Response to Treatment With Larotrectinib

Luis Raez, MD: 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 New England Journal of Medicine 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.

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+