FDA Approves FoundationOne CDx for Larotrectinib in NTRK+ Tumors

The FDA has approved the FoundationOne CDx comprehensive genomic test as a companion diagnostic for larotrectinib (Vitrakvi) to identify patients with NTRK1/2/3 gene fusions across all solid tumors.

The FDA has approved the FoundationOne CDx (F1CDx) comprehensive genomic test as a companion diagnostic for larotrectinib (Vitrakvi) to identify patients with NTRK1/2/3 gene fusions across all solid tumors.

FoundationOne CDx is currently the sole FDA-approved tissue-based comprehensive genomic profiling assay that is indicated to detect NTRK1/2/3 fusions across all solid malignancies and identify those who may be appropriate for treatment with the TRK inhibitor.

Larotrectinib is approved for the treatment of adult and pediatric patients with solid tumors that have a 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 therapy.

“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,” said Brian Alexander, MD, MPH, 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.”

The FDA approved larotrectinib in November 2018 based on findings from patients with TRK-positive tumors enrolled across 3 clinical trials. In results published in the New England Journal of Medicine (NEJM) in February 2018, larotrectinib induced an objective response rate (ORR) of 75% (95% CI, 61-85) by independent review and 80% (95% CI, 67-90) by investigator assessment in 55 evaluable patients. Per the independent assessment, there were 7 (13%) complete responses (CRs), 34 (62%) partial responses (PRs), and 7 (13%) patients with stable disease (SD).

The FDA reviewed data from 55 adult and pediatric patients with TRK fusion—positive cancers enrolled across a phase I adult trial (LOXO-TRK-14001), the phase II NAVIGATE trial, and the phase I/II SCOUT pediatric trial. In the studies, adult patients received oral larotrectinib at 100 mg orally twice daily and pediatric patients (aged ≤18 years) were treated with larotrectinib at 100 mg/m2 up to a maximum of 100 mg orally twice daily. Treatment was received until disease progression or unacceptable toxicity. The data cutoff for the NEJM findings was July 17, 2017.

The breakdown by tumor type included salivary gland tumor (n = 12), other soft-tissue sarcoma (n = 11), infantile fibrosarcoma (n = 7), thyroid tumor (n = 5), colon cancer (n = 4), lung cancer (n = 4), melanoma (n = 4), GIST (n = 3), cholangiocarcinoma (n = 2), appendix tumor (n = 1), breast cancer (n = 1), and pancreatic cancer (n = 1).

The median patient age was 45 years (range, 0.3-76.0), with 56% of patients ≥40 years of age. A third of patients (35%) had received ≥3 prior systemic chemotherapies. Twenty-four patients had an ECOG performance status of 0, 27 had a status of 1, and 4 had a status of 2.

The ORR by tumor type was salivary gland tumor (83%), other soft-tissue sarcoma (91%), infantile fibrosarcoma (100%), thyroid tumor (100%), colon cancer (25%), lung cancer (75%), melanoma (50%), GIST (100%), cholangiocarcinoma (best response, SD), appendix tumor (best response, SD), breast cancer (progressive disease), and pancreatic cancer (best response, SD).

At 1 year, results showed that 71% of responses were ongoing. More than half (55%) of patients remained progression-free at 1 year. The median duration of response had not been reached after a median follow-up of 8.3 months. The same was true for median progression-free survival after a median follow-up of 9.9 months.

Updated findings from the integrated analysis, which were published in Lancet Oncology in March 2020, showed that larotrectinib elicited a 79% ORR (95% CI, 72-85) in 153 evaluable patients across multiple tumor types. This comprised a CR rate of 16% (n = 24) and a PR rate of 63% (n = 97). SD was achieved as best response in 12% of patients, leading to a 91% clinical benefit rate.

The most common all-grade treatment-related adverse events (TRAEs) were increased ALT/AST level (38%), dizziness (25%), fatigue (16%), nausea (16%), constipation (16%), vomiting (11%), increased body weight (11%), anemia (9%), decreased neutrophil count (9%), and diarrhea (5%).

Grade 3 TRAEs included increased ALT/AST level (5%), anemia (2%), decreased neutrophil count (2%), nausea (2%), and dizziness (2%). There were no grade 4/5 TRAEs. Dose reductions were required in 8 of the 55 patients.

TRK gene fusions are genetic alterations that appear across a wide range of tumors—including breast and colorectal cancer, infantile fibrosarcoma, lung cancer, melanoma, and various sarcomas—and lead to uncontrolled TRK signaling and tumor growth. Such fusions are rare, but they are expressed in dozens of adult and pediatric tumor types. To date, researchers have identified more than 50 different partner genes that fuse with 1 of 3 TRK genes (NTRK 1, 2, and 3).


  1. FoundationOne CDx receives FDA-approval as a companion diagnostic for VITRAKVI (larotrectinib) to identify patients with NTRK fusions across all solid tumors. News release. Foundation Medicine. October 23, 2020. Accessed October 23, 2020. https://bit.ly/2HtgzDV
  2. Drilon A, Laetsch TW, Kummar S, et al. Efficacy of larotrectinib in TRK fusion—positive cancers in adults and children. N Engl J Med. 2018; 378:731-739. doi: 10.1056/NEJMoa1714448.
  3. Hong DS, DuBois SG, Kummar S. Larotrectinib in patients with TRK fusion-positive solid tumours: a pooled analysis of three phase 1/2 clinical trials. Lancet Oncol. doi: 10.1016/S1470-2045(19)30856