Dr Marshall explores the current dosing strategy of oncology agents and shares his own dosing and scheduling strategies.
Monopoly Concerns with Oncology Acquisitions: Should We Be Worried
[00:00:05] John Marshall, MD: John Marshall, MD: Hey, everybody, John Marshall with Oncology Unscripted, even though I've got a little bit of a script right here, but don't tell anybody. Today, we're going to talk all about dosing of medicine, and do we have it right or not, particularly with some of our newer cancer medicines. And I'm going to really drill down on a couple that I know a lot about that I hope you will use in your own practice, quite honestly, and make your life a little easier, and, more importantly, your patient's life a little easier.
[00:00:34] Let's look a little bit at the business side of what's going on. You know, I've been kind of watching this big takeover of McKesson and Florida Cancer Specialists. Well, wouldn't you know what? There's in fact, of course, been some Federal Trade Commission pushback that this creates sort of, how could it not be a monopoly, when you've got everything from insurance to providers to drug people and everybody in the same game. It ends up becoming a monopoly out there. And, you know, I think it's right that we look at this because, you know, we do predict that there's going to be just, you know, just a few huge health care systems out there in our country. And we need to figure out how best to manage all of that to continue to provide the best care we can, for all of our patients and give access to everybody that we can get access to. So. Important stuff going on out there still, of course, in our business world.
Science Snapshot [00:01:34]
From a science perspective, I just came across, really yesterday, in the New England Journal, an article that that piqued my interest. Because it only went very nicely with the theme of our episode today, but around dosing, but really value in terms of what's it worth to get a little bit more survival.
And this was a study as a metastatic lung cancer study in the New England Journal of Medicine. I've got an actual copy of it. Right there. There it is. And this is by Cho et al. It's a very important study. It's the MARIPOSA study. You all know about it. It's amivantamab, there you go, plus lazertinib, which is, I guess, like Lazarus from the New Testament, maybe, maybe not. But this is in patients with EGFR-mutated non-small cell lung cancer, and, of course, the current standard of care is osimertinib. A relatively easy medicine to take has some side effects. The doublet wins in the end of the day, by a small amount, and that's with both PFS and trending towards OS. But I went to the toxicity table because do we have the doses of these medicines correct? And so maybe that's reflected in tox, and I'll come back to this in a little bit, but you know, there's not equal toxicity at all. In fact, the doublet therapy has essentially double the amount of grade three toxicity, and the investigators are fairly bold in saying, however, the incidents of grade four, which is almost dead, and five, dead, or discontinued treatment, were similar between the two groups. So now we've elevated it. Don't pay attention to grade three toxicity, we know that's going to be different here, let's look at dead and almost dead grade four and five and see if that's different. And it really struck me when I looked at the deltas on the advantages, the clinical outcomes, and the deltas on the toxicity that, is this really worth it? Should this become a new standard of care? New England Journal usually doesn't print things that it doesn't think are at least at risk for being the new standard of care. So, those folks out there who take care of lung cancer are going to have to figure out if this really reflects a new change and is that worth it.
Are You Overdosing Your Patients? [00:04:08]
And really why I picked that paper, it's important, but, to me, it's all about dose. And I think we are overdosing people. I am old enough to remember that when chemotherapy was the thing that we needed to get to what we call the maximum tolerated dose. And this was how much could you give you all know what this means. How much could you give without bumping the patient off, because the principle was that more was better.
I want to reflect on this a little bit because we learned pretty clearly in some cancers, that was true, germ cell cancer, some leukemias, maybe adjuvant breast cancer, but that dose intensity mattered in those diseases. But let's look at adjuvant breast cancer, because when I was a junior faculty member here, we were doing bone marrow transplants in the adjuvant setting for stage two and three breast cancers. So, we were doing marrow ablative, myeloablative therapies because more was better. And if you know that story, you know that the people who were leading some of those papers out of South Africa ended up committing fraud. Their results were fraudulent, and many, many women were exposed to bone marrow transplants because of their data suggesting it might be helpful, when in fact it was not. So, more was not better in that scenario.
And the other place that I was living at the time, again, 20, 30 years ago, was the advent of capecitabine. Simple drug. You use it a lot in your practice, I am sure, but what dose and schedule do you use? Do you remember, were you around when the actual dose studies were done? Back in the day, we would not only do something called maximum tolerated dose, we would then have a supplemental study of recommended phase two dosing. And very often that meant a randomized clinical trial of different doses and schedules of the medicine looking for both toxicity and efficacy to see which one works the best. Yep, they did that with capecitabine back in the day. And they looked at continuous dosing, right? Just giving it continuously at a certain dose. They looked at 2 weeks on 1 week off with leucovorin. Two weeks on, one week off, without leucovorin. Those two doses were a little different. And guess what? All three had exactly the same outcome in terms of response rate and progression free survival. All of that, exactly the same. The continuous dosing had the lowest toxicity. But guess what? We picked the one that used the most capecitabine pills. Not leucovorin, you could use fewer pills if you threw a little leucovorin in, but this was just capecitabine at what we now know as its dose, two weeks on, one week off. That sold the most pills, not because of benefit, but because dose intensity at the time mattered. And we are still clinging on to that dose and schedule. Many, many people are, whether it's a XELOX regimen or just capecitabine or maintenance capecitabine, but it's not correct.
How Does Dr Marshall Dose Capecitabine? [00:07:34]
The correct way to give capecitabine by John Marshall. Fixed dosing, never use the small pills, only use 500 milligram pills, size up your patient. Do an estimate of creatinine, clearance, because this is a renally cleared drug. Most patients I start at 1500 milligrams, three pills in the morning, after breakfast, 1500 after dinner. Monday through Friday, because you know what if radiation doesn't work on the weekend neither does chemotherapy, every week. Okay, so if you're a two-week one-week offer, you're giving it 14 days every three weeks. My way, I'm actually giving it 15 days every three weeks. And because you give that little weekend off, the hand foot syndrome is less, it doesn't build up nearly as much. Are you given the right dose? If somebody comes back in within a month or two and starts to have some hand foot syndrome, if it's mild, you're probably at the right dose. If there's no toxicity, you think about increasing it. If there's a lot of toxicity, you need to decrease it. We all are pretty clear on that. Some of us like to decrease it by pill count and keep the continuous dosing. Others like to do one week on, one week off as a modification. One little trick to know that you're giving the right amount, check your patient's MCV. If they've been on capecitabine for, I don't know, a couple months, you'll notice that MCV will be going up because that's the antifolate effect that you're seeing. You got your own little built-in micro-biomarker in your CBC of every patient that you're giving capecitabine. So, I'm telling you, switch out to this dosing and you can give your ox every two weeks or every three weeks. I'll leave that up to you. That's another matter altogether.
Consider Dose-Escalating Regorafenib [00:09:21]
Tony Saab taught us how to use regorafenib, Stivarga. Because we knew that if we gave full doses, 160 milligrams daily, it was too much, too spicy. Lots of patients said, forget it. I'm not taking that drug ever again. Tony showed that if you started lower at 80 and then inched it up, and then inched it up, you did a lot better
Should We Rethink TKI and Immunotherapy Dosing? [00:09:34]
Now, what's the right dose of a tyrosine kinase inhibitor? The studies are done with maximum tolerated dose. Give as much as you can give. More is better. Use that in the clinical trial. But more and more, we are seeing that you don't need to give that much. But are we comfortable in dose-reducing? Are we okay with saying, all right, I'll just cut the dose back because Marshall said it's okay. No, we're not. Because we don't want to regret that it was our dose that maybe it didn't work. So, we're feeling compelled to give the dose. Even the insurance companies are mandating that we give the dose that is in the package insert. When, for a lot, maybe most, of these TKIs, we don't need to give nearly that much.
I believe the same is true for immunotherapy. Because let's face it those patients whom we stop for IO toxicities, you know, they seem to be doing okay. So maybe we don't need to do nearly the duration or as often. If the way the drugs work is the way they say they work, then you wouldn't need to have it continuously exposed all the time to patients. So, we're probably overdosing TKIs all the time, and we're probably overdosing immunotherapy.
What Schedule Does Dr Marshall Use for Trifluridine/Tipiracil? [00:10:56]
Another colon cancer drug that I think is important to understand is Lonsurf dosing, trifluridine/tipiracil. What a crazy regimen that was. So, five days on, two days off, five days on, two weeks off. It takes forever just to coach the patient on what to take, and there are two pill sizes and all of that, and myelosuppression is the big side effect of that regimen. We just looked at that and said, that's crazy, just give it every other week. So we still stick with our Monday through Friday because it's easier for patients to remember. And instead of two weeks in a row, we give it every other week. And believe it or not, that is essentially solved a lot of the cumulative suppression, myelosuppression, the nausea, all of that stuff that you see with that drug by getting away from the package insert. dose reducing, maybe a little using only one pill size, again, to get your optimum dose and schedule.
So, we need to understand better how to dose these medicines. The problem is, we don't use them that often, many of them, so we're dependent upon looking stuff up, and what the package insert, and what the insurance company, what the guidelines say. We all don't have a person who's an expert on speed dial that you can say, well, what would you do if you were giving this patient this treatment? So, we clearly need an improved resource for all of us to understand what the correct dose is that we need to use day in and day out to optimize our patients, both benefit but also toxicity, so that we know that we are doing the best job possible.
Up Next: A Candid Conversation with Dr Mark Ratain on Drug Dosing [00:12:36]
And, so, to that end, I have invited not only a lifelong, career long friend and mentor, but really what I think is maybe the world's expert in this space. And that's Dr Mark Ratain from the University of Chicago. He cares passionately about this and is actually doing something about it. So, listen to this interview with Mark Ratain, MD.
Dose Matters with Dr Mark Ratain
[00:12:58] John Marshall, MD: I only get the best people to interview for every major topic, and I am lucky enough to have known the gentleman next to me right now for almost all of my career. Dr Mark Ratain at the University of Chicago has been one of the world's leaders in not only drug development, but really the pharmacology of novel chemotherapy, novel biologics, etc., of really optimizing dose, schedule, efficacy. He's the real guru of this, and, honestly, is one of the few, let me put it this way, anchors or rudders in our overall cancer development pathway and system that's really keeping us honest about what we're doing. And it's not an easy position for him to take, but he continues to work on this, and I think has had a major influence on many, many cancer patients, and our practice over his great career.
[00:13:58] So, Mark, first, thank you very much for joining and talking about this important topic of dosing treatment. Mark J. Ratain, MD: Thank you, John, for having me.
[00:14:07] John Marshall, MD: So, let, let's just dive in. You and I are old salts. We've been doing drug development a long time. We used to have these great, you know, dose finding trials where we compare different doses that seems to have fallen off by the wayside. So, we have a sort of maximum tolerated dose for everything that gets approved out there. We all recognize as clinicians, it's too spicy, but we also don't wanna cut doses back because we don't want to shortchange patients. So, tell us a little bit about where this is, why that evolved, and maybe some of the newer projects that are going on in that space.
[00:14:41] Mark J. Ratain, MD: Well, it evolved because in the old days of, the start of chemotherapy, we didn't have effective drugs. We were treating diseases like leukemia and Hodgkin's disease and with drugs for which more is better. And so, we did the right thing. But as we began using chemotherapy for less sensitive diseases and with drugs that were less effective, like using 5-FU for colorectal cancer, more is not necessarily better. And yet we stayed with the more is better paradigm for decades and then even worse, when we developed better drugs, including, you know, targeted monoclonal antibodies, tyrosine kinase inhibitors, we kept the same paradigm, despite the lack of scientific justification.
[00:15:35] John Marshall, MD: You think you have a good reason of why we didn't sort of rethink this? Were we afraid that we might lose benefit and patients with cancer?
[00:15:45] Mark J. Ratain, MD: No, I think it's because, the way we've been doing it was quick and dirty from the standpoint of a company developing a drug. It's very quick to determine the maximally tolerated dose. That's an easy study to do. You don't need to be smart. You just need to push and push and push until the patient can't take it anymore. And so, you treat a bunch of patients, and you say, oh, we found our dose. And so that was quick.
[00:16:15] John Marshall, MD: Well, and I also think along with that, I keep thinking every time I see a new presentation of a novel therapy or a clinical trial, they pop that tox table up in front of us. And we've learned to just accept a fairly high burden of grade three toxicities, or a lot of patients getting grade one, two toxicities without really challenging the dose in that. So, we're co-conspirators, in some way, on this of accepting these doses and toxicities.
[00:16:42] Mark J. Ratain, MD: Well, not only that, we've trained patients to expect these toxicities.
[00:16:47] John Marshall, MD: If you don't get sick, it won't work. Right?
[00:16:49] Mark J. Ratain, MD: And, in fact, oncologists say, well, that's what we do. We manage side effects of drugs. Like if we didn't manage side effects what would we really do here? And so, no, it is, is part of the culture of both being an oncologist and being a cancer patient.
And you hear people say, well, cancer is such a bad disease, you've got to push the dose, you've got to accept side effects. Well, in the greatest medical crisis of our lifetime, COVID, I don't recall a single drug development program in which any sponsor said we've got to push the dose. The remdesivir development, which was the first drug approved, did a careful, dose optimization study. The logic is completely flawed, it’s just part of the culture of oncology, and that culture, quite frankly, has harmed patients.
[00:17:49] John Marshall, MD: Totally agree. And you've been really helping to lead this, you know, carry this flag for us and point this out so that we can be better physicians, better, better providers, better outcomes even. And I know you'd had some discussions with one of your faculty colleagues and also FDA lead Rick Pazdur around this Project Optimus. Tell us a little bit about that encounter.
[0018:11] Mark J. Ratain, MD: These discussions have been going on for many years, but the most recent major interaction was in the fall of 2020 during the pandemic when the University of Chicago Comprehensive Cancer Center gave Rick Pazdur our annual award, and he virtually visited us. And as part of that virtual visit, we had a group discussion, a group Zoom, involving our cancer center leadership and his center leadership at FDA. And during that I said, Rick, I don't know why you don't make companies optimize the dose before approval. And he said, Mark, you're right we're going to make them do that. And about 6 months later, he announced Project Optimus. That in many ways might be the history. I don't know what other discussions were ongoing at FDA prior to that meeting, but some of my FDA friends say that was a major moment for the FDA oncology leadership, that discussion that day.
[00:19:18] John Marshall, MD: Well, take that to the next step. has that been applied anywhere? Where, where are we going with that kind of thinking?
[00:19:24] Mark J. Ratain, MD: Well, the first thing that happened was when, FDA approved sotorasib In May of 2021 at a dose of 960 milligrams, they basically said in the review, we're pretty sure 960 milligrams is the wrong dose. There's no relationship between dose and response. There's no relationship even between dose and plasma concentration because the drug's not absorbed very well. but the only dose of which. There was sufficient data to evaluate, efficacy was 960 mg, so we'll approve the drug, but require the sponsor Amgen to conduct a post marketing trial, 960 mg versus 240 mg.
[00:20:10] John Marshall, MD: But let me interrupt right there real quick. So, if I go on right now as an oncologist and I've got a patient who's been maybe a candidate for sotorasib and I look online, 960 is what pops up on their official website and everything, and that's what that insurance provider is looking to provide. That's what the pharmacy we riffed on PBMs earlier, that's what they're expecting to provide. There's a business around this too. But, anyway, there's a study looking at two different doses,
[00:20:39] Mark J. Ratain, MD: So that study was completed, and that study was published recently in the European Journal of Cancer. And that study was presented last fall at a virtual ESMO ACR plenary session in which I was one of two discussants, the other one Sanjay Popat from the Royal Marsden. And we strongly disagreed with the presenters that 960 was the correct dose. The progression free survival was identical for 240 and 960. The progression free survival was the primary endpoint in the phase 3 trial versus docetaxel. The treatment related adverse events, grade 3 or higher, was significantly increased with the higher dose. And so, we wrote an editorial. That was just published earlier this month about that paper basically saying 960 is the wrong dose, that FDA may think it's the right dose, but they're wrong. The European payers and regulators should do their own due diligence. And it shouldn't be covered at 960. That's what we published in this European journal. Well, about a week or so ago, FDA published their interpretation of the data. The lead author is Harpreet Singh, who is no longer at FDA.
[00:22:07] John Marshall, MD: Right.
[00:22:07] Mark J. Ratain, MD: She left for industry. And basically, in the paper,
[00:22:13] John Marshall, MD: She's quite a social media person too, by the way.
[00:23:16] Mark J. Ratain, MD: Well, in that paper they basically don't even mention the progression free survival. That's all. Okay, they say the overall survival was longer with the higher dose, but overall survival is meaningless if there's no improvement in progression free survival, because that's only survival after you stop the drug, that's not an effect of the drug. There's no mention of the clinical pharmacology data. And there is mention of the colorectal cancer data saying, oh, well, 960 was better than 240 in colorectal cancer. They actually tabulated data for colorectal cancer in combination with panitumumab in support of a dosing decision for 960 in lung cancer, not mentioning the fact that in the New England Journal paper, reporting the colorectal study, the pharmacokinetic results for 960 and 240 were indistinguishable. In other words, 960 can't be better than 240 because you don't get more absorbed, and any differences are due to chance, not due to drug.
[00:23:30] John Marshall, MD: You know, this isn't really that new of a story. The battle that's made me think about this topic is the dosing of capecitabine. I mean, you'll remember back a thousand years ago when we did dose finding studies for capecitabine, that low dose continuous actually was either equal or superior to the two-week-on-one-week-off higher dose, but Roche picked that dose. I always joked, even back then, because it would sell more pills. In the end, they would sell more pills, and dose intensity was still believed to be true back then. And getting folks to get away from those doses, to a more sort of, you know, prolonged and better tolerated dose has been a real struggle for me even to this day.
The newer colorectal cancer drugs, the same issue is there, whether it's regorafenib, or fruquintinib, they all have the same issue of overdosing, if you will. And so, to kind of bring this full circle, I keep thinking about pills, numbers of pills, and pricing. You know, what's your take on this being sort of a business emphasis that, you know, they make a pill size, they get an MTD, they set a price based on that, and there is some objective to sell pills. What's your take?
[00:24:49] Mark J. Ratain, MD: They're going to set a price before approval, and then they'll price it in a way that matches, that's consistent with that. The problem Amgen had was at the time of approval, they had a single formulation, 120 milligrams, and therefore, if the dose got changed to 240 milligrams, they would take a 75 percent haircut. And so, they have steadfastly stuck to 960 milligrams. This got the attention of Senator Durbin. He sent a letter to Amgen in May of this year, basically saying you're putting profits over patients. Now, unfortunately, it looks like FDA actually is part of the problem here that they incorrectly have supported Amgen's, you know, assessment that 960 is superior dose. And basically, on the basis of this, in part, you know, due to these small studies and they say, well, we don't know that 240 is non-inferior to 960. Of course you don't. But that's not the question. The question is, is there any evidence of 960 is superior to 240? And if you don't get more drug absorbed, it can't possibly be superior. Unless, I mean, I'm interested to see FDA's model for how unabsorbed drug increases efficacy. In defense of the office of clinical pharmacology at FDA, they were excluded from authorship on the paper.
So, it excludes FDA experts, and FDA opinions, and the FDA review of that dose-finding study is not publicly available. And I don't know whether when it will be publicly available. I have a pending FOIA request for it. And I will be sure to make that public once I get a hold of it.
[00:26:59] John Marshall, MD: Yeah, let's sort of close on some advice and actually, I struggle with this myself. So, in my world of GI, I feel like I'm pretty good with the drugs I hand out. But you think about a general oncologist who's seeing these drugs, maybe once a year, maybe not even, and they are trying to figure out what the right dose is, and how best to take care of the patients in front of us. To my knowledge, there really isn't a, a great resource beyond what industry already provides us that would help coach us all on optimizing dose. Do you know of one and what's your advice to the oncologist out there with this stuff?
[00:27:41] Mark J. Ratain, MD: Well, we have a grant from Arnold Ventures. We've completed the analysis. We're building the website, and we'll have it. We've done it for all oral oncology drugs, all non-generic oral oncology drugs, and that will be available next year.
[00:27:59] John Marshall, MD: That's so cool. We're working on sort of a similar one where every drug, every gene, where we do a little short, you know, tick tock videos for our docs out there to say, what would you do, you know, in a patient with a certain medicine and the like? So, I'm glad to hear that you're doing that. Cause I do think we need that kind of resource and we'll be happy to help drive and, and, you know, get, get folks to use that. Because, honestly, in the end, what's going to have to happen is that consumer boots on the ground is going to have to recognize that, maximum tolerated dose isn't always the right answer. and in fact, it's increasingly less and less the right answer. And not only will that be a cost savings but a toxicity savings and maintenance of, of outcomes.
So, Dr. Mark Ratain, you're awesome as always and I know you will not let go of this flag and you'll continue to plant it further and further down the field to make sure that our patients get the best care they can in this cancer world we both live in. So, Mark, great seeing you and thank you for your time.
[00:29:00] Mark J. Ratain, MD: Thanks, John.
[00:29:02] John Marshall, MD: You know, the chance to get to talk to you guys through this vehicle is just really amazing and to get to really share the thoughts that I'm hearing, that I've experienced myself, with you in a sort of an unscripted process.
I hope that as we end out this year, as we transition leadership in this country, that we are all okay, that we will make it, that we will continue to do a fabulous job in doing what we do to try and cure cancer and take care of patients, but also make sure that every day we try to wake up and say, how am I going to make the world today a little better?
So, I hope this time with me may help you see some way in your own head of how you too could make the world a better place. Until next time, John Marshall for Oncology Unscripted.
Oncology Unscripted With John Marshall: Episode 9: Are You Overdosing Your Patients?
Monopoly Concerns with Oncology Acquisitions: Should We Be Worried
[00:00:05] John Marshall, MD: John Marshall, MD: Hey, everybody, John Marshall with Oncology Unscripted, even though I've got a little bit of a script right here, but don't tell anybody. Today, we're going to talk all about dosing of medicine, and do we have it right or not, particularly with some of our newer cancer medicines. And I'm going to really drill down on a couple that I know a lot about that I hope you will use in your own practice, quite honestly, and make your life a little easier, and, more importantly, your patient's life a little easier.
[00:00:34] Let's look a little bit at the business side of what's going on. You know, I've been kind of watching this big takeover of McKesson and Florida Cancer Specialists. Well, wouldn't you know what? There's in fact, of course, been some Federal Trade Commission pushback that this creates sort of, how could it not be a monopoly, when you've got everything from insurance to providers to drug people and everybody in the same game. It ends up becoming a monopoly out there. And, you know, I think it's right that we look at this because, you know, we do predict that there's going to be just, you know, just a few huge health care systems out there in our country. And we need to figure out how best to manage all of that to continue to provide the best care we can, for all of our patients and give access to everybody that we can get access to. So. Important stuff going on out there still, of course, in our business world.
Science Snapshot [00:01:34]
From a science perspective, I just came across, really yesterday, in the New England Journal, an article that that piqued my interest. Because it only went very nicely with the theme of our episode today, but around dosing, but really value in terms of what's it worth to get a little bit more survival.
And this was a study as a metastatic lung cancer study in the New England Journal of Medicine. I've got an actual copy of it. Right there. There it is. And this is by Cho et al. It's a very important study. It's the MARIPOSA study. You all know about it. It's amivantamab, there you go, plus lazertinib, which is, I guess, like Lazarus from the New Testament, maybe, maybe not. But this is in patients with EGFR-mutated non-small cell lung cancer, and, of course, the current standard of care is osimertinib. A relatively easy medicine to take has some side effects. The doublet wins in the end of the day, by a small amount, and that's with both PFS and trending towards OS. But I went to the toxicity table because do we have the doses of these medicines correct? And so maybe that's reflected in tox, and I'll come back to this in a little bit, but you know, there's not equal toxicity at all. In fact, the doublet therapy has essentially double the amount of grade three toxicity, and the investigators are fairly bold in saying, however, the incidents of grade four, which is almost dead, and five, dead, or discontinued treatment, were similar between the two groups. So now we've elevated it. Don't pay attention to grade three toxicity, we know that's going to be different here, let's look at dead and almost dead grade four and five and see if that's different. And it really struck me when I looked at the deltas on the advantages, the clinical outcomes, and the deltas on the toxicity that, is this really worth it? Should this become a new standard of care? New England Journal usually doesn't print things that it doesn't think are at least at risk for being the new standard of care. So, those folks out there who take care of lung cancer are going to have to figure out if this really reflects a new change and is that worth it.
Are You Overdosing Your Patients? [00:04:08]
And really why I picked that paper, it's important, but, to me, it's all about dose. And I think we are overdosing people. I am old enough to remember that when chemotherapy was the thing that we needed to get to what we call the maximum tolerated dose. And this was how much could you give you all know what this means. How much could you give without bumping the patient off, because the principle was that more was better.
I want to reflect on this a little bit because we learned pretty clearly in some cancers, that was true, germ cell cancer, some leukemias, maybe adjuvant breast cancer, but that dose intensity mattered in those diseases. But let's look at adjuvant breast cancer, because when I was a junior faculty member here, we were doing bone marrow transplants in the adjuvant setting for stage two and three breast cancers. So, we were doing marrow ablative, myeloablative therapies because more was better. And if you know that story, you know that the people who were leading some of those papers out of South Africa ended up committing fraud. Their results were fraudulent, and many, many women were exposed to bone marrow transplants because of their data suggesting it might be helpful, when in fact it was not. So, more was not better in that scenario.
And the other place that I was living at the time, again, 20, 30 years ago, was the advent of capecitabine. Simple drug. You use it a lot in your practice, I am sure, but what dose and schedule do you use? Do you remember, were you around when the actual dose studies were done? Back in the day, we would not only do something called maximum tolerated dose, we would then have a supplemental study of recommended phase two dosing. And very often that meant a randomized clinical trial of different doses and schedules of the medicine looking for both toxicity and efficacy to see which one works the best. Yep, they did that with capecitabine back in the day. And they looked at continuous dosing, right? Just giving it continuously at a certain dose. They looked at 2 weeks on 1 week off with leucovorin. Two weeks on, one week off, without leucovorin. Those two doses were a little different. And guess what? All three had exactly the same outcome in terms of response rate and progression free survival. All of that, exactly the same. The continuous dosing had the lowest toxicity. But guess what? We picked the one that used the most capecitabine pills. Not leucovorin, you could use fewer pills if you threw a little leucovorin in, but this was just capecitabine at what we now know as its dose, two weeks on, one week off. That sold the most pills, not because of benefit, but because dose intensity at the time mattered. And we are still clinging on to that dose and schedule. Many, many people are, whether it's a XELOX regimen or just capecitabine or maintenance capecitabine, but it's not correct.
How Does Dr Marshall Dose Capecitabine? [00:07:34]
The correct way to give capecitabine by John Marshall. Fixed dosing, never use the small pills, only use 500 milligram pills, size up your patient. Do an estimate of creatinine, clearance, because this is a renally cleared drug. Most patients I start at 1500 milligrams, three pills in the morning, after breakfast, 1500 after dinner. Monday through Friday, because you know what if radiation doesn't work on the weekend neither does chemotherapy, every week. Okay, so if you're a two-week one-week offer, you're giving it 14 days every three weeks. My way, I'm actually giving it 15 days every three weeks. And because you give that little weekend off, the hand foot syndrome is less, it doesn't build up nearly as much. Are you given the right dose? If somebody comes back in within a month or two and starts to have some hand foot syndrome, if it's mild, you're probably at the right dose. If there's no toxicity, you think about increasing it. If there's a lot of toxicity, you need to decrease it. We all are pretty clear on that. Some of us like to decrease it by pill count and keep the continuous dosing. Others like to do one week on, one week off as a modification. One little trick to know that you're giving the right amount, check your patient's MCV. If they've been on capecitabine for, I don't know, a couple months, you'll notice that MCV will be going up because that's the antifolate effect that you're seeing. You got your own little built-in micro-biomarker in your CBC of every patient that you're giving capecitabine. So, I'm telling you, switch out to this dosing and you can give your ox every two weeks or every three weeks. I'll leave that up to you. That's another matter altogether.
Consider Dose-Escalating Regorafenib [00:09:21]
Tony Saab taught us how to use regorafenib, Stivarga. Because we knew that if we gave full doses, 160 milligrams daily, it was too much, too spicy. Lots of patients said, forget it. I'm not taking that drug ever again. Tony showed that if you started lower at 80 and then inched it up, and then inched it up, you did a lot better
Should We Rethink TKI and Immunotherapy Dosing? [00:09:34]
Now, what's the right dose of a tyrosine kinase inhibitor? The studies are done with maximum tolerated dose. Give as much as you can give. More is better. Use that in the clinical trial. But more and more, we are seeing that you don't need to give that much. But are we comfortable in dose-reducing? Are we okay with saying, all right, I'll just cut the dose back because Marshall said it's okay. No, we're not. Because we don't want to regret that it was our dose that maybe it didn't work. So, we're feeling compelled to give the dose. Even the insurance companies are mandating that we give the dose that is in the package insert. When, for a lot, maybe most, of these TKIs, we don't need to give nearly that much.
I believe the same is true for immunotherapy. Because let's face it those patients whom we stop for IO toxicities, you know, they seem to be doing okay. So maybe we don't need to do nearly the duration or as often. If the way the drugs work is the way they say they work, then you wouldn't need to have it continuously exposed all the time to patients. So, we're probably overdosing TKIs all the time, and we're probably overdosing immunotherapy.
What Schedule Does Dr Marshall Use for Trifluridine/Tipiracil? [00:10:56]
Another colon cancer drug that I think is important to understand is Lonsurf dosing, trifluridine/tipiracil. What a crazy regimen that was. So, five days on, two days off, five days on, two weeks off. It takes forever just to coach the patient on what to take, and there are two pill sizes and all of that, and myelosuppression is the big side effect of that regimen. We just looked at that and said, that's crazy, just give it every other week. So we still stick with our Monday through Friday because it's easier for patients to remember. And instead of two weeks in a row, we give it every other week. And believe it or not, that is essentially solved a lot of the cumulative suppression, myelosuppression, the nausea, all of that stuff that you see with that drug by getting away from the package insert. dose reducing, maybe a little using only one pill size, again, to get your optimum dose and schedule.
So, we need to understand better how to dose these medicines. The problem is, we don't use them that often, many of them, so we're dependent upon looking stuff up, and what the package insert, and what the insurance company, what the guidelines say. We all don't have a person who's an expert on speed dial that you can say, well, what would you do if you were giving this patient this treatment? So, we clearly need an improved resource for all of us to understand what the correct dose is that we need to use day in and day out to optimize our patients, both benefit but also toxicity, so that we know that we are doing the best job possible.
Up Next: A Candid Conversation with Dr Mark Ratain on Drug Dosing [00:12:36]
And, so, to that end, I have invited not only a lifelong, career long friend and mentor, but really what I think is maybe the world's expert in this space. And that's Dr Mark Ratain from the University of Chicago. He cares passionately about this and is actually doing something about it. So, listen to this interview with Mark Ratain, MD.
Dose Matters with Dr Mark Ratain
[00:12:58] John Marshall, MD: I only get the best people to interview for every major topic, and I am lucky enough to have known the gentleman next to me right now for almost all of my career. Dr Mark Ratain at the University of Chicago has been one of the world's leaders in not only drug development, but really the pharmacology of novel chemotherapy, novel biologics, etc., of really optimizing dose, schedule, efficacy. He's the real guru of this, and, honestly, is one of the few, let me put it this way, anchors or rudders in our overall cancer development pathway and system that's really keeping us honest about what we're doing. And it's not an easy position for him to take, but he continues to work on this, and I think has had a major influence on many, many cancer patients, and our practice over his great career.
[00:13:58] So, Mark, first, thank you very much for joining and talking about this important topic of dosing treatment. Mark J. Ratain, MD: Thank you, John, for having me.
[00:14:07] John Marshall, MD: So, let, let's just dive in. You and I are old salts. We've been doing drug development a long time. We used to have these great, you know, dose finding trials where we compare different doses that seems to have fallen off by the wayside. So, we have a sort of maximum tolerated dose for everything that gets approved out there. We all recognize as clinicians, it's too spicy, but we also don't wanna cut doses back because we don't want to shortchange patients. So, tell us a little bit about where this is, why that evolved, and maybe some of the newer projects that are going on in that space.
[00:14:41] Mark J. Ratain, MD: Well, it evolved because in the old days of, the start of chemotherapy, we didn't have effective drugs. We were treating diseases like leukemia and Hodgkin's disease and with drugs for which more is better. And so, we did the right thing. But as we began using chemotherapy for less sensitive diseases and with drugs that were less effective, like using 5-FU for colorectal cancer, more is not necessarily better. And yet we stayed with the more is better paradigm for decades and then even worse, when we developed better drugs, including, you know, targeted monoclonal antibodies, tyrosine kinase inhibitors, we kept the same paradigm, despite the lack of scientific justification.
[00:15:35] John Marshall, MD: You think you have a good reason of why we didn't sort of rethink this? Were we afraid that we might lose benefit and patients with cancer?
[00:15:45] Mark J. Ratain, MD: No, I think it's because, the way we've been doing it was quick and dirty from the standpoint of a company developing a drug. It's very quick to determine the maximally tolerated dose. That's an easy study to do. You don't need to be smart. You just need to push and push and push until the patient can't take it anymore. And so, you treat a bunch of patients, and you say, oh, we found our dose. And so that was quick.
[00:16:15] John Marshall, MD: Well, and I also think along with that, I keep thinking every time I see a new presentation of a novel therapy or a clinical trial, they pop that tox table up in front of us. And we've learned to just accept a fairly high burden of grade three toxicities, or a lot of patients getting grade one, two toxicities without really challenging the dose in that. So, we're co-conspirators, in some way, on this of accepting these doses and toxicities.
[00:16:42] Mark J. Ratain, MD: Well, not only that, we've trained patients to expect these toxicities.
[00:16:47] John Marshall, MD: If you don't get sick, it won't work. Right?
[00:16:49] Mark J. Ratain, MD: And, in fact, oncologists say, well, that's what we do. We manage side effects of drugs. Like if we didn't manage side effects what would we really do here? And so, no, it is, is part of the culture of both being an oncologist and being a cancer patient.
And you hear people say, well, cancer is such a bad disease, you've got to push the dose, you've got to accept side effects. Well, in the greatest medical crisis of our lifetime, COVID, I don't recall a single drug development program in which any sponsor said we've got to push the dose. The remdesivir development, which was the first drug approved, did a careful, dose optimization study. The logic is completely flawed, it’s just part of the culture of oncology, and that culture, quite frankly, has harmed patients.
[00:17:49] John Marshall, MD: Totally agree. And you've been really helping to lead this, you know, carry this flag for us and point this out so that we can be better physicians, better, better providers, better outcomes even. And I know you'd had some discussions with one of your faculty colleagues and also FDA lead Rick Pazdur around this Project Optimus. Tell us a little bit about that encounter.
[0018:11] Mark J. Ratain, MD: These discussions have been going on for many years, but the most recent major interaction was in the fall of 2020 during the pandemic when the University of Chicago Comprehensive Cancer Center gave Rick Pazdur our annual award, and he virtually visited us. And as part of that virtual visit, we had a group discussion, a group Zoom, involving our cancer center leadership and his center leadership at FDA. And during that I said, Rick, I don't know why you don't make companies optimize the dose before approval. And he said, Mark, you're right we're going to make them do that. And about 6 months later, he announced Project Optimus. That in many ways might be the history. I don't know what other discussions were ongoing at FDA prior to that meeting, but some of my FDA friends say that was a major moment for the FDA oncology leadership, that discussion that day.
[00:19:18] John Marshall, MD: Well, take that to the next step. has that been applied anywhere? Where, where are we going with that kind of thinking?
[00:19:24] Mark J. Ratain, MD: Well, the first thing that happened was when, FDA approved sotorasib In May of 2021 at a dose of 960 milligrams, they basically said in the review, we're pretty sure 960 milligrams is the wrong dose. There's no relationship between dose and response. There's no relationship even between dose and plasma concentration because the drug's not absorbed very well. but the only dose of which. There was sufficient data to evaluate, efficacy was 960 mg, so we'll approve the drug, but require the sponsor Amgen to conduct a post marketing trial, 960 mg versus 240 mg.
[00:20:10] John Marshall, MD: But let me interrupt right there real quick. So, if I go on right now as an oncologist and I've got a patient who's been maybe a candidate for sotorasib and I look online, 960 is what pops up on their official website and everything, and that's what that insurance provider is looking to provide. That's what the pharmacy we riffed on PBMs earlier, that's what they're expecting to provide. There's a business around this too. But, anyway, there's a study looking at two different doses,
[00:20:39] Mark J. Ratain, MD: So that study was completed, and that study was published recently in the European Journal of Cancer. And that study was presented last fall at a virtual ESMO ACR plenary session in which I was one of two discussants, the other one Sanjay Popat from the Royal Marsden. And we strongly disagreed with the presenters that 960 was the correct dose. The progression free survival was identical for 240 and 960. The progression free survival was the primary endpoint in the phase 3 trial versus docetaxel. The treatment related adverse events, grade 3 or higher, was significantly increased with the higher dose. And so, we wrote an editorial. That was just published earlier this month about that paper basically saying 960 is the wrong dose, that FDA may think it's the right dose, but they're wrong. The European payers and regulators should do their own due diligence. And it shouldn't be covered at 960. That's what we published in this European journal. Well, about a week or so ago, FDA published their interpretation of the data. The lead author is Harpreet Singh, who is no longer at FDA.
[00:22:07] John Marshall, MD: Right.
[00:22:07] Mark J. Ratain, MD: She left for industry. And basically, in the paper,
[00:22:13] John Marshall, MD: She's quite a social media person too, by the way.
[00:23:16] Mark J. Ratain, MD: Well, in that paper they basically don't even mention the progression free survival. That's all. Okay, they say the overall survival was longer with the higher dose, but overall survival is meaningless if there's no improvement in progression free survival, because that's only survival after you stop the drug, that's not an effect of the drug. There's no mention of the clinical pharmacology data. And there is mention of the colorectal cancer data saying, oh, well, 960 was better than 240 in colorectal cancer. They actually tabulated data for colorectal cancer in combination with panitumumab in support of a dosing decision for 960 in lung cancer, not mentioning the fact that in the New England Journal paper, reporting the colorectal study, the pharmacokinetic results for 960 and 240 were indistinguishable. In other words, 960 can't be better than 240 because you don't get more absorbed, and any differences are due to chance, not due to drug.
[00:23:30] John Marshall, MD: You know, this isn't really that new of a story. The battle that's made me think about this topic is the dosing of capecitabine. I mean, you'll remember back a thousand years ago when we did dose finding studies for capecitabine, that low dose continuous actually was either equal or superior to the two-week-on-one-week-off higher dose, but Roche picked that dose. I always joked, even back then, because it would sell more pills. In the end, they would sell more pills, and dose intensity was still believed to be true back then. And getting folks to get away from those doses, to a more sort of, you know, prolonged and better tolerated dose has been a real struggle for me even to this day.
The newer colorectal cancer drugs, the same issue is there, whether it's regorafenib, or fruquintinib, they all have the same issue of overdosing, if you will. And so, to kind of bring this full circle, I keep thinking about pills, numbers of pills, and pricing. You know, what's your take on this being sort of a business emphasis that, you know, they make a pill size, they get an MTD, they set a price based on that, and there is some objective to sell pills. What's your take?
[00:24:49] Mark J. Ratain, MD: They're going to set a price before approval, and then they'll price it in a way that matches, that's consistent with that. The problem Amgen had was at the time of approval, they had a single formulation, 120 milligrams, and therefore, if the dose got changed to 240 milligrams, they would take a 75 percent haircut. And so, they have steadfastly stuck to 960 milligrams. This got the attention of Senator Durbin. He sent a letter to Amgen in May of this year, basically saying you're putting profits over patients. Now, unfortunately, it looks like FDA actually is part of the problem here that they incorrectly have supported Amgen's, you know, assessment that 960 is superior dose. And basically, on the basis of this, in part, you know, due to these small studies and they say, well, we don't know that 240 is non-inferior to 960. Of course you don't. But that's not the question. The question is, is there any evidence of 960 is superior to 240? And if you don't get more drug absorbed, it can't possibly be superior. Unless, I mean, I'm interested to see FDA's model for how unabsorbed drug increases efficacy. In defense of the office of clinical pharmacology at FDA, they were excluded from authorship on the paper.
So, it excludes FDA experts, and FDA opinions, and the FDA review of that dose-finding study is not publicly available. And I don't know whether when it will be publicly available. I have a pending FOIA request for it. And I will be sure to make that public once I get a hold of it.
[00:26:59] John Marshall, MD: Yeah, let's sort of close on some advice and actually, I struggle with this myself. So, in my world of GI, I feel like I'm pretty good with the drugs I hand out. But you think about a general oncologist who's seeing these drugs, maybe once a year, maybe not even, and they are trying to figure out what the right dose is, and how best to take care of the patients in front of us. To my knowledge, there really isn't a, a great resource beyond what industry already provides us that would help coach us all on optimizing dose. Do you know of one and what's your advice to the oncologist out there with this stuff?
[00:27:41] Mark J. Ratain, MD: Well, we have a grant from Arnold Ventures. We've completed the analysis. We're building the website, and we'll have it. We've done it for all oral oncology drugs, all non-generic oral oncology drugs, and that will be available next year.
[00:27:59] John Marshall, MD: That's so cool. We're working on sort of a similar one where every drug, every gene, where we do a little short, you know, tick tock videos for our docs out there to say, what would you do, you know, in a patient with a certain medicine and the like? So, I'm glad to hear that you're doing that. Cause I do think we need that kind of resource and we'll be happy to help drive and, and, you know, get, get folks to use that. Because, honestly, in the end, what's going to have to happen is that consumer boots on the ground is going to have to recognize that, maximum tolerated dose isn't always the right answer. and in fact, it's increasingly less and less the right answer. And not only will that be a cost savings but a toxicity savings and maintenance of, of outcomes.
So, Dr. Mark Ratain, you're awesome as always and I know you will not let go of this flag and you'll continue to plant it further and further down the field to make sure that our patients get the best care they can in this cancer world we both live in. So, Mark, great seeing you and thank you for your time.
[00:29:00] Mark J. Ratain, MD: Thanks, John.
[00:29:02] John Marshall, MD: You know, the chance to get to talk to you guys through this vehicle is just really amazing and to get to really share the thoughts that I'm hearing, that I've experienced myself, with you in a sort of an unscripted process.
I hope that as we end out this year, as we transition leadership in this country, that we are all okay, that we will make it, that we will continue to do a fabulous job in doing what we do to try and cure cancer and take care of patients, but also make sure that every day we try to wake up and say, how am I going to make the world today a little better?
So, I hope this time with me may help you see some way in your own head of how you too could make the world a better place. Until next time, John Marshall for Oncology Unscripted.