CSF1R inhibition with emactuzumab in locally advanced diffuse-type tenosynovial giant cell tumours of the soft tissue: a dose-escalation and dose-expansion phase 1 study.

BACKGROUND: Diffuse-type tenosynovial giant cell tumour (dt-GCT) of the soft tissue (alternatively known as pigmented villonodular synovitis), an orphan disease with unmet medical need, is characterised by an overexpression of colony-stimulating factor 1 (CSF1), and is usually caused by a chromosomal translocation involving CSF1. CSF1 receptor (CSF1R) activation leads to the recruitment of CSF1R-expressing cells of the mononuclear phagocyte lineage that constitute the tumor mass in dt-GCT. Emactuzumab (RG7155) is a novel monoclonal antibody that inhibits CSF1R activation. We have assessed the safety, tolerability and activity of emactuzumab in patients with Dt-GCT of the soft tissue. METHODS: In this phase 1, first-in-human dose-escalation and dose-expansion study, eligible patients were aged 18 years or older with dt-GCT of the soft tissue with locally advanced disease or resectable tumours requiring extensive surgery, an Eastern Cooperative Oncology Group performance status of 1 or less, measurable disease according to Response Evaluation Criteria In Solid Tumors version 1.1, and adequate end-organ function. Patients with GCT of the bone were not eligible. Patients received intravenous emactuzumab at 900 mg, 1350 mg, or 2000 mg every 2 weeks in the dose-escalation phase and at the optimal biological dose in a dose-expansion phase. The primary objective was to evaluate the safety and tolerability of emactuzumab, and to determine the maximum tolerated dose or optimal biological dose. All treated patients were included in the analyses. Expansion cohorts are currently ongoing. This study is registered with ClinicalTrials.gov, number NCT01494688. FINDINGS: Between July 26, 2012, and Oct 21, 2013, 12 patients were enrolled in the dose-escalation phase. No dose-limiting toxicities were noted in the dose-escalation cohort; on the basis of pharmacokinetic, pharmacodynamic, and safety information, we chose a dose of 1000 mg every 2 week for the dose-expansion cohort, into which 17 patients were enrolled. Owing to different cutoff dates for safety and efficacy readouts, the safety population comprised 25 patients. Common adverse events after emactuzumab treatment were facial oedema (16 [64%] of 25 patients), asthenia (14 [56%]), and pruritus (14 [56%]). Five serious adverse events (periorbital oedema, lupus erythematosus [occurring twice], erythema, and dermohypodermitis all experienced by one [4%] patient each) were reported in five patients. Three of the five serious adverse events-periorbital oedema (one [4%]), lupus erythematosus (one [4%]), and dermohypodermitis (one [4%])-were assessed as grade 3. Two other grade 3 events were reported: mucositis (one [4%]) and fatigue (one [4%]). 24 (86%) of 28 patients achieved an objective response; two (7%) patients achieved a complete response. INTERPRETATION: Further study of dt-GCT is warranted and different possibilities, such as an international collaboration with cooperative groups to assure appropriate recruitment in this rare disease, are currently being assessed. FUNDING: F Hoffmann-La Roche.

Hepcidin as a predictor of response to epoetin therapy in anemic cancer patients.

BACKGROUND: Hepcidin is thought to be the central regulator of iron metabolism. Iron deficiency is associated with low hepcidin concentrations, and anemia in patients with cancer is associated with high concentrations of hepcidin. STUDY OBJECTIVES: Our main objective was to assess the potential role of hepcidin for predicting response to epoetin therapy in anemic cancer patients. We also aimed to identify a cutoff value for hepcidin as a potential predictive marker for response to epoetin therapy. METHODS: Using data from 525 anemic cancer patients enrolled in 5 studies, we assessed serum hepcidin concentrations in 408 of these patients at baseline and analyzed pooled data from the 408 patients. The analysis population was separated into 2 categories using a threshold hepcidin concentration of 13 nmol/L: low hepcidin (< 13 nmol/L) and high hepcidin (> or = 13 nmol/L). RESULTS: A significantly higher percentage of responders (defined as hemoglobin increase > or = 10 g/L or > or = 20 g/L from baseline) was observed in the low hepcidin group compared with the high hepcidin group (P = 0.04 for > or = 10 g/L increase and P = 0.009 for > or = 20 g/L from baseline). There was also a statistically significant difference between the 2 groups for hematopoietic response (hemoglobin rise at least once > or = 20 g/L from baseline or at least once > or = 120 g/L) to epoetin therapy (P = 0.0004). CONCLUSIONS: The results of this analysis suggest a potential role of hepcidin serum concentrations in predicting the response to epoetin therapy.

What is the impact of antithrombotic therapy and risk factors on the frequency of thrombovascular events in patients with metastatic breast cancer receiving epoetin beta?

UNLABELLED: PURPOSE, PATIENTS AND METHODS: This retrospective analysis of the BRAVE study evaluated the impact of baseline risk factors and antithrombotic therapy on the risk of thrombovascular events (TVEs) in patients receiving epoetin compared to patients not receiving epoetin. RESULTS: Baseline risk factors have a significant impact on TVE risk under epoetin therapy. More than 2 risk factors increased the risk of TVEs in patients receiving epoetin (hazard ratio [HR] 2.89, confidence interval [CI] 1.04-8.02, p value [p]=0.04). In patients on epoetin without antithrombotic therapy, the risk for TVEs was higher (HR 4.11, CI 1.37-12.4, p=0.01) compared to those who received antithrombotics (HR 1.37, CI 0.59-3.18, p=0.45). CONCLUSIONS: Our analysis has identified several risk factors which may impact the risk of TVEs under epoetin therapy. These data suggest that antithrombotic therapy may have the potential to reduce the risk of TVEs under epoetin therapy. These findings are hypothesis-generating and need to be confirmed in a prospective, randomised study.

Effect of once-weekly epoetin beta on survival in patients with metastatic breast cancer receiving anthracycline- and/or taxane-based chemotherapy: results of the Breast Cancer-Anemia and the Value of Erythropoietin (BRAVE) study.

PURPOSE: The Breast Cancer-Anemia and the Value of Erythropoietin (BRAVE) study evaluated whether epoetin beta would improve survival in patients with metastatic breast cancer (MBC). PATIENTS AND METHODS: BRAVE was an open-label, randomized, multicenter study in patients with MBC treated with anthracycline- and/or taxane-based chemotherapy. Patients (hemoglobin [Hb] < 12.9 g/dL) were randomly assigned (1:1) to epoetin beta 30,000 U subcutaneously once weekly or control for 24 weeks. The primary efficacy variable was overall survival. Secondary efficacy outcomes included progression-free survival, transfusion- and severe anemia-free survival, Hb response, safety, and quality of life (QoL). RESULTS: After 18 months of follow-up, 62 (27%) of 231 patients survived with epoetin beta therapy and 63 (27%) of 232 with control. No difference was detected in overall survival (hazard ratio [HR] = 1.07; 95% CI, 0.87 to 1.33, P = .522) or progression-free survival (HR = 1.07; 95% CI, 0.89 to 1.30, P = .448). There was a statistically significant benefit on transfusion- and severe anemia-free survival compared with control (HR = 0.59; P = .0097). Median Hb level increased with epoetin beta (11.7 g/dL at baseline to 13.3 g/dL at 24 weeks) but did not change with control (11.5 v 11.4 g/dL). Patients receiving epoetin beta experienced more thromboembolic events (TEEs) compared with controls (13% v 6%; P = .012) with no difference in serious TEEs (4% v 3%). Epoetin beta did not significantly improve QoL in this study where patients had a high baseline Hb value. CONCLUSION: In patients with MBC receiving chemotherapy and initial Hb less than 12.9 g/dL, epoetin beta increased Hb. No difference was detected in overall survival. Because of its superiority design, this study cannot, however, exclude clinically important differences in survival with absolute certainty.