No abstract

ROS1 -rearranged (also known as ROS1 fusion-positive) non-small-cell lung cancer is an uncommon but distinct molecular subgroup seen in approximately 1–2% of cases. Oncogene addiction due to constitutive ROS1 tyrosine kinase activation has allowed development of molecularly targeted therapies with remarkable anti-tumor activity. Both crizotinib and entrectinib, multitargeted tyrosine kinase inhibitors (TKIs) have now received approval by the FDA for treatment of patients with advanced ROS1 -rearranged lung cancers; however, the clinical efficacy and safety of these drugs have been derived from expansion cohorts of single-arm phase I or basket clinical trials with relatively small populations of this clinically and molecularly distinct subgroup. Both drugs lead to high objective response rates (approximately 70–80%) and have manageable side effects, although only entrectinib has potent intracranial efficacy. Lorlatinib is an oral brain-penetrant ALK/ROS1 TKI with activity in both TKI-naïve and some crizotinib-resistant settings (albeit with limited potency against the crizotinib/entrectinib-resistant ROS1 -G2032R mutation). We describe cases of advanced ROS1 -rearranged lung cancer receiving crizotinib, entrectinib, and/or lorlatinib in first and later line treatment settings to dissect the current state of evidence supporting management decisions for these patients. The next generation ROS1 TKIs (repotrectinib and DS-6051b), owing to their broad activity against kinase mutations including ROS1 -G2032R in preclinical studies, hold promise to transform the current treatment paradigm and permit even further gains with regards to long-term outcomes in this subset of patients.

Background: When compared with warfarin, low-molecular-weight heparin (LMWH) reduces the incidence of recurrent venous thromboembolism (VTE) in cancer.However, a survival benefit of LMWH over warfarin for the treatment of cancerassociated VTE has not been established. Methods: Using the Surveillance, Epidemiology and End Results and Medicare linked database from 2007 through 2016, we identified Medicare beneficiaries (aged ≥66 years) who were: (1) diagnosed with primary gastric, colorectal, pancreatic, lung, ovarian, or brain cancer; (2) diagnosed with cancer-associated VTE; and (3) prescribed LMWH or warfarin within 30 days. The primary outcome was overall survival (OS). Patients were matched 1:1 using exact matching for cancer stage and propensity score matching for cancer diagnosis, age, year of VTE, and time from cancer diagnosis to index VTE. Cox proportional-hazards regression was performed to estimate hazard ratios (HR) and 95% confidence intervals (95% CI).Results: A total of 9706 patients were included. Warfarin was associated with a significant improvement in OS compared with LMWH (median OS, 9.8 months [95% CI, 9.1-10.4] vs. 7.2 months [95% CI, 6.8-7.8]; HR, 0.86; 95% CI 0.83-0.90; p < .001). The survival advantage was most pronounced in pancreatic (HR 0.82 [95% CI, 0.74-0.90], p < .001) and gastric cancers (HR 0.82 [95% CI, 0.68-0.98], p = .03). The observed differences in survival were consistent across subgroups including cancer stage, age, comorbidity burden, and year of VTE. Conclusions:In this population-based study, warfarin was associated with improved OS compared with LMWH for the treatment of cancer-associated VTE.