Durable Clinical Response to Entrectinib in NTRK1-Rearranged Non-Small Cell Lung Cancer.

INTRODUCTION: Chromosomal rearrangements involving neurotrophic tyrosine kinase 1 (NTRK1) occur in a subset of non-small cell lung cancers (NSCLCs) and other solid tumor malignancies, leading to expression of an oncogenic TrkA fusion protein. Entrectinib (RXDX-101) is an orally available tyrosine kinase inhibitor, including TrkA. We sought to determine the frequency of NTRK1 rearrangements in NSCLC and to assess the clinical activity of entrectinib. METHODS: We screened 1378 cases of NSCLC using anchored multiplex polymerase chain reaction (AMP). A patient with an NTRK1 gene rearrangement was enrolled onto a Phase 1 dose escalation study of entrectinib in adult patients with locally advanced or metastatic tumors (NCT02097810). We assessed safety and response to treatment. RESULTS: We identified NTRK1 gene rearrangements at a frequency of 0.1% in this cohort. A patient with stage IV lung adenocrcinoma with an SQSTM1-NTRK1 fusion transcript expression was treated with entrectinib. Entrectinib was well tolerated, with no grade 3-4 adverse events. Within three weeks of starting on treatment, the patient reported resolution of prior dyspnea and pain. Restaging CT scans demonstrated a RECIST partial response (PR) and complete resolution of all brain metastases. This patient has continued on treatment for over 6 months with an ongoing PR. CONCLUSIONS: Entrectinib demonstrated significant anti-tumor activity in a patient with NSCLC harboring an SQSTM1-NTRK1 gene rearrangement, indicating that entrectinib may be an effective therapy for tumors with NTRK gene rearrangements, including those with central nervous system metastases.

Prognostic factors following curative resection for pancreatic adenocarcinoma: a population-based, linked database analysis of 396 patients.

OBJECTIVE: To analyze prognostic factors influencing pancreatic cancer survival following curative resection, using prospectively collected, population-based data. SUMMARY BACKGROUND DATA: Several studies have analyzed the determinants of long-term survival in postresection pancreatic cancer patients, but the majority of these have been single-institutional chart reviews yielding inconsistent results. METHODS: This retrospective cohort study examined 396 Medicare-eligible patients over age 65 who were diagnosed with nonmetastatic pancreatic adenocarcinoma and who underwent surgical resection with curative intent while residing in one of the 11 Survival, Epidemiology, and End Results (SEER) registries between January 1991 and December 1996. Linked Medicare data provided information on treatment and comorbidity, while linked census tract data supplied sociodemographic characteristics. RESULTS: Median survival for the overall study population was 17.6 months, with 1- and 3-year survival rates of 60.1% and 34.3%, respectively. Survival appears to be gradually improving over time, concomitant with a rise in the proportion of patients undergoing surgery in teaching centers. Prognostic variables significantly diminishing survival on univariate analysis included African American race, treatment not in a teaching hospital, lack of adjuvant chemoradiation therapy, as well as histopathologic factors that included tumor size larger than 2 cm in diameter, moderate to poor histologic grade, and positive lymph node metastases. Higher socioeconomic status was associated both with an increased likelihood of receiving adjuvant therapy and improved overall survival. Multivariate analyses indicated the strongest predictors of survival were adjuvant combined chemoradiotherapy, small tumors (<2 cm in diameter), negative lymph nodes, well-differentiated histology, undergoing surgery in a teaching hospital, and high socioeconomic status. CONCLUSIONS: Although biologic characteristics remain important predictors of survival for patients with resected pancreatic cancer, the most powerful determinant is postoperative adjuvant chemoradiation therapy. An interesting finding that warrants further investigation is the effect of socioeconomic status on both the likelihood of receiving adjuvant treatment and subsequent survival, indicating a possible relationship between the quality of care delivered and outcomes.