medical Oncology (ESMO) congress.
In fact, total ctDNA clearance at 9 weeks was observed in more than a third of tebentafusp-treated patients, and the median OS was nearly tripled in this group compared to those without clearance (29.6 vs 10.2 months), according to the findings, which were published simultaneously in the New England Journal of Medicine.
Part of a class of molecules termed immune-mobilizing monoclonal T-cell receptors against cancer (ImmTAC), tebentafusp was approved last year based on initial findings from this trial (IMCgp100-202); the ImmTAC represents the only agent specifically indicated for unresectable or metastatic uveal melanoma.
While this tumor type is considered rare, at 3% to 5% of all melanomas, it is the most common primary intraocular malignancy among adults, according to the NIH. (Approximately 45% of individuals in the U.S. are HLA-A*02:01-positive.)
Piperno-Neumann reported that the new findings are the first to demonstrate a long-term survival benefit in this patient population. But a challenge with tebentafusp is that typical response evaluations by RECIST (response evaluation criteria in solid tumors) underestimate the survival benefit, she said.
“The role of ctDNA cannot be overemphasised here as an indicator of initial benefit that is missed in RECIST,” said ESMO discussant Omid Hamid, MD, of the Angeles Clinic and Research Institute in Los Angeles.
Exploratory ctDNA analysis of tebentafusp-treated patients showed that 88% had some form of reduction at 9 weeks, with 44% having a reduction of 50% or more and 37% having total clearance. Within the tebentafusp arm, reductions in ctDNA of 50% or greater were associated with improved OS as well (HR 0.41, 95% CI 0.25-0.67).
Hamid added that “even patients that have been called progressers had major cytologic response with circulating tumor DNA.”
From March 2017 to June 2020, the open-label IMCgp100-202 trial randomized 378 HLA-A*02:01-positive patients with previously untreated metastatic uveal melanoma in a 2:1 ratio to either tebentafusp or investigator’s choice of single-agent pembrolizumab (Keytruda; 82%), ipilimumab (Yervoy; 13%), or dacarbazine (6%). The exploratory analysis of ctDNA response included 123 evaluable patients from the tebentafusp arm.
Baseline characteristics were generally well balanced, said Piperno-Neumann. Median participant age was about 65, half were women, and 36% had elevated LDH (a stratification factor). Half had extrahepatic metastatic lesions and 45% had at least one metastatic lesion of 3 cm or greater.
At ESMO, Piperno-Neumann presented the 3-year efficacy and safety data (median follow-up 43 months) of the trial, which had a primary endpoint of OS.
In line with prior reports, median OS was a superior 21.6 months in the tebentafusp arm versus 16.9 months in the control arm (HR 0.68, 95% CI 0.54-0.87), while median progression-free survival was 3.4 and 2.9 months, respectively (HR 0.76, 95% CI 0.60-0.97).
Investigators recorded more objective responses in the tebentafusp arm (11%; one complete response) versus the control arm (5%; none) and higher rates of stable disease (35% vs 22%), resulting in disease control rates of 46% with tebentafusp and 27% with investigator’s choice of therapy.
Median duration of response was 11.1 months versus 9.7 months, respectively, with a third of tebentafusp responders maintaining their response for 18 months or beyond as compared with none of the responders in the control arm. Even patients with stable disease on tebentafusp have tumor shrinkage that behaves like a partial response, said Piperno-Neumann.
Among patients considered to have progressive disease as their best response to either therapy, treatment with tebentafusp still demonstrated superior OS (15.1 vs 10.1 months; HR 0.62, 95% CI 0.44-0.89), and the separation in curves was still visible at 3 years, said Piperno-Neumann.
In terms of tebentafusp’s safety, treatment-related adverse events (AEs) largely consisted of rash (83%), pyrexia (76%), pruritus (70%), and hypotension (38%). Grade 3/4 treatment-related AEs occurred in 47%, with rash (19%) and elevated aspartate aminotransferase level (6%) most common.
Most of the toxicity was seen in the first 4 weeks of tebentafusp treatment and decreased over time both in frequency and severity, despite repeated dosing, said Piperno-Neumann. “At the end, AEs were manageable, with a very low rate of discontinuation [2%] and no treatment-related deaths.”
The study was funded by Immunocore.
Piperno-Neumann disclosed relationships with Immunocore, Novartis, and Pierre Fabre Pharmaceuticals. Co-investigators reported numerous relationships, including with the study funder.
New England Journal of Medicine
Source Reference: Hassel JC, et al “Three-year overall survival with tebentafusp in metastatic uveal melanoma” N Engl J Med 2023; DOI: 10.1056/NEJMoa2304753.