Safety of combining dabrafenib plus trametinib in elderly BRAF V600 mutation-positive advanced melanoma patients: real-world data analysis of Spanish patients (ELDERLYMEL).

Efficacy and safety of dabrafenib and trametinib in metastatic melanoma have been demonstrated in two-phase III and one-phase I/II clinical trials. However, patients at least 75 years old (y.o.) were largely underrepresented. Additionally, the safety profile of dabrafenib and trametinib based on age is unknown. ELDERLYMEL is a retrospective noninterventional multicenter study, describing the effectiveness and safety of at least 75 y.o. patients compared with less than 75 y.o. patients with advanced BRAF V600-mutated melanoma treated with dabrafenib plus trametinib or dabrafenib monotherapy. A total of 159 patients were included, 130 less than 75 y.o. and 29 at least 75 y.o. Clinical features were similar between the groups, except in the number of comorbidities, number of metastatic sites, Eastern Cooperative Oncology Group (ECOG) performance status, and BRAF V600-mutation type. Five patients per group received dabrafenib monotherapy. There were no differences in adverse events (AEs) rate or grade between the groups. However, AE profiles were different between the groups, being pyrexia infrequent in patients at least 75 y.o. (13.8% vs. 42.3%; P = 0.005). Dabrafenib and trametinib dose intensities were lower in at least 75 y.o. patients ( P = 0.018 and P = 0.020), but there were no differences in effectiveness between the groups. Finally, in a multivariate analysis, sex (female) was the only variable independently associated with an increased risk of AE grade ≥3. Data from the ELDERLYMEL study demonstrate that dabrafenib plus trametinib is safe and effective in at least 75 y.o. patients with advanced BRAF V600-mutated melanoma without increasing toxicity. Additionally, we describe a different safety profile depending on age and sex.

High plasma levels of soluble P-Selectin and Factor VIII predict venous thromboembolism in non-small cell lung cancer patients: The Thrombo-Nsclc risk score.

INTRODUCTION: Venous thromboembolism (VTE) is common in non-small cell lung cancer (NSCLC) patients undergoing systemic chemotherapy. The usefulness of Khorana score (KRS) to predict risk in lung cancer patients is limited, and the identification of patients who would benefit most from thromboprophylaxis is challenging. We aimed to identify variables whose values before chemotherapy helped in predicting VTE occurrence, and build a model to assess VTE risk. MATERIALS AND METHODS: A cohort of newly diagnosed NSCLC patients to undergo outpatient chemotherapy, not under anticoagulant treatment, was recruited. Pre-chemotherapy demographic, clinical, analytical and tumor-specific variables were collected. Patients were prospectively followed-up for 12 months to record VTE events. Bivariate and multivariate analyses were performed to identify VTE-associated variables, and a prediction model was built and compared with KRS. RESULTS: 90 patients were recruited, 18 of whom had a VTE event during follow-up. High baseline levels of factor VIII (FVIII) and, especially, soluble P-selectin (sP-selectin), were independently associated with VTE risk (hazard ratio [HR] 4.15, 95% confidence interval [CI] 1.17-14.71, and 66.40 [8.70-506.69], respectively). Our so-called Thrombo-NSCLC risk score, which assigns 1 and 3 points to high FVIII and sP-selectin values, respectively, was significantly better than KRS in predicting VTE (area under the curve [AUC] 0.93 vs. 0.55, sensitivity 94.4 vs. 35.0%, specificity 93.1 vs. 60.0%). Our prediction model showed significant discriminating capacity between high risk vs. intermediate/low risk patients, while KRS did not. CONCLUSIONS: The Thrombo-NSCLC risk score may be useful to identify those NSCLC patients who would benefit most from thromboprophylaxis.

Dabrafenib plus trametinib for compassionate use in metastatic melanoma: A STROBE-compliant retrospective observational postauthorization study.

The main objective of the study was to evaluate the efficacy and safety of dabrafenib alone or combined with trametinib for compassionate use in patients with metastatic melanoma.This retrospective, observational study involved 135 patients with unresectable stage IIIC or stage IV melanoma from an expanded-access program at 30 Spanish centers.Forty-eight patients received dabrafenib monotherapy and 87 received combination dabrafenib and trametinib; 4.4% and 95.6% of the patients had stage IIIC and IV melanoma, respectively. All patients showed BRAF mutations in their primary or metastatic lesions; 3 were positive for V600K while the remainder had V600E or V600+. A positive response to treatment was reported in 89.3% of the patients. Overall survival rates at 12 and 24 months were 59.6% (95% confidence interval [CI], 52.5-68.9%) and 36.4% (95% CI, 27.8-45%), respectively. Progression-free survival rates at 12 and 24 months were 39.3% (95% CI, 31.1-47.5%) and 21.6% (95% CI, 14.5-28.7%), respectively. Fifty-seven patients (42.2%) reported cutaneous toxicity of any type, mainly hyperkeratosis (14.8%) and rash (11.9%). The most frequent adverse events were pyrexia (27.4%), asthenia (19.3%), arthralgia (16.9%), and diarrhoea (13.2%).Our results suggest that both dabrafenib alone or in combination with trametinib are effective for compassionate use in terms of response and/or survival rates. However, differences in patients' prognostic features ought to be considered. No new findings were revealed regarding the safety profiles of either regimen. This is the first study to evaluate the efficacy of these 2 selective BRAF and mitogen-activated extracellular signal-regulated kinase inhibitors in a real-world setting in Spain.

Biochemotherapy in the treatment of metastatic melanoma in selected patients.

INTRODUCTION: Bioimmunochemotherapy (BCT) is a combination of biological agents and cytostatics that has shown an increase in response rate (RR) in metastatic melanoma patients. The aim of the study is to evaluate RR, progression- free survival (PFS), overall survival (OS) and treatment toxicity. MATERIALS AND METHODS: Retrospective analysis of 11 metastatic melanoma patients treated from January 2002 to June 2008 with cisplatin 20 mg/m(2) i.v. days 1.4, dacarbazine 800 mg/m(2) i.v. day 1, vinblastine 1.5 mg/m(2) i.v. days 1.4, interleukin (IL)-2 9 MIU/m(2) s.c. 5.8 days and interferon (IFN)-alpha-2b 5 MIU/m2 s.c. days 5.9, 11, 13 and 15, with the support of granulocyte colony-stimulating factor (G-CSF) and antibiotics. Patients with ECOG 0, age < or = 65 years and with measurable disease were included. The planned number of courses was 4. RR was measured by Revised Evaluation Criteria in Solid Tumour (RECIST) criteria (computed tomography [CT]+/-proton emission tomography [PET]). Toxicity was measured according to the National Cancer Institute (NCI) common toxicity criteria. RESULTS: Observed RRs were 18% complete response (CR), 27% partial response (PR), 9% stable disease (SD) and 46% disease progression. The median PFS was 4 months (95% CI, 0.10 m), with a 23% one-year PFS. Median OS was 4.6 months (95% CI, 0.9.19 m), with a 29% one-year OS. Eighty-three percent of patients experienced grade 3-4 toxicity, mainly due to neutropenia, thrombocytopenia and flu-like syndrome. CONCLUSIONS: Treatment with BCT shows an increase in RR, some achieving durable CR; nevertheless it cannot be considered a standard treatment and should be employed only in selected patients.