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Tumor Discovery Expert consensus of NUT carcinoma

are currently no prospective randomized controlled trials bromodomain-chromatin interaction sites and histone
that demonstrate the effectiveness of immunotherapy in tails, disrupting the binding of BRD4 protein to chromatin.
improving the survival of NUT carcinoma patients. A case This inhibition affects gene transcription during the
report of primary thyroid NUT carcinoma revealed a PD-L1 M and G1 phases, impairs mitosis, induces squamous
combined positive score of ≥30, with the patient surviving differentiation, and exerts antiproliferative effects. Non-
for 10 months following a combination of chemotherapy BRD4::NUTM1 fusion NUT carcinomas, such as those
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and immunotherapy. Some studies have reported cases with BRD3::NUTM1, NSD3::NUTM1, or ZNF532::NUTM1
of thoracic NUT carcinoma patients with high PD-L1 fusions, also rely on BRD4 for oncogenicity, as the NUT
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expression who were treated with immunotherapy, leading fusion partners interact with BRD2, BRD3, and BRD4.
to significantly prolonged survival. These patients, who This dependency makes BET inhibitors a promising
also received combined surgery, chemotherapy, and other therapeutic option. A statistical analysis of clinical trials
treatments, survived for over 7.5 years. In contrast, other involving BET inhibitors revealed tumor control rates
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studies suggest that PD-L1-negative NUT carcinoma ranging from 75% to 87.5%, with the highest control
patients can experience tumor shrinkage after receiving rate observed at 87.5%, notably surpassing the efficacy of
immune checkpoint inhibitors. While a few patients have chemotherapy. 82-84 In a Phase I study of birabresib (OTX015/
shown partial or complete remission, these responses have MK-8628), the recommended dose of BET inhibitors was
generally been short-lived, with lesions rapidly relapsing 80 mg once daily orally. The response durations ranged
or metastasizing. Moreover, there are cases in which a from 1.4 to 8.4 months. Among nine NUT carcinoma
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combination of immunotherapy and oncolytic viruses has patients, three showed PRs, three had stable disease (SD),
relieved both primary and metastatic lesions in patients. 78 two experienced disease progression (PD), and one was
(a) Recommendation 7 not evaluated (NE). Dose-limiting toxicities included
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For NUT carcinoma patients who are PD-L1/PD-1 thrombocytopenia and hyperbilirubinemia. In a Phase I
positive, it is strongly recommended to consider combined clinical trial of RO6870810, administered subcutaneously,
eight NUT carcinoma patients showed two PRs, five SDs,
immunotherapy as part of standard anti-tumor treatment. and one PD, yielding an objective response rate of 25%.
For patients who are PD-L1/PD-1 negative, the decision to Treatment-related adverse events included fatigue (42%),
use combined therapy should be made based on individual decreased appetite (35%), and injection site erythema
patient preference and circumstances (level of evidence: (35%). The Phase I trial of molibresib, which enrolled the
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level 4; recommendation grade: strongly recommended).
largest cohort of NUT carcinoma patients (N=19), showed
4.8.5. Targeted therapy primary adverse events, including thrombocytopenia
(51%), gastrointestinal discomfort (e.g., diarrhea, vomiting,
Early research suggests that BET inhibitors or HDAC nausea, anorexia, and taste disturbances; 22 – 42%), anemia
inhibitors can induce epithelial differentiation of NUT (22%), and fatigue (20%). The recommended dose was
carcinoma cells and inhibit cell proliferation. This event, 80 mg, and the efficacy assessment revealed 4 PRs (21.1%),
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along with a deeper understanding of NUT carcinoma’s 8 SDs (42.1%), 4 PDs (21.1%), and 3 NEs (15.8%). Several
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pathogenesis, has spurred the development of targeted clinical trials related to BET inhibitors (e.g., NCT02516553
therapies, particularly given the limited long-term efficacy and NCT03936465) are ongoing, though formal data
of conventional treatments.
specific to NUT carcinoma have not been reported. NUT
Histone deacetylase inhibitors, such as vorinostat, can carcinoma has been observed in children and an ongoing
induce histone acetylation, squamous differentiation, and Phase I clinical trial is recruiting pediatric patients with
growth arrest. For example, an 11-year-old patient with solid tumors, brain tumors, and lymphomas to assess the
BRD4::NUTM1 fusion salivary gland NUT carcinoma therapeutic effects of BET inhibitors (BMS-986158 and
experienced partial remission of both primary and BMS-986378) on pediatric NUT carcinoma. Given the
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metastatic lesions after undergoing four cycles of poor prognosis associated with conventional treatments,
chemotherapy (IFO+etoposide) combined with the HDAC BET inhibitors are poised to become a crucial option for
inhibitor vorinostat as part of multimodal therapy. first-line therapy. However, it is important to note that
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While some cases with favorable prognoses have been the blood-brain barrier may impede the entry of BET
reported, the evidence on using HDAC inhibitors for NUT inhibitors into the brain, which could affect their efficacy
carcinoma treatment remains insufficient and requires in treating brain metastases. 85,86
further investigation. 80,81 Given the poor prognosis of NUT carcinoma and
Bromodomain and extra-terminal domain inhibitors its propensity for recurrence and metastasis, targeted
work by competing with acetylated histones at therapies like BET inhibitors demonstrate superior control

Volume 3 Issue 4 (2024) 21 doi: 10.36922/td.4904