Larotrectinib in NTRK Fusion-Positive Lung Cancer


Luis Raez, MD: 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. NTRK fusions are an amazing example because in a paper in the New England Journal of Medicine, 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 NTRK fusions. And already, BRAF mutations are tumor agnostic. They’re present in more than 4 or 5 different tumors. Soon, RET fusions will also be tumor agnostic because RET fusions are present in different tumor types. A lot of patients in clinical trials have RET fusions. I receive referrals for patients with colon cancer, pancreas cancer, and thyroid cancer who also have RET 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.

Transcript edited for clarity.

Case: A 67-Year-Old Man With NTRK Fusion-Positive Metastatic Non-Small Cell Lung Cancer

Initial presentation

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

PMH/SH: hypercholesterolemia, never smoker

PE: right-sided wheezing on auscultation

Clinical workup

Labs: WNL

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

Molecular and genomic testing:NTRK+, BRAF-, EGFR-, ALK-, ROS1-,KRAS-, PD-L1 0%

Stage T1cN2M1b; ECOG PS 1

Treatment and Follow-Up

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

Repeat genomic testing: NTRK+

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