Tebentafusp (Kimmtrak)

Aaron C. Johnson, PharmD candidate 2023
University of Michigan, College of Pharmacy
Ann Arbor, MI

Shawna Kraft, PharmD, BCOP
University of Michigan, College of Pharmacy
University of Michigan, Rogel Cancer Center
Ann Arbor, MI

Background Uveal Melanoma
Uveal melanoma (UM) is an especially rare cancer, occurring in 1 per 200,000 Americans per year.¹ While it shares a name with cutaneous melanoma, it is its own distinct entity. Uveal melanomas have specific biomarkers, stemming from oncogenic mutations, that set it apart from the cutaneous or mucosal melanomas. UM prognosis is dependent on disease severity; patients with localized disease have an 85% or better probability of survival 5 years from diagnosis, whereas those with metastatic disease have a less 20% probability of being alive at 5 years.^2-4 The lack of reliability amongst current treatments for UM presents a unique opportunity to engage innovative therapies for the treatment of this aggressive and difficult to treat cancer.

UM arises from the melanocytes located in the uveal tract of the eye. UM tumors rarely reveal metastasis at the primary diagnosis, but 50% of patients develop metastasis despite eradication of the primary tumor. This correlation poses the possibility of dormant micrometastases that remain undetected for many years.⁴

The low mutation burden of UM, less than one single nucleotide variation (SNP), is far lower than many other cancer types.⁴ Two proposed mutations of UM are guanine nucleotide-binding protein alpha Q (GNAQ) and guanine nucleotide-binding protein alpha (GNA11). Each of these mutations regulate the exchange of GDP for GTP which regulates the growth, differentiation, and migration of tumors, however, they are not directly correlated to the rates of metastasis. The deubiquitinating of proteins is a key step in the regulation of cellular proliferation. Ubiquitin carboxyl-terminal hydrolase (BAP1) is a deubiquitinating enzyme linked to having a high presence in multiple domains of UM tumors.^5,6 Functioning as a tumor suppressor gene, BAP1 has a plethora of downstream functions directly linked to the maintenance of the cell cycle, but its ultimate role on metastasis of UM is still unknown.⁶

Effective treatments are lacking for metastatic UM. Systemic treatments from previously reported trials include intravenous chemotherapy such as dacarbazine, cisplatin or nitrosourea, all having modest impact on overall survival.⁵ Ipilimumab is approved in the U.S. for treatment of unresectable melanoma, however, with response rates less than 10%, the data reflects a slow and delayed response to a minority of metastatic UM patients.² Thus until recently, the National Comprehensive Cancer Network (NCCN) recommended pursuit of a clinical trial as front line therapy for metastatic UM, with liver-directed therapies, radiation strategies, or best supportive care as alternatives.⁷

Tebentafusp-tebn Characteristics
Tebentafusp-tebn is the first FDA T-cell receptor therapy approved for HLA-A*02:01-positive adult patients with unresectable or metastatic uveal melanoma.⁹ Tebentafusp-tebn is a bispecific protein composed of a modified T-cell receptor fused to an anti-CD3 single chain fragment. This medication is classified as an immune-mobilizing T-cell receptors against cancer (ImmTAC) which are proteins specifically modified to target protein-HLA complexes. Uveal melanoma cells overexpress gp100 protein and display gp100/HLA-A*02:01 complex on their surface. Tebentafusp-tebn binds this complex on the UM cells and bring them into contact with cytotoxic T-cells10,11 Binding of this ImmTAC molecule to T-cells result in T-cell activation and cytokine release, which lead to immune-mediated UM cell death.¹²

Clinical Trial Summary
A randomized, open-label, multi-center, phase III clinical trial assessed tebentafusp-tebn as first-line systemic treatment for metastatic UM.13 A total of 378 patients were randomly assigned in a 2:1 ratio to receive tebentafusp-tebn (n=252) or investigator choice therapy (n=126) consisting of pembrolizumab (n=106), ipilimumab (n=16), or dacarbazine (n=7). Tebentafusp-tebn was administered intravenously over 15-20 minutes at doses of 20 μg on day 1, 30 μg on day 8, and then 68 μg weekly while being monitored overnight due to risk of cytokine release syndrome after each of the first 3 doses. Key inclusion criteria were having HLA-A*02:01–positive tumors, no previous systemic or liver directed treatments, an Eastern Cooperative Oncology Group performance status score of 0 or 1, and at least one measurable lesion. Patients being treated with glucocorticoids for autoimmune disorder, displaying symptoms of central nervous system metastases, or receiving systemic immunosuppressive treatment were all excluded from this trial.¹³ The primary endpoint was overall survival analyzed in a time-to-event format. Secondary endpoints consisted of disease control categorized into complete response, partial response, or stable disease for more than 2 weeks as well as objective response (complete or partial response to therapy) and progression-free survival (measured on a time-to-event analysis). Safety was also evaluated.13

The primary endpoint of 1-year overall survival was 73% (95% confidence interval [CI], 66 to 79) in the tebentafusp-tebn group and 59% (95% CI, 48 to 67) in the control group (HR 0.51 [ 95% CI, 0.37 to 0.71]; P<0.001). The estimated median duration of overall survival for the tebentafusp-tebn arm was 21.7 months (95% CI, 18.6 to 28.6) compared to 16.0 months for the control group (95% CI, 9.7 to 18.4). Progression free survival at 6 months was higher with tebentafusp-tebn (31%) than in the control group (19%); HR=0.73; 95% CI, 0.58 to 0.94; P = 0.01. An objective response was seen in 9% of patients receiving tebentafusp-tebn and 5% of those in the control group. The median duration of response was 9.9 months in the tebentafusp-tebn group and 9.7 months in the control group. The percentage of patients who had disease control was 46% in the tebentafusp-tebn group (95% CI, 39 to 52) compared to 27% in the control group (95% CI, 20 to 36). Disease control was defined as a complete response, partial response or stable disease for ≥12 weeks.¹³

Authors from the trial reported that a majority of the treatment related adverse events stemmed from cytokine-related adverse events, such as pyrexia (76%), chills (47%), and hypotension (38%), and skin-related adverse events, such as rash (83%), pruritus (69%), and erythema (23%). Pre-medications to prevent adverse events were not allowed empirically and were employed if a patient experienced a side effect. A sub-analysis was performed to assess the overall survival benefit of developing a rash within 1 week of initiating tebentafusp-tebn. However, the sub-analysis did not support week 1 rash as an independent predictor of overall survival. Most patients experienced only grade 1 (12%) or 2 (76%) cytokine release syndrome and typically this presented within a few hours of their first dose. Only 1% of patients experienced grade 3 CRS and there were no reports of grade 4 or 5 CRS. Patients reported decreased symptoms of CRS as they progressed through the treatment cycles with majority of the patients reporting a decrease in adverse effects following the third week of dosing tebentafusp-tebn. Only 2% of patients in the tebentafusp-tebn group withdrew from the trial due to adverse effects. There were no treatment related deaths reported in this trial.¹³

Conclusion
The ImmTAC protein tebentafusp-tebn has the potential to emerge as the leading therapy for people diagnosed with HLA-A*02:01 positive metastatic UM. The Phase III trial demonstrated that treatment with this novel agent results in increased overall survival with a manageable adverse event profile compared to traditional cytotoxic chemotherapy. Future studies should address optimizing tebentafusp-tebn utilization and alternative treatment strategies to ensure improved patient outcomes.

REFERENCES

1. Singh AD, Turell ME and Topham AK. Uveal melanoma: trends in incidence, treatment, and survival. Ophthalmology. 2011;118:1881–1885.
2. Bishop KD and Olszewski AJ. Epidemiology and survival outcomes of ocular and mucosal melanomas: A population-based analysis. Int J Cancer. 2014 Jun 15;134(12):2961-71.
3. Lane AM, Kim IK and Gragoudas ES. Survival rates in patients after treatment for metastasis from uveal melanoma. JAMA Ophthalmol. 2018 Sep 1;136(9):981-986.
4. Smit KN, Jager MJ, Klein AD and Kilic E. Uveal melanoma: Towards a molecular understanding. Prog Retin Eye Res. 2020 Mar;75:100800.
5. Carvajal RD, Schwartz GK, Tezel T, et al. Metastatic disease from uveal melanoma: treatment options and future prospects. Br J Ophthalmol. 2017;101:38–44.
6. Eletr ZM and Wilkinson KD. An emerging model for BAP1’s role in regulating cell cycle progression. Cell Biochem Biophys. 2011 Jun;60(1-2):3-11.
7. National Comprehensive Cancer Network. Melanoma: Uveal. (Version 2.2022), https://www.nccn.org/professionals/physician_gls/pdf/uveal.pdf. Accessed June 2, 2022.
8. Damato BE, Desjardins L, Jager MJ, Kivelä T. (Eds.). (2011). Current Concepts in Uveal Melanoma (Vol. 49). S. Karger AG.
9. Kimmtrak. Package Insert. Immunocore Limited; 2022.
10. Damato BE, Dukes J, Goodall H and Carvajal RD. Tebentafusp: T Cell redirection for the treatment of metastatic uveal melanoma. Cancers. 2019; 11(7):971.
11. Wagner SN, Wagner C, Schultewolter T and Goos M. Analysis of Pmel17/ gp100 expression in primary human tissue specimens: implications for melanoma immuno- and gene-therapy. Cancer Immunol Immunother. 1997 Jun;44(4):239-47.
12. Oates J, Hassan NJ and Jacobsen BK. ImmTACs for targeted cancer therapy: Why, what, how, and which. Molecular Immunology. 2015;67(2): 67-74.
13. 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.