Is it possible for one drug to treat multiple cancers?

Author: Wang Jin (Shanghai Institute of Immunology)

The article comes from the Science Academy official account (ID: kexuedayuan)

Because of the difficulty and cost of treatment, it goes without saying how terrible cancer is to the general public.

If there is a drug that can effectively treat multiple cancers at the same time, it would be a great blessing!

But does such a drug exist?

In November 2018, Bayer and Loxo Oncology jointly launched a new anti-cancer drug: Vitrakvi, also known as larotrectinib. Now many people know this drug, not because of its good reputation (few people use it, so it can't be said to have a good reputation), but because of the constant discussion and reversal on the Internet about whether it is a miracle drug.

Is it a miracle drug? Is it possible that there is a miracle drug that can cure many types of cancer?

Let's take some time to figure out what cancer is and what Vitrakvi is before we draw any conclusions.

What exactly is Vitrakvi?

First, let’s talk about what Vitrakvi is.

Vitrakvi is the first oral TRK inhibitor and is indicated for adults and children with advanced solid tumors, provided that the tumor has NTRK gene fusion and no known acquired resistance mutations.

Why do we need to emphasize that the scope of application is patients with NTRK gene fusion in their tumors?

Let’s first look at the oncogenic mechanism of NTRK fusion:

Figure 1: a. Location of NTRK genes on human chromosomes

b. Active form (phosphorylated) of the protein TRK encoded by the NTRK gene (Image source: created by the author)

NTRK is a gene encoding neurotrophin receptor tyrosine kinase. There are three copies of NTRK in the human genome, located on chromosomes 1, 9, and 15 (Figure 1, a). The corresponding encoded proteins are called TRKA, TRKB, and TRKC.

So what is TRK?

A gene and the protein it encodes have similar but different names, just like the relationship between cows and milk, and goats and goat milk.

For the animal (gene) NTRK, the milk (the protein it encodes) is called TRK. Normally encoded TRK proteins participate in multiple signal transduction processes related to the proliferation, survival, and regeneration of nerve cells (Figure 1, b).

Since NTRK is called neurotrophin receptor tyrosine kinase receptor, as the name suggests, the protein TRK it encodes should be expressed only in small amounts in nerve cells under normal circumstances and be strictly regulated by multiple growth factor signals.

However, in some cases, NTRK undergoes gene rearrangement and fusion with other genes, taking advantage of the promoters of other genes to express some chimeric proteins that still have kinase activity and are randomly expressed in other tissues. These chimeric proteins actively and continuously participate in signal transduction, promoting abnormally active proliferation and growth of non-neuronal cells, and eventually turning into a malignant tumor (Figure 2).

Figure 2: Chromosomal rearrangement leads to NTRK fusion, producing a chimeric protein with kinase activity (Image source: produced by the author)

In human NTRK fusion tumor patient samples, there are more than 60 different 5' partner genes (genes that provide promoters), and the cancers caused include glioblastoma, pancreatic cancer, lung cancer, etc.

Since the essence of TRK is kinase, if there is a drug that can specifically inhibit the activity of TRK kinase, it can effectively inhibit the activity of the chimeric protein expressed by NTRK gene fusion, thereby inhibiting tumor growth.

This is the anti-cancer principle of Vitrakvi.

So everyone was excited when Vitrakvi came out.

This is why many people say it is a miracle drug - no matter what kind of cancer it is in, as long as it is caused by NTRK fusion, taking this drug can effectively relieve the symptoms.

Is Vitrakvi a miracle drug?

Since the day Vitrakvi passed the approval, people have been arguing online about whether it is a miracle drug.

First, many articles said that its cure rate was as high as 75%, and then many articles said: This is not true! The truth is this and that!

Although everyone seems to be keen on seeing plot twists, we are more interested in studying what the facts are.

On November 28, 2018, Loxo Oncology, one of the co-developers of this drug, issued a press release with some key information:

Figure 3: Loxo Oncology’s press release on Vitrakvi’s approval

Source: https://www.loxooncology.com/

The title first explains what this drug is and who it is suitable for, and then highlights the clinical trial data:

Complete response: patients with complete remission (all tumor lesions disappeared and no new lesions appeared), accounting for 22% of the total subjects;

Partial response: 53% of patients had partial remission (the sum of tumor diameters shrank by more than 30% but did not completely disappear).

These two types of patients together accounted for 75% of the total subjects.

Total subjects: 55, 95% CI: 61%-85%

(Image source: produced by the author)

This is very good data and good news for the relevant trial patients.

However, some experts pointed out that although Vitrakvi is good, it is only suitable for a very small number of patients.

Why do I say so?

Many people have a misunderstanding: they simply divide cancer into different categories based on the location of the tumor, such as gastric cancer, lymphoma, and liver cancer, and believe that the causes of the same cancer are the same. In fact, even tumors in the same location can be driven by different gene mutations.

Taking primary liver cancer as an example, mutations in the two genes K-ras and p53 can lead to liver cancer, and targeted drugs need to be designed for these two genes respectively. Cancer is just a general term. If you want to treat cancer accurately, you need to design different targeted drugs for different genes (targets) to treat the disease.

This is also the difficulty in developing broad-spectrum anti-cancer drugs, because it is too difficult to find a target that is applicable to most cancers!

Although there are many types of cancers caused by NTRK fusion, malignant tumors driven by NTRK fusion due to chromosomal rearrangement only account for about 1% of solid tumors; that is to say, only 1% of cancer patients (here only solid tumors, excluding blood and lymphomas) are suitable for Vitrakvi.

Although 1% is small, it is actually not small considering the patient base.

According to the data provided on the Vitrakvi website, the incidence of NTRK fusion in salivary gland cancer, infantile fibrosarcoma, secretory breast cancer, and congenital mesoblastic nephroma is higher than 80%. The frequency of occurrence in some common cancers is shown in the figure below.

Figure 4: Frequency of NTRK fusions in some common cancers

Source: https://www.hcp.vitrakvi-us.com/

In this regard, the official advice is: first use second-generation sequencing and fluorescence in situ hybridization (FISH) to determine whether NTRK fusion exists, and then choose the medication.

Having said that, everyone can definitely make their own judgment on whether Vitrakvi is a miracle drug.

To sum up in one sentence: Vitrakvi is not a true broad-spectrum drug. It may not be appropriate to call it a miracle drug, but no one should refute that it is a good drug.

At the same time, we also need to pay attention to the toxic side effects of Vitrakvi.

Bayer Pharmaceuticals' official website also points out that Vitrakvi has certain hepatotoxicity, neurotoxicity, and fetotoxicity. It has been found that more than 20% of the subjects have clinical side effects such as elevated aspartate aminotransferase or alanine aminotransferase, anemia, fatigue, nausea, etc. Therefore, patients with liver diseases should be particularly cautious when taking the drug.

Figure 5: Timeline from the discovery of TRK as a tumor suppressor gene to the development of corresponding targeted drugs

Source: Reference 2

It has been 36 years since NTRK was discovered as an oncogene by Mariano Barbacid and his colleagues in 1982, and the new drug Vitrakvi was launched in November 2018. We hope that the drug can be approved in China as soon as possible and then included in medical insurance so that more patients can benefit.

At this stage, don’t rely on broad-spectrum miracle drugs for cancer treatment

If you pay a little attention to biological research, you will find that from basic research to clinical trials, there are research advances on different cancers every day. Active basic scientific research has revolutionized cancer treatment.

In terms of immunotherapy, the State Food and Drug Administration approved the first CAR-T treatment clinical trial application in China in March 2018; in the same year, related research won the Nobel Prize in Physiology or Medicine, and inhibitors corresponding to the two immune checkpoints PD-1 and CTLA-4 have also been launched. Targeted therapy, which became popular earlier than immunotherapy, involves more drugs. In recent years, Olaparib, a PARP inhibitor, has a considerable effect on ovarian cancer and breast cancer patients with BRCA gene mutations. This time, Vitrakvi is also a targeted drug.

At present, except for a few cancers that can only be treated with a single treatment method, most cancers are clinically treated with combined treatment methods, such as surgery + radiotherapy/chemotherapy. Mainstream treatment methods include surgery, radiotherapy, chemotherapy, immunotherapy, targeted drugs, and hormone therapy for breast cancer and prostate cancer. The successful combination of scientific research and clinical practice has also allowed us to redefine the concept of cancer - except for the high cost of treatment, cancer is no longer a terminal illness.

So, why should we rely on a single broad-spectrum miracle drug to cure cancer? When it comes to cancer, the right medicine for the right condition, individualized comprehensive treatment is the best way.

References and websites:

1.Kummar, S. and UN Lassen, TRK Inhibition: A New Tumor-Agnostic Treatment Strategy. Target Oncol, 2018. 13(5): p. 545-556.

2.Cocco, E., M. Scaltriti, and A. Drilon, NTRK fusion-positive cancers and TRK inhibitor therapy. Nat Rev Clin Oncol, 2018. 15(12): p. 731-747.

3.Amatu A, Sartore-Bianchi A, Siena S NTRK gene fusions as novel targets of cancer therapy across multiple tumor types ESMO Open 2016;1:e000023. doi: 10.1136/esmoopen-2015-000023