Brain metastasis and survival outcomes after first-line therapy in metastatic melanoma: a multicenter DeCOG study on 1704 patients from the prospective skin cancer registry ADOREG.

BACKGROUND: Despite the availability of effective systemic therapies, a significant number of advanced melanoma patients develops brain metastases. This study investigated differences in incidence and time to diagnosis of brain metastasis and survival outcomes dependent on the type of first-line therapy. METHODS: Patients with metastatic, non-resectable melanoma (AJCCv8 stage IIIC-V) without brain metastasis at start of first-line therapy (1L-therapy) were identified from the prospective multicenter real-world skin cancer registry ADOREG. Study endpoints were incidence of brain metastasis, brain metastasis-free survival (BMFS), progression-free survival (PFS), and overall survival (OS). RESULTS: Of 1704 patients, 916 were BRAF wild-type (BRAFwt) and 788 were BRAF V600 mutant (BRAFmut). Median follow-up time after start of 1L-therapy was 40.4 months. BRAFwt patients received 1L-therapy with immune checkpoint inhibitors (ICI) against CTLA-4+PD-1 (n=281) or PD-1 (n=544). In BRAFmut patients, 1L-therapy was ICI in 415 patients (CTLA-4+PD-1, n=108; PD-1, n=264), and BRAF+MEK targeted therapy (TT) in 373 patients. After 24 months, 1L-therapy with BRAF+MEK resulted in a higher incidence of brain metastasis compared with PD-1±CTLA-4 (BRAF+MEK, 30.3%; CTLA-4+PD-1, 22.2%; PD-1, 14.0%). In multivariate analysis, BRAFmut patients developed brain metastases earlier on 1L-therapy with BRAF+MEK than with PD-1±CTLA-4 (CTLA-4+PD-1: HR 0.560, 95% CI 0.332 to 0.945, p=0.030; PD-1: HR 0.575, 95% CI 0.372 to 0.888, p=0.013). Type of 1L-therapy, tumor stage, and age were independent prognostic factors for BMFS in BRAFmut patients. In BRAFwt patients, tumor stage was independently associated with longer BMFS; ECOG Performance status (ECOG-PS), lactate dehydrogenase (LDH), and tumor stage with OS. CTLA-4+PD-1 did not result in better BMFS, PFS, or OS than PD-1 in BRAFwt patients. For BRAFmut patients, multivariate Cox regression revealed ECOG-PS, type of 1L-therapy, tumor stage, and LDH as independent prognostic factors for PFS and OS. 1L-therapy with CTLA-4+PD-1 led to longer OS than PD-1 (HR 1.97, 95% CI 1.122 to 3.455, p=0.018) or BRAF+MEK (HR 2.41, 95% CI 1.432 to 4.054, p=0.001), without PD-1 being superior to BRAF+MEK. CONCLUSIONS: In BRAFmut patients 1L-therapy with PD-1±CTLA-4 ICI resulted in a delayed and less frequent development of brain metastasis compared with BRAF+MEK TT. 1L-therapy with CTLA-4+PD-1 showed superior OS compared with PD-1 and BRAF+MEK. In BRAFwt patients, no differences in brain metastasis and survival outcomes were detected for CTLA-4+PD-1 compared with PD-1.

Randomized standard-of-care-controlled trial of a silica gel fibre matrix in the treatment of chronic venous leg ulcers.

BACKGROUND: Chronic venous leg ulcers (CVU) are a common, unresolved medical problem. Silica gel fibre (SGF) is a novel biodegradable inorganic material developed to serve as a carrier substrate for the local release of pharmaceutical agents facilitating tissue repair. OBJECTIVES: To assess the performance and safety of SGF in subjects with CVU. METHODS: Open, randomized, standard-of-care-controlled, multi-centre trial. Subjects (ITT 120 patients) received either SGF in addition to standard treatment or standard-of-care treatment (S-o-C) alone. The primary performance variable was the time to healing of the target ulcer until the end of a 12 week treatment period. RESULTS: SGF was well tolerated. Mean time to healing up to week 12 was 85.62 days for the SGF group (SE ± 1.5) and 79.66 days for the S-o-C group (SE ± 1.77) (p-value = 0.217). There was no statistically relevant difference regarding the incidence of complete healing of the target ulcers by weeks 12 and 24 between the SGF and the S-o-C groups (p-value >0.05). CONCLUSION: SGF is well tolerated and offers a promising perspective as a carrier substrate for the local release of active pharmaceutical agents into the wound site to promote tissue repair.