​Targeting Cancers Based on Their Genetics

The molecularly targeted therapeutic entrectinib is the second therapeutic of its kind approved by the FDA for use based on tumor biomarker rather than the site where the cancer originated.

The U.S. Food and Drug Administration (FDA) recently approved a second molecularly targeted therapeutic for treating patients who have any type of cancer provided the cancer tests positive for a specific biomarker. Anticancer therapeutics approved for use in this way are sometimes called tissue-agnostic therapeutics.

The approval of entrectinib (Rozlytrek) is for treating certain adults and adolescents age 12 and older who have solid tumors that have specific types of NTRK gene alterations called NTRK gene fusions

Among patients with NTRK gene fusion positive–tumors, entrectinib is intended for those who have metastatic disease or would likely have serious complications during surgery, and who have no satisfactory alternative treatments or have disease that has progressed following other treatments.

Entrectinib is the second molecularly targeted therapeutic to be approved for use based on a common biomarker across different types of cancers rather than the location in the body where the cancer originated. It is also the third anticancer therapeutic to be approved for use in this tissue-agnostic way. The first approved for such use was the immunotherapeutic pembrolizumab (Keytruda), in May 2017. The second overall and first molecularly targeted therapeutic approved for such use was larotrectinib (Vitrakvi), in November 2018, for treating children and adults who have solid tumors that test positive for the NTRK gene fusion.

Entrectinib, like larotrectinib, targets three related proteins called TRKA, TRKB, and TRKC, which are encoded by the genes NTRK1, NTRK2, and NTRK3, respectively.

Researchers have found that genetic alterations known as chromosomal translocations that involve the three NTRK genes and lead to the production of TRK fusion proteins drive the growth of up to 1 percent of all solid tumors. These solid tumors encompass a wide array of cancer types that occur in adults and children, including many rare cancers, such as mammary analogue secretory carcinoma of the salivary gland, infantile fibrosarcoma, and cholangiocarcinoma.

The approval of entrectinib for the treatment of NTRK gene fusion–positive solid tumors was based on integrated data from 54 patients enrolled in one of several phase I and phase II clinical trials. The data showed that among 54 patients with NTRK gene fusion–positive solid tumors who were treated with entrectinib, four (7.4 percent) had complete tumor shrinkage and 27 (50 percent) had partial tumor shrinkage. Tumor shrinkage was reported for a range of cancer types, including non–small cell lung cancer, mammary analogue secretory carcinoma of the salivary gland, breast cancer, colorectal cancer, thyroid cancer, pancreatic cancer, and sarcomas.

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