64MO A phase (ph) II, multi-center study of the safety and efficacy of tebentafusp (tebe) (IMCgp100) in patients (pts) with metastatic uveal melanoma (mUM)

Sacco, Joseph J.; Butler, Marcus O.; Shoushtari, Alexander N.; Hassel, Jessica C.; Ikeguchi, Alexandra; Hernandez‐Aya, Leonel F.; Nathan, Paul; Hamid, Omid; Rodriguez, J.M. Piulats; Rioth, Matthew J.; Johnson, Douglas B.; Luke, Jason J.; Espinosa, Enrique; Leyvraz, Serge; Goodall, Howard; Holland, Christopher P.; Abdullah, Shaad E.; Sato, Takami

doi:10.1016/j.annonc.2020.10.552

Cited by 29 publications

(25 citation statements)

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“…The primary end point was overall survival as evaluated in a time-to-event analysis. On the basis of a phase 2 study that showed an association between rash and survival, 17 we performed a prespecified analysis of overall survival in patients in the tebentafusp group in whom a rash of any grade had developed within 1 week after initiation of tebentafusp treatment, as compared with all the patients in the control group. Secondary end points included disease control (defined as complete response, partial response, or stable disease for ≥12 weeks, according to RECIST, version 1.1), objective response (defined as complete response or partial response, according to RECIST, version 1.1), and progression-free survival as evaluated in a time-to-event analysis, and safety.…”

Section: End Points and Assessmentsmentioning

confidence: 99%

“…12, [14][15][16] In a single-group, phase 2 study involving 127 patients with previously treated metastatic uveal melanoma, tebentafusp monotherapy showed more promising overall survival than historical controls. 17 Traditional responses, as defined according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, were observed, but this surrogate end point did not sufficiently predict long-term survival benefit. Clinical benefit included indolent tumor growth and slow tumor shrinkage.…”

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confidence: 99%

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Overall Survival Benefit with Tebentafusp in Metastatic Uveal Melanoma

et al. 2021

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Background: Uveal melanoma is a disease that is distinct from cutaneous melanoma, with a low tumor mutational burden and a 1-year overall survival of approximately 50% in patients with metastatic uveal melanoma. Data showing a proven overall survival benefit with a systemic treatment are lacking. Tebentafusp is a bispecific protein consisting of an affinity-enhanced T-cell receptor fused to an anti-CD3 effector that can redirect T cells to target glycoprotein 100-positive cells. Methods: In this open-label, phase 3 trial, we randomly assigned previously untreated HLA-A*02:01-positive patients with metastatic uveal melanoma in a 2:1 ratio to receive tebentafusp (tebentafusp group) or the investigator's choice of therapy with single-agent pembrolizumab, ipilimumab, or dacarbazine (control group), stratified according to the lactate dehydrogenase level. The primary end point was overall survival. Results: A total of 378 patients were randomly assigned to either the tebentafusp group (252 patients) or the control group (126 patients). Overall survival at 1 year was 73% in the tebentafusp group and 59% in the control group (hazard ratio for death, 0.51; 95% confidence interval [CI], 0.37 to 0.71; P<0.001) in the intentionto-treat population. Progression-free survival was also significantly higher in the tebentafusp group than in the control group (31% vs. 19% at 6 months; hazard ratio for disease progression or death, 0.73; 95% CI, 0.58 to 0.94; P = 0.01). The most common treatment-related adverse events in the tebentafusp group were cytokine-mediated events (due to T-cell activation) and skin-related events (due to glycoprotein 100-positive melanocytes), including rash (83%), pyrexia (76%), and pruritus (69%). These adverse events decreased in incidence and severity after the first three or four doses and infrequently led to discontinuation of the trial treatment (2%). No treatment-related deaths were reported. Conclusions: Treatment with tebentafusp resulted in longer overall survival than the control therapy among previously untreated patients with metastatic uveal melanoma. (Funded by Immunocore; ClinicalTrials.gov number, NCT03070392; EudraCT number, 2015-003153-18.).

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Section: End Points and Assessmentsmentioning

confidence: 99%

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confidence: 99%

Overall Survival Benefit with Tebentafusp in Metastatic Uveal Melanoma

et al. 2021

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“…OS was statistically significantly improved in patients randomized in the experimental group compared to the control group in the first pre-planned interim analysis (OS hazard ratio of 0.51, and estimated 1-year OS rate of 73% for the study drug versus 58% with the investigator's choice) [127,128]. These data confirm the positive survival benefit of the phase II clinical trial, and might likely support the use of this drug as a potential new treatment for cancer patients with this highly unmet need.…”

Section: Discussionmentioning

confidence: 99%

New Therapeutic Perspectives in the Treatment of Uveal Melanoma: A Systematic Review

Toro

Gozzo

Tracia³

et al. 2021

Biomedicines

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Uveal melanoma (UM) is a rare disease, but the most common primary intraocular cancer, mostly localized in the choroid. Currently, the first-line treatment options for UM are radiation therapy, resection, and enucleation. However, although these treatments could potentially be curative, half of all patients will develop metastatic disease, whose prognosis is still poor. Indeed, effective therapeutic options for patients with advanced or metastatic disease are still lacking. Recently, the development of new treatment modalities with a lower incidence of adverse events, a better disease control rate, and new therapeutic approaches, have merged as new potential and promising therapeutic strategies. Additionally, several clinical trials are ongoing to find new therapeutic options, mainly for those with metastatic disease. Many interventions are still in the preliminary phases of clinical development, being investigated in phase I trial or phase I/II. The success of these trials could be crucial for changing the prognosis of patients with advanced/metastatic UM. In this systematic review, we analyzed all emerging and available literature on the new perspectives in the treatment of UM and patient outcomes; furthermore, their current limitations and more common adverse events are summarized.

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“…48 For TCR mimetics, this has likely been achieved with the recently presented data on tebentafusp (IMCgp100) that showed clinical benefit, including target lesion reduction. 49 Tebentafusp is a solution of soluble TCRs stabilized by a disulfide bond and fused to an anti-CD3 scFv (a so-called "ImmTAC molecule"). Early data from a phase II trial in patients with HLA-A*0201 + gp100 + metastatic uveal melanoma showed that, although the overall response rate by response evaluation criteria in solid tumors was low (5%), it was accompanied by a reduction in target lesion in 44% of patients.…”

Section: New Biologics Can Also Enable the Impossiblementioning

confidence: 99%

Taking Aim at the Undruggable

Coleman

Rodón

2021

American Society of Clinical Oncology Educational Book

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The term “undruggable” is used to describe a protein that is not pharmacologically capable of being targeted; recently, however, substantial efforts have been made to turn these proteins into “druggable” targets. Thus, “difficult to drug” or “yet to be drugged” are perhaps more appropriate terms. In cancer, a number of elusive targets fall into this category, including transcription factors such as STAT3, TP53, and MYC. Pharmacologically targeting these intractable proteins is now a key challenge of modern drug development, requiring innovation and the development of new technologies. In this article, we discuss some of the recent technologic and pharmacologic advances that have underpinned the erosion of the concept of undruggability. We describe recent successes in drugging the undruggable RAS ( KRAS G12C and HRAS), and discuss the advances that have led to the validation of further targets previously believed to be undruggable, such as HIF-2α, BCL-2, MDM2, and MLL. Finally, we look to the future and describe important advances that are likely to have a major impact on targeting undruggable targets, such as the advent of proteolysis-targeting chimeras and protein-protein modulators, which are leading to considerable excitement surrounding the development of cancer targets.

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64MO A phase (ph) II, multi-center study of the safety and efficacy of tebentafusp (tebe) (IMCgp100) in patients (pts) with metastatic uveal melanoma (mUM)

Cited by 29 publications

References 0 publications

Overall Survival Benefit with Tebentafusp in Metastatic Uveal Melanoma

Overall Survival Benefit with Tebentafusp in Metastatic Uveal Melanoma

New Therapeutic Perspectives in the Treatment of Uveal Melanoma: A Systematic Review

Taking Aim at the Undruggable

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