The SoraTram trial is a basket study designed to evaluate a new concept for treating a wide range of tumors with kinase-inactivating BRAF mutations. The BRAF enzyme is an important link in the RAS/RAF/MEK/ERK signaling chain that promotes cell division and, as a result of mutations, is present in a hyperactive state in many tumors. Drugs that inhibit the hyperactive oncoprotein BRAF V600E are already used to treat a number of cancers. The sequencing of tumor genomes has also identified increasing numbers of non-V600E mutations. In most cases, the clinical significance of these and their susceptibility to drugs have not yet been described. A sub-group of these non-V600E BRAF mutations inhibit the enzyme activity of the BRAF kinase. Paradoxically, however, these inactive BRAF mutants activate the ERK signaling chain and stimulate the onset of tumors. Preclinical models have shown that sorafenib, a drug that was approved several years ago for the treatment of kidney and liver cancer, can block the paradoxical effect of kinase-inactive BRAF mutants. The combination of sorafenib and the inhibitor trametinib is even more effective at blocking tumor growth. The effectiveness of this SoraTram combination has already been demonstrated in an index case with a metastatic melanoma. (1) 

The SoraTram study, which is planned to run at all DKTK sites, aims to

• identify patients in the DKTK MASTER network with tumors harboring non-V600 BRAF mutations 

• characterize mutations in terms of their susceptibility to BRAF, CRAF and MEK inhibitors and combinations of these

• treat 30 DKTK MASTER patients harboring non-V600 BRAF mutations that respond to CRAF/MEK inhibition following in vitro testing, with sorafenib and trametinib in a prospective multicenter Phase II trial

Comprehensive tumor sequencing in the DKTK network, especially through the MASTER program, is currently identifying many novel BRAF mutations whose significance remains unclear. These will be validated and verified during the study, both in terms of their kinase-inactivating potential and their oncogenic potential and susceptibility to pharmacological intervention. The cataloging of all non-V600E mutations can then be used for personalized therapy recommendations.

(1) Hoefflin R, Geißler AL, Fritsch R, Claus R, Wehrle J, Metzger P, et al. Personalized clinical decision making through implementation of a molecular tumor board – a German single-center experience.  JCO Precision Oncology. 2018; DOI: 10.1200/PO.18.00105 JCO Precision Oncology - published online August 16, 2018