The sorafenib safety profile in European community-based practice settings was similar to that reported in clinical trials. The heterogeneous advanced RCC patient population in EU-ARCCS permitted assessment of sorafenib in important subpopulations of advanced RCC patients.

This study did not meet its primary end point of improved OS when sorafenib was added to first-line gemcitabine/cisplatin in patients with advanced nonsquamous NSCLC. Identification of predictive biomarkers is warranted in future trials of sorafenib.

Introduction: The research objective was to systematically review evidence on neurotrophic tyrosine receptor kinase ( NTRK) gene fusion frequency in solid tumors. Methods: Using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a systematic literature review (SLR) was conducted of studies published from January 1987 to 2 January 2020. Selected studies were appraised for use in meta-analysis, with frequency reported as a point estimate with confidence intervals, to estimate NTRK gene fusion tumor incidence and prevalence. Results: The SLR identified 222 studies from North America ( n = 122), Europe ( n = 33), Asia ( n = 41), Brazil ( n = 5), Australia ( n = 2), and multi-continental ( n = 19) reporting NTRK gene fusion frequencies across 101 histologies. Studies were prospective ( n = 43) and retrospective ( n = 179). Testing methods involved DNA ( n = 93), RNA ( n = 72), combined DNA/RNA ( n = 48), protein [immunohistochemistry (IHC), n = 5], and unreported ( n = 5). Sample sizes ranged from 1 to 66,871. Of the 222 studies, 107 were suitable for meta-analysis. Highest NTRK gene fusion frequencies were reported in rare cancers: infantile/congenital fibrosarcoma (90.56%, 95% CI 67.42–100.00), secretory breast cancer (92.87%, 95% CI 72.62–100.00), and congenital mesoblastic nephroma (21.52%, 95% CI 13.06–32.20). Lower frequencies were reported in non-small cell lung cancer (0.17%, 95% CI 0.09–0.25), colorectal adenocarcinoma (0.26%, 95% CI 0.15–0.36), cutaneous melanoma (0.31%, 95% CI 0.07–0.55), and non-secretory breast carcinoma (0.60%, 95% CI 0.00–1.50). Reported frequency was ~0% for some cancers: mesothelioma, renal cell carcinoma, prostate cancer, and bone sarcoma. Estimated global overall NTRK gene fusion tumour incidence and 5-year prevalence in 2018 was 0.52 and 1.52 per 100,000 persons, respectively. Conclusion: This research confirms the rarity and varying frequency of NTRK gene fusion across tumor types. Limitations included relatively low historic NTRK gene fusion testing and reporting, limited study samples for some cancers, and suboptimal molecular testing methods. In this rapidly developing area, gold-standard testing methods and companion diagnostics are needed to capture all NTRK gene fusions.

Method:The safety of oral sorafenib up to a maximum protocol-specified dose combined with dacarbazine in patients with metastatic, histologically confirmed melanoma was investigated in a phase I dose-escalation study and the activity of the combination was explored in an open-label phase II study.Results:In the phase I study, three patients were treated with sorafenib 200 mg twice daily (b.i.d.) plus 1000 mg m−2 dacarbazine on day 1 of a 21-day cycle and 15 patients had the sorafenib dose escalated to 400 mg b.i.d. without reaching the maximum tolerated dose of the combination. In the phase II study (n=83), the overall response rate was 12% (95% CI: 6, 21): one complete and nine partial, with median response duration of 46.7 weeks. Stable disease was the best response in 37% median duration was 13.3 weeks. Median overall survival (OS) was 37.0 weeks (95% CI: 33.9, 46.0).Conclusion:Oral sorafenib combined with dacarbazine had acceptable toxicity and some antineoplastic activity against metastatic melanoma.

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