Latest / Medicine Matters: The Springer Medicine Podcast / Episode 22: Celebrating 25 years of TKIs in CML

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Episode 22: Celebrating 25 years of TKIs in CML · Medicine Matters: The Springer Medicine Podcast

• 0:07
  Speaker 2: Welcome to Medicine Matters, the Springer Medicine podcast.
• 0:12
  Speaker 2: I'm Dr Jane Godseland, and in this episode, we're taking a slightly different approach and getting up close and personal with an expert who has lived a life at the core face of cancer research and patient care.
• 0:27
  Speaker 2: As we celebrate twenty-five years since the discovery that transformed cancer care, the advent of tyrosine kinase inhibitors for chronic myeloid leukemia, We speak to one man who has been there from the beginning.
• 0:41
  Speaker 2: Targeted TKI therapies redefine CML survival and reshaped our understanding of precision oncology.
• 0:49
  Speaker 2: And so we're delighted you're going to join us on a genuine bench to bedside journey as Dr.
• 0:55
  Speaker 2: Cortes shares his stories from the very first glimmers of hope in the laboratory to his ongoing care of some of the very earliest trial participants.
• 1:06
  Speaker 1: Hello.
• 1:07
  Speaker 1: I'm Shreya Nanda, a Senior Clinical Content Manager at Springer Medicine, focusing on oncology and rheumatology.
• 1:13
  Speaker 1: I'm absolutely delighted to welcome as my guest today Dr.
• 1:16
  Speaker 1: Jorge Cortez from the Georgia Cancer Center in the USA to discuss the incredible impact that tyrosine kinase inhibitors, or TKIs, have had on the treatment of chronic myeloid leukemia, or CML.
• 1:28
  Speaker 1: And the reason we're talking about it this year is because it's the twenty-fifth year since the first reports of the phase two and three trials of the very first TKI.
• 1:36
  Speaker 1: Welcome to the show, Dr.
• 1:37
  Speaker 1: Cortez.
• 1:38
  Speaker 0: Thank you for having me.
• 1:40
  Speaker 1: Before we get going, can you just tell our listeners a little bit about yourself?
• 1:44
  Speaker 0: Sure.
• 1:45
  Speaker 0: My name is Jorge Cortez.
• 1:46
  Speaker 0: I'm the director of the Georgia Cancer Center.
• 1:50
  Speaker 0: I actually, originally from Mexico, I did my medical school there and actually I trained in hematology in Mexico and then came to the US, repeated my training and I spent twenty seven years at the MD Anderson Cancer Center.
• 2:06
  Speaker 0: I led the Kid My Lord and Chronic My Lord leukemia program there.
• 2:12
  Speaker 0: And then I came here to the Georgia Cancer Center six years ago.
• 2:18
  Speaker 0: My career has been all in leukemia, all doing clinical trials.
• 2:21
  Speaker 0: And I've been very involved with CML for many, many years.
• 2:27
  Speaker 0: So it's been a fascinating trajectory there.
• 2:32
  Speaker 1: We look forward to hearing a bit more about that as we go through.
• 2:35
  Speaker 1: this podcast.
• 2:37
  Speaker 1: Let's start off with a bit of a history lesson.
• 2:40
  Speaker 1: So what was the treatment for CML before TKI's?
• 2:44
  Speaker 1: And then what was the prognosis for patients?
• 2:47
  Speaker 0: As I mentioned, I'm originally from Mexico, so I actually see it from the very early beginnings and places where there are much less resources.
• 2:58
  Speaker 0: So when I started my training, In Mexico, we did not even have hydroxyurea.
• 3:04
  Speaker 0: We were using Biosulfan.
• 3:07
  Speaker 0: So that was all we had for many years, Biosulfan or hydroxyurea.
• 3:12
  Speaker 0: And it is a chronic leukemia.
• 3:15
  Speaker 0: So patients would leave for a few years, but on average, four, five years, and inevitably everybody would progress to a blast phase.
• 3:25
  Speaker 0: And there was really not much you could do for patients at that point.
• 3:32
  Speaker 0: A major breakthrough was the introduction of interferon.
• 3:36
  Speaker 0: And I was very fortunate to, when I moved to the U.S.
• 3:43
  Speaker 0: and started working as a fellow at MD Anderson, one of my great mentors was Dr.
• 3:48
  Speaker 0: Marcia Talpas who started the interferon story for CML.
• 3:54
  Speaker 0: And that was incredible because clearly some patients were able to have much longer survival expectations.
• 4:03
  Speaker 0: We started seeing what was then called a complete cytogenetic response.
• 4:08
  Speaker 0: Those labels of response were introduced then because it was novel, it was unique.
• 4:15
  Speaker 0: It was a difficult treatment, very, very difficult for patients.
• 4:19
  Speaker 0: Many side effects and the response rates were low.
• 4:24
  Speaker 0: but it was encouraging to see that at least some patients were starting to respond.
• 4:28
  Speaker 0: At the same time, transplant started becoming a realistic option for many patients.
• 4:37
  Speaker 0: It was also very limited because the risks of mortality and all that were high.
• 4:45
  Speaker 0: The donor options were not great.
• 4:47
  Speaker 0: In those days, we really relied on family members.
• 4:53
  Speaker 0: identical donors.
• 4:56
  Speaker 0: And there was a hard cap at age fifty-five.
• 5:02
  Speaker 0: So there was a debate between interferon and transplant, but for the reality is that few patients qualified for transplant because of age or because of donors or all of that.
• 5:12
  Speaker 0: And then if you had interferon and that didn't work, then there was not much else.
• 5:17
  Speaker 0: There was a time where we were using Homo Haringtonin.
• 5:20
  Speaker 0: That was the best thing that you could do for that.
• 5:25
  Speaker 0: Then the combination of interferon plus Lodo-Cytorabine came and that improved some.
• 5:32
  Speaker 0: But that was all we had.
• 5:34
  Speaker 0: Again, treatments that were effective but limited by toxicity, by the rate of responses, by availability.
• 5:46
  Speaker 0: And there was not much that you could do after that.
• 5:49
  Speaker 0: So it was, for many patients, it was still a fatal disease for the majority of patients in a relatively short period of time.
• 6:01
  Speaker 1: And I think I read somewhere that the kind of five-year overall survival rates were about thirty percent.
• 6:05
  Speaker 1: Is that correct?
• 6:07
  Speaker 0: Yeah, something like that.
• 6:09
  Speaker 0: And you would have very few patients that would leave beyond ten years, you know, single digits.
• 6:17
  Speaker 0: It was and sure, many patients are diagnosed in their fifties and sixties.
• 6:25
  Speaker 0: But even in your fifties and sixties, you're not expecting to leave only five years.
• 6:30
  Speaker 0: So so it was.
• 6:32
  Speaker 0: it was devastating.
• 6:34
  Speaker 1: It definitely sounds like the prognosis wasn't great and the options weren't that great.
• 6:39
  Speaker 1: So then just staying with the history.
• 6:42
  Speaker 1: So what was the starting point for the development of TKI?
• 6:46
  Speaker 1: What was the research that started it all off?
• 6:49
  Speaker 0: Well, the big breakthrough was research that, you know, like in medicine, usually there's a lot of people who contribute.
• 6:59
  Speaker 0: But unquestionably, Dr.
• 7:02
  Speaker 0: Brian Drucker, who was initially, when he started working on these at Harvard, He started the research on these new molecule that was initially called GCP-Five-seven-one and then became STI-Five-seven-one and then became imatinib.
• 7:26
  Speaker 0: But he started doing the research in the laboratory and he published incredible paper in nature, showing that it was very selective, very effective in cells that had the Philadelphia chromosome, that had the BCR able.
• 7:47
  Speaker 0: And so it was now shifting from chemotherapy or from the interferon to a very specifically targeted agent.
• 8:01
  Speaker 0: And initially, there was not much interest in continuing to develop this drug.
• 8:08
  Speaker 0: You know, it was very new.
• 8:10
  Speaker 0: It was a completely different concept.
• 8:14
  Speaker 0: The size of the population was not as large, and there was a lot more interest in defining something for breast cancer or colon cancer, you know, those tumors that are much more common and where more patients die.
• 8:28
  Speaker 0: But he really played a big role, not only in doing that initial research, but also in convincing the company that it was worth pursuing, that there was a good rationale there, that there was a need, that there was much to be gained.
• 8:49
  Speaker 0: And so that started the phase one study.
• 8:51
  Speaker 0: And the phase one study, I remember, was three institutions, three lead investigators.
• 9:01
  Speaker 0: Brian Drucker was one of them, Charles Sawyers was the other one, and the third one was my mentor, Moshe Talpas.
• 9:09
  Speaker 0: So I had the fortune to see some of the very first patients treated at MDS in that phase one study.
• 9:20
  Speaker 0: That was around nineteen ninety eight with these drug STI five seven one.
• 9:28
  Speaker 0: And I have in my mind very distinctively, Moshe Talpas coming out of the room and saying, this thing works, you know, it was just so incredible to see these things that we had never seen before with appeal, well tolerated, even in a phase one study.
• 9:46
  Speaker 0: So that was remarkable.
• 9:48
  Speaker 1: Yeah, it's a good thing.
• 9:49
  Speaker 1: Dr.
• 9:49
  Speaker 1: Droga kind of kept the pressure on to develop it, didn't you?
• 9:53
  Speaker 1: Oh, yeah.
• 9:54
  Speaker 1: So you've alluded to this already a little bit because you have been involved in this early research.
• 9:59
  Speaker 1: Did you know then that this was the cutting edge of science or did you anticipate the effect?
• 10:07
  Speaker 0: No, I didn't.
• 10:09
  Speaker 0: Very quickly, we converted into strong believers of these, but early on it was another phase one drug and hope and expectation.
• 10:22
  Speaker 0: But you always have a lot of doubts, and are we going to see toxicities?
• 10:26
  Speaker 0: Is it going to be sustained, the responses, and all these things?
• 10:31
  Speaker 0: But as I mentioned, as we were enrolling more patients on that phase one study, and we started seeing another response and another response, and patients feeling well.
• 10:42
  Speaker 0: And keep in mind, all these patients were coming from interference.
• 10:46
  Speaker 0: So for these patients, the transformation of how they were feeling.
• 10:51
  Speaker 0: The side effect profile and all of that was night and day.
• 10:55
  Speaker 0: It was an incredible shift for those patients who had experienced what it was to be an interferon, not only from the point of view of not having had a good response, but all the side effects and even the inconvenience of a subcontinuous injection versus appeal.
• 11:15
  Speaker 0: So very quickly, it became very clear that this was something major.
• 11:21
  Speaker 0: And it started creating a lot of expectation from investigators, from physicians and all of that.
• 11:28
  Speaker 0: But even it started to become known among patients and more patients were starting to go to these centers where these studies were going, were happening because they started hearing from their fellow patients, from media, from the reports in conferences, et cetera, that this was something unique.
• 11:51
  Speaker 1: What a time to be involved in the research.
• 11:53
  Speaker 1: I can't even imagine what that feels like with my little PhD on fruit flies.
• 11:58
  Speaker 0: It was fantastic.
• 11:59
  Speaker 0: And I remember when we started the phase two study, end of nineteen ninety nine, and by then patients knew about it and everybody wanted to be enrolled in that study.
• 12:11
  Speaker 0: So the first week when we opened the trial, just at MD Anderson, which is where I was.
• 12:16
  Speaker 0: By then I was already on faculty and I remember it was a week when my older son was born.
• 12:29
  Speaker 0: But I couldn't be there all the time because we had so many patients that we wanted to enroll.
• 12:33
  Speaker 0: We enrolled, I don't know, a hundred patients in a week, an incredible number.
• 12:38
  Speaker 0: that was just amazing.
• 12:40
  Speaker 0: Because there were so many patients who wanted to get into that trial.
• 12:44
  Speaker 0: so that was incredible.
• 12:46
  Speaker 1: Yes, nobody wanted to be on the control on that one.
• 12:49
  Speaker 0: No, no, no, no, no.
• 12:52
  Speaker 1: So then just talking about these phase two and phase three studies, so then let's talk about the impact of TKI is like what has it meant for patient care for their prognosis?
• 13:01
  Speaker 1: How would you describe the impact?
• 13:03
  Speaker 0: Well, this was clearly transformational.
• 13:07
  Speaker 0: For CML for sure, but for medicine in general, for cancers specifically.
• 13:13
  Speaker 0: You know, the outcome of patients in terms of efficacy, in terms of survival, in terms of side effects, you know, in terms of quality of life, in terms of their ability to continue their normal life activities, enjoy life, etc.
• 13:34
  Speaker 0: It was just a complete night and day, and it has continued to be that way.
• 13:43
  Speaker 0: Of course, with the new generations and the next generations of TKI's more and more, but we continue learning and advancing.
• 13:53
  Speaker 0: A good example of how this continues to evolve is that at the beginning, we never thought about stopping therapy.
• 14:00
  Speaker 0: Everybody knew that This was great.
• 14:03
  Speaker 0: You just need to take appeal for the rest of your life.
• 14:05
  Speaker 0: Eventually, we learned that at least some patients can stop therapy.
• 14:09
  Speaker 0: Not enough.
• 14:10
  Speaker 0: Not everybody.
• 14:11
  Speaker 0: We need more.
• 14:12
  Speaker 0: But even that was a big transformation.
• 14:16
  Speaker 0: Another thing that was remarkable is that, yes, we have newer drugs, newer generations, probably better drugs.
• 14:23
  Speaker 0: But imagine if remains a remarkable drug.
• 14:27
  Speaker 0: It's a great drug.
• 14:29
  Speaker 0: You know, I frequently say, you know, we're in a situation here that we don't have a good TKI and a bad TKI.
• 14:35
  Speaker 0: We have a very good TKI and better TKIs, but the baseline is very good.
• 14:40
  Speaker 0: You know, imagine it was a great draw.
• 14:42
  Speaker 0: He's a great draw.
• 14:44
  Speaker 1: As you say, that's such an unusual situation to be in because as we've seen with other targeted therapies, the ones that came earlier do go out of use and they get replaced, but imagine it has not gone down that path.
• 14:57
  Speaker 1: clearly a transformative treatment.
• 14:59
  Speaker 1: It has changed the lives of patients, but you alluded to it a little bit.
• 15:03
  Speaker 1: There are still challenges that remain.
• 15:06
  Speaker 1: So can you talk about some of the challenges and how they could be overcome with future work?
• 15:12
  Speaker 0: Definitely we have challenges.
• 15:15
  Speaker 0: I mentioned one of them is the ability to stop therapy.
• 15:21
  Speaker 0: And I see it not as a need in the sense of having to take a pill long term, whether that's going to have impacts in organs or something like that.
• 15:34
  Speaker 0: We fortunately have not seen that on patients that have been on these drugs for twenty five years.
• 15:40
  Speaker 0: So that's not the concern.
• 15:42
  Speaker 0: But I do think that, you know, for a patient being able to stop therapy, I think it is a big hallmark.
• 15:50
  Speaker 0: It's like finishing, you know, your radiotherapy or chemotherapy or whatever, you're done.
• 15:57
  Speaker 0: And sometimes for a patient, the only reminder of the disease is taking the pill, even if they're doing well.
• 16:04
  Speaker 0: So at least giving that option to patients.
• 16:08
  Speaker 0: Some may not want to stop therapy, but right now, that is available successful in about twenty five, thirty percent of the patients.
• 16:19
  Speaker 0: We need to, at the very least, double that, if not much more.
• 16:25
  Speaker 0: So that's one of the challenges, one of the areas of great focus on how do we get there.
• 16:32
  Speaker 0: Another important one is, particularly for the ones who cannot stop therapy, when you think about the history as we've been doing now and all the side effects with interferon and mortality with transplant and all these things, these drugs are incredibly better tolerated.
• 16:55
  Speaker 0: well-tolerated drugs, most patients can do normal life.
• 17:00
  Speaker 0: But when you're taking them for the rest of the life, there's no question that they have an impact in some side effects.
• 17:09
  Speaker 0: And here, the problem is not so much the severity of the side effects.
• 17:15
  Speaker 0: It's the continuation, the no end of that.
• 17:19
  Speaker 0: I frequently tell people, it's like having a little stone in your shoe.
• 17:25
  Speaker 0: It's not a serious discomfort.
• 17:27
  Speaker 0: It's okay.
• 17:27
  Speaker 0: You can keep walking.
• 17:29
  Speaker 0: But if you're going to walk two miles or five miles or ten miles, at some point you have to stop because that's too much for that length.
• 17:38
  Speaker 0: And that's the same thing.
• 17:39
  Speaker 0: You have a little bit of diarrhea, a little bit of pain.
• 17:43
  Speaker 0: It's not that it's life-threatening.
• 17:47
  Speaker 0: But if you're going to have to live with that for the rest of your life, how much is that going to impact your ability to work, to enjoy?
• 17:53
  Speaker 0: So improving the tolerability and focusing on quality of life becomes an important focus because we either stop therapy or we improve the quality of life for those who cannot stop therapy.
• 18:08
  Speaker 0: Survival, yeah, we've gotten to normal life expectancy, but now patients don't just want to live more, they want to live better.
• 18:15
  Speaker 0: That's what we need to focus on.
• 18:18
  Speaker 1: Yeah, absolutely.
• 18:19
  Speaker 1: I have full faith that we will get there.
• 18:22
  Speaker 1: So we talked about the patients who can stop therapy and then the others who need to be on therapy.
• 18:28
  Speaker 1: But there is still also a small proportion who don't have an optimal response in the first place.
• 18:33
  Speaker 1: So then what are the options for them and how can their prognosis be improved?
• 18:38
  Speaker 0: That's where the development of the new drugs.
• 18:40
  Speaker 0: Unfortunately, there's still research in developing new drugs.
• 18:44
  Speaker 0: And some of the new drugs that are coming are perhaps not dramatically different.
• 18:52
  Speaker 0: You know, the biggest step was interfering to imatinib.
• 18:55
  Speaker 0: Second generation to imatinib was a nice next step, but it was a little more incremental.
• 19:01
  Speaker 0: Now, newer drugs feel smaller gaps.
• 19:07
  Speaker 0: Now, there are others that are focusing that they have less side effects and things like that.
• 19:12
  Speaker 0: So those new drugs are useful because we still have patients, as you mentioned, that a drug doesn't work, or maybe they just cannot take it because of side effects.
• 19:24
  Speaker 0: So even now, these are niche indications, which makes it challenging to develop and to get the drugs approved in the market and all that.
• 19:34
  Speaker 0: But they're important because For those relatively few patients who need another drug and another drug, you cannot tell them that it's no longer a big problem.
• 19:46
  Speaker 0: For that one individual, that is a big problem.
• 19:50
  Speaker 0: So those drugs, fortunately, there's still a lot of research.
• 19:54
  Speaker 0: There's three or four very exciting drugs being developed now, as well as combinations with drugs that work in different ways.
• 20:04
  Speaker 0: And those are particularly interesting in the context of eliminating the residual cells.
• 20:10
  Speaker 0: so we can stop more therapy.
• 20:12
  Speaker 0: So I think that those are the new approaches that some of these drugs, I think, are going to be very helpful, again, for a subset of patients, but a subset that's very important we don't forget about.
• 20:23
  Speaker 1: No, absolutely.
• 20:24
  Speaker 1: No patient left behind, I think.
• 20:25
  Speaker 0: Absolutely.
• 20:26
  Speaker 0: And
• 20:27
  Speaker 1: you've addressed this a little bit already in terms of talking about the newer drugs and the combinations.
• 20:33
  Speaker 1: What do you think the future holds for TKI's in CML and also more generally for CML treatment?
• 20:39
  Speaker 0: I think we're gonna get to that possibility of Stopping therapy in more patients.
• 20:50
  Speaker 0: What I think we have to do is figure out a way to understand why we cannot do it in individual patients, not just on populations.
• 21:02
  Speaker 0: Because I think that the reasons why some patients cannot stop therapy vary from patient to patient.
• 21:13
  Speaker 0: And an approach of combining with drug eggs, for example, may work for some, but not for others.
• 21:19
  Speaker 0: But that doesn't mean that nothing's going to work for those others.
• 21:22
  Speaker 0: Maybe we just need to.
• 21:23
  Speaker 0: So understanding those individual needs and biologic circumstances that guide their persistence of the disease.
• 21:36
  Speaker 0: I think that that's what's coming up.
• 21:40
  Speaker 0: And I think that's an exciting research.
• 21:43
  Speaker 0: Now we have better tools to try to understand these things.
• 21:47
  Speaker 0: Again, going back in history, when you think what Brian had available to do this research, The tools that he had back then were not the tools that we have now.
• 21:57
  Speaker 0: I mean, now you have all these fascinating technology that allows you to dig a little bit deeper and not only to do the experiments, but also to analyze the data, you know, artificial intelligence and big data analysis, bioinformatics that I think are gonna let us dig a little bit deeper into that individuality of those patients who are not doing well.
• 22:21
  Speaker 0: why and how we can improve that.
• 22:25
  Speaker 0: And also, you know, understand better, you know, what drug works best for each patient.
• 22:32
  Speaker 0: It's not a matter of saying, this drug is better, everybody should take this drug.
• 22:37
  Speaker 0: Because as I said, you might think it's still a good drug, we just need to develop smarter approaches to define, this is the best drug for this patient, this is the best drug for this patient, and so on.
• 22:49
  Speaker 0: So And I think we're going to get there.
• 22:54
  Speaker 0: As we start more into the refinement process, those are the things that we're going to be focusing on.
• 23:00
  Speaker 1: Lots of different avenues to look at.
• 23:03
  Speaker 1: Just as my last question, I'm going to kind of go back to something you alluded to very briefly when we were talking about the impact.
• 23:09
  Speaker 1: And TKI's have not just had an impact on CML.
• 23:12
  Speaker 1: I think they've had a much wider impact.
• 23:14
  Speaker 1: So can you speak to that a little bit?
• 23:17
  Speaker 0: Yeah, this is being, as I mentioned at the beginning, transformational for cancer in general, because I frequently correct my patients when they tell me I'm taking chemotherapy.
• 23:30
  Speaker 0: I said, and you know, I correct it because that's a big transformation that happened.
• 23:36
  Speaker 0: You know, I tell them, you know, chemotherapy is a bomb.
• 23:40
  Speaker 0: You throw it in, you want to kill the bad guys and hope that not many of the good guys die.
• 23:47
  Speaker 0: These drugs are missiles.
• 23:50
  Speaker 0: You're directing them specifically against the bad sales and protecting the good sales.
• 23:56
  Speaker 0: Now, no question, they still have side effects on whatever, but that introduced that concept very realistically into cancer.
• 24:04
  Speaker 0: Now it worked.
• 24:05
  Speaker 0: Now it really was proven that that principle of something very targeted would be effective, would be less toxic.
• 24:17
  Speaker 0: And also that it helps to start understanding the mechanisms of resistance, which is also very important in CML and in other cancers because that's a way of, okay, how do we not only overcome but prevent that from happening?
• 24:34
  Speaker 0: So I think that the impact of these initial discovery from Brian and all the push for the clinical.
• 24:46
  Speaker 0: really has transformed the way we manage cancer.
• 24:50
  Speaker 0: You know, just like, for example, checkpoint inhibitors with immunology was another big step later on more recently, but it's another big advance.
• 25:01
  Speaker 0: That one has not applied in CML, but it's, you know, these are some of these transformational discoveries that really start shifting how we think, how we practice.
• 25:16
  Speaker 0: and how we do research.
• 25:17
  Speaker 1: For you to have just been part of that journey from the beginning through to now, it must be, I can't even imagine the feeling.
• 25:25
  Speaker 0: It's an incredible journey and I'm very fortunate to still be able to follow some of those very, very early patients that had gone through interference and transplants and had had horrible outcomes.
• 25:43
  Speaker 0: And then they switched.
• 25:44
  Speaker 0: And now, you know, here they are, twenty-five years later, doing their life.
• 25:50
  Speaker 0: So, you know, when you see one of those patients, you know, it reminds you on how remarkable this has been.
• 25:57
  Speaker 1: Just incredible.
• 25:58
  Speaker 1: And I feel very fortunate to have spent this time with you talking about it all.
• 26:03
  Speaker 1: So thank you so much for taking the time to speak to me.
• 26:06
  Speaker 1: I could talk for another half hour, but I know you're busy, so I'm going to let you go.
• 26:11
  Speaker 0: Thank you very much.
• 26:11
  Speaker 0: I've enjoyed it and it's been a pleasure.
• 26:16
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