The U.S. Food and Drug Administration (FDA) has approved FoundationOne®CDx for the use as the first companion diagnostic to help identify neurotrophic receptor tyrosine kinase (NTRK) gene fusion-positive patients for whom treatment with larotrectinib (Vitrakvi®; Bayer HealthCare Pharmaceuticals) may be appropriate.
Detection of genomic alterations that drive the growth and spread of the tumor can guide treatment decisions for cancer therapies, including available biomarker driven treatments.
FoundationOne CDx is the only FDA-approved tissue-based comprehensive genomic profiling (CGP) test for all solid tumors that incorporates multiple companion diagnostic indications, which will advance broader biomarker testing access for the cancer community.
The test analyzes substitutions, insertion and deletion alterations (indels), and copy number alterations (CNAs) in 324 genes as well as select rearrangements and genomic signatures across all solid tumors, and is now approved to detect NTRK gene fusions (NTRK1, NTRK2 and NTRK3), to inform treatment decisions across all solid tumor types and identify patients who may be appropriate for treatment with larotrectinib. 
NTRK fusion positive cancer
NTRK fusion positive cancer occurs when a piece of the chromosome containing the NTRK gene breaks off and binds to another chromosome. These NTRK gene fusions produce TRK fusion proteins, which may cause cancer cells to grow. 
NTRK fusions are more commonly found in rare cancer types, such as secretory carcinoma of the breast or salivary gland and infantile fibrosarcoma, but they can also occur across many more common cancer types including glioma, melanoma and carcinomas of the lung, thyroid and colon.
A comprehensive approach
“Taking a comprehensive and validated approach to genomic testing is critical for all advanced cancer patients, but especially for those harboring rare mutations that can be missed with alternative testing methods,” explained Brian Alexander, M.D., M.P.H., chief medical officer at Foundation Medicine.
“Not only will this approval improve access to genomic testing and reinforce the role it plays in rare cancers, but it also confirms the incredible progress made toward tumor-agnostic cancer care. We’re proud of the impact this will have on NTRK fusion positive cancer patients,” Alexander added.
“Many patients with rare conditions, like NTRK fusion positive cancer have limited treatment options and poor access to targeted therapies,” said Susan Spinosa, co-chair and patient founder of the NTRKers.
“This companion diagnostic approval is a critical step forward in addressing this challenge as it provides this patient population with broader access to comprehensive genomic testing and appropriate treatment options,” she concluded
Larotrectinib is approved is in 42 countries, including the U.S., Canada, Brazil and the European Union (EU), for the treatment of adult and pediatric patients with solid tumors that have an NTRK gene fusion without a known acquired resistance mutation, are metastatic or where surgical resection is likely to result in severe morbidity, and have no satisfactory alternative treatments or that have progressed following treatment.
This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
TRK fusion cancer
TRK fusion cancer occurs when an NTRK gene fuses with another unrelated gene, producing an altered TRK protein. The altered protein, or TRK fusion protein, becomes constitutively active or overexpressed, triggering a signaling cascade.
These TRK fusion proteins act as oncogenic drivers promoting cell growth and survival, leading to TRK fusion cancer, regardless to where it originates in the body. TRK fusion cancer is not limited to certain types of tissues and can occur in any part of the body.
TRK fusion cancer occurs in various adult and pediatric solid tumors with varying frequency, including lung, thyroid, GI cancers (colon, cholangiocarcinoma, pancreatic and appendiceal), sarcoma, CNS cancers (glioma and glioblastoma), salivary gland cancers (mammary analogue secretory carcinoma) and pediatric cancers (infantile fibrosarcoma and soft tissue sarcoma).
Development and approval
The approval of larotrectinib was based on data from three multicenter, open-label, single-arm clinical trials. Identification of positive NTRK gene fusion status was prospectively determined in local laboratories using next generation sequencing (NGS) or fluorescence in situ hybridization (FISH).
NTRK gene fusions were inferred in three pediatric patients with infantile fibrosarcoma who had a documented ETV6 translocation by FISH. The major efficacy outcome measures were overall response rate (ORR) and response duration, as determined by a blinded independent review committee according to RECIST 1.1.
The clinical validation to support the FoundationOne CDx NTRK companion diagnostic approval was then achieved through a clinical bridging study between the local clinical trial assays and FoundationOne CDx.
“Larotrectinib has a demonstrated clinical profile and is the only approved treatment specifically developed for patients with TRK fusion cancer,” said Robert LaCaze, Member of the Executive Committee of the Pharmaceuticals Division and Head of the Oncology Strategic Business Unit at Bayer.
“The U.S. FDA approval of FoundationOne CDx for Vitrakvi allows patients who may benefit from this treatment to be identified in a more precise way. We look forward to continuing our global collaboration with Foundation Medicine by expanding access to testing and determining the right treatment options for patients with cancer.”
A Study to Test the Safety of the Investigational Drug Larotrectinib in Adults That May Treat Cancer – NCT02122913
A Study to Test the Safety and Efficacy of the Drug Larotrectinib for the Treatment of Tumors With NTRK-fusion in Children (SCOUT) – NCT02637687
A Study to Test the Effect of the Drug Larotrectinib in Adults and Children With NTRK-fusion Positive Solid Tumors (NAVIGATE) – NCT02576431
 National Cancer Institute. NTRK Gene Fusion. Online. Last accessed.
 Solomon JP, Benayed R, Hechtman JF, Ladanyi M. Identifying patients with NTRK fusion cancer. Ann Oncol. 2019 Nov;30 Suppl 8:viii16-viii22. doi: 10.1093/annonc/mdz384. Epub 2019 Dec 24. PMID: 32223934.
Featured image: Bayer employee filling cell culture media in a flask. Photo courtesy: © 2016 – 2020 Bayer. used with permission.