FDA Approved the First Tissue-Agnostic Molecularly Targeted Therapeutic for Cancer

The FDA approval makes larotrectinib the first molecularly targeted therapeutic approved for use based on a tumor biomarker rather than the site where the cancer originated.

The U.S. Food and Drug Administration (FDA) recently announced the highly anticipated approval of the first molecularly targeted therapeutic for use based on whether a patient’s tumor tests positive for a specific genetic biomarker and not where in the body the tumor originated. Anticancer therapeutics approved for use in this way are called tissue-agnostic therapeutics.

The approval of the molecularly targeted therapeutic larotrectinib (Vitrakvi) is for treating certain adults and children who have solid tumors that have specific types of NTRK gene mutations.

Among patients with these NTRK mutation positive tumors, larotrectinib 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.

Although larotrectinib is the first tissue-agnostic molecularly targeted therapeutic approved by the FDA, it is the second tissue-agnostic anticancer therapeutic. The first was the immunotherapeutic pembrolizumab (Keytruda), which was approved in May 2017 for treating certain patients who have solid tumors positive for biomarkers known as microsatellite instability-high or mismatch repair-deficient.

Larotrectinib, which was known as LOXO-101 during its early development, targets three related proteins called TRKA, TRKB, and TRKC. These proteins are encoded by the genes NTRK1, NTRK2, and NTRK3, respectively.

Genetic mutations known as chromosomal translocations that involve the three NTRK genes and lead to the production of TRK fusion proteins have been identified in a diverse array of cancer types that occur in adults and children. These include many types of cancer that are classed as rare, such as mammary analogue secretory carcinoma of the salivary gland, infantile fibrosarcoma, and cholangiocarcinoma. Overall, researchers estimate that NTRK gene fusions drive the growth of up to 1 percent of all solid tumors.

The approval of larotrectinib was based on data from 55 children and adults who had solid tumors with an NTRK gene fusion and who were enrolled in one of three clinical trials. Early data from one of the trials, a phase I clinical trial testing larotrectinib as a treatment for adults who had an advanced solid tumor with an NTRK gene fusion, were presented at the AACR Annual Meeting 2016. At that time, five of six patients had been confirmed to have partial tumor shrinkage.

The data for the 55 patients treated with larotrectinib, which were published earlier in 2018 in The New England Journal of Medicine, showed that 75 percent of them had complete or partial tumor shrinkage. Seven (13 percent) of the patients had complete tumor shrinkage and 34 (62 percent) had partial tumor shrinkage. Most of these responses were durable: 73 percent lasted at least six months and 39 percent had lasted a year or more at the time the results were analyzed.

There were 17 types of cancer represented among the group of 55 patients, including 12 mammary analogue secretory carcinomas of the salivary gland, seven infantile fibrosarcomas, five thyroid tumors, four colon tumors, four lung tumors, four melanomas, three gastrointestinal stromal tumors, and two cholangiocarcinomas. Responses were seen across the different types of cancer.

There are several other molecularly targeted therapeutics under development for treating cancer based on tumor biomarkers rather than site of tumor origin. With clinical trials testing some of these therapeutics already reporting promising early data, it is likely that the number of therapeutics to be approved for use in a tissue-agnostic way will increase in the near future.

The FDA approval was rendered on Nov. 26, 2018.