FDA Approves First Targeted Therapeutic Based on Tumor Biomarker, Not Tumor Origin

On Monday, the U.S. Food and Drug Administration (FDA) announced the highly anticipated approval of the molecularly targeted therapeutic larotrectinib (Vitrakvi) 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.

Larotrectinib is the first molecularly targeted therapeutic approved for treating patients with any of an array of cancer types based on the presence of a specific tumor biomarker rather than the site at which the cancer originated. However, it is the second anticancer therapeutic to be approved for use in this tissue-agnostic way. 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.

As discussed in a previous post on this blog, 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, and thereby TRK fusion proteins, 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 in New Orleans. At that time, five of six patients had confirmed partial responses.

The data for the 55 patients were published earlier in 2018 in The New England Journal of Medicine. The overall response rate among the 55 patients was 75 percent; 13 percent of the patients had a complete response and 62 percent had a partial response. Moreover, 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 irrespective of tumor type and the type of NTRK fusion.

There are several other molecularly targeted therapeutics under development for treating cancer based on tumor biomarkers rather than site of tumor origin, as highlighted in a previous post on this blog. 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.