Tebentafusp improves OS in advanced uveal melanoma
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Tebentafusp significantly prolonged OS compared with immune checkpoint inhibitors and other standard therapies among previously untreated patients with metastatic uveal melanoma, results of a randomized phase 3 study showed.
The investigational bispecific fusion protein also had a manageable safety profile, according to the findings, presented during the virtual American Association for Cancer Research Annual Meeting.
“Uveal melanoma is a rare cancer with a high medical need, as patients have a very poor prognosis once the disease is metastatic. In addition, immune checkpoint blockers, which are of great benefit for patients with cutaneous melanoma, are of limited effect,” Jessica C. Hassel, MD, associate professor and section head of dermato-oncology in the department of dermatology at the National Center for Tumor Diseases of University Hospital Heidelberg in Germany, told Healio. “Therefore, other treatment strategies are urgently needed. Tebentafusp [IMCgp100, Immunocore] was developed as a bispecific fusion protein consisting of a soluble T-cell receptor that detects HLA-A*02:01, which is present in gp100 peptides, and an anti-CD3 chain that binds and activates T cells. It redirects T cells to the uveal melanoma metastases, enabling an immune attack.”
Hassel and colleagues randomly assigned 378 patients with previously untreated HLA-A*02:01-positive metastatic uveal melanoma 2:1 to tebentafusp (n = 252) or investigator’s choice of therapy, which included the PD-1 inhibitor pembrolizumab (Keytruda, Merck; n = 103), the CTLA-4 inhibitor ipilimumab (Yervoy, Bristol Myers Squibb; n = 16) or the chemotherapeutic dacarbazine (n = 7).
OS among the intention-to-treat population and OS among patients assigned tebentafusp who developed rash during week 1 of treatment served as co-primary endpoints. Secondary endpoints included investigator-assessed objective response rate and PFS.
Median follow-up was 14.1 months.
Results showed an estimated 1-year OS rate of 73.2% in the tebentafusp group vs. 58.5% in the investigator’s choice group (median, 21.7 months vs. 16 months; HR = 0.51; 95% CI, 0.36-0.71), with benefit observed across patient subgroups.
When compared with specific treatments in the investigator’s choice group, the OS benefit remained significant with tebentafusp compared with those who received pembrolizumab (HR = 0.51; 95% CI, 0.35-75) and dacarbazine (HR = 0.29; 95% CI, 0.09-0.86).
Tebentafusp also conferred a significant PFS benefit (median, 3.3 months vs. 2.9 months; HR = 0.73; 95% CI, 0.58-0.94), Hassel said, and demonstrated a disease control rate of 45.2% (95% CI, 39-51.6) vs. 27.8% (95% CI, 20.2-36.5) with investigator’s choice.
Compared with 5% of patients assigned investigator’s choice, 9% of patients assigned tebentafusp responded to treatment, including 22 patients with a partial response and one with a complete response.
Results of a post-hoc landmark OS analysis including patients with a best response of disease progression also showed superior OS with tebentafusp (HR = 0.4; 95% CI, 0.24-0.64).
“Most adverse events occurred within the first cycles of tebentafusp and decreased in severity and frequency with treatment continuation,” Hassel said. “Forty-five percent of patients developed grade 3 to grade 4 adverse events, most of which were skin-related and most likely induced by an immune attack against gp100-expressing skin melanocytes. Interestingly, patients’ skin became a bit faint and some developed gray hair. We did biopsies on the skin and are examining this. It appears that they do not lose the melanocytes, but it is a rarefication and that the skin and hair are simply ‘getting old.’ There are fewer melanocytes.”
A smaller proportion of patients in the tebentafusp group discontinued treatment due to adverse events (2% vs. 4.5%).
The next step will be to advance tebentafusp into the routine treatment setting for patients with uveal melanoma, Hassel added.
“Tebentafusp is the first therapy to improve OS in advanced uveal melanoma,” she said. “Interesting remaining questions to evaluate include whether a combination with immune checkpoint blockers may increase the benefit of tebentafusp. Also, as patients with a low tumor load seem to benefit the most, it would be interesting to evaluate the benefit of adjuvant treatment in high-risk patients after treatment of the primary. Moreover, as tebentafusp is only active in patients with HLA-A*02:01, which is the most frequent HLA type in white patients, it should also be developed for other HLA types. Last, but not least, tebentafusp has shown activity in cutaneous melanoma in a phase 1 trial and, therefore, it would be of interest to further investigate the agent for PD-1-resistant cutaneous melanoma.”
Perspective
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Antoni Ribas, MD, PhD, FAACR
This study has several firsts. It is the first-ever study that has shown an improvement in OS among patients with uveal melanoma. For patients with metastatic uveal melanoma, no effective treatment exists. During more than 50 to 60 years of research, there has never been a treatment that has shown improvement in OS — this agent is the first.
Tebentafusp is the first therapeutic targeting melanoma antigens that has shown improvement in a randomized trial. This is a practice-changing study and we hope to be able to use this agent in the clinic.
UCLA Health
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Sapna P. Patel, MD
The bispecific fusion protein molecule tebentafusp has achieved something that no other drug has achieved in uveal melanoma: improvement in OS.
HLA-A*02:01 is purported to be the most common HLA-A allele in white individuals, the racial group most frequently diagnosed with uveal melanoma. Although the overall response rate to tebentafusp was marginally better than among controls (9% vs. 5%), at median follow-up of 14.1 months, patients assigned tebentafusp had nearly half the risk for death. The 1-year OS rate also was superior in the tebentafusp group (73.2% vs. 58.5%), which represents a notable achievement in an orphan disease that affects approximately half of the six-per-million individuals diagnosed with uveal melanoma each year and stands to be practice-changing for the subset of patients with HLA-A*02:01 expression.
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Piperno-Neumann S, et al. Abstract CT002. Presented at: American Association for Cancer Research Annual Meeting (virtual meeting); April 10-15, 2021.
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