The bispecific antibody achieves another success, halving the risk of death from metastatic uveal melanoma

Metastatic uveal melanoma (mUM) currently lacks standard treatment options.
Potential treatment options include chemotherapy, targeted therapy, and immunotherapy, but no method has shown satisfactory results so far
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Immune checkpoint inhibitors have a better effect on skin melanoma, but they have not shown the same effect on uveal melanoma
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Patients with mUM urgently need effective treatment drugs
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On September 23, 2021, the New England Journal of Medicine (NEJM) published a phase 3 clinical trial of a new immunotherapy drug tebentafusp for the treatment of metastatic uveal melanoma.
The results confirmed that tebentafusp can significantly improve the overall outcome of patients with metastatic uveal melanoma.
Lifetime
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Professor Antoni Ribas, chairman of the American Society for Cancer Research (AACR), said that the study "is the first study ever to improve the overall survival of metastatic uveal melanoma.
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it will change the clinical treatment practice of metastatic uveal melanoma
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"NEJM Frontiers of Medicine" invited the team of Professor Wei Wenbin from Beijing Tongren Hospital of Capital Medical University to comment on this research in depth
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To read the full text translation, please visit the official website and APP of "NEJM Medical Frontier" or click on the picture of the WeChat applet
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Li Yitong, Wei Wenbin *Department of Ophthalmology, Beijing Tongren Hospital, Capital Medical University; School of Ophthalmology, Capital Medical University* Corresponding author, Uveal melanoma is the primary malignant tumor with the highest incidence in the adult eye, and about 12% to 49% of patients are affected Distant metastasis will occur within 10 years after diagnosis [1]
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Due to the low mutation load of uveal melanoma [2] and the special immune exemption mechanism [3], the current immune checkpoint inhibitors [4], tumor vaccines [5] and adoptive T cell therapy [6] are not effective Very ideal
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Once distant metastasis occurs, the median survival time of the patient is less than one year [7]
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There is an urgent need for drugs that are effective for mUM to prevent disease progression and prolong patient survival
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Encouragingly, studies have found that tebentafusp (IMCgp100), a monoclonal T-cell redirection bispecific fusion protein targeting gp100 for anti-cancer immune mobilization (ImmTAC), seems to be the most effective drug for mUM at present[ 8]
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Once it binds to the specific peptide-HLA complex on the surface of the target cell, it can recruit and activate the target cell, thereby redirecting CD3+ T cells and inducing cell lysis [9]
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In a previously published phase 2 multicenter study on tebentafusp, 127 patients received 68 mg of tebentafusp, and the 12-month overall survival rate was 62%, showing good results [10]
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On September 23, 2021, the results of the Phase 3 clinical trial of tebentafusp were published in NEJM, further supporting its therapeutic effect on mUM and providing new possibilities for the treatment of mUM patients in the future [11]
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This study is a phase 3 clinical study led by Professor Paul Natha of Mount Vernon Cancer Center.
It finally enrolled 378 HLA-A*02:01-positive mUM patients who met the criteria, of which 252 were included in the tebentafusp group, and the remaining 126 were It was included in the control group (82% received pembrolizumab, 13% received ipilimumab, and 6% received dacarbazine)
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Only 2% of patients in the tebentafusp group discontinued the trial due to adverse events, and no treatment-related deaths were reported
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The median follow-up time was 14.
1 months
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In terms of the overall survival rate of the intention-to-treat population, the 1-year overall survival rate was 73% (95% CI, 66%~79%) in the tebentafusp group and 59% (95% CI, 48%~67%) in the control group
.

The estimated median overall survival of the tebentafusp group was 21.
7 months (95% CI, 18.
6-28.
6), and the control group was 16 months (95% CI, 9.
7-18.
4)
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The risk ratio of death was 0.
51 (95% CI, 0.
37 to 0.
71), indicating that tebentafusp is more effective
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What's more commendable is that the significant efficacy of tebentafusp is universally seen in the pre-specified subgroups.
This result can further increase the credibility of the drug's efficacy
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The study set 4 secondary endpoints at the same time, and tebentafus showed good results in each endpoint
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In terms of disease progression-free survival, the progression-free survival rate at 6 months in the tebentafus group was 31%, and the control group was 19%, and the stratified hazard ratio for disease progression or death was 0.
73 (95% CI, 0.
58~0.
94); In terms of the objective disease response rate, the proportion of patients with objective response in the tebentafus group was 9%, and that in the control group was 5%
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Among the patients with the best therapeutic effect within 100 days of treatment, the median survival time of the tebentafus group was 15.
3 months and that of the control group was 6.
5 months, and this difference was not related to baseline prognostic factors
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In terms of disease control, the proportion of the tebentafus group was 46% (95% CI, 39%~52%), and the control group was 27% (95% CI, 20%~36%)
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Unfortunately, the tumor regression in the tebentafusp group did not meet the RECIST partial remission criteria, but no matter whether the tumor shrinks or not, a survival benefit was observed in the tebentafus group
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The most common adverse events caused by tebentafus treatment are cytokine release syndrome and skin-related adverse events, such as rash (83%), fever (76%), pruritus (69%); adverse events in most (57%) patients The incident occurred during the dose escalation period
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However, adverse reactions did not affect compliance (2% and 5% of patients in the tebentafusp group and the control group discontinued the trial), the appearance of rash or anti-tebentafusp antibodies did not affect the overall survival, and there were no treatment-related deaths in the test group and the control group.

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The current guidelines mainly recommend local treatment for mUM [12]
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The guidelines encourage more patients to participate in clinical trials, because systemic treatment still lacks strong evidence to support any drug
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This study shows the results of the Phase 3 study of the new drug tebentafusp, with outstanding overall efficacy and not serious adverse reactions.
If approved for clinical use, it may provide new treatment ideas for patients with uveal melanoma
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However, the mechanism of action of tebentafusp suggests that it may only be effective for patients with specific HLA alleles
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If the drug is put into use in China, it needs the cooperation of corresponding genetic testing technology.
The economic burden, clinical treatment costs and technical requirements brought about by this may limit its wide application
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Its effectiveness and safety need to be further confirmed by a large sample of phase 4 clinical trials.
At the same time, for non-HLA*02:01-positive patient groups, it is also necessary to continue to study other potentially effective drugs or therapies
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Tebentafusp in the treatment of metastatic uveal melanoma Tebentafusp in Metastatic Uveal Melanoma September 23, 2021 Reader: Dr.
Stephen Morrissey, NEJM Executive Editor Reference 1.
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Metastasis of uveal melanoma millimeter-by-millimeter in 8033 consecutive eyes.
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2.
Durante MA, Rodriguez DA, Kurtenbach S, et al.
Single-cell analysis reveals new evolutionary complexity in uveal melanoma.
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Review of ocular immune privilege in the year 2010: Modifying the immune privilege of the eye.
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4.
Algazi AP, Tsai KK, Shoushtari AN, et al.
Clinical outcomes in metastatic uveal melanoma treated with PD-1 and PD-L1 antibodies.
Cancer 2016;122:3344-53.
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Twelve-year survival and immune correlates in dendritic cell-vaccinated melanoma patients.
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Ann Oncol.
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Role of immune checkpoint inhibitors and novel immunotherapies in uveal melanoma.
Chin Clin Oncol 2018;7:8.
9.
Boudousquie C, Bossi G, Hurst JM, et al.
Polyfunctional response by ImmTAC (IMCgp100) redirected CD8+ and CD4+ T cells.
Immunology 2017;152:425-38.
10.
Sacco JJ, Carvajal R, Butler MO, et al.
A phase (ph) II,multi-center study of the safety and efficacy of tebentafusp (tebe) (IMCgp100) in patients (pts) with metastatic uveal melanoma (mUM).
Ann Oncol 2020;31:S1442-S1443.
11.
Nathan P, Hassel JC, Rutkowski P , et al.
Overall survival benefit with tebentafusp in metastatic uveal melanoma.
N Engl J Med 2021;385:1196-206.
12.
NCCN Guidelines for Uveal Melanoma Version 2021.
https:// professionals/ physician_gls/pdf/ uveal.
pdf.
Author introduction Wei Wenbin, Deputy Dean and Director of Ophthalmology Department of Beijing Tongren Hospital Affiliated to Capital Medical University, Associate Dean and Doctoral Supervisor of the School of Ophthalmology, Capital Medical University, Director of the Key Laboratory of Medical Artificial Intelligence Research and Verification, Ministry of Industry and Information Technology, Intraocular Tumor Director of Beijing Key Laboratory of Diagnosis, Treatment and Research// professionals/ physician_gls/pdf/uveal.
pdf.
Author introduction Wei Wenbin, Deputy Dean and Director of Ophthalmology Department of Beijing Tongren Hospital Affiliated to Capital Medical University, Associate Dean and Doctoral Supervisor of School of Ophthalmology, Capital Medical University, Medicine Director of the Key Laboratory of the Ministry of Industry and Information Technology for Artificial Intelligence Research and Verification, Director of the Beijing Key Laboratory of Intraocular Tumor Diagnosis and Treatment// professionals/ physician_gls/pdf/uveal.
pdf.
Author introduction Wei Wenbin, Deputy Dean and Director of Ophthalmology Department of Beijing Tongren Hospital Affiliated to Capital Medical University, Associate Dean and Doctoral Supervisor of School of Ophthalmology, Capital Medical University, Medicine Director of the Key Laboratory of the Ministry of Industry and Information Technology for Artificial Intelligence Research and Verification, Director of the Beijing Key Laboratory of Intraocular Tumor Diagnosis and Treatment
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He is currently the associate editor of "Chinese Journal of Ophthalmology", "Chinese Journal of Ophthalmology", "International Ophthalmology Overview", "Ophthalmology", "Journal of Practical Blindness Prevention Technology"
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Chairman of the Ophthalmology Committee of the Chinese Society of Medical Education, Deputy Leader of the Ophthalmology Group of the Standing Committee of the Ophthalmology Branch of the Chinese Medical Association, Deputy Director of the Ophthalmology Professional Committee of the Standing Committee of the Ophthalmology Branch of the Chinese Medical Doctor Association, President of the Beijing Ophthalmology Society, Ophthalmology Branch of the Beijing Medical Association Chairman-designate, standing director of the seventh board of directors of China Soong Ching Ling Foundation
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