BACKGROUND Fusions involving one of three tropomyosin receptor kinases (TRK) occur in diverse cancers in children and adults. We evaluated the efficacy and safety of larotrectinib, a highly selective TRK inhibitor, in adults and children who had tumors with these fusions. METHODS We enrolled patients with consecutively and prospectively identified TRK fusion–positive cancers, detected by molecular profiling as routinely performed at each site, into one of three protocols: a phase 1 study involving adults, a phase 1–2 study involving children, or a phase 2 study involving adolescents and adults. The primary end point for the combined analysis was the overall response rate according to independent review. Secondary end points included duration of response, progression-free survival, and safety. RESULTS A total of 55 patients, ranging in age from 4 months to 76 years, were enrolled and treated. Patients had 17 unique TRK fusion–positive tumor types. The overall response rate was 75% (95% confidence interval [CI], 61 to 85) according to independent review and 80% (95% CI, 67 to 90) according to investigator assessment. At 1 year, 71% of the responses were ongoing and 55% of the patients remained progression-free. The median duration of response and progression-free survival had not been reached. At a median follow-up of 9.4 months, 86% of the patients with a response (38 of 44 patients) were continuing treatment or had undergone surgery that was intended to be curative. Adverse events were predominantly of grade 1, and no adverse event of grade 3 or 4 that was considered by the investigators to be related to larotrectinib occurred in more than 5% of patients. No patient discontinued larotrectinib owing to drug-related adverse events. CONCLUSIONS Larotrectinib had marked and durable antitumor activity in patients with TRK fusion–positive cancer, regardless of the age of the patient or of the tumor type. (Funded by Loxo Oncology and others; ClinicalTrials.gov numbers, NCT02122913, NCT02637687, and NCT02576431.)

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Loxo Oncology Inc.

Aneurysmal bone cysts (ABCs) are benign bone lesions arising predominantly in the pediatric population that can cause local pain, swelling, and pathologic fracture. Primary lesions, which constitute roughly two thirds of all ABCs, are thought to be neoplastic in nature, with one third of ABCs arising secondary to other tumors. Diagnosis is made with various imaging modalities, which exhibit characteristic features such as Bfluid-fluid levels,^although biopsy is critical, as telangiectatic osteosarcoma cannot be excluded based on imaging alone. Currently, the standard of care and most widely employed treatment is intralesional curettage. However, tumor recurrence with curettage alone is common and has driven some to propose a multitude of adjuvants with varying efficacy and risk profiles. Historically, therapies such as en bloc resection or radiation therapy were utilized as an alternative to decrease the recurrence rate, but these therapies imposed high morbidity. As a result, modern techniques now seek to simultaneously reduce morbidity and recurrence, the pursuit of which has produced preliminary study into minimally invasive percutaneous treatments and medical management.

CREB is a transcription factor that functions in glucose homeostasis, growth factor-dependent cell survival, and memory. In this study, we describe a role of CREB in human cancer. CREB overexpression is associated with increased risk of relapse and decreased event-free survival. CREB levels are elevated in blast cells from patients with acute myeloid leukemia. To understand the role of CREB in leukemogenesis, we studied the biological consequences of CREB overexpression in primary human leukemia cells, leukemia cell lines, and transgenic mice. Our results demonstrate that CREB promotes abnormal proliferation and survival of myeloid cells in vitro and in vivo through upregulation of specific target genes. Thus, we report that CREB is implicated in myeloid cell transformation.