NEW YORK – Precision Oncology has rapidly moved from something of concern or interest for just a few subsets of cancer patients to a concept expanding across the practice of oncology, with biomarker-driven treatments now mainstream in several cancer types and exploration of genetic or other molecular determinants of response becoming a crucial aspect of drug development and research.
Chi Van Dang, editor in chief of the journal Cancer Research, scientific director of the Ludwig Institute for Cancer Research and a professor at the Wistar Institute, has been at the forefront as this paradigm continues to evolve from the bench to the bedside.
Reflecting on both his experiences in clinical practice and on some of the promising research emerging in the scientific press, he discussed the major breakthroughs now moving out into community practice, the challenges the field faces, and some of the most promising new areas that oncologists might want to keep track of in earlier-stage trials.
Below is a lightly edited transcript of our interview with Dang.
As someone who's been in a position to see this precision oncology movement from the forefront, I'm curious how you would describe the kind of change that we've seen in the space over the last couple of years for those who are more of the rear guard, or are just starting to engage with this more right now?
I see this from a couple perspectives because I was also a head of a cancer center before I [became EIC of Cancer Research]. Basically I think that it's been a really exciting time over the last five years, where after many years of research … looking at various components of the pathways that drive cancer to grow, we have been able to make a drug to target many of them and fortunately a number of these drugs have worked.
The largest class of course is the kinase class. And many of these have met with significant success [such that] … today we have clinicians, particularly at academic centers, routinely sending patient tumor samples to molecular profiling … where you can get these reports back and then you can tailor the therapy for that particular patient, whether it's a melanoma patient with BRAF mutations or lung cancers, which have various mutations with multiple drug choices.
This is now becoming more routine in the academic centers, and they are [in turn] now going out into the community. My own experience with the University of Pennsylvania is that we have a number of community hospitals attached … [and so this has] been permeating out into community practice. The penetrance is probably incomplete though … so I think there's still more outreach and education that needs to be done to make sure these drugs get to the patients.
That said, there are always going to be remaining challenges. We know now that in many many cases the initial response to the drug can be quite dramatic, but then one of the biggest challenges, of course, is that tumors are heterogeneous. If you have a few cancer cells that are laying around that can resist the therapy by mutating themselves, they come roaring back as virtually a new cancer. Resistance becomes a real problem, and I think this is where pharmaceutical companies and academics are now basically running in circles trying to chase down how to keep ahead of these recurrences of resistant clones, and that is now the state of the art.
Investigators are looking in two directions: First, can we develop additional drugs that hit the same target when [a cancer] tries to escape the old drug. The other approach would be to look for combinations that can come closer to curing patients. And, of course, I can't get away from mentioning that the emergence of immunotherapy really allows us this opportunity. One conceptual framework would be to use targeted therapy to reduce the bulk of the tumor that should respond. But any residual tumor, perhaps by awakening the immune system [and] checkpoint inhibitors, you could then eradicate and essentially put the patient into a curative condition.
Before we talk more about what's next, do you feel like there is a certain drug or certain cancer type that really illustrates how we've seen the promise of this realized? Lung cancer is often discussed, but are there are other areas that you see as really exemplifying the concept of precision oncology?
Clearly lung cancer is kind of poster child of having different mutations … and the response has been quite good, not uniformly good, but quite good. The other poster child of course is melanoma with the BRAF mutations with some pretty dramatic response there as well. Some of the other tumors are a little bit more challenging, breast cancer being one ... even with the CDK4/6 inhibitors. Colon cancer has also shown a more heterogeneous response. But I think if you look across the commonly occurring cancers they all have some patients that will respond.
We are seeing this reflected in pan-cancer trials and drug approvals, right?
Yes, so what that has led to is something that excites the academic community and it's now reaching into the community hospitals as well, which are these so-called basket trials, where patients come in and it's not so much what type of cancer you have but what kind of mutations do your cancers have — and then they are tailored just to that drug and you start seeing some very interesting results, albeit in small subsets.
I think the excitement is still there that these therapies really are molecularly targeted. Are we there yet? No. There are still a lot of challenges because even in the best cases we're still talking about less than 50 percent response overall.
Off the top of your head are there any interesting new pathways emerging in earlier research, where they're getting good data that may point to where the next drugs are going to come out that further evolve the practice of precision oncology?
So, this is kind of my bias from being in the field myself for a while. I think there is still promise in terms of interfering with metabolism, and this is very much different than kinases. There are now several drug companies that are developing drugs targeting specific pathways and metabolism, and I can mention a few that have been published. One example is a drug that's in Phase I trials at MD Anderson that targets a mitochondrion … and they are starting to see some very interesting responses even during Phase I, which has been reported at ASCO.
I think that this is a new opportunity. This is a completely different pathway, and there is a hope it's going to play at least some role in our repertoire of drugs to fight cancer. The other example along the same line — although I have a conflict to declare that I advised this company — is Rafael Pharmaceuticals. They are now going into Phase III, again with a drug that targets a mitochondrion and that has seen complete responses in Phase I studies of metastatic pancreatic cancer patients. So both experiences — MD Anderson with their compound and the experience with this company with its compound — suggest that there's something there that holds some promise.
And other companies are now looking at targeting metabolism to not only to hurt the cancer cells but also simultaneously to awaken the immune system. That is still very early days but I'm very hopeful that this will open up a completely new gate to new therapies outside of the usual pathways we've been thinking about.
Another area [to keep an eye on is] the epigenetic drugs, a whole other class that I think is going to become more exciting over the next five years. Initially when they were starting to come out, the toxicities were high with not very good response because [these drugs] act so generally. But now [there is a] concept that perhaps by tweaking the epigenome just enough, we might be able to change patients' immune profile status to make them respond to immunotherapy ... or change their molecular status enough to make them more amenable to targeted therapy. I think that's where the field is starting to see some really interesting data out there from the research arena that I think will evolve into clinical trials and we'll see some major impact there as well.
What about the aspect of immunotherapy where we are still not quite sure know who are the subset of patients who benefit and the need for better biomarkers to kind of define that?
This is another area where there's tremendous excitement, having seen that we can potentially use the word cure in some of these patients with the durable responses being so long. But again, if you look on the glass half-empty side, we're talking about the minority of patients not the majority of the patients. That means that something is going on in those patients who don't respond. Why don't these patients respond? Is it because their tumors are secreting certain things that silence the immune system? Are their immune cells getting too tired to work? What do we know about this that we can harness the immune system and awaken them to go after the tumor cells?
Checkpoint inhibitors are clearly big time right now, but the major drug companies that have these [compounds] are — I would use the word struggling — to figure out why certain patients don't respond. So, one thing we are seeing is that some of these companies actually are focusing more on targeted therapies [and] going back to look at other targets they might have left on the floor. As they open that back up a little bit we might see other new drugs coming out of the pipeline.
Researchers are very focused on trying to understand the genetic and biological mechanisms of non-response to immunotherapies. People are discovering different pathways that can silence T cells, and if we know those pathways we can then make drugs to block them. And then there's a whole area of research right now in terms of immuno-metabolism where the T cells that fight cancer can go into a [sleepy] metabolic state, which we are understanding much more now, and which we think we can reawaken them from. I think the next five years we're going to see some new things coming up into the clinic because of all these new efforts.
You mentioned this briefly in the beginning, that as all of this is evolving and we have all of these new ways to treat patients, not everybody is having the same access necessarily and that seems to be a challenge. So with all of the research that's been done, all of the important findings and new drug development, if we can actually get that to the patients isn't that an issue?
In terms of a level playing field for all patients, I think one of the lessons that can be learned from this if you look at the French health system, they were one of the very first to look at targeted therapy in lung cancer, and because they have a national health system they're able to actually gather data to answer [crucial] questions. The drugs are expensive. But if you actually look at the patients who get tested and get targeted therapy versus those who don't get tested and go to [non-targeted] therapy, it turns out that the patients who do get tested and get targeted therapy save the health system more money than those who didn't get tested.
Even in academic centers, at the University of Pennsylvania, for example, we actually did a study of lung cancer patients that, again very similar to the French data, found that yes, the people who actually got tested over a six-month course of treatment, the total cost for those patients was less than those who didn't get genomic testing.
The point I'm trying to make through that is that I think that while physicians have ownership of this to some extent, we don't have control over everything. Health insurers [perhaps] also should have some responsibility to understand that there's an economic advantage to them to get the word out that getting patients tested actually will save money to their health system. Not only is it the right thing to do ethically, but it really is economic, too. And maybe that's a way to get the word out, for health insurance to get it out to the physicians, you know "we'll pay for this."
We have been hearing more and more about liquid biopsy and blood-based mutation detection, and that was initially something that seemed like it was going to be mainly kind of an adjunct to tissue testing for identifying actionable biomarkers for precision medicine. But people are really trying to move it into early detection and screening, and I wonder how oncologists should be thinking about all of this. Are they going to be put out of a job?
I'll tell you frankly I think if you talk to most, at least of the people I know, we would like to be put out of a job. I've had conversations with colleagues about how it would be nice one day that it's just cardiovascular medicine that's still there and we can all find other jobs.
But to answer your question, I think the excitement about liquid biopsy right now is [around] the ability to assess response to the therapy [or] help both the diagnosis and guide therapy when you have a tumor that is inaccessible for biopsy.
In terms of prevention, this is an area where I have kind of an intellectual interest because I'm an advisor for a foundation that actually focuses a lot on prevention. I think there's a lot of excitement for prevention — if we know that you have a signal in your blood that you are developing cancer. The hypothesis is that our cells will make mistakes. Some of these cells will look cancer-like, but most of the time our immune system … would recognize these cells and get rid of them. So, when, in a weak moment when our immune system is not working, these cells start taking off and they have these mutations that we can detect in the blood. If we detect it early enough and sensitively enough, people are now thinking about how to then find out where these cells are ... and then to go in and eradicate them directly ... or go after them with drugs.
There are still a lot of research questions surrounding this but there's a lot of excitement, too, and this is where a lot of investment is right now because we do want to prevent.
You talked about monitoring, too, which could be a whole other way of personalizing or making cancer care more precise. How would you categorize the strength of the data that people are seeing there?
I would say that the technologies are getting better and better, and the field is still evolving. If you still benchmark liquid biopsy to standard imaging techniques, I don't think there is one right now where I would say "stop doing the imaging and just do liquid biopsies only." That said, the progress has been quite remarkable. There have been examples where you can't see the tumor altering anymore by imaging, but you can actually monitor it by liquid biopsies.
The other thing that's exciting is in examples like breast cancer, where the majority of patients would come in and go into remission after surgery, radiation, chemo, but then about 10 percent would relapse in anywhere from three to 10 years. We know the risk characteristics of patients who might relapse, but we don't know who exactly. But imagine that you can come in every six months and get your blood drawn, and then at the earliest sign of trouble an oncologist can go in and search it down and intervene rather than you coming back with a tumor that now can be seen by a CT scan or an MRI.
So, it is a really exciting time. It's good to watch all the research that's happening. I think there is a lot of hope, and I'm sure we're going to start seeing real milestones being met.