The Newly Added Broad-Spectrum Anti-Cancer Drug Larotrectinib to Health Insurance: Which Childhood Tumors Can Benefit?

The Newly Added Broad-Spectrum Anti-Cancer Drug Larotrectinib to Health Insurance: Which Childhood Tumors Can Benefit?

 

Published by: Sunflower Children  

Author: Zhou Yebin  

Editor: Zhengty  

Date: December 24, 2024  

 

On November 28, 2024, the world's first precision-targeted drug without tumor type limitations, Vitrakvi (Larotrectinib sulfate capsules and oral solution), was included in the National Basic Medical Insurance, Work Injury Insurance, and Maternity Insurance Drug Catalog (2024).  

 

As a broad-spectrum anti-cancer drug that has attracted global attention, Larotrectinib targets mutations present in various childhood tumors, making its inclusion in health insurance a significant benefit for patient families and the overall treatment of childhood tumors in China.  

 

What is Larotrectinib?  

 

Larotrectinib was initially developed by a biopharmaceutical company called Loxo Oncology (which has since been acquired by Eli Lilly) and later developed and promoted in collaboration with Bayer Pharmaceuticals. Mechanistically, it belongs to the class of small-molecule anti-cancer drugs that target NTRK fusion genes. When it received FDA approval for market entry in 2018, it sparked widespread discussion about broad-spectrum anti-cancer drugs.  

 

Due to its early fame, this drug has been referred to by many names in related reports, such as Loxo-101, Larotrectinib, Vitrakvi, and its Chinese name, 拉罗替尼. So, what should it be called?  

 

Loxo-101 was the code name for the drug during its clinical trial phase. Such code names are assigned by pharmaceutical companies for their unapproved development products, and they typically use this code (like during pre-approval clinical trials) before they are marketed.  

 

Larotrectinib is the name of the drug molecule. Every drug has a molecule that performs the therapeutic function (which can be a small molecular compound or an antibody), and this molecule will have its own name. The therapeutic molecule in Loxo-101 is called Larotrectinib, which translates to 拉罗替尼.  

 

Here’s a common naming pattern for drug molecules: the "nib" at the end of Larotrectinib indicates that it is a small-molecule kinase inhibitor. Many drug names end with "nib," such as the well-known cancer drug Gleevec from the movie "Dying to Survive," which is called Imatinib in molecular terms.  

 

Vitrakvi is the brand name chosen by Loxo and Bayer for this new drug, and its Chinese brand name is 维泰凯. After a drug is marketed, it circulates under its brand name, which is the name we typically see on drug packaging.  

 

Once a drug is on the market, the code name used during development is no longer utilized. Therefore, Larotrectinib now generally appears in the forms of Vitrakvi (Larotrectinib) or 维泰凯 (拉罗替尼), which includes both the brand name and indicates the active ingredient.  

 

How does Larotrectinib work?  

 

Since Larotrectinib is a small-molecule anti-cancer drug targeting NTRK fusion genes, what is NTRK?  

 

First, let’s take a look at neurotrophic factors (NT). Neurotrophic factors are proteins crucial for the survival, growth, and development of nerve cells. However, to exert these important effects, neurotrophic factors must first bind to another type of protein on the surface of nerve cells. Currently, it is known that this protein includes two types, one of which is called tyrosine receptor kinase (TRK), which binds strongly to neurotrophic factors and is therefore very important.  

 

The gene corresponding to tyrosine receptor kinase is called the NTRK gene, which includes three genes: NTRK1, NTRK2, and NTRK3. In 1982, scientists first discovered that the NTRK1 gene fused with another gene in colon cancer, forming a fusion gene known as NTRK1. Unlike the activity of NTRK genes, which is precisely regulated within cells, the NTRK fusion gene is uncontrolled within cells, promoting tumor development.  

 

Researchers have found that the presence of NTRK fusion genes can increase the likelihood of cells becoming cancerous. Moreover, both preclinical and clinical trial data have shown that NTRK inhibitors can effectively inhibit tumor development in tissues with NTRK fusions.  

 

How did Larotrectinib become a broad-spectrum anti-cancer drug?  

 

First, let’s clarify a common misunderstanding about "broad-spectrum." When people hear "broad-spectrum," they may think that this drug can treat all types of cancer, which is inaccurate. Traditional cancer classification is based on the location of tumor occurrence. For example, lung cancer occurs in the lungs, whereas leukemia occurs in blood cells. Previous anti-cancer drugs were generally developed based on this classification, resulting in specific drugs for lung cancer and others for breast cancer.  

 

The biggest difference between Larotrectinib and other traditional tumor drugs is that its entire development and clinical trials were based on one molecule—the NTRK fusion gene—without specific limitations to any type of tumor. In fact, molecular markers in cancer have long been used in the development of anti-cancer drugs. For instance, the famous breast cancer drug Herceptin is based on the expression of the Her2 protein in some breast cancers. The difference is that earlier anti-cancer drug development, while also based on a molecular marker, was still limited to certain tumors. For example, Herceptin is only for breast cancer. However, the development of Larotrectinib only focused on the NTRK fusion gene without restricting to specific cancers. Ultimately, the approved patient population by regulatory authorities only required the presence of the molecular marker.  

 

This development approach is a historical first. Because Larotrectinib targets tumors with NTRK gene fusions, these tumors can occur anywhere in the human body, and according to traditional cancer classifications, it would cover multiple cancers, leading to the term "broad-spectrum."  

 

However, NTRK gene fusions are a relatively rare target, with eligible patient populations accounting for less than 1% of all cancer patients. From another perspective, if we classify cancer purely based on molecular markers, then Larotrectinib becomes a drug targeting a single molecular marker and is no longer "broad-spectrum."  

 

What is the treatment effect of Larotrectinib? Is it effective for childhood tumors?  

 

As a broad-spectrum anti-cancer drug, how effective is Larotrectinib?  

 

When it was approved by the FDA in 2018, Larotrectinib integrated data from three small clinical trials to obtain its marketing license. At that time, the combined total of the three clinical trials included only 176 patients (all with NTRK gene fusions, including 44 pediatric patients). All data were used to demonstrate the safety of Larotrectinib.  

 

The drug's efficacy was derived from the first 55 patients to enter the trial (data on the treatment effects of later patients were not available then). The overall response rate for the 55 patients was 75%, with a complete response rate of 22%. These figures were indeed impressive. A 75% overall response rate is quite high, demonstrating that Larotrectinib is effective for patients with NTRK gene fusions, especially since many of these patients had no other treatment options available.  

 

For those concerned about childhood tumors, Larotrectinib stood out during that time. In a Phase I clinical trial involving 24 pediatric tumor patients, including infantile fibrosarcoma, soft tissue sarcoma, and papillary thyroid cancer, the objective response rate for patients with NTRK gene fusion tumors reached 93%. This means that 93% of patients experienced a significant tumor reduction after treatment, maintaining that reduction for a certain period.  

 

Special mention should be made of infantile fibrosarcoma, a rapidly growing soft tissue sarcoma that typically manifests before the age of one. In traditional treatments, some children may require amputation due to the tumor's size, making effective removal impossible. In 1998, scientists discovered a specific NTRK gene fusion mutation (ETV6-NTRK3) closely associated with the occurrence of this tumor. In the aforementioned clinical trial, two infants had the opportunity to have limb-sparing surgery due to tumor shrinkage, with their quality of life remaining unaffected.  

 

Now, six years have passed since Larotrectinib was launched globally, and scientists have provided more data, especially regarding long-term anti-tumor effects.  

 

For example, comprehensive long-term data from three Larotrectinib clinical trials published in 2023 showed that among 289 patients, the median response duration reached 43.3 months, with a median progression-free survival time of 30.8 months and a four-year overall survival rate of 65%. This indicates that Larotrectinib demonstrates a durable anti-tumor effect, providing survival benefits for patients.  

 

This data comes from patients who had previously received other treatments. This year, another update on long-term clinical trial data for Larotrectinib was released, focusing on its use as a first-line treatment. This means using Larotrectinib as the first-targeted drug for patients diagnosed with NTRK fusion genes. The published data showed that among 101 patients (including 41 pediatric tumor patients), the five-year overall survival rate reached 76%, demonstrating that Larotrectinib is also significantly effective as a first-line medication.  

 

How is NTRK fusion mutation detected?  

 

Since Larotrectinib only works for tumors with NTRK gene fusions, confirming whether a patient can use this drug requires first testing for NTRK gene fusions. Currently, many technical methods can successfully detect NTRK gene fusions.  

 

For instance, FISH (Fluorescence In Situ Hybridization) and PCR (Polymerase Chain Reaction) are two methods that are fast and relatively inexpensive but can only test for one type of NTRK gene fusion at a time. For recurrent tumors with a high frequency of NTRK gene fusions, NGS (Next-Generation Sequencing) is a better choice.  

 

The commonly used clinical testing method—immunohistochemistry (IHC)—can also be used to detect the expression of the TRK gene in tumor tissues, serving as an indicator for the possible existence of NTRK gene fusions. If patients need it, they can directly consult their attending physician about suitable companies offering relevant services.  

 

Are there similar broad-spectrum anti-cancer drugs like Larotrectinib?  

 

Yes, and there are more emerging. Specifically targeting NTRK gene fusions, there are now three drugs approved globally: besides Larotrectinib, there is also entrectinib, which received FDA approval in 2019, and repotrectinib, which received FDA approval in July of this year.  

 

Leading the way, Larotrectinib was the first to receive FDA approval for market entry in the United States in 2018 and subsequently obtained approval from the National Medical Products Administration in China in 2022. Entrectinib also gained approval from the National Medical Products Administration in China the same year.  

 

Interestingly, unlike Larotrectinib, which only targets NTRK, both entrectinib and repotrectinib can inhibit another well-known oncogenic gene fusion: ROS1. The indication for repotrectinib targeting ROS1 has been approved by the National Medical Products Administration in China, and the application for the indication targeting NTRK has also been accepted.  

 

The ROS1 gene fusion is very famous in the field of lung cancer and is referred to as a "diamond mutation" alongside ALK alterations due to its very favorable prognosis when targeted by corresponding drugs. Some childhood tumors, such as gliomas, also exhibit ROS1 mutations, while about 10% of neuroblastoma cases have ALK alterations. Therefore, drugs targeting ROS1 or ALK have the potential to benefit some pediatric tumor patients.  

 

With advancements in medicine, we can expect more broad-spectrum targeted drugs like Larotrectinib to emerge, bringing hope to patients. With its inclusion in health insurance, the economic burden of using Larotrectinib will also significantly decrease, making this broad-spectrum anti-cancer drug more accessible and benefiting more patients.  

 

References:  

1. Cocco E, Scaltriti M, and Drilon A. NTRK fusion-positive cancers and TRK inhibitor therapy. Nat Rev Clin Oncol. 2018;15(12):731-47.  

2. DuBois SG, Laetsch TW, Federman N, Turpin BK, Albert CM, Nagasubramanian R, et al. The use of neoadjuvant larotrectinib in the management of children with locally advanced TRK fusion sarcomas. Cancer. 2018;124(21):4241-7.  

3. Knezevich SR, McFadden DE, Tao W, Lim JF, and Sorensen PH. A novel ETV6-NTRK3 gene fusion in congenital fibrosarcoma. Nat Genet. 1998;18(2):184-7.  

4. Laetsch TW, DuBois SG, Mascarenhas L, Turpin B, Federman N, Albert CM, et al. Larotrectinib for pediatric solid tumors harboring NTRK gene fusions: phase 1 results from a multicenter, open-label, phase 1/2 study. Lancet Oncol. 2018;19(5):705-14.  

5. Moreno L. An active drug for TRK-positive pediatric solid tumors. Lancet Oncol. 2018;19(5):594-5.  

6. Rolfo C, Ruiz R, Giovannetti E, Gil-Bazo I, Russo A, Passiglia F, et al. Entrectinib: a potent new TRK, ROS1, and ALK inhibitor. Expert Opin Investig Drugs. 2015;24(11):1493-500.  

7. Stransky N, Cerami E, Schalm S, Kim JL, and Lengauer C. The landscape of kinase fusions in cancer. Nat Commun. 2014;5:4846.  

8. NTRK fusion-positive cancers and TRK inhibitor therapy. Nat Rev Clin Oncol. 2018;15(12):731-47.  

9. Chen Y, and Chi P. Basket trial of TRK inhibitors demonstrates efficacy in TRK fusion-positive cancers. J Hematol Oncol. 2018;11(1):78.  

10. Drilon A, Laetsch TW, Kummar S, DuBois SG, Lassen UN, Demetri GD, et al. Efficacy of Larotrectinib in TRK Fusion-Positive Cancers in Adults and Children. N Engl J Med. 2018;378(8):731-9.  

11. Tran TH, Shah AT, and Loh ML. Precision Medicine in Pediatric Oncology: Translating Genomic Discoveries into Optimized Therapies. Clin Cancer Res. 2017;23(18):5329-38.  

12. https://www.clinicaloncology.com/FDA-Watch/Article/11-18/FDA-Approves-Vitrakvi-for-Solid-Tumors-With-NTRK-Gene-Fusions/53466  

13. https://www.annalsofoncology.org/article/S0923-7534(23)02691-1/fulltext  

14. https://oncologypro.esmo.org/meeting-resources/esmo-congress-2024/efficacy-and-safety-of-larotrectinib-as-first-line-treatment-for-patients-pts-with-trk-fusion-cancer-an-updated-analysis  

 

Disclaimer: This article aims to popularize the science behind cancer treatment and is not a drug promotional material, nor is it a recommendation for treatment plans. For guidance on disease treatment plans, please visit a reputable hospital.  

 

Author: Zhou Yebin  

Layout: Xia Yu  

Proofreader: Ya Li