Updates on Biomarker-Directed Therapy for Solid Tumors: Focus on NTRK, RET, and NRG-1 - Episode 7

Treatment Options for NRTK Fusion–Positive Solid Tumors

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Benjamin Levy, MD, reviews the available treatment options for patients whose tumors harbor NRTK fusions.

Mark Socinski, MD: Ben, talk to us about available treatment options if you find 1 of these NRTK fusions.

Benjamin Levy, MD: It is important to delve into a little of the history of NRTK fusions. The first NRTK1 gene fusion was discovered as an oncogene in 1982 in colon cancer. It only took 35 years to then develop a therapy, or therapies, that are NRTK directed. Thankfully, we have those now. The first drug that came onto the scene for NRTK fusions of cancer was larotrectinib. This was a study that enrolled, at the time, 55 patients—the study reported on 55 patients—with 17 unique NRTK fusion–positive tumor types. It was pretty remarkable because there were different cancers. The age range for the trial was also pretty remarkable. Patients were 6 months all the way to 70 years of age. The study featured a wide range of patients, with different ages and tumor types. These patients were highly pretreated. About a third of these patients had received 3 or more lines of therapy. A majority of these patients had received prior lines of therapy.

What we saw with this single-agent, oral TKI [tyrosine kinase inhibitor] was a response rate of north of 70%. We have learned, in later iterations of this study, that there are meaningful responses intracranially, in the brain. These responses are durable. Going back to the question you asked before, about the fusion partner, it didn’t seem to matter in this study. The drug was active regardless of fusion type, tumor type, or age. This is your perfect basket study that is emblematic of targeted therapy. Based on this study, larotrectinib was approved.

More recently we have experimented with entrectinib. This is a drug that is a potent TRK inhibitor, but it also hits ROS1 and ALK a little. It was designed to cross the blood-brain barrier, and we have data on this as well that are published. A small number of patients—50 to 60, I believe—showed lower response rates of around 60%. But these responses are durable, and there are intercranial responses as well. It is a perfect story for targeted therapy: higher, durable, and intercranial response rates, given the proclivity of some of these lung cancers to go to the brain.

The last thing I will say about both these drugs is that they are reasonably well tolerated. They do not offer any new adverse effects that we have not seen before, minus a few on-target adverse effects that we see, with proprioception, hyperphagia, as well as increased weight. Most of the adverse effects from both these drugs are reasonable and manageable. The clinical implementation, development, and implementation of these drugs highlights what we have said already. You must test. You need to cast that wide net in the lake. Then you can identify these fusions, and these patients can go on to genotype-directed therapy with NRTK inhibition and NRTK inhibitor therapy.

Mark Socinski, MD: It sounds as if you are describing Coke and Pepsi. How does one decide?

Benjamin Levy, MD: It is hard. Obviously, we do not have any cross-trial comparisons, and I have already shown you my cards. I have treated only 1 patient for this. I used larotrectinib in that setting, and the patient did reasonably well and continues to do well. I do not know if I would necessarily think there is a specific advantage of 1 over the other. 

We certainly have intercranial response rates for these drugs, so they are both reasonable options. I am not trying to play it safe, because I do like to put my nickel down on a choice, but both are reasonable. In my case, I chose larotrectinib because it was around at the time of identification, and entrectinib had yet to be approved.

Mark Socinski, MD: I am involved with Elsevier, formerly Via Oncology’s Via Pathways. Ross Camidge and I are the cochairs of the lung committee. We obviously approved the pathway of larotrectinib because it was the only 1 in town at the time. When entrectinib was approved, we were asked by Via Oncology’s Via Pathways to make a decision based first on efficacy and then on toxicity. The committee could not differentiate based on either efficacy or toxicity.

The third variable is cost, and there was a significant cost difference between the 2 agents. That was a decision from the Via Oncology’s Via Pathways’ point of view, based simply on the cost of the 2 drugs. I will leave you hanging in terms of what the outcome of that was.