TRK Inhibitors: Precision Medicine in Oncology - Episode 2

Significance of TRK Inhibitors for Solid Tumors

Transcript: Benjamin P. Levy, MD: Let’s shift over to TRK fusions and just provide some context, Marcia, before I talk to you about what your thoughts are. This is a rare genotype. It’s not found in a lot of solid tumor malignancies, although it is highly enriched in pediatric cancers. Clearly the design of the trial, the basket trial, leading to a genotype-directed therapy approval based on a rare genotype…. Because of the availability of TRK inhibitors for these rare niche NTRK fusions, are we moving the field forward with this?

Marcia S. Brose, MD, PhD: I would say, yes, very much so. And the other thing about it is that everything that Ed was saying actually leads directly into our ability to make strides in cancers that are more rare. Historically, we couldn’t get a lot of these agents because we didn’t have enough patients. We couldn’t enroll in the trials. There wouldn’t be enough to show your 5% or 10% difference. Now that you can do a study, get 55 patients, and show activity, this is really a new day for the rarer cancer population who were historically left out of a lot of these trials.

The second thing is that there are not enough patients to do a lot of that exploratory work. In lung cancer, you’ve got hundreds of patients, and you can do the BATTLE trial type of study and get data on 240 patients. That won’t happen necessarily with rarer cancers. So now the fact that we can actually get drugs that are possible for these rarer cancers, immediately identify them, and move forward with therapies is a new thing that we could do that we couldn’t do previously.

And when they are enriched, it’s straightforward. But also, a lot of these rare cancers don’t have just 1 molecular marker that can be targeted. Sometimes they have multiple ones. And so just doing a really good test that finds those now can create hope for a patient who otherwise would have nothing.

John L. Marshall, MD: You know, I was thinking that these rare cancers, Marcia, are teaching us molecular lessons. If it’s a rare cancer, you can get to the bottom of what’s going on with that. The cancers that Philip and I take care of are messy, multiple gene abnormality things. It would be impossible to sometimes figure out what the drivers are. But the rare cancers often have a single driver. Then when you figure that out, you think, “Well, is it involved in any of these cancers?” And we pick them up. So it’s sort of those nice rare-cancer folks who are teaching us the lessons.

Marcia S. Brose, MD, PhD: Yeah, that’s why I have a job now.

Benjamin P. Levy, MD: I’m also wondering if 1 of the lessons to pull off a clinical trial with this rare genotype is that it takes exceptional cooperation among institutions and physicians. Is this a lesson as well—that we all are in this together, and it takes the communication, the cross talk, to get these patients on to these trials, given how rare this gene is?

Marcia S. Brose, MD, PhD: I think people who’ve worked in pediatric cancers have always known that. But in rare cancers, that’s always been acquired. Now everything is sort of becoming a rare cancer, if you’re going to start pulling off these very small-percentage genotypes in even the most common of cancers.

Mark Agulnik, MD: It essentially evens the playing field out a little bit. For those of us who treat the rare cancers, you always saw the drugs first get approved in lung cancer or in breast cancer. Then you have access to them or could try to try to get access to them. Now the patients with these rare tumors are invited right up front. You need them in these trials. The trials are enriched for them because they’re desperate for trials. There aren’t the phase II, phase III trials, and the patients and the physicians are willing to collaborate. It has created a really uniform way for how we approach patient care now, which is wonderful.

Benjamin P. Levy, MD: It has sparked a lot of interest from the patient’s side. With these rare tumors and knowing that some of these tumors are highly enriched for these rare mutations, we can offer targeted therapies. And it’s not all chemotherapy, and we can make meaningful differences for these patients.

John L. Marshall, MD: I’ll give you an example, though, and Philip knows this well, where I think it went too far, actually: When the MSI [microsatellite instability] indication came out for all tumors with MSI, 1 of the pancreas advocacy groups put on their website, “New drug for pancreas cancer.” Well, the reality is that it’s less than 1%. And actually, as a community, we thought that was overstating the benefit. These make for great press releases. This is really a dramatic impact for individual patients. But we also have to balance that enthusiasm against the chances that you’re going to actually have 1 of these.

Benjamin P. Levy, MD: Yeah. Edward?

Edward S. Kim, MD: I think an important aspect also, to interject in here, tags on to what other people have talked about: We are wanting to include more patients because of the targets that are more specific. We’ve come to this dilemma of having a patient in our own field with an EGFR mutation who’s a performance status 3, who by no means would be included in any clinical trial out there. But clinically, we would definitely treat them because we know there’s an 80% to 90% response rate, and they’re probably going to be just fine in 2 weeks. But we would never not consider treating them. So what has evolved in our clinical trial sort of experience, and this was a group that I helped lead from ASCO [the American Society of Clinical Oncology] with Friends of Cancer Research, was to actually change the eligibility criteria. We’ve modified 7 criteria which CTEP [Cancer Therapy Evaluation Program] has now accepted. If you download the protocol templates, they’ve accepted our minimum age requirements, brain metastases modifications, creatinine clearance, HIV, and other things. We’re actually launching a version 2 now to get rid of those washout periods, which make no sense.

Benjamin P. Levy, MD: Right.

Edward S. Kim, MD: And the 30-day testing limits and other things. What we need is a real-world population. We don’t need the folks who are traveling long distances to come to centers. We need folks who have these different molecular abnormalities, where they live. The commercial testing out there is so prevalent. We need to help capture these patients so that they have these opportunities to be in these studies.

Benjamin P. Levy, MD: Yeah, I would agree with that. I think it’s important that identification of these rare genotypes not only changes the trial design, as you were talking about with BATTLE and these umbrella trial designs, but also actually lends a little more flexibility to trial eligibility so that you can include these patients. I’ll balance that with what John said. Yes, I think there’s been a lot of effort out there to celebrate a lot of different drugs that may only fit a particular patient. I think 1 of our new jobs, as physicians, which we never thought we would have—and perhaps this is emblematic of the embarrassment of riches we have with therapies—is to temper the enthusiasm sometimes. I think we have to make sure we’re giving the right drug to the right patient but also sending out the message to these patients who are calling to say, “This drug is most likely not for you.”

Philip Agop Philip, MD, PhD, FRCP: If you look at it, there are small percentages. But if you multiply by the number of people around with a cancer, the sad fact is that I’m sure, as we speak, there are a number of patients who do carry this mutation, and no one knows about it. And these are people who can easily be benefiting from an improvement in survival with maybe less toxicity and other things.

Marcia S. Brose, MD, PhD: Also, we don’t necessarily always know the percentages. If it’s a fusion, that testing has been around for what, 1 or 2 years?

Benjamin P. Levy, MD: Right.

Marcia S. Brose, MD, PhD: And even the data that we have may have been like all-comers. I’ll take thyroid cancer as my pet. When we have the numbers that are all-comers, 90% of those patients will never even see my doors because so many people will be cured. But who has actually gone and figured out what the rate in the people who recur and have metastatic disease is? No one. So we don’t necessarily even know the implications and how far these are going to reach.

Edward S. Kim, MD: And commonality is also something where everybody looks at lung cancer. Ben and I manage a lot of lung cancer and they think, “Oh, it’s everywhere. Everyone’s got that.” Well, as we’re seeing now, it’s actually a big conglomeration of small subsets. I have a soft spot for sarcoma. People think, “Sarcoma—it’s not a rare cancer.” But it is. We have a group that helps raise money for us back home, The Paula Takacs Foundation for Sarcoma Research, and they’re dedicated to raising money to help patients with sarcoma. And so I’ve become very involved with it. I know more about sarcoma now than probably thyroid cancer, which I used to know, Marcia. But it is a very complex area that is in need of some sort of magnitude of jump-in therapy with targeted therapies.

Benjamin P. Levy, MD: Yeah. I’ll just add 1 more thing and piggyback on what Philip said. Yes, this is a rare genotype. But, across the country….

Philip Agop Philip, MD, PhD, FRCP: Or the globe.

Benjamin P. Levy, MD: Or the globe, this is a large group of patients. This reminds me of when the ALK story came out. There is a great slide that shows that there are more ALK-[positive] patients out there than there are CML [chronic myelogenous leukemia] patients. And so. we have to push forward this message that there are actually more in sheer number. This is a celebration to all the work we’ve done, but we also have to make sure that these patients get to the drug.

Transcript Edited for Clarity