TRK Inhibitors: Precision Medicine in Oncology - Episode 1

Precision Medicine in Solid Tumor Malignancies


Benjamin P. Levy, MD: Hello, and thank you for joining this OncLive Peer Exchange® titled, “TRK Inhibitors: Precision Medicine in Oncology.” TRK inhibitors represent a significant leap forward for oncology precision medicine, providing remarkable efficacy with this first FDA-approved tumor-agnostic therapy for malignancies harboring NTRK gene fusions. Challenges remain, however, in screening for this rare genomic entity to determine which patients should be considered for this novel therapy.

In this OncLive Peer Exchange® discussion, I’m joined by a panel of experts with experience in this area. Together, we will guide you through the practical considerations surrounding the use of TRK inhibitors. I’m Dr Benjamin Levy, an associate professor of oncology for Johns Hopkins University School of Medicine and the clinical director of medical oncology for the Johns Hopkins Sidney Kimmel Cancer Center at Sibley Memorial Hospital in Washington, DC.

Participating today on our distinguished panel are: Dr Mark Agulnik, a professor of medicine in the division of hematology-oncology and the head of the sarcoma program at Northwestern University Feinberg School of Medicine in Chicago, Illinois; Dr Marcia Brose, an associate professor at the University of Pennsylvania Perelman School of Medicine in Philadelphia, Pennsylvania, and the director of the thyroid cancer therapeutics program and the Center for Rare Cancers and Personalized Therapy at the Abramson Cancer Center in Philadelphia, Pennsylvania; Dr Edward Kim, chair of the department of solid tumor oncology and investigational therapeutics, and the Donald S. Kim Distinguished Chair for Cancer Research at the Levine Cancer Institute, Atrium Health in Charlotte, North Carolina; Dr John Marshall, the director of clinical care of the Ruesch Center for the Cure of GI [Gastrointestinal] Cancers at the Georgetown University Medical Center in Washington, DC, and the chief of the division of hematology-oncology at MedStar Georgetown University Hospital in Washington, DC; and Dr Philip Philip, a professor of oncology and leader of the gastrointestinal and neuroendocrine multidisciplinary team at the Barbara Ann Karmanos Cancer Institute in Detroit, Michigan.

Thank you so much for joining us. Let’s begin.

So I think we’ve all been assembled here today as somewhat of a sign of how far we’ve moved in personalized medicine. I think this is predicated on the fact that we now have a more firm understanding at least of the genomic underpinnings of the tumor that allow us to wed these patients to targeted therapies that are effective. This has created a tremendous amount of excitement, and at the same time, I think a little confusion [is] embedded into all this. John, I’ll start with you. Maybe you can provide for us some historical context or perspective of precision medicine: Where we were and where we are currently in the field for solid tumor malignancies.

John L. Marshall, MD: Yes, thanks. When you reflect back, and as old as I am, old as dirt, the only molecular test we really did when I was a fellow many years ago was, I think, ER [estrogen receptor and and] PR [progesterone receptor] for breast cancer. If you think about where we’ve come to, in almost no solid tumors, and I think the same is true for hematologic malignancies, HNE is not enough. We’re not just saying that everything is an adenocarcinoma. It needs to be further characterized by its molecular subtype. And so it evolved from no molecular testing to what is sort of oligo, or à la carte testing. We had clear abnormalities for specific diseases that had clear evidence and clinical utilities for the sort of short list of genes and molecular tests. Now we are doing much, much broader testing in the hopes of finding unusual targetable abnormalities. And so this transformation we’ve seen over the last 5 to 10 years has really transformed our standard of care. And I think the reason we’re all gathered here is, in some way, a celebration of that breakthrough, away from where the disease started to now a place [in which] we’re measuring the molecular underbellies of all our tumors.

Benjamin P. Levy, MD: Yeah, I have said this before. I went into lung cancer 10 to 15 years ago because it was easy. It was just several chemotherapy drugs and maybe anti-angiogenesis, and then we would call it a day. And I agree with you. Over the past 10 to 15 years I’ve witnessed unprecedented advances in our understanding of this that really have allowed us to parse things out into these molecular subsets and offer patients therapies that we could not before. This has affected trial design, as we’ve moved forward, in terms of how we design our clinical trials around these molecular underpinnings. Ed, do you want to talk about some of your involvement and maybe provide some context on how these trials are changing globally? What was your involvement with the BATTLE trial as 1 of the first trials out there in lung cancer that was really on to this concept of biomarker-driven therapies?

Edward S. Kim, MD: We were very frustrated with where the field was going, comparing really cytotoxic chemotherapy versus other cytotoxic chemotherapies and looking for slivers of differences between those regimens. We felt, at the time, back in 2006, that something had to change. We didn’t need another taxane or another platinum.

So we thought, “Why don’t we biopsy people again?” And surprisingly, we received a lot of backlash about that. We wanted to rebiopsy people who had been diagnosed already, and it was unbelievable how much people inside the system—other colleagues—said, “Well, that’s unethical. How can you put patients through that?” We tried to be as safe as we could with patients. We found oral therapies that were targeted agents at the time. Many of them had multiple targets. We called it a step toward personalizing medicine. We knew we weren’t going to solve this. People confused BATTLE. It wasn’t a phase III randomized design. It was a phase II pilot using a Bayesian adaptive randomization profile. It was actually a really fun trial. It was a lot of work, but it was a fun trial to do. The reason it was fun was because we enrolled 254 patients on that study in less than 3 years.

Benjamin P. Levy, MD: Yes. A lot of enthusiasm from both physicians and patients.

Edward S. Kim, MD: Right, and the patients wanted to be part of it because they are inherently altruistic. If it can’t help them, they want to help their next patient down the road. That’s what this trial did. It learned from every patient. And so the beauty was that we were able to collect tissue and collect blood. This was at a time when you were going to treat someone and not the archive tissue from 2 or 3 years ago that now the tumor has been exposed to with multiple lines of chemotherapy. I think what we’ve learned, as we’ve become more custom to integrating a biomarker approach, is that active drugs are just that: active. You’re not going to look for subtle signals when you’re looking for actual targeted therapy. The days of these subtle responses, or what have you, especially in biomarker-directed populations, are no longer. Those drugs should not be approved. We need to have a higher standard. We need to put active drugs out there. You know it when it works. That’s why you don’t need these randomized phase IIIs anymore. You can do a phase Ib expansion cohort, as we’ve seen with drugs we’ll talk about today, in 50 or 60 patients. When that response rate hits 50% to 75%, you know it’s working.

Benjamin P. Levy, MD: Yeah. So the paradigm change and the clinical trials predicated on these biomarkers have also shifted what the metric is for getting these drugs approved. I don’t think the days of the phase II [and] phase III trials are gone, but I think they’re slowly getting replaced with these types of trials that we’ll talk about in terms of basket trials or umbrella trials.

Transcript Edited for Clarity