Anna F. Farago, MD, PhD
An updated analysis of patients with NTRK
fusion–positive non–small cell lung cancer (NSCLC), including patients with central nervous system (CNS) metastases, showed that the TRK inhibitor larotrectinib (Vitrakvi) demonstrates significant activity, according to updated findings that were presented at the 2019 World Conference on Lung Cancer.
Previous phase II data from the NAVIGATE trial (NCT02576431) demonstrated efficacy with larotrectinib in adults and children with NTRK
fusion–positive solid tumors, and a previous phase I study (NCT02122913) assessed the safety of larotrectinib in adult cancers harboring an NTRK
In the updated results of these studies, specifically of patients with advanced NTRK
fusion–positive NSCLC, it was found that larotrectinib is highly active, including those with CNS metastases, along with favorable safety profile.
In November 2018, the FDA granted an accelerated approval to larotrectinib for the treatment of adult and pediatric patients with solid tumors that have an NTRK
gene fusion without a known acquired resistance mutation, are metastatic or where surgical resection is likely to result in severe morbidity, and have no satisfactory alternative treatments or that have progressed following treatment.
In an interview with OncLive
during the 2019 World Conference on Lung Cancer, Anna F. Farago, MD, PhD, assistant professor of medicine, Harvard Medical School, discussed the updated activity of larotrectinib in NTRK
fusion–positive lung cancer.OncLive: Could you discuss the analysis of larotrectinib in NSCLC?Farago:
The data that I presented looked at patients with NSCLC harboring an NTRK
gene fusion and outcomes for those patients who were treated with larotrectinib, which is a selective TRK inhibitor.
Generally, patients with NSCLC who do not have a targetable oncogenic driver, are treated with chemotherapy, or chemotherapy plus immunotherapy and sometimes single-agent immunotherapy. We see a range of responses and durability of responses to treatment. Based on many studies in EGFR-mutant lung cancers, ALK-fusion lung cancers, and ROS1-positive lung cancer, we know that patients who have a targetable oncogenic driver do much better with targeted therapies than they do with traditional chemotherapy. That has been shown in randomized studies in EGFR
- and ALK
-positive lung cancers.NTRK
fusion–positive lung cancers are a much smaller population. We estimate that NTRK
fusions occur in 0.2% of all lung cancers, so, these are very uncommon events. It would be very hard to imagine putting together a randomized study where you're comparing outcomes with chemotherapy versus a targeted TRK inhibitor in patients with this alteration because it's such a small population.What new data are being presented in this analysis?
We now have single-arm data for outcomes in patients with an NTRK
fusion who were treated with larotrectinib, and the results are very encouraging. What it shows is that larotrectinib is highly active in this population, which is very consistent with what we've seen with targeted therapies for other oncogenic drivers in lung cancer. We saw a response rate of 75% among 12 patients with NTRK
fusion–positive lung cancer who were treated with larotrectinib. Among those, there were 6 patients with brain metastases and 4 of those had partial responses to larotrectinib; the response rate there was 60%.
We don't have a head-to-head comparison to tell us that it's definitively better than chemotherapy, but we can extrapolate from everything we know based on other oncogene-driven cancers that targeted therapy is the option for these patients.What has the impact of the approval of larotrectinib been for patients with lung cancer?
Larotrectinib was approved by the FDA at the end of 2018, based on data across a wide number of cancer types, showing an overall response rate of 81% among those patients with NTRK
gene fusions. What is striking is that larotrectinib has activity in a tumor-agnostic manner, so, regardless of the tumor type, if there is an NTRK
fusion present, it tends to act as an oncogenic driver. And, it also predicts a high likelihood of response to larotrectinib.