Sorafenib

Orally available multi-kinase inhibitor (see below tyrosine kinase inhibitors), which inhibits proliferation and angiogenesis by inhibiting Raf-kinases (CRAF, BRAF), KIT, VEGF-receptor 2 and 3 (see below VEGF) as well as PDGF-receptor (platelet derived grwoth factor) and FLT-3. Sorafenib is a relatively weak B-RAF inhibitor.

Approved for the therapy of hepatocellular carcinoma, for the treatment of patients with advanced renal cell carcinoma in whom a previous interferon-α- or interleukin-2-based therapy has failed or who are not suitable for such therapy.

Results on malignant melanoma ( off-label use):

• In a randomized, placebo-controlled phase II study in stage III (patients with non-resectable lymph node metastases) and IV (distant metastases), the efficacy of dacarbazine (DTIC) alone or in combination with sorafenib was investigated. The patient population included 101 patients in stage III or IV who had not previously received chemotherapy. Median progression-free survival was 21.1 weeks for patients receiving both drugs compared to 11.7 weeks for patients in the group treated with dacarbazine and an oral placebo (p = 0.07). The progression-free survival rate after 180 days was 41% for sorafenib + DTIC and 18% for the control group. The remission rate was 12% for DTIC + placebo, compared to 24% for DTIC + sorafenib. The administration of sorafenib in addition to standard chemotherapy with DTIC resulted in a doubling of progression-free survival and remission rate. These results need to be verified in a Phase III trial.
• The combined administration of sorafenib with carboplatin/paclitaxel chemotherapy does not extend progression-free survival or overall survival.
• The combination of temozolomide and sorafenib showed good treatment results in a Phase II trial in clinical stage IV melanoma patients with cerebral metastasis. This phase II study investigated the efficacy of sorafenib (400 mg p.o. daily) plus temozolomide at different doses (standard dose 150 mg/m2 KO and 75 mg/m2 KO) in four arms in patients with and without brain metastases. Total emission rate: 19%. In 35 patients who had not yet been pretreated with temozolomide, partial remission was achieved in 17% of cases and stabilisation of the disease in 50% of cases.

Cutaneous Symptoms:

• exanthema to erythroderma
• Hair loss (about 30% of cases)
• Hand-foot syndrome (30%)
• Pruritus (about 20%)
• Cheilits
• Splinter hemorrhages of the nails
• Pain and hyperkeratosis of the nipples
• Milia
• Reactive perforating collagenosis
• epidermoid cysts
• diffuse xeroderma with planar hyperkeratoses.
• Extracutaneous side effects: diarrhea, lymphopenia, bleeding, arterial hypertension, nausea, vomiting, fatigue syndrome.

1. Autier J (2008) Prospective study of the cutaneous adverse effects of sorafenib, a novel multikinase inhibitor. Arch Dermatol 144:886-892

2. Hauschild A et al (2008) Systemic therapy of melanoma. Current clinical trials. Dermatologist 59: 484-492

3. Vega Díez D et al (2020) Reactive perforating collagenosis: a rare side effect associated with sorafenib. Rev Esp Enferm Dig 112:960-961.

4. Wozel G et al (2010) Adverse dermatologic effects associated with therapeutic inhibition of the VEGF pathway. JDDG 8: 243-249