Initial chemotherapy for locally advanced and metastatic NUT carcinoma

Introduction NUT carcinoma (NC) is an underdiagnosed and aggressive poorly differentiated/ squamous cell cancer. A subset of NC is sensitive to chemotherapy, but the optimal regimen is unknown. Experts have recommended platinum- and ifosfamide-based therapy based on case reports. Methods Patients with pathologically confirmed NC with known survival outcomes after chemotherapy and consented to participate in a worldwide registry were studied. Results were summarized using descriptive methods. Results The study included 118 patients with NC. Median age was 34 (range: 1-82), 39% were women, and 61% harbored a BRD4::NUTM1 fusion. Patients received platinum (74%) or ifosfamide (26%, including regimens with both, 13%). Of 62 patients with non-metastatic disease, 40% had a thoracic primary. Compared with platinum-based chemotherapy, patients who received ifosfamide-based chemotherapy had nominally higher PFS (12-month: 59% [95% CI 32-87] vs. 37% [95% CI 22-52], hazard ratio [HR] = 0.68 [0.32,1.42], p=0.3) but not OS. Among the 56 patients with metastatic disease, 80% had a thoracic primary. Ifosfamide had an objective response rate (ORR) of 75% (6/8) and platinum had an ORR of 31% (11/36). However, there was no difference in PFS or OS. The 3-year OS of the entire cohort was 19% (95% CI 10-28%). Of the 11 patients alive >3 years, all presented with non-metastatic and operable/resectable disease. Conclusion There is a numerically higher ORR for ifosfamide-based therapy compared to platinum-based therapy, with limited durability. OS at 3 years is only 19%, and development of effective therapies is an urgent unmet need for this patient population.