Larotrectinib: A Tumor-Agnostic Therapy

Luis Raez, MD: The treatment for NTRK 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 NTRK 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 BRAF 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 NTRK 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.

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+