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Loxo's Pan-Cancer Drug Garners FDA Approval for Patients With NTRK Fusions

NEW YORK (GenomeWeb) – The US Food and Drug Administration yesterday approved the second tumor-agnostic precision oncology drug targeting NTRK gene fusions, called Vitrakvi (larotrectinib).

Loxo Oncology’s TRK inhibitor is approved for the treatment of adult and pediatric patients with solid tumors characterized by an NTRK gene fusion and without an acquired resistance mutation. Patients have to have metastatic disease, have progressed on the treatment they’re receiving, be without other treatment options, and not be candidates for surgical resection of their tumor.

NTRK gene fusions are rare events in cancer but occur across a variety of tumor types. In a statement, Loxo noted that patients receiving Vitrakvi must have NTRK gene fusions to be eligible for the drug, and the gene fusions may be detected using next-generation sequencing and fluorescence in situ hybridization-based tests.

The FDA did not approve a companion diagnostic alongside Vitrakvi. However, earlier this year Loxo announced plans to develop a sequencing-based, pan-cancer companion diagnostic for Loxo’s targeted oncology drugs based on a version of Illumina's TruSight 170 panel that will run on the NextSeq 550Dx platform. 

At the time of the announcement in April, the partners said they intended to validate this panel for NTRK fusions and RET fusions/mutations as a Class III FDA-approved diagnostic in conjunction with Vitrakvi and another drug, LOXO-292. A spokesperson for the company said that test is still under development.

The FDA based its accelerated approval of Vitrakvi based on pooled data from three studies involving a total of 55 adult and pediatric patients with various tumors types, including soft tissue sarcoma, salivary gland, infantile fibrosarcoma, thyroid, lung, melanoma, colon, gastrointestinal stromal tumor, cholangiocarcinoma, appendix, breast, and pancreas. A spokesperson from Bayer, which codeveloped Vitrakvi with Loxo, told GenomeWeb that researchers used pan-TRK immunohistochemistry, cell-free DNA analysis, and tissue analysis to identify patients with NTRK gene fusions in the adult Phase I trial, the NAVIGATE Phase II trial, and the pediatric Phase I/II SCOUT trial.

In these studies, 75 percent of patients saw their tumors shrink while receiving the drug, with 22 percent of patients achieving a complete response and more than half having a partial response. Among patients who responded, 73 percent continued to respond for six months or longer at the time of data cut off, and median duration of response and progression-free survival hadn’t been reached.

The drugmakers are working with diagnostic firms and laboratories to ensure that current and future tests are able to detect NTRK fusions in cancer patients. "While there is still work to be done to ensure genomic testing is part of routine clinical practice, we are encouraged by recent advancements to help increase genomic testing rates," the Bayer spokesperson said, noting the FDA's recent approvals of NGS cancer panels and the Centers for Medicare & Medicaid Services' national coverage determination (NCD) of such tests.

The NCD was triggered by Foundation Medicine's bid for parallel review by the FDA and CMS of its FoundationOne CDx, which detects genetic variants in 324 genes known to drive cancer and gauges two genomic signatures — microsatellite instability (MSI) and tumor mutational burden (TMB) — in solid tumors of any type. According to the FoundationOne CDx label, it can detect all classes of genomic alterations including gene rearrangements, such as fusions, and the test label lists NTRK1 and NTRK2 as among the gene rearrangements detected by the test.

Although these genes are not among the FDA-approved companion diagnostic indications for FoundationOne CDx, cancer patients receiving the test for any of these indications would find out if their tumors harbored NTRK fusions."In the medium or long-term, there is a high likelihood that many patients with advanced cancer types will have their tumors comprehensively profiled," the Bayer spokesperson noted. "We are working to ensure that NTRK gene fusions can be detected as part of this routine process."

This is the second tumor-agnostic cancer drug approved by the FDA, following last year's approval of Merck's Keytruda (pembrolizumab) for a tumor-agnostic indication, though the drug had already been on the market in other indications. Loxo highlighted in a statement that Vitrakvi is the first cancer drug to receive its initial approval in a tumor-agnostic indication. 

"Today’s approval marks another step in an important shift toward treating cancers based on their tumor genetics rather than their site of origin in the body," FDA Commissioner Scott Gottlieb said in a statement. "Its approval reflects advances in the use of biomarkers to guide drug development and the more targeted delivery of medicine … This type of drug development program, which enrolled patients with different tumors but a common gene mutation, wouldn’t have been possible a decade ago because we knew a lot less about such cancer mutations."

The FDA highlighted that Vitrakvi was developed based on principles the FDA outlined in guidance recently for tissue-agnostic therapies. "We're committed to continuing to advance a more modern framework of clinical trial designs that support more targeted innovations across disease types based on our growing understanding of the underlying biology of diseases like cancer," Gottlieb said.