Targeted Treatment in NTRK Fusion-Positive Cancer

Luis Raez, MD: Usually, when we have an oncogenic driver that we have discovered, such as the NTRK, ALK, ROS, or EGFR, we achieve much better quality of life and response when we use targeted agents. Usually, we start therapy with a targeted agent. That’s part of our international guidelines and NCCN [National Comprehensive Cancer Network] Guidelines. Later, if these patients fail the targeted agents and we don’t have more targeted agents to give them, that’s the time when we will use chemoimmunotherapy and clinical trials and other options for them.

The treatment for this patient, used successfully, was larotrectinib. Larotrectinib is a tyrosine kinase inhibitor. As more of these genetic alterations have been discovered and treatments have been developed for them, we have discovered that the tyrosine kinase inhibitors inhibit the oncogenic drivers that are responsible for creating proliferation of the cancer, tumorigenesis, metastasis, and all the negative effects that cancers can bring. All these genes are normal genes that we have. For example, the NTRK genes are normal genes that we have. All of us have these genes. For example, the NTRK genes are in charge of proprioception. They are linked to the development of the central nervous system, so they have good effects in a person.

Once they become oncogenic, that is a problem. They become drivers of the development of the metastasis and growth of the tumor. That is why the tyrosine kinase inhibitors that very selectively inhibit these receptors create a difference. That is also a major breakthrough, because years ago, we developed other tyrosine kinase inhibitors—these are not the first agents that we have had—but they were not very selective.

There are agents, for example, such as sunitinib in kidney cancer. They are tyrosine kinase inhibitors, but they are not selective. They are not specific. They target 4 or 5 genetic alterations or receptors. For that reason, they are not as accurate as larotrectinib. And for the same reason, they have more toxicity. If you compare sunitinib or sorafenib with larotrectinib, the difference is amazing. The former agents are very, very toxic. They leave a lot of adverse effects compared with these new, specific, and highly selective tyrosine kinase inhibitors that are normally very effective. Their response rates are very high, around 70%. But also, the number of adverse effects is much fewer than with the less selective tyrosine kinase inhibitors.

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+