Larotrectinib Success Underscores Need for NGS to Detect TRK Fusion-Positive Cancers

Alexander Drilon, MD

Larotrectinib (Vitrakvi) has shown promising activity in patients with TRK fusion—positive cancers who also have brain metastases or primary central nervous system (CNS) tumors, said Alexander Drilon, MD. Results from 2 clinical trials further underscore the need for expanded testing for these fusions across all tumor types.

In research presented at the 2019 ASCO Annual Meeting, investigators identified patients with non-primary CNS solid tumors and either brain metastases or primary CNS tumors harboring a TRK fusion who were given larotrectinib in 2 clinical trials (NCT02637687; NCT02576431). Patients received the agent until disease progression, withdrawal, or unacceptable toxicity.

“This data set is unique because we are presenting [these subgroups] for the first time and characterizing their response to larotrectinib,” explained Drilon.

A total of 14 patients were identified; of these patients, 5 had non-primary CNS solid tumors (3 lung cancer, 2 thyroid cancer), while 9 had primary CNS tumors (3 glioma, 2 glioblastoma, 1 astrocytoma, and 3 not otherwise specified).

In the patients with non-primary CNS tumors, the best objective response to therapy was a partial response (PR) achieved in 3 patients (60%, pending confirmation), stable disease (SD) in 1 patient (20%), and not evaluable (NE) in 1 patient (20%). The duration of response ranged from 9 months to 13 months.

Disease control was achieved in all patients with primary CNS tumors. The best objective response to larotrectinib in this group was a PR in 1 patient (11%, pending confirmation), SD in 7 patients (78%), and NE in 1 patient (11%).

Although the number of patients who fall within these subgroups is relatively small, testing with next-generation sequencing (NGS) assays should be considered, said Drilon.

“The fact that you find [these fusions] across many other cancers really homes in on the fact that we should not be biased in terms of whom we select to do these comprehensive panels,” added Drilon. “Although the frequency might be rare—one out of 100 patients that you're testing—when you find the event it might be very, very meaningful for that patient.”

In an interview with OncLive, Drilon, medical oncologist and research director of Early Drug Development at Memorial Sloan Kettering Cancer Center, provided insight into his study on the role of larotrectinib in the treatment of patients with TRK fusions and brain metastases or those with primary CNS disease.

OncLive: Could you provide some background on larotrectinib and the work presented at the 2019 ASCO Annual Meeting?

Drilon: [The approval of larotrectinib] was really a landmark [decision] because it was a tumor-agnostic approval of the first targeted therapy for a genomic signature, regardless of what the cancer looks like under a microscope. The abstract [presented at the 2019 ASCO Annual Meeting] features the intracranial activity of larotrectinib, and that is very important for a few reasons. Many of these cancers that harbor TRK fusions like lung cancers, breast cancers, and melanoma have a proclivity for brain metastases. As such, characterizing the activity of larotrectinib in patients with CNS disease is critical.

In the patients with brain metastases, the first important observation is that in this data set, of the 121 patients treated with larotrectinib who had a TRK fusion, the frequency of brain metastases was low; it was only 6 out of 121 cases, meaning 5%. In those 6 cases, however, there were 5 patients who had evaluable disease, and the overall response rate (ORR) in those patients was 60%. These were patients who had a PR to therapy or SD, meaning none of them had primary progression in CNS. In fact, if you pull out just the patients who had measurable target lesions in the brain, all 3 patients had substantial regression of these intracranial lesions, which highlights the fact that larotrectinib can get into the CNS compartment very well.

Moving on to the primary brain tumors, there were 18 patients with primary CNS tumors harboring a TRK fusion. Amazingly, in these patients, we achieved both complete responses (CRs) and PRs for an ORR of 36%. This was a mix of both adult and pediatric patients; however, close to 80% of the cases were pediatric. This is very meaningful because achieving a CR in a primary brain tumor is not something that we very commonly see with other systemic therapies. Finally, like with what was seen in the patients with brain metastases, no patients had primary disease progression on larotrectinib.

This all boils down to testing. For both solid tumors or primary brain tumors, community doctors, advanced practice providers, and others who are treating patients with these cancers need to focus on looking for an assay that reliably detects TRK fusions. The complicated aspect of this is that the best way to test for a TRK fusion is to look at the RNA level. As such, it's good to look for a NGS assay that [evaluates] both DNA and RNA. If you find these patients, it's comforting to know that larotrectinib can work well in the CNS.

Could you expand on the importance of performing these tests? Why is this practice not as widespread across community practices as it should be?

The importance of doing a comprehensive assay is not just because we have approval of larotrectinib for TRK fusions. We should remember that there's also tumor-agnostic approval of pembrolizumab (Keytruda) for microsatellite instability—high tumors. Additionally, for any given cancer, there may be other biomarkers that we want to test that would be included in the same panel. Take the example of lung cancer, which is the poster child for targeted therapy. The best possible scenario would be to do a comprehensive NGS test that looks for ALK, RET, ROS1, EGFR, BRAF V600E, and also potentially [tests for] tumor mutational burden, which is emerging as a possible biomarker for immunotherapy. The punchline is that we are not just doing single-gene testing with one assay; we are now employing one big test that captures many different drivers you might be interested in, including TRK fusions. That's an important message.

What is the future role of larotrectinib, pending additional research?

This new data set of the activity of larotrectinib in primary brain tumors is something that would be very interesting to bring toward a regulatory approval, hopefully. The approval of larotrectinib was not for patients with primary CNS tumors; [those patients] weren't [included] in that data set. However, we need to take a step back and refocus our clinical trial work to now look at these actionable signatures across many different cancers, We shouldn’t just home in on one histology, as we've historically done.

Drilon AE, DuBois SG, Farago AF, et al. Activity of larotrectinib in TRK fusion cancer patients with brain metastases or primary central nervous system tumors. J Clin Oncol. 2019;37(suppl 15, abstr 2006). doi: 10.1200/JCO.2019.37.15_suppl.2006.