The Story Behind Imatinib, the First Targeted Cancer Treatment

TRANSCRIPT:

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Dr. Charles Ryan: This is The Good News About Cancer. I'm Dr. Chuck Ryan.

Dr. Alicia Morgans: And I'm Dr. Alicia Morgans.

Chuck: We're oncologists, and we've spent our careers working to understand cancer. We believe that there's more progress now in research and treatment than there ever has been, and we're here to share that with you. 

Alicia: In each episode of this show, we talk to one of our colleagues about a new development in cancer treatment or diagnosis. We'll break down what's new, why it matters, and how it points the way forward. 

Dr. Brian Druker: And it was just this unbelievable time where we'd see patients who had failed every other therapy, their blood counts were out of whack, off the charts, and in three to six weeks they were normal again, and they were feeling great.

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Chuck: So, Alicia, the first season of The Good News About Cancer would not be complete if we didn't spend some time talking about Imatinib and the diseases that it treats. Most notably a disease called chronic myelogenous leukemia, or CML. 

Alicia: I could not agree with you more. So CML, you and I both know, is a blood cancer, a chronic blood cancer, meaning that it's not imminently aggressive. It kind of sputters along for a bit of time, usually a couple of years, but then can turn into this really aggressive form of leukemia that ultimately, if untreated, will kill someone. 

And the exciting thing about Imatinib is that it seems to stop this CML in its tracks, stop it from becoming AML and also really transform people's lives back into being what they were before they had the diagnosis, in many cases. 

So really exciting and so important, especially after we talked to Dr. Kolb in a recent episode about the way that his society, The Leukemia and Lymphoma Society, continues to celebrate this discovery. 

Chuck: I think it's fair to say that this is among the most significant developments in oncology in the last quarter century. For the 9,500 or so patients who are diagnosed with CML every year, of course. But it also turned the corner in oncology and in cancer science where we said: if we can identify targets within the cancer that we can exploit, we can come up with individualized targeted treatments. And that has opened up a lot of doorways that has allowed us to improve the outcomes, improve the survival, and the quality of life for many patients with many cancers.

We had an opportunity to sit down with Brian Druker, who is a professor of medicine at Oregon Health Sciences University. And Dr. Druker was the first doctor to administer this medication back in the late 1990s. And he went on to lead the development of clinical trials with it. 

I also want to say that he and his colleagues, Nicholas Lydon and Charles Sawyers, they went on to receive the Lasker Award for Clinical Medical Research, which is often called the American Nobel Prize, for their work on Imatinib. He also – Dr. Druker – has won the Shoberg Prize, the Japan Prize, and the Tang Prize. He's won some of the most notable prizes and notable recognitions in all of medicine and medical science. 

Alicia: So of course we were really excited to sit down with him and talk about his work on this. Let's hear our conversation with Dr. Brian Druker.

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Chuck: Well, Brian Druker, it is a pleasure to have you on the podcast. 

I wonder if you could just take us back to the very beginnings, not even of your beginning with this approach, but really take us back to the 1950s when I think this development process began. 

Brian: Well, Chuck, Alicia, thanks for having me on and, and telling this story. And this is actually a miracle of modern medical research. And the modern history dates back to about 1959, 1960 when two pathologists, David Hungerford and Peter Nowell, working in Philadelphia, were looking at chromosomes in people with cancer. 

And they looked at the bone marrow and blood of people with this leukemia called chronic myeloid leukemia, and they found this shortened chromosome in everybody that had it. Working in Philadelphia, they called it the Philadelphia chromosome, figuring there would be lots of others discovered.

Chuck: So the Philadelphia chromosome encodes a protein that we sometimes refer to as BCR-ABL. What do we mean by that? And do we still use that term? 

Brian: Yes. So BCR-ABL is still a term we use. In about 1973 when Janet Rowley, working at the University of Chicago, had been working on improved techniques to look at chromosomes, and she was identify– actually identified, in fact, this wasn't a shortened chromosome 22, but a swap between two chromosomes, chromosome 9 and 22.

After Janet Rowley had identified this chromosome translocation where one chromosome broke off and joined to another, people began to map what genes were at that break point junction. One gene was called BCR, called “breakpoint cluster region,” and the other was an enzyme that regulates cell growth called ABL.

And these two genes got together and it was like sticking a light switch on. This ABL enzyme now drove the growth of white blood cells. And this chimeric enzyme – two genes brought together – is called BCR-ABL. And that immediately led to people thinking: could that be targetable? And that's where I picked up this story in the late 1980s.

Alicia: I think one of the most inspiring stories I heard in medical school was about Peter Nowell and these sort of discoveries around this Philadelphia chromosome. Because I went to medical school in Philadelphia and heard a lecture by him and was very much inspired. 

But I think that, in this whole discovery, part of understanding the importance is understanding: what is chronic myelogenous leukemia, what is CML, and why was it even important for us to understand that particular driver? And what opportunity might it give us as we're trying to prevent maybe more intense leukemias that are extremely aggressive and end up in, in very devastating ways?

Brian: So chronic myeloid leukemia, CML for short, is one of the four common leukemias. It affects about one person per 100,000, and we really don't have a clue as to what causes it. 

Historically, we would tell patients that were diagnosed with this leukemia: you've got three to five years to live. In three to five years, this leukemia is going to transform from a chronic leukemia into an acute leukemia. And the initial therapies were directed at controlling people's white blood count. So a normal white blood count is 5,000 to 10,000. Average white count at diagnosis for somebody with CML is anywhere between 50,000 to 500,000.

So there are medications that can decrease the proliferation of white blood cells. The common one was hydroxyurea. That was the mainstay of therapy in the fifties, sixties and seventies. And all it did was control the white blood count, but did nothing to improve survival. 

In the seventies and eighties, bone marrow transplant was introduced and bone marrow transplant can be curable. But in the early days it was– had a very high mortality rate. And even in the 1980s, it still had about a 50% mortality rate. So you might be cured, but it might also kill you in the first six months. So not necessarily a great option. 

And then interferon came along in the 1980s. It prolonged survival in some patients by a couple of years, but it made everybody miserable. And so think about the worst cold or flu you've ever had. Your body produces massive amounts of interferon to help you fight the infection, and it makes you, gives you fevers, chills, muscle and joint aches, make you want to stay in bed all day because of fatigue. 

We would give that to our patients and have them take that every single day for the rest of their lives. And it worked well in maybe 10 or 20% of patients, but as I said, it made everybody miserable. So that was a state of the art even in the 1980s. It was a horrible diagnosis and one that was inevitably fatal. 

Alicia: So as you were picking this up and you decided: this is how I can try to interfere with this particular protein that's essentially gone rogue, it's turned itself on, it's turning on the production of all of these white blood cells, which are inevitably going to cause harm to this person. How did you essentially solve the puzzle and make a drug that could target this protein that had gone rogue? 

Brian: When I got into this field late 1980s, 1990, I was a biochemist. I was working on kinases, enzymes that regulate cell growth. That's something I knew really well, and I figured: why not develop something that could shut down this enzyme? Sort of like turning the light switch off. So that was the path I decided to pursue. 

At the time I was at Dana-Farber Cancer Institute, I was working in Tom Roberts’ lab. He was a kinase expert. And investigators from the drug company, which was then Ciba-Geigy, now is Novartis, came to our lab and wanted to establish what's called a kinase inhibitor program, meaning shutting down these enzymes. And they sought our expertise. 

And Nick Lydon, who was the lead of this program, sat down with me. And this was 1988 and I wasn't even working on CML at the time, and I said, “Hey Nick, you know, CML is probably going to be the first disease that's going to fall to this targeted therapy approach. You really should think about that one.” 

By 1990, I had actually now moved all my lab work into CML because I followed my own advice, I'm a physician, why don't I work on CML? Dana-Farber had inked an agreement with Ciba-Geigy's arch rival, Sandoz, and they were two drug companies on the opposite sides of the river. And because of that agreement, we could no longer work with Ciba-Geigy.

But in 1993, I moved out to Oregon – and there's always a story there – but when I arrived in Oregon, I had one goal. I was going to find an inhibitor of BCR-ABL and I was going to get it into clinic. So I called up Nick Lydon and I said, “Hey Nick. Do you have anything that might inhibit this enzyme?” And he said, “Well, as a matter of fact, we do, and we're looking for somebody to test it. Can I send you our compounds?”

So his group at Ciba-Geigy had been developing kinase inhibitors. I had developed all the capabilities of testing drugs in my laboratory, and the two of us began to collaborate on the drugs that he had. 

Chuck: So just to give listeners a little bit of perspective, we talked about 1959 as the year that the Philadelphia chromosome was discovered. We talked about the subsequent 30 plus years where it was characterized. And now you're looking at kinase inhibitors, you're looking at drug prototypes, let's call them that, in the mid nineties. And I see that you published perhaps the first evidence of that in 1996 in Nature Medicine. So we're now 37 years after the discovery. 

Then things really accelerate, because in 2001 you published in the New England Journal of Medicine, essentially a study of a small group of patients, but very, very impressive results. Tell us about that transition from the lab to the clinic. 

Brian: I wish it was as simple as you make it sound, Chuck! But you have to realize that there was still enormous skepticism. Even in the 1980s and early 1990s, oncologists were still a pretty pessimistic bunch. And when has a single agent for any cancer ever worked?

But the biggest problem was: it's going to cost over a billion dollars to develop this drug. It's going to go on the market. It's never going to make enough money to justify that investment because it probably won't work anyway!

So the drug company, which was now Novartis, looked at it and thought, why would we ever take a chance on this unknown guy out in Oregon on a drug that will probably never work? And even if it did, it'll never make us any money!

But as it turns out, I wasn't just a researcher, I'm also a physician. I was seeing patients with CML and ultimately Nick Lydon had left Novartis, had started a biotech company of his own, and we approached Novartis to license it out. And what they decided was, you know, let's give it a chance in a small scale phase one. 

And we started enrolling patients in June of 1998. And by January of 1999, every single one of our patients was responding. And it was just this unbelievable time where we'd see patients who had failed every other therapy, their blood counts were out of whack, off the charts, and in three to six weeks they were normal again, and they were feeling great. And within three years, we had FDA approval. Record time. 

Chuck: So three years from the first patient being dosed to FDA approval. I remember those times. That was a big headline in the national news that they accelerated that approval. 

Just for listeners, phase one trials are the first in-human clinical trials that we do with a new drug that we think has potential to treat cancer or any other condition. And frequently we don't know the dose of the drug at that point. We don't know the side effects of the drug at that point, and we in particular don't always see great benefits for those particular patients on the phase one trials because in many cases we're just testing the dose and the side effects. And so to see a high rate of response at a phase one trial is a very big deal.

Alicia: Can you share sort of what you must have been feeling as that was happening and what were your thoughts? Because that's highly, highly unusual. 

Brian: Well, one unique aspect of– typically, in a phase one cancer drug development, you treat anybody with any cancer who's failed their standard therapy. We actually convinced the drug company: the only people who are going to benefit from this drug have CML. So let's confine our phase one trial to people with CML, because not only will we learn about the safety, but we'll get a really quick and early hint of whether the drug is working. 

Ultimately, that was what we did. We only enrolled patients with CML who had failed their prior therapy, and people would come in with white blood counts of 50, a hundred thousand, and when they went on Imatinib, they continued to feel well, and in six weeks they were normal.

The most remarkable thing was: we can also look for the Philadelphia chromosome in their blood and bone marrow. With Imatinib, we had people who had complete disappearance of the Philadelphia chromosome after six months on therapy. And that was truly remarkable, even in a phase two or three trial. But to see that in a phase one trial, that was virtually unheard of.

Chuck: So when we evaluate cancer drugs, we talk about response as we just did, and then we talk about durability of response. Speak to that. 

Brian: Well, the durability was critical, and I remember one day, it was April of 1999, we had just reached effective doses and I'm thinking: What if this doesn't last? Who's going to care? If this is just a drug that lowers the blood counts and people feel a little bit better for a few months, that's not going to make a very big impact. 

But I went to clinic that day in April, and I had three patients in a row who told me: Dr. Druker, I'm feeling so much better. My blood counts are normal. I haven't felt this good in years. My hope for the future's been restored. I'm planning a trip. I'm going to buy a new car. I'm going to do something that I've always wanted to do. 

And I remember I– they were crying, I was crying, and I just remember thinking, if these patients have embraced this drug, I need to embrace it too. 

And I’m actually seeing one of those patients this afternoon in clinic, from April of 1999, who had been told: get your affairs in order, there's nothing left to do. He found his way to our clinical trial. And he's still here.

Chuck: And you’re seeing him this afternoon? 

Brian: I'm seeing him this afternoon in my clinic. 

Chuck: Amazing. I've said this before on the podcast. I'm going to say it again: these are the moments that oncologists dream of. And that's a remarkable story.

Alicia: You know, I know you call yourself a physician scientist and you seem to have a foot in two worlds, both in the clinic and in the lab. What has it meant to you and how important are these kinds of researchers in terms of bringing science and discovery to cancer care? 

Brian: The importance of a physician scientist is that many of us focus on: how do we make an impact for patients based on laboratory studies? And ultimately that's what I wanted.

I remember one day I was working in the lab, I was doing some very basic research. And I was thinking, if I am just doing this basic research, why did I get the MD? What diseases could I be working on that would allow me to translate the knowledge I've generated as a scientist into patient benefit? And that was when I decided to change all my lab work into CML because I recognize my background uniquely suited me to work on that disease.

And what's also unique about this is I, I remember early on when I moved to Oregon, I would see patients and I'd walk from my lab to the clinic and I'd think about: what do I need to do to manage my patients? On the way back, I'd think about: what can I do to help make my patients better in my laboratory that will lead to an impact for them?

And it was always that kind of binary. Shifting your brain from being a doctor to being a scientist, but trying to integrate that in a way that's going to benefit and impact people. 

Chuck: That's, that's outstanding. 

I want to bring up a couple of other areas where Imatinib has gone on to have some benefits. We haven't mentioned it yet, but there's another form of leukemia, ALL, where I believe the Philadelphia chromosome is instrumental and imatinib is used. Tell us a little bit of what's the story there. And then there's also a stomach cancer, gastrointestinal stromal tumor, in which it is used as a routine. 

Brian: So we always knew when Imatinib was under development that there were likely going to be additional diseases where it could be of benefit. And one of them was acute lymphoblastic leukemia, or ALL, with about 20% of adults that get that leukemia carry the Philadelphia chromosome.

And historically this adult leukemia was treated with high doses of chemotherapy and a bone marrow transplant if a patient had an eligible donor. Now we can use essentially chemotherapy-free regimens with Imatinib plus an antibody that targets the leukemia cells and achieve remissions. And again, that's just a remarkable advance in the management and care of patients with leukemia. 

Chuck: And gastrointestinal stromal tumors? 

Brian: Yeah, gastrointestinal stromal tumors is a great story. When Imatinib came into my laboratory, I knew two enzymes that it inhibited, and these enzymes are like a family tree, and there are really close relatives and not so close relatives. And I decided I needed to test Imatinib against all of its closest relatives, and one of the enzymes it inhibited was an enzyme called Kit, KIT.

In 1998, a Japanese group published that KIT mutations are present in patients with this rare intestinal tumor, called gastrointestinal stromal tumor. But ultimately, a patient with gastrointestinal stromal tumor got treated with Imatinib and their intestinal tumor just melted away. And again, just a remarkable response. And now it is the mainstay of therapy for patients with this intestinal tumor. 

Chuck: Yeah, I've read some statistics that it tripled the survival when given to patients with advanced disease from a few months to a few years, and then there's even greater benefits when given after surgery as a what we call adjuvant therapy.

Brian: Yes. Again, it's just been absolutely remarkable and very, very good news for those patients. 

Chuck: Can you reflect– it's been now 25 years since the approval of Imatinib. Time flies, I suppose. What's your advice to young people entering the field, whether they are working in research labs, whether they want to be clinical cancer doctors, oncologists, or they want to work in nursing or other fields. What's your projection for them, and advice for them? 

Brian: Well, a couple of things, Chuck. And first of all, one of the greatest privileges we have is to take care of our patients through this really difficult journey. And for anybody who manages patients with cancer, we develop a really close bond with those patients, but then to be able to impact them in a substantial way is truly, truly meaningful. And what I would say to people entering the medical profession, taking care of patients with cancer, is: there's never been a better time for patients and for research. 

To think, when I started out, my very first experiment was I sequenced one gene. That was 1985, and to sequence one gene, I put it in my grant and I was so proud! I can sequence a gene! And you're laughing because you know, in 2001, we sequenced the first human genome. Today we can sequence single cells, the entire genome, and put together a spatial map of the tumor. 

That's the kind of progress and technology we can bring to bear on cancer, and those types of experiments are going to let us unlock the mysteries that still exist in cancer that are going to get us to even better treatments. 

There is still a lot of work to be done. And we savor our successes and we need to do everything we can to accelerate that progress, because there's somebody that needs our help today. 

Alicia: Well, that is a beautiful way to end this conversation and certainly an inspiring thought as we all move forward and continue to create the good news that we get to talk about on this podcast. I so appreciate you taking the time with us today, Brian. 

Brian: Alicia, Chuck, absolutely my pleasure. Thanks for doing this and bringing good news to the world.

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Chuck: You know, Alicia, as I was listening to Dr. Druker talk, I was thinking about that old saying about “try to live your life in such a way that you will be proud of the first line of your obituary.” And Brian Druker still has a lot of gas in the tank and a lot of years ahead of him, of course. But you wonder if this person, you know, will, will go down in history as one of the people who cured a cancer.

And of course he deserves not all of the credit, but he's really been the flagbearer for the development of Imatinib and its current clinical use. And so it's quite a legacy that he's created for himself in oncology. 

Alicia: I completely agree, and I think that the people that are continuing to benefit, even those first patients who are continuing to benefit from those early trials that he led would absolutely agree with you as well. And I think that it was an exciting way to end season one of our podcast to have him on the show. 

Chuck: There have been so many great conversations, and one of the things that I've realized in completing this first season is that we're just scratching the surface and there are a lot of other stories to tell, and actually there's a lot of news coming out which we will be able to report as good news about cancer, I think. 

Alicia: I agree! And you know, just to reflect, we talked about HPV vaccination. We talked about early detection of cancers, perhaps even before they become cancers. We talked about genetic screening for breast cancer and ways that we can stamp out cancer in families perhaps for generations to come. There are so many exciting things, and so for anyone who has not listened, please take a minute and go back and listen to season one.

But remember too, we're working on a second season, so make sure you subscribe to this show wherever you are listening. Go do it right now, hit that subscribe button, and get ready for season two because it is on its way. 

My name's Alicia Morgans at Dana-Farber Cancer Institute in Boston. I am really excited to have the next season to go, and thank you for listening to season one. Chuck?

Chuck: Thanks for listening to The Good News about Cancer. I'm Dr. Chuck Ryan at Memorial Sloan Kettering Cancer Center in New York. The views we express on this show are our own and do not represent the views or opinions of the institutions where we work.

Alicia: Thanks to Lilly for support of the show. Our production partner for this series is Citizen Race Car. This episode was produced by Anna Van Dine with post-production by Alex Brouwer 

Chuck: And there's a whole lot more good news to talk about. So make sure you subscribe to this wherever you listen to your podcasts.

And if you like the show, share it with someone you think might find it interesting. And as we like to say, even if you don't like the show, share it with somebody, because they probably will. 

Alicia: We'll be back again soon with more good news about cancer.