The Future of Cancer Drugs: A Conversation with Dr. Charles Sawyers

Dr. Diane Reidy-Lagunes:

As technology explodes – and it is exploding – so does medical research, and the race to bring better cancer drugs to market intensifies. But how does it all work? Today we will talk to someone who has revolutionized cancer treatment. Twenty years ago, Gleevec's astonishing success paved the way for targeted drugs and became the north star that many researchers followed. Today we talk to Gleevec's founding father about what's next. Hello, I'm Dr. Diane Reidy-Lagunes from Memorial Sloan Kettering Cancer Center and welcome to Cancer Straight Talk. We're bringing together national experts and patients fighting these diseases to have evidence-based conversations. Our mission is to educate and empower you and your family members to make the right decisions and live happier and healthier lives. For more information on the topics discussed here, or to send your questions, please visit us at mskcc.org/podcast.

Virginia Garner:

In 1997, when I was diagnosed with chronic myelogenous leukemia, or CML, I thought it was a death sentence. And as I suffered through the daily torture of the treatment I'd been put on, my husband was glued to his computer, doing research to see if he could find a way to extend my life. He found out that the clinical trial we'd heard about when I went for my second opinion had opened up, and I was fortunate to be admitted. As I entered the trial, I wondered if I had sealed my fate. But it turned out it was so successful, it became the new standard treatment for CML. And the fact that I'm alive today proves how successful it is. Today I'm not only grateful everyday, but I also realize I've become a part of history.

Dr. Diane Reidy-Lagunes:

Virginia Garner was enrolled as patient number fifteen in the clinical trials for the drug that later became known as Gleevec. Her miraculous recovery was soon duplicated across nearly all patients treated for CML. The drug was celebrated as an actual silver bullet. That was 20 years ago and it changed everything. Joining me today is Dr. Charles Sawyers, who with a team of researchers, came up with, tested, and pushed this game-changing drug to market. And it wasn't easy. Dr. Sawyers leads our translational program at MSK, which means he oversees Sloan Kettering's top-notch scientists that are changing the world of cancer by taking the discoveries at the bench and bringing them directly to the bedside. And we are absolutely thrilled to have him today. Welcome Charles.

Dr. Charles Sawyers:

Thanks Diane for having me.

Dr. Diane Reidy-Lagunes:

So it's the 20th anniversary of Gleevec and with full disclosure, Gleevec is a drug owned by Novartis for which you sit on the board, but I wanted to ask what was the clinical landscape like prior to Gleevec? And why was this such a game-changer?

Dr. Charles Sawyers:

Well, in the case of the disease that my patient Virginia Garner has – chronic myeloid leukemia – there were basically two treatments. One was an injection called Interferon that caused a lot of side effects and sometimes helped, but most patients would give it up after a year. The other is a bone marrow transplant or stem cell transplant. And that definitely works, but it's a very big deal procedure, and at the time we could only offer that treatment to patients who were under 40 because of the safety problems. So most patients with CML had a death sentence. And then the reason Gleevec was such a home run, if you will, is that it's a pill that you just take once a day, and it has very minimal side effects – nothing like the side effects of chemotherapy – and not only does it control the blood counts, it puts the disease in remission and it lasts for years. In fact, Virginia was on the phase one clinical trial more than 20 years ago. So it was astounding and it remains astounding.

Dr. Diane Reidy-Lagunes:

Wow, amazing. And like you said, only patients under 40 were even eligible for a transplant, and I could imagine that was several weeks, if not longer, in the hospital. And then you changed that to a pill. Tell us how the patient advocacy literally and figuratively saved the day for our patients with CML at that time.

Dr. Charles Sawyers:

So I'm going to have to take you back, you know, like 25 years, when really all drugs came from drug companies, pharmaceutical companies. The biotech sector was much smaller than it is now. And a disease like chronic myeloid leukemia was not on anyone's radar in that industry. The diseases that were most attractive were diseases like hypertension and cholesterol because there were huge markets to sell the drugs to. So no company was at all interested in CML. Gleevec was kind of an accident. It was originally intended for heart disease. To the credit of scientists at Novartis – particularly Nick Leiden – they recognized that it also had been implicated in cancer. So that's when Brian Druker and I were called in to get things going. But it was very hard to convince a big company like Novartis to spend the money on a little small disease like CML. But we were able to convince them to do a phase one clinical trial. We had a one-and-done shot at this. If we didn't show that it had any activity, the project was over. Once we got to the right dose, it worked in everybody. It exceeded our wildest dreams. So now the problem is that a company which wasn't really interested in this disease has a success on its hands, and it's kind of caught flat-footed. They hadn't planned to make enough drug to take it to phase two and all the additional testing that had to happen. And quite frankly, the top leadership of Novartis wasn't really aware of this project. And so it required advocacy, first of all on the part of the investigators, but what was really amazing was the advocacy of the patient community. And again, I have to sort of take you back 20 plus years. This is the early days of the internet. One of the patients had started a website called newcmldrug.com and it was kind of a chat room. But what was amazing to me is that after my clinic visits, I could log onto that website that night and I could hear almost verbatim the advice and so forth I was giving my own patients. The word got out really quickly on the website that the drug was working. So I'm pretty open with my patients and I was saying, it's not clear that Novartis is going to have the wherewithal to really pull it together and take it to the next level quickly. They organized themselves on the internet and put together a petition of roughly five thousand CML patients. So that's an enormous community. And they sent that to the then-CEO of Novartis and he turned the ship around. I mean, to their credit, they stepped up to the plate and Gleevec went from first dose in the first patient to approval in three years, which is at the time, I think was a record.

Dr. Diane Reidy-Lagunes:

That is absolutely remarkable. And, you know, even today 20 years later, when things happen and it works well, news travels fast. With the internet today, for sure. Can you talk to us a little bit about, just in the simplest terms, how does a drug come to market in that way? You talked a little bit about that phase one trial, which is obviously making sure it's safe for our patients, but how do we actually get it to our patients in a way that's faster than people feel like it's just not fast enough for many reasons?

Dr. Charles Sawyers:

Well I mean, it's never fast enough, but we have to have a safe process by which drugs are studied and then approved because there's stories in the past of sort of bad behavior and drugs that should not have been approved. So we go through this series of regulatory steps, you know, controlled by the Food and Drug Administration, for permissions. And we start with phase one, which is the first time that a human being is taking the drug. And as you said, that's primarily for safety, but more and more, we can pick the patients for phase one who are most likely to benefit. And so we can get clinical evidence of response, even in phase one. When that happens, the drug starts to really move much more quickly. There's just tremendous enthusiasm on everyone's part to move it faster. So the next step is generally what is called phase two, obviously. That's when we now enroll more patients at the same dose and try to see how well does the drug actually work. Once we see the signal there, the most formal way to get a drug approved is to move to what is called phase three. And that's generally comparing the new drug to whatever the standard of care is. And that's what patients all know as being randomized between those two groups. It's called a randomized controlled clinical trial. That's the gold standard of getting a drug approved. But again, because of the activity we're seeing in phase one without even a control group, sometimes we can get a drug approved just on phase two. That's happening more and more. So, I mean, just in my career, which is now pushing 30 years, this has just been a complete sea change in the pace at which we move forward.

Dr. Diane Reidy-Lagunes:

Absolutely. Just a short question on drug prices because it's hard to have a talk on drug therapies without sort of having the elephant in the room not discussed. Why are they so high, these prices?

Dr. Charles Sawyers:

It's a complicated topic fraught with a lot of issues. But it is true that research to develop a drug like I've described costs a lot of money. There has to be an economic incentive for a company to spend that money. And we can't really develop drugs at that level and speed in the academic community. We just don't have the resources and infrastructure to do it properly. And there's one other point: a lot of drugs fail. You think they're going to work. They even get to phase two or even phase three and they can still fail. So now you have to factor in how much a company spends for the failed drugs. The reality is it does cost a lot of money. So then the question is how do you price the drug? Well, a rational way I think would be to say, well what is the drug that you're replacing cost? But something happened during the Bush administration in the early 2000s in which Medicare, which is the largest purchaser of cancer drugs, was not allowed to negotiate the drug price, which is very different from other countries. And so the US drug pricing has become kind of a broken model for economic reasons. And I have no idea where it's going to shake out, but I think we all know that drug pricing is out of control.

Dr. Diane Reidy-Lagunes:

Yeah, absolutely. So there's a lot of buzz about precision oncology and this sort of personalized approach to treatment, which, clearly in the setting of the technology exploding, allows us to get there. But we really haven't replicated Gleevec, that silver bullet. Like you said, it's a home run. It would be sort of grand slam, right? I think we may have had singles and doubles, if you will, in other therapies, but they really haven't been that 20-year-progression-free-survival-controlling-the-disease like you talked about before. Could you talk to us a little bit about why that's the case?

Dr. Charles Sawyers:

Sure. I would actually push back a little bit on the way you sort of raise this question because I think Gleevec sort of launched a revolution in how we do targeted therapies that has been more successful than I could have imagined. But you're right, we don't have single drug silver bullets like Gleevec. I think the reason for that, that Gleevec is that special case, is CML is kind of a special disease. It's a disease we can catch early enough when it only has one major mutation that's causing the cancer. So we only have one enemy we need to attack. But most cancers are diagnosed a bit later in their life when they've now accumulated more and more mutations. But you know, the reason I want to push back is because for the first five or six years after Gleevec, everyone would say, "Well, that's a great story but it's a one-off. Is this really going to scale? Are there going to be any other targeted therapies that work?" And the first one that worked was actually a drug for which Gleevec is a treatment, and that's a type of sarcoma, which is a bad cancer, and it's life-saving for those patients. But to me, the real sort of breakthrough actually happened here amongst our colleagues at Sloan Kettering, and was the recognition that a certain percentage of patients with lung cancer would have dramatic responses with one of these targeted therapies, and this is a drug sometimes known as Tarceva, or other names, that targets a similar driver. But those remissions don't last forever, but some last many, many years. But these are like the toeholds in to getting control of the cancer. They serve as incredibly instructive cases to then guide the development of the next set of drugs. In the end, the problem is that the tumors can develop resistance, but this is a topic that's receiving incredible attention. And through laboratory work and also work in studying the tissue samples from patients on these trials who respond and then progress, we have really good clarity on what to do next. So I am quite optimistic that we're going to get better and better at this.

Dr. Diane Reidy-Lagunes:

Tell us about Enzalutamide. Can you explain to us a little bit about that discovery and what was different from say, for example, Gleevec?

Dr. Charles Sawyers:

Sure. So Enzalutamide is a drug that's used for prostate cancer. And in this case it's different from Gleevec because Gleevec targets, if you will, the root cause of the cancer. Enzalutamide doesn't do that. This is a trick to take advantage of the fact that there's a hormone receptor that the tumor cells need, as well as the cells that surround the tumor. If you target the hormone receptor, you can put the disease into at least a quiescent state, if not a remission. It's not a brand new way of thinking about how to treat cancer, but it's moving away from just the tumor cell itself to what we call the tumor micro-environment. And that tumor micro-environment also includes immune system cells that infiltrate into the tumor, and they're trying to fight the tumor but they get suppressed or turned off. In fact, a very famous set of drugs that I know a lot of our patients know, are these immune checkpoint inhibitors – famous ones such as Keytruda and Opdivo – that also were tested here at Sloan Kettering. And they've revolutionized the way we now, instead of treating the tumor itself, we treat the cells surrounding the tumor. So again, all adding up to an incredible arsenal of strategies to go after cancer.

Dr. Diane Reidy-Lagunes:

Beautiful. Are you optimistic? And cancer – clearly the more we learn, the more we realized how many hundreds, if not thousands, of different diseases fall into the umbrella term cancer. So when there may not be one smoking gun, but what do you think about all of that?

Dr. Charles Sawyers:

Well, I think you can't be an oncologist unless you're optimistic.

Dr. Diane Reidy-Lagunes:

Amen.

Dr. Charles Sawyers:

But also, I'm looking at the span of my 30 year career and it's unbelievable what's happened. I think in a way we've oversimplified cancer for so long. It's hundreds of diseases. And as we gain that clarity, we realize that we have to treat this one different from that one. And so it's an extremely complex problem. Multifaceted. It's not going to be solved overnight, but I'm very optimistic.

Dr. Diane Reidy-Lagunes:

What would you recommend or give advice in terms of our patients of today? How does that patient know what's the ideal clinical trial for that patient to consider, and how do you navigate such a daunting process?

Dr. Charles Sawyers:

That's a great question. And I think it's even more daunting now than it was in the past, because if you go on to clinicaltrials.gov, you'll find many thousands of clinical trials. So it's impossible to digest that information. My advice is seek out a disease expert in exactly what you have. I would strongly advise getting a second opinion at an NCI designated cancer center like ours or one near where you live. There's just nothing that can replace that expertise. I've also been very impressed with the quality of information that is available, I hesitate to say on the internet because there's so much bad information out there, but if you go to patient-organized websites that are experts in that disease, and generally organized through a society like the Leukemia and Lymphoma Society or others, you can do a lot of important homework. You know, as much as I do about how to steer people or patients in that direction.

Dr. Diane Reidy-Lagunes:

Absolutely. And I would just sort of emphasize the fact that, in a designated cancer center, often what we're very fortunate to have is the ability to put the genetics of that patient's tumor into our big database. So when a trial comes up, actually the computer will spit back to me that there's a trial that's available.

Dr. Charles Sawyers:

It's very hard for a patient newly diagnosed to navigate that, but with an expert to help them, they can.

Dr. Diane Reidy-Lagunes:

Could you talk to us a little bit more about machining learning and AI? And do you think that piece of technology is really going to help fast-forward the whole process of drug acceleration to market?

Dr. Charles Sawyers:

I think there is a bit of a hype on certain aspects of machine learning, but there's no doubt that machine learning is going to improve the accuracy of pathology diagnosis, and also radiology measurements, and also the ability to sift through these very complicated gene sequencing tests. Our colleagues at MSK have developed one called OncoKB, that stands for Oncology Knowledge Base, that annotates all of these mutations and helps guide this rapid turn of information so that a patient gets the most current advice possible. Machine learning is also coming into the process of real drug discovery. It's still early days, but you can actually predict the structure of a drug that would fit into a pocket of a protein you're trying to make a drug against with much greater precision and accuracy than you could in the past. Instead of an occult art, it's probably going to move faster,

Dr. Diane Reidy-Lagunes:

Amazing. Very quickly, you were part of Moonshot. Could you tell us what that was all about and what was the takeaway from Moonshot?

Dr. Charles Sawyers:

So Moonshot was actually created during the Obama administration as part of the 21st Century Cures Act. A lot of us probably remember the State of the Union address when President Obama turned to then-Vice President Biden and said, "I'm putting you in charge." The powerful motive was the death of his son Bo from glioblastoma. So it ended up allocating about $1.8 billion to the National Cancer Institute in a special sort of seven-year assessment. It was experts across the cancer community in all kinds of disciplines. We coalesced over a period of months and lots of work and consulting with outside experts, et cetera, around several themes that should be the focus. And one of those areas is drug resistance, which is clearly a major, major issue. Hopefully the Congress will re-up on this because we're coming to the very end of the seven years actually this year.

Dr. Diane Reidy-Lagunes:

There's so much to be excited about. Do you have one area of the science in terms of cancer research that most excites you right now?

Dr. Charles Sawyers:

I have to maybe pick two things. One is, we can diagnose cancer so accurately now. We've talked about these gene tests. What's amazing is you can do these gene tests now on a blood test, on a blood draw. That is like total science fiction.

Dr. Diane Reidy-Lagunes:

Do you perceive like we could just do a blood test and somebody could tell you in real time you have prostate cancer or colon cancer?

Dr. Charles Sawyers:

That is what is being argued now by a test that a company called Grail is starting to sell. I mean, it hasn't been through all the regulatory bits, but that would be to detect cancer before it can actually be seen to early detection. But what we're doing here and other cancer centers is: a patient comes in with cancer, they've had a biopsy of their lung tumor, and now we want to get a full diagnosis of the genetics. We can get it from the blood now. I would've never believed this was possible five years ago. But the second thing I'm excited about is we have a list of the genes that cause cancer now. We call these drivers. And it's the mutation in CML that's maybe the granddaddy, or first one, of those drivers that we really understood. And we have drugs against some of those drivers but not all of those drivers, and because they're in categories of genes that we call undruggable. But we're now making headway in making them druggable. It's a lot of detail that would only be for the science geeks listening to the podcast. I'm happy to talk to them offline, but there's real progress happening there, and I'm excited.

Dr. Diane Reidy-Lagunes:

Amazing. Well we are so blessed to have you part of MSK, and so on behalf of all of us and our patients, thank you so much for everything you do everyday and for joining us today.

Dr. Charles Sawyers:

Well, thank you Diane for everything you do and for this podcast because it's really cool.

Dr. Diane Reidy-Lagunes:

Thank you for listening to Cancer Straight Talk from Memorial Sloan Kettering Cancer Center. For more information, or to send us any questions you may have, please visit us at mskcc.org/podcasts. Help others find this helpful resource by rating and reviewing this podcast at Apple Podcasts or wherever you listen to your podcasts. These episodes are for you, but are not intended to be a medical substitute. Please remember to consult your doctor with any questions you have regarding medical information. I'm Dr. Diane Reidy-Lagunes. Onward and upward.