Luis E. Raez, MD

Luis E. Raez, MD, the medical director and chief scientific officer at Memorial Cancer Institute, Memorial Health Care System, discusses the treatment of 

 fusion-positive lung cancers in the past and the present.

 fusions are a relatively new target in the lung cancer space, says Raez. Despite their novelty, 

 fusions are important because they are changing the face of cancer treatment. The reach of 

 fusions spans 18 different adult and pediatric cancers, he explains.

The original data around the TRK inhibitor, larotrectinib (Vitrakvi) showed that patients will respond to TRK inhibition. This research was revolutionary for lung cancers and other solid tumors because it further solidified the role of genetic testing and targeted therapy for these patient groups.

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Luis E. Raez, MD, discusses the treatment of TRK fusion-positive lung cancers in the past and the present.

TRK Inhibition Continues to Advance the Lung Cancer Field

 fusions has been very revolutionary because, first of all, we have discovered 1 more type of fusion that we have therapy for now, despite the fact that a lot of people ask us lung cancer doctors, “This is a very uncommon genetic alteration. Why would you worry about that?” We have so many lung cancer patients in the United States: around 225,000, and a few more every year. Even if only 0.3% carry this genetic alteration, there is a significant number of Americans who have benefited from that. Worldwide, we believe that more than 8000 to 10,000 patients may carry these genetic alterations and can benefit from new treatments. That was 1 point.

The other point is the fact that we’re using tumor-agnostic therapies. This is the beginning of tumor-agnostic therapy, and it is amazing that in the papers, there were 17 different types of tumors responding. Not only were the tumors different, but there were also tumors in adults and in children. We never crossed over before, we never gave the same treatment to adults and children. These are 2 different sciences. Pediatric oncology and adult oncology were very separated, but not anymore. If we do tumor-agnostic therapy, we’ll be able to treat patients, regardless if they are adults or children.

The other important things we learned about tyrosine kinase inhibitors are their quality of life, tolerability, and low toxicity profile. We’re providing patients with cancer therapy that may do very well for them. It does not impair their quality of life, and they can stay on it longer. In lung cancer, we always said that we are trying to make this a chronic disease. Certainly, these types of treatments are helping us to make lung cancer a chronic disease because we monitor these patients maybe once a month. But the survivors don’t like to come in. After 2 or 3 years, they say, “Oh, nothing happens, so I will wait 2 or 3 months until I need to do my scan.” That’s amazing. In our lifetime—most of us have been treating lung cancer for 20, 25 years—it’s amazing to see this difference. That’s all with good quality of life.

Given all these aspects, I think the treatment of these 

 oncogenes is very important and has been impactful because we have used this example to look for other types of tumor-agnostic therapy, such as with 

 and other genes. That’s why I think it’s a very amazing, very successful story.

We are not going to find these patients if we don’t use testing and education. We’re empowering the patients to request to be tested. Even if, for example, the testing comes back negative because it’s tissue based, we can use liquid biopsies, and these 

 alterations can be found even in liquid biopsies. That’s why I think doing this is very good for our patients, for the doctors, and for education.

For me, the most important unmet need is to do the testing. Our statistics show that we aren’t testing all patients yet, and they need to be tested. Our statistics show that not all the patients tested with positive oncogene results are getting targeted therapy because of several different problems: access to the drug, problems with the payers, insurance, and things like that. Sometimes, test results take 2 or 3 weeks, and the patient becomes impatient. They are already waiting months to meet with a medical oncologist. By the time they get a chest x-ray and meet with the medical oncologist, it may be 2 or 3 months.

When you’re talking with the patients and saying, “Let’s wait 3 weeks for your results,” the patients sometimes say, “No, I want my chemotherapy tomorrow.” There are many of these aspects that we need to work together to improve. Patients need to understand, for example, that it’s worth being tested for these alterations. They can attain not only several extra months of life but also a very good quality of life. That is why for me, the most important thing is to increase testing and increase access to these drugs.

 Fusion-Positive Metastatic Non-Small Cell Lung Cancer

A 67-year old man presented with a 2-month history of cough and dyspnea on exertion

PMH/SH: hypercholesterolemia, never smoker

Chest X-ray showed a right-side mass ~2.5 cm

Chest/abdomen/pelvic CT showed a 2.7-cm solid pulmonary lesion in the right lobe, ipsilateral mediastinal lymph node involvement

CT‐guided core needle biopsy of the lung lesion and lymph node revealed lung adenocarcinoma, grade 3

Contrast‐enhanced MRI of the head showed a small lesion (0.6 cm); indicating CNS metastasis

Larotrectinib 100 mg PO BID was initiated; treatment was well-tolerated

Stereotactic radiosurgery of the brain was deferred due to location and increased risk of post-operative morbidity

Imaging at 2 months showed stable disease; sustained response upon follow-up

Imaging at 18 months showed decreased size of pulmonary and brain lesions

Larotrectinib: A Tumor-Agnostic Therapy

We repeat molecular profiling when patients progress, especially patients who have fusions like 

. We do that because there is very good documentation that these fusions suffer mutations. These mutations are creating resistance to the tyrosine kinase inhibitors. In the specific case of 

, we have a whole library of well-known resistance mutations that arise while these patients are treated with tyrosine kinase inhibitors. We learned that from the 

 patient history, and now we’re learning the same of these patients treated with larotrectinib or entrectinib. By the time we had all these data published, we had already seen that several of these patients treated with larotrectinib or entrectinib developed resistance mutations. For that reason, it is necessary to document the resistance mutations to try to find the next treatment.

resistance mutations, because in the case of 

 we already have 5 FDA-approved agents and 2 or 3 drugs being researched. If you have a patient with an 

 alteration who develops resistance, you have so many options for him. We really need to retest. The question is how you retest these patients. It depends. If it’s convenient, you can perform a tissue biopsy. For example, if the patient develops a new, single liver metastasis and you are going to use some form of local therapy, maybe it’s convenient to take a biopsy before you administer local therapy like stereotactic radiation or radiofrequency ablation.

If you don’t have a large volume of tumor, maybe the easiest method is to use a liquid biopsy, sequence DNA in the blood, and try to identify the resistance mutation and get more information from these patients. That’s why I think repeating the genomic profiling of the patient is very important. Of course, it is more focused. However, we know that the patients are going to develop mechanisms of resistance, such as 

 amplification. That’s why it’s very important to do the genomic profiling. That is a controversial topic. A lot of people will say, “Oh, we are not ready. Why are you doing that? Just put them on chemotherapy, and forget about this.” But this is something that is evolving as we speak, and when we are doing research, it’s very important that we repeat the molecular profiling for all these genetic fusions in lung cancer.

For NTRK-targeted therapies, we already have some resistance mutations that have been well described, not only in lung cancer but also arising in patients with other cancers. We have treated a lot of fibrosarcomas and other types of tumors that carry these 

 fusions. That’s why we have been developing an agent called LOXO-195. Other companies have other potential agents that can help us treat these patients to overcome resistance. There are already presentations of LOXO-195 that show the drug is able to rescue patients with resistance mutations. That is why I’m very optimistic about the future. At least we now have a second-generation NTRK inhibitor that will be able to rescue patients who fail the first line of defense.

The role of next-generation sequencing [NGS] is very important because that’s what we use now. Everybody agrees that we have to use next-generation sequencing and DNA testing at least once in every patient with lung cancer. There is a little bit of controversy about using NGS at progression. It’s important to understand that because of 

 patients have different variants that may not be captured by the DNA sequencing. It’s necessary that we add the RNA sequencing to complement that and be able to discover the genetic alterations that we cannot discover when we analyze only DNA.

We know that we can use, in specific cases, immunohistochemistry. The pan-TRK antibody seems to be good. As I said, we know more or less which genetic alteration we’re going to find. If I know for certain, for example, that this is a patient subset with a high incidence of 

 genetic alteration and secretory breast carcinomas, I can pinpoint and look for that genetic alteration, and I don’t have to worry about all the other 

That’s why there is a little bit of room to be more flexible and incorporate pan-TRK immunohistochemistry. I understand, you cannot use next-generation sequencing so often because it’s a very expensive test. However, the cost is hopefully going to go down like everything else in science. It’s amazing. We will be able to use it more often, but until then, we have to find other ways to work. Certainly, we would love to see accurate pan-TRK immunohistochemistry so that all of us can use it in any part of the United States in any small hospital in the most cost-effective way.

Treatment Resistance Due to Gene Mutation

The management of these toxicities is not very complicated because the toxicities are what is commonly seen. For example, with larotrectinib, some patients have anemia, but the management of anemia is very easy. We don’t do anything until the hemoglobin goes down to around 7g/dL, and sometimes we transfuse patients. Weight gain is something that doesn’t matter to our patients because some of our patients are malnourished and underweight. We monitor the liver function tests, certainly, and we will dose reduce if we see toxicity.

We monitor the leukocyte count, the white blood cell count, and the ANC, or absolute neutrophil count. There has been a very low incidence of leucopenia or neutropenia, and certainly we will use a dose adjustment if that’s the case with these agents. Something peculiar with these agents is the dizziness. Patients feel a little dizzy. But most of the patients say that does not affect their daily activities, that it’s something that can be tolerated until we can find a better way to administer these agents.

What is important to know about duration of response is that it provides extra time to the patient and prolongs their survival, because we are delaying the onset of palliative chemotherapy that has a well-known outcome. Duration of response opens the possibility of hope. For example, this patient in the case that we are discussing today has been on larotrectinib for 18 months. You already have 18 months of extra life. However, during these 18 months, there is another agent, LOXO-195, that has been developed to overcome resistance. Now this patient doesn’t have to be on chemotherapy. When he started the clinical trial, maybe the only option was larotrectinib and then chemotherapy; whereas nowadays, the patient has a second option because there has been a durable response. That’s the benefit. Nowadays, we are developing drugs very quickly. Even a durable response and stable disease is worth it because we can find something when the patients progress, and we don’t have to put them on chemotherapy right away.

Management of Toxicities of Larotrectinib

The patient’s response to therapy was very good. With entrectinib, we know that patients can stay on treatment for around 11 months. The progression-free survival is around 11.2 months. With larotrectinib, the progression-free survival was still ongoing when we published the data. The patient in this case has been on the drug for 18 months, and that’s why we can call this type of response amazing and successful. That’s exactly what we are looking at, because now when this patient progresses, we can do another clinical trial with another TKI [tyrosine kinase inhibitor] and hopefully buy more time before this patient has to start palliative chemotherapy. I have to add that this patient had a response in the brain. That’s another success story, because this agent is changing the standard of care in the management of brain metastases.

The study that led to the approval of LOXO-101 [larotrectinib] was very interesting. At the beginning, it was a phase I study for adults; then it was a study for children; and then it was a phase I/II study for adults and adolescents. Basically, with these uncommon genetic alterations, we need to put together several studies, because it’s very hard even for 1 study to accrue because of the low incidence of these genetic alterations. That’s why the publication in the 

 had 55 patients from 3 different studies.

The same happened with entrectinib. Entrectinib collected data that had been presented in several meetings from another 2 or 3 studies that were available for this agent. These studies are revolutionary because we are using tumor-agnostic therapy. The studies were not only for patients with lung cancer or breast cancer or pancreas cancer, as we used to do. This study was a basket trial, meaning that we could have several different tumor types enrolled. In the case of larotrectinib, there were 17 different types of tumors, and they enrolled adults or children regardless of age. This was a very revolutionary, very innovative, and very successful design.

In the case of dosing these tyrosine kinase inhibitors, it was not very hard to find the larotrectinib dosage because they started by testing 50 mg once a day and correcting the dosage. We ended up identifying 100 mg twice a day as the right dosage because we already have responses with larotrectinib. Something similar happened with entrectinib. At these doses, the adverse effects are well tolerated. They are not life-threatening adverse effects, and we’ve already seen response rates up to 70% for each agent for solid tumors in general. These are amazing responses. There was no need to continue increasing the doses for these agents. In the specific case of lung cancer, larotrectinib and entrectinib also achieve a response rate of around 70%.

That’s why I think we deal very well with the doses. We mentioned before that maybe 9% of patients on larotrectinib need a dose reduction and around 27% of entrectinib patients need a dose reduction. Very, very few patients need to discontinue the drug: in the case of larotrectinib, around 1%; and entrectinib, around 4%. That’s why it was not very complicated. These TKIs are well-tolerated agents. It’s not like in the old times, when we used to use dose escalation for chemotherapy and there was a lot of toxicity. Nowadays, targeted therapies are very different, to the point that with a lot of these biologic agents or targeted agents, we don’t even know what the maximum tolerated doses are because we have no need to reach them. You already achieve responses at lower doses.

Response to Treatment With Larotrectinib

These agents are very well tolerated. In the specific case of larotrectinib and entrectinib, at the standard dosages—with larotrectinib, 100 mg twice a day; for entrectinib, 600 mg once a day—the tolerability is very good. The number of adverse effects is not very concerning, and usually, the dose-reduction rate is only around 9% for larotrectinib and 27% for entrectinib. The rate of discontinuation of these agents is very low. For larotrectinib, it’s around 1%. For entrectinib, it’s around 4%. That means that most of the patients, a huge number of patients, will not discontinue these drugs because they’re well tolerated. Patients have a very good quality of life.

Major adverse effects of larotrectinib include anemia, which is something that happens frequently. Patients have fatigue; that happens frequently. Sometimes you don’t know if you should blame the tumor for fatigue or the drug. Patients are also monitored for changes in dizziness, but it’s something that most of my patients say doesn’t impair their driving or daily activities. Patients may gain a little bit of weight. There are not really any life-threatening adverse effects or anything too worrisome. As with any other agent, tyrosine kinase inhibitors, or even chemotherapy or immunotherapy, we need to monitor laboratory tests. We monitor liver function because there is a little bit of an increase on liver function tests. We monitor kidney function. We monitor the white blood cell count because there can be a decrease of the white blood cell count. But this is pretty standard.

In general, if you treat a patient with chemotherapy, you probably have to see him 2 or 3 times a month depending on what type of regime he receives. Sometimes you have to see him for chemotherapy and you have to see him for laboratory tests. With these patients on tyrosine kinase inhibitors, you can see them once a month and on the same day that you do the laboratory tests, or maybe every 6 weeks. When the patients have long-term survival, they don’t even want to come every month. They like to come in every 2 or 3 months because nothing will happen. They are very stable and have a good quality of life. That’s what we do in general, and not only for these tyrosine kinase inhibitors but for all of them. If I have a patient on a tyrosine kinase inhibitor for more than 3 years, I will likely see him only every 2 or 3 months.

This is amazing because oncology is going to change. I’ve been practicing oncology now for 20 years. I am an expert in lung cancer. For 20 years, I have been treating lung cancer tumors. We thought that the behavior of the cancer is related to the place where the cancer has arisen. As a lung cancer doctor, I think the cancer’s behavior is due to it being lung cancer. That is why even when we find metastases of lung cancer in the liver, they are going to respond to lung cancer therapy. However, when we discovered microsatellite instability [MSI]—and how tumors that carry microsatellite instability respond to immunotherapy, in the specific case of pembrolizumab—it was very interesting to find that it doesn’t matter where the tumor is located. That is why it was historic that the FDA approved pembrolizumab for tumors that are MSI-high. They can have this microsatellite instability regardless of where the tumor is located.

It was the first time in history that approval of a drug was based on a molecular alteration and not on an organ. That is why we call it a tumor-agnostic therapy. 

 fusions are an amazing example because in a paper in the 

, across 55 patients we had 17 different types of tumors, including tumors in children and tumors in adults. It’s also the first time in history that we’re using a treatment that may work for children and adults. As you probably know, most of us as oncologists are trained to treat either adults or children. We don’t cross over. But it’s amazing. We have a type of treatment that works on fibrosarcomas in children, not only lung cancer in children.

That’s why it’s very interesting. We call them tumor-agnostic treatments, and this is the future of oncology. There is pembrolizumab for MSI-high disease, and there are tyrosine kinase inhibitors for 

 mutations are tumor agnostic. They’re present in more than 4 or 5 different tumors. Soon, 

 fusions will also be tumor agnostic because 

 fusions are present in different tumor types. A lot of patients in clinical trials have 

 fusions. I receive referrals for patients with colon cancer, pancreas cancer, and thyroid cancer who also have 

 fusions. Our basket trials allow us to treat these patients, and that’s why it’s amazing. This is a very important topic. The treatment of cancer in the future is tumor agnostic, and that is probably a more successful approach than what we were doing before.

Luis E. Raez, MD | Authors

Articles

TRK Inhibition Continues to Advance the Lung Cancer Field

Larotrectinib: A Tumor-Agnostic Therapy

Treatment Resistance Due to Gene Mutation

Management of Toxicities of Larotrectinib

Response to Treatment With Larotrectinib

Larotrectinib in NTRK Fusion-Positive Lung Cancer