Initial chemotherapy for locally advanced and metastatic NUT carcinoma: A report from the NUT carcinoma registry.
Authors: Luo Jia , Lee Elinton , Sanchez Michelle , Finstein Bryanna , Hertzler Hans , Luong Nhi , Tamen Rubii , Nguyen Tom , Paik Paul K. , Chaft Jamie E. , Piha-Paul Sarina A. , Janne Pasi A. , Sholl Lynette M. , Cheng Michael L. , DuBois Steven G. , Hanna Glenn J. , Nishino Mizuki , Shapiro Geoffrey , French Christopher Alexander 
Published: June 2023

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Background: NUT carcinoma (NC) is an uncommon squamous cell cancer. This disease is driven by a NUTM1 gene fusion, most commonly encoding a BRD4-NUT fusion oncoprotein, that enhances transcription of numerous genes including MYC. BET bromodomain inhibitors (BBDi), which block oncoprotein binding, are being studied in clinical trials. A subset of NC is sensitive to chemotherapy, but the optimal regimen is unknown; experts have recommended platinum- (PLAT) and ifosfamide-based (IFOS) therapy based on case reports. Methods: Patients with NC with known chemotherapy treatment and survival outcomes who consented to participate in a worldwide registry were included. Cohorts of patients with non-metastatic and metastatic disease were of interest. Medical records were manually reviewed. Results were summarized using 95% confidence intervals (95CI) and Kaplan Meier survival estimates, when appropriate. Results: A total of 60 patients with NC were included and received either PLAT (83%) or IFOS (17%); 38% were female and the median age was 37 (range 10-82); 55% of tumors were thoracic primaries, 48% had squamous differentiation, and 70% were driven by BRD4-NUTM1 (n = 43 with known fusion status). Of 31 patients with non-metastatic disease, 32% had a thoracic primary; 23% received peri-operative chemotherapy and 77% received concurrent chemoradiation (cRT). The most common chemotherapies used for cRT were cisplatin (n = 12), platinum-taxane (n = 6), and platinum-etoposide (n = 5). Of 4 non-metastatic patients who received IFOS, 4 (100%) had a disease-free survival (DFS) > 3 months and 1 (25%) had a DFS > 1 year. By comparison, of the 27 patients who received PLAT, the estimated 3-month and 1-year DFS was 70% (95CI 48-84%) and 53% (95CI 30-71%) respectively. Of the 29 patients with metastatic disease, 79% had a thoracic primary; 6 received IFOS and 23 received PLAT. The most common chemotherapies were platinum-taxane (52%), platinum-etoposide (17%), and ifosfamide-etoposide (14%). ORR of IFOS vs PLAT was 50% (95CI 12-88%) vs 23% (95CI 7-44%). Compared to IFOS, PLAT had similar 3-month and 6-month PFS (3;6mo: PLAT est: 36% [95CI 18-56%]; 9% [95CI 2-25%] vs IFOS 50%; 17%). The estimated 1-year OS and 1-year OS were 18% (95CI 6-35%) vs 33% for PLAT vs IFOS respectively. Of the 5 patients (8%) with a known OS > 3 years, all had a non-thoracic primary, non-metastatic disease, and had received PLAT. Conclusions: NUT carcinoma is a highly aggressive disease. There may be a numerically higher ORR for ifosfamide-based therapy as compared to platinum-based therapy, with limited durability. Development of effective combination targeted therapies, eg. combinations with BBDis, is an urgent unmet need for this patient population.