The FDA granted the approval of Rozlytrek™ (entrectinib) for the treatment of adults with ROS1-positive, metastatic non-small cell lung cancer (NSCLC), The FDA has also granted accelerated approval to Rozlytrek for the treatment of adult and pediatric patients 12 years of age and older with solid tumors that have a neurotrophic tyrosine receptor kinase (NTRK) gene fusion without a known acquired resistance mutation that are metastatic or where surgical resection is likely to result in severe morbidity and have progressed following treatment or have no satisfactory alternative therapy. Here is a link to the press release. https://www.gene.com/media/press-releases/14802/2019-08-15/fda-approves-genentechs-rozlytrek-entrec
What is an NTRK fusion?
By Jerry Call, LRG Data Analyst
The Trk receptor family comprises three proteins referred to as Trk A, B and C (TrkA, TrkB and TrkC) receptors, and are encoded by the NTRK1, NTRK2 and NTRK3 genes, respectively. These receptor tyrosine kinases (TK) are expressed in human neuronal tissue and play an essential role in both the physiology of development and function of the nervous system through activation by neurotrophins (NTs). When an NTRK fusion occurs, a portion of a gene gets swapped with another gene (whether the same chromosome or different chromosomes). These fusions are reported in cancers, with the most common being salivary gland tumors, soft tissue sarcoma, infantile fibrosarcoma, and thyroid cancer.
How is this important to GIST?
Who should get tested?
Although this mutation is very rare in GIST, the response rate to the proper medication is extremely high. In 54 patients with NTRK fusion tumors, the response rate to entrectinib was 57% with 7.4% achieving a complete response. This makes testing extremely important. In patients where no mutation was found after basic mutational testing (KIT and PDGFRA mutation testing), advanced testing should be performed and should test for a number of different mutations as well as SDHB staining (IHC). Advanced testing is most efficiently done with testing panels that test for many different mutations at one time including NTRK fusion mutations. Laboratories that have panels that have been specifically designed to include the rare mutations that occur in GIST include Knight Diagnostic Laboratories and Foundation Medicine (there may be others as well).
For patients with previous negative testing (no mutation found) in multiple genes, they should check to ensure that NTRK fusions were included in that testing and if not, should be retested for NTRK fusion mutations. Dr. Jason Sicklick, a GIST specialist currently with Moores Cancer Center, University of California, San Diego, presented data several years ago, in a webinar for the LRG, entitled New Insights into Gene Fusions in GIST from a project he did in collaboration with Foundation Medicine and observed that patients with these fusions typically range in age between 30-50s. His data also showed that the fusions are more common in men than women and that the tumors can occur anywhere in GI tract. Additionally, one-third of tumors are associated with lymph metastases and 40% are associated with distant metastatic disease.