ONCAlert | Upfront Therapy for mRCC

TRK as Ideal Candidate for Targeted Therapy

Targeted Oncology
Published Online:12:06 PM, Mon July 15, 2019

David Hong, MD: Welcome to this Targeted Oncology™ presentation in precision medicine called “TRK Inhibitors: A Tumor Agnostic Approach to the Treatment of Solid Tumors.” I am Dr David Hong, deputy director of the Department of Investigational Therapeutics [and an] associate vice president of clinical research at The University of Texas MD Anderson Cancer Center in Houston, Texas.
 
Targeted therapies continue to move toward the forefront of treatment of patients with cancer. Today we’re going to talk about an important new therapeutic class, called TRK [tropomyosin receptor kinase] inhibitors, that has shown great promise among several advanced malignancies, include thyroid tumors and sarcomas. These agents represent a paradigm-changing advance in precision oncology and drug development for rare mutation-driven cancers.

Please welcome my colleague, Dr Marcia Brose, the director of the Center for Rare Cancers and Personalized Therapy at the University of Pennsylvania School of Medicine in Philadelphia, Pennsylvania. And joining us later in the series is Dr Corey Langer, an associate professor at the Hospital of the University of Pennsylvania, Perelman Center for Advanced Medicine, University of Pennsylvania.

Let’s get started.

Marcia Brose, MD, PhD: Good morning, David. Can you please tell us a little bit more about TRK and why is it an attractive target for therapy?

David Hong, MD: NTRK [neurotrophic receptor tyrosine kinase] is a very unique target. NTRK is a family of genes—NTRK1, NTRK2, and NTRK3—that encodes these family receptors—TRK A, B, and C. Initially these receptors were identified in the 1980s and ’90s, to be really key for neurosignaling. For example, pain, weight, temperature regulation, proprioception, etc. But later on, researchers in oncology identified that there were unique translocations, or fusions, of these NTRK genes with other partners that led to constitutive or continued signaling in cancer cells, truly driving their growth and their metastases.

Marcia Brose, MD, PhD: Can you tell me what variants of TRK fusions are found in solid tumors overall and [at] what frequency?

David Hong, MD: That’s a really good question. I don’t think at this time we know all the variants of NTRK, and we’ve discovered many different variants. The most common variants are ETV6 and TRK3, and they are identified across different histologies. There’s not necessarily 1 specific NTRK fusion gene that is identified in 1 specific tumor type, but we do see ETV6 and TRK3 being the most common across different histologies.

Marcia Brose, MD, PhD: Are there other NTRK mutations or amplifications that are important?

David Hong, MD: To date, mutations have really not been identified as key drivers of these NTRK pathways. And also amplifications, it’s unknown whether or not they are significant drivers of the pathway. In the phase I trial that we conducted, we did enroll a number of NTRK-mutation patients, [because] we do not know whether or not these patients would actually benefit or not at that time. One of these patients that we enrolled in the phase I actually had benefit.

Marcia Brose, MD, PhD: How common is it for people with NTRK fusions to have multiple, targetable mutations?

David Hong, MD: We think that the prevalence of NTRK fusions exists in about 1% of all histologies. There are certain types of tumors—such as MAS [mamillary analog secretory] tumors, carcinomas of the head and neck, certain pediatric tumors such as infantile fibrosarcomas—that we think it’s almost pathognomonic. It was 100% likely that they will have these fusions. What’s interesting is that in more common tumors like lung and colorectal, although the prevalence is very low—1% or lower—the patients who have no mutations, other than NTRK fusions, seem to be the ones who probably harbor these fusions. There are, however, a subset of tumors, MSI [microsatellite instability]–high tumors, particularly MSI-high colorectal cancers, that seem to also have a higher prevalence of NTRK fusions.

Transcript edited for clarity.

David Hong, MD: Welcome to this Targeted Oncology™ presentation in precision medicine called “TRK Inhibitors: A Tumor Agnostic Approach to the Treatment of Solid Tumors.” I am Dr David Hong, deputy director of the Department of Investigational Therapeutics [and an] associate vice president of clinical research at The University of Texas MD Anderson Cancer Center in Houston, Texas.
 
Targeted therapies continue to move toward the forefront of treatment of patients with cancer. Today we’re going to talk about an important new therapeutic class, called TRK [tropomyosin receptor kinase] inhibitors, that has shown great promise among several advanced malignancies, include thyroid tumors and sarcomas. These agents represent a paradigm-changing advance in precision oncology and drug development for rare mutation-driven cancers.

Please welcome my colleague, Dr Marcia Brose, the director of the Center for Rare Cancers and Personalized Therapy at the University of Pennsylvania School of Medicine in Philadelphia, Pennsylvania. And joining us later in the series is Dr Corey Langer, an associate professor at the Hospital of the University of Pennsylvania, Perelman Center for Advanced Medicine, University of Pennsylvania.

Let’s get started.

Marcia Brose, MD, PhD: Good morning, David. Can you please tell us a little bit more about TRK and why is it an attractive target for therapy?

David Hong, MD: NTRK [neurotrophic receptor tyrosine kinase] is a very unique target. NTRK is a family of genes—NTRK1, NTRK2, and NTRK3—that encodes these family receptors—TRK A, B, and C. Initially these receptors were identified in the 1980s and ’90s, to be really key for neurosignaling. For example, pain, weight, temperature regulation, proprioception, etc. But later on, researchers in oncology identified that there were unique translocations, or fusions, of these NTRK genes with other partners that led to constitutive or continued signaling in cancer cells, truly driving their growth and their metastases.

Marcia Brose, MD, PhD: Can you tell me what variants of TRK fusions are found in solid tumors overall and [at] what frequency?

David Hong, MD: That’s a really good question. I don’t think at this time we know all the variants of NTRK, and we’ve discovered many different variants. The most common variants are ETV6 and TRK3, and they are identified across different histologies. There’s not necessarily 1 specific NTRK fusion gene that is identified in 1 specific tumor type, but we do see ETV6 and TRK3 being the most common across different histologies.

Marcia Brose, MD, PhD: Are there other NTRK mutations or amplifications that are important?

David Hong, MD: To date, mutations have really not been identified as key drivers of these NTRK pathways. And also amplifications, it’s unknown whether or not they are significant drivers of the pathway. In the phase I trial that we conducted, we did enroll a number of NTRK-mutation patients, [because] we do not know whether or not these patients would actually benefit or not at that time. One of these patients that we enrolled in the phase I actually had benefit.

Marcia Brose, MD, PhD: How common is it for people with NTRK fusions to have multiple, targetable mutations?

David Hong, MD: We think that the prevalence of NTRK fusions exists in about 1% of all histologies. There are certain types of tumors—such as MAS [mamillary analog secretory] tumors, carcinomas of the head and neck, certain pediatric tumors such as infantile fibrosarcomas—that we think it’s almost pathognomonic. It was 100% likely that they will have these fusions. What’s interesting is that in more common tumors like lung and colorectal, although the prevalence is very low—1% or lower—the patients who have no mutations, other than NTRK fusions, seem to be the ones who probably harbor these fusions. There are, however, a subset of tumors, MSI [microsatellite instability]–high tumors, particularly MSI-high colorectal cancers, that seem to also have a higher prevalence of NTRK fusions.

Transcript edited for clarity.
Copyright © TargetedOnc 2019 Intellisphere, LLC. All Rights Reserved.