Vemurafenib

Selective, orally administrable inhibitor of the oncogene B-RAF, a serine/threonine kinase (serine-theronine kinase inhibitor - see also tyrosine kinase inhibitors).

B-RAF, a serine/threonine kinase is hyperactive in about 70% of malignant melanomas. In thyroid cancer in 30-70%, in ovarian carcinoma in 15-30% and in colorectal carcinoma in 5-20% . The cause is activating mutations of the protooncogene B-RAF in position 600 (V600). In these mutations, 90% of valine (V in position 600) is exchanged for glutamate (E) (B-RAF-V600E). The mutant kinase is characterized by increased activity. Since the B-RAF protein is an important part of the RAF-RAS signaling pathway regulating cellular growth and survival, its over- or continuous activation leads to over-activation of the mitogen-activating protein kinase pathway, cell growth and anti-antiapoptosis.

Vemurafenib deactivates B-RAF and leads to melanoma cell regression via apoptosis.

About 50-70% of malignant melanomas have the mutation V600E in B-RAF (replacement of the amino acid valine by glutamic acid at position 600). Vemurafenib is only effective in this genotype.

In several Phase III studies response rates (6% complete remissions, 47% partial remissions), life prolongation (progression-free survival time was 6.8 months) and superiority over dacarbazine could be demonstrated in >50% of patients .

From the results of clinical trials (Phase I and II), a temporary tumor response to the drug was observed in patients. It is assumed that the cause for the development of resistance is a switch of the tumor cells to another signaling pathway. An increased expression of PDGFRB (Platelet Derived Growth Factor Receptor) has been observed in some cells with resistance formation. This leads to an alternative survival pathway (instead of B-RAF). In other resistant cells the activation of the oncogene NRAS (Neuroblastoma RAS) was observed. This reactivates the normal B-RAF survival pathway.

Metastatic malignant melanoma

Systemic Langerhans cell histiocytosis and non-Langerhans cell histiocytosis.

The most common side effects are:

Keratoacanthoma

squamous cell carcinoma (about 10%).

These side effects occur after 8-12 weeks.

Frequently (in almost 70% of patients) are observed UAW such as maculo-papular, also multiforme exanthema; furthermore, joint pain, fatigue (fatigue), diffuse alopecia and hypersensitivity to sunlight.

Less common are plantar hyperkeratosis, erythema nodosum, neutrophilic panniculitis(panniculitis, neutrophilic, lobular), and neutrophilic dermatitis(Sweet syndrome).

Increased skin toxicity is regularly observed under vemurafenib therapy (has also been demonstrated with other BRAF inhibitors such as dabrafenib,) under adjuvant radiotherapy (Strobel SB et al. 2017); even under a very low total cumulative dose.

Photosensitivity: already detectable at the start of therapy (affects mainly the UVA spectrum).

More rarely, the occurrence of keratosis pilaris is reported under this therapy (Braunstein I et al. 2014) .

Vemurafenib is approved as Zelboraf®.

B-RAf V600 mutations are also detected in melanocytic nevi and about 50% in non- and Langerhans cell histiocytosis .

Vemurafenib is currently in Phase II clinical trials in patients with malignant melanoma with brain metastases.

There is evidence that hyposensitization is possible in vemurafenib-induced non-allergic exanthema (example of a practical procedure: interruption of oncological therapy, initiation of a steroidal systemic therapy (1mg prednisolon/kgkgkg IV); with continuous steroid reduction to 50% of the initial dose, after 14 days renewed administration of vemurafenib (half dose). In the absence of weekly ADRs, increase the antineoplastic therapy up to the targeted initial dose while continuously reducing the steroid therapy (down to 0).

1. Braunstein I et al (2014) Vemurafenib-induced interface dermatitis manifesting as radiation-recall and a keratosis pilaris-like eruption. J Cutan Pathol 41:539-543.
2. Haroche J et al (2013) Dramatic efficacy of vemurafenib in both multisystemic and refractory Erdheim-Chester disease and Langerhans cell histiocytosis harboring the BRAF V600E mutation. Blood 121:1495-500.
3. Klossowski N et al (2015) Successful drug desensitization after vemurafinib-induced drug exanthema. Dermatologist 66: 221-223
4. Sosman JA et al (2012) Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med 366:707-714
5. Shi H et al (2012) Melanoma whole-exome sequencing identifies (V600E)B-RAF amplification-mediated acquired B-RAF inhibitor resistance. Nat Commun 3:724.
6. Strobel SB et al (2017) Radiosensitization by BRAF inhibitors. J Dtsch Dermatol Ges 16: 703-708.