‘Histology-independent’ Treatment for Solid Tumors Recommended for Approval in the EU

Bayer scientist analyzing biopsy specimen in a lab in Berlin. | In einem Labor in Berlin untersucht eine Bayer-Forscherin Krebszellen. Photo Courtesy: Bayer AG
Bayer scientist analyzing biopsy specimen in a lab in Berlin. | In einem Labor in Berlin untersucht eine Bayer-Forscherin Krebszellen. Photo Courtesy: Bayer AG

Earlier this month the European Medicines Agency’s human medicines committee (CHMP) recommended granting a marketing authorization in the European Union for larotrectinib (Vitrakvi®; Bayer), also known as LOXO-101, for the treatment of adult and pediatric patients with solid tumors that display a Neurotrophic Tyrosine Receptor Kinase (NTRK) gene fusion.[1]

Originally discovered by Array BioPharma, the drug was licensed to Loxo Oncology. In February 2019, following the acquisition of Loxo Oncology by Eli Lilly and Company, Bayer obtained the exclusive licensing rights for the global development and commercialization for larotrectinib.

Uncommon genetic change
Tumors with this type of genetic change are not common, however, they can be found in cancers of the salivary gland, thyroid, lung, and soft tissue sarcoma.

Treatment with larotrectinib is recommended for patients whose disease has spread or cannot be surgically removed, and who have no other satisfactory treatment options.

First ‘histology-independent’ treatment
Larotrectinib is the first so-called ‘histology-independent’ cancer treatment recommended for approval in the EU. This means that it can be used to treat non-hematological (i.e. that do not begin in the blood or bone marrow) tumors with this specific mutation, regardless of where in the body the tumor originated. Before patients can be started on the medicine, the presence of the mutation in the tumor should be confirmed by a validated test.

Larotrectinib targets a very specific genomic alteration of a patient’s tumor. This occurs when NTRK genes that encode specific proteins are abnormally fused to a gene. This mutation, called NTRK-gene fusion, leads to the development of proteins that can cause cancer cells to grow.

Larotrectinib inhibits or blocks the action of these proteins – the tropomyosin receptor kinases (Trk) receptor family which includes 3 transmembrane proteins referred to as Trk A, B and C (TrkA, TrkB and TrkC), which are encoded by the genes NTRK1 (located on chromosome 1q21-q22), NTRK2 ( located on chromosome 9q22.1) and NTRK3 (located on chromosome 15q25), respectively and in doing so inhibits the growth of the cancer.

Chromosomal rearrangements involving in-frame fusions of these genes with various partners can result in so called constitutively activated chimeric TRK fusion proteins, which can act as oncogenic drivers in promoting cell proliferation and survival in tumor cell lines.

Rare cancers
NTRK-gene fusions can be observed very frequently in a certain number of rare cancer types that affect both adults and children. In addition, this gene fusion occurs rarely in some of the most common cancer types.

The efficacy and safety of larotrectinib were studied in three single-arm trials (i.e. studies with no control group) that included a total of 102 adults and children with cancer that were evaluated. These patients had either already received standard therapy, or would have had to undergo disfiguring surgery, or were unlikely to respond to available therapies.

The share of patients who responded to treatment with larotrectinib was 67%. Of those, the response lasted six months or longer in 88% and 12 months or longer in 75%. Tumor responses were seen both in rare tumour types such as infantile fibrosarcoma and salivary gland tumors, as well as in common diseases such as lung and colon cancer.

Adverse events
The most common side effects included tiredness, increased levels of liver enzymes, dizziness, cough, constipation, nausea, anemia (low red blood cell count), and vomiting.

To check liver function, regular blood tests are needed while women who are pregnant or breastfeeding or are planning to get pregnant should are encouraged not take use the drug. Finally, patients are encouraged to report signs of neurologic reactions such as dizziness.

The CHMP recommended a conditional approval for this medicine. This is one of the EU’s regulatory mechanisms to facilitate early access to medicines that fulfill an unmet medical need.

This type of approval allows the Agency to recommend a medicine for marketing authorization with less complete data than normally expected, in cases where the benefit of a medicine’s immediate availability to patients outweighs the risk inherent in the fact that not all the data are yet available.

Intermediate step
The opinion adopted by the CHMP is an intermediary step on larotrectinib’s path to patient access. The opinion will now be sent to the European Commission for the adoption of a decision on an EU-wide marketing authorization. Once the marketing authorization has been granted, decisions about price and reimbursement will take place at the level of each Member State, taking into account the potential role/use of this medicine in the context of the national health system of that country.

United States
In November 2018, the Food and Drug Administration (FDA) approved larotrectinib was approved in the United States for the treatment of adult and pediatric patients with solid tumors that have a NTRK-gene fusion without a known acquired resistance mutation.

The FDA-approval also applied to patients with tumors with an NTRK-gene fusion that are either metastatic or where surgical resection is likely to result in severe morbidity, and for patients who have no satisfactory alternative treatments or whose cancer has progressed following treatment.

The FDA approved larotrectinib using several approaches designed to speed up the availability of drugs to treat serious diseases, including breakthrough therapy designation, priority review status, and accelerated approval. The drug was also granted orphan drug designation, which provided financial incentives to encourage the development of drugs for rare diseases.

The FDA-approval in November 2018 was based on data on objective response rates and response duration from three single-arm clinical trials (NCT02122913, NCT02637687, NCT02576431) in adult and pediatric patients with unresectable or metastatic solid tumors with an NTRK gene fusion.

These patients were required to have disease progression after systemic therapy or would have required surgery with significant morbidity for locally advanced disease. The identification of positive NTRK gene fusion status was prospectively determined using next-generation sequencing or fluorescence in situ hybridization. Adult patients received 100 mg orally twice daily, and pediatric patients (≤ 18 years) received 100 mg/m2, up to a maximum dose of 100 mg orally twice daily.

Clinical trials

  • Larotrectinib in Treating Patients With Previously Untreated TRK Fusion Solid Tumors and TRK Fusion Relapsed Acute Leukemia – NCT03834961
  • Larotrectinib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With NTRK Fusions (A Pediatric MATCH Treatment Trial) – NCT03213704
  • Expanded Access to Provide Larotrectinib for the Treatment of Cancers With a NTRK Gene Fusion – NCT03025360
  • A Study to Test the Effect of the Drug Larotrectinib in Adults and Children With NTRK-fusion Positive Solid Tumors (NAVIGATE) – NCT02576431
  • 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 Safety of the Investigational Drug Larotrectinib in Adults That May Treat Cancer – NCT02122913
  • Targeted Therapy Directed by Genetic Testing in Treating Patients With Advanced Refractory Solid Tumors, Lymphomas, or Multiple Myeloma (The MATCH Screening Trial) – NCT02465060
  • A Study to Test the Safety and Efficacy of the Drug Larotrectinib for the Treatment of Tumors With NTRK-fusion in Children (SCOUT) – NCT02637687

Reference
[1] VITRAKVI [package insert]. Stamford, CT: Loxo Oncology, Inc.; November 2018.
[2] Amatu A, Sartore-Bianchi A, Siena S. NTRK gene fusions as novel targets of cancer therapy across multiple tumour types. ESMO Open. 2016;1(2):e000023.
[3] Laetsch TW, DuBois SG, Mascarenhas L, et al. Larotrectinib for paediatric solid tumours harbouring NTRK gene fusions: phase 1 results from a multicentre, open-label, phase 1/2 study. Lancet Oncol. 2018;19(5):705-714.