Larotrectinib Is Highly Active in Patients With NTRK Fusion+ NSCLC

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 fusion.

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.

It's exciting to have an approval by the FDA for a targeted therapy in a tumor-agnostic manner. Also, this approval doesn't just impact lung cancer, it impacts all solid tumors because we see these fusions across solid tumors. They are uncommon events in most cancer types. In lung cancer the frequency is about 0.2%; that's not a lot of patients. Proportionally, however, there are a lot of patients with lung cancer as a general population. Therefore, numerically there are a fair number of people out there who could potentially benefit from this drug in the lung cancer community.

Looking at other cancer types, there's a variable incidence of NTRK fusions. They can be quite common in some rare cancer types, such as infantile fibrosarcoma or mammary analogue secretory carcinoma. However, because they can occur in any cancer type, we need to be looking for NTRK gene fusions, regardless of the cancer tissue of origin. And, if these fusions are identified, then larotrectinib represents an exciting treatment option for patients.

What other agents are showing promise for targeting NTRK fusions?

In lung cancer specifically, we're already routinely screening patients for gene alterations in EGFR, ALK, and ROS1. We should be [testing for] RET and making the case for BRAF, NRG1, and others. Adding NRTK to a gene fusion panel shouldn't be too much of a burden for people. We should be asking our molecular pathologists or our commercial vendors to be adding NTRK to their panels if it's not already included. It's not practical to screen for NTRK fusions only in this population, because those are such rare events. But, it is practical to screen for all of these events simultaneously using a multi-gene next-generation sequencing—based assay.

What should oncologists take away from this presentation on the activity of larotrectinib in TRK fusion lung cancer?

In lung cancer, there are now a growing number of somatic alterations that are potentially treatable with highly active targeted therapies. These alterations include EGFR, ALK, ROS1, RET, NTRK, and BRAF. All patients with advanced or metastatic NSCLC should undergo testing with broad multi-flexed testing to look at all of these mutations simultaneously at the time of diagnosis so that we can identify these patients early and direct them to the appropriate targeted therapy.

<<< 2019 World Conference on Lung Cancer