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Dose Matters with Dr Mark Ratain
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Released: November 13, 2024

John Marshall
John Marshall, MD
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Dose Matters with Dr Mark Ratain

[00:00:05] 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.

[00:01:04] Mark J. Ratain, MD: So, Mark, first, thank you very much for joining and talking about this important topic of dosing treatment. Thank you, John, for having me.

[00:01:14] 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.

[00:01:41] 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.

[00:01:49] 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.

[00:02:43] 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?

[00:02:52] 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.

[00:03:22] 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.

[00:03:49] Mark J. Ratain, MD: Well, not only that, we've trained patients to expect these toxicities.

[00:03:54] John Marshall, MD: If you don't get sick, it won't work. Right?

[00:03:56] 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.

[00:04:54] 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.

[00:05:15] Tell us a little bit about that encounter.

[00:05:18] 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.

[00:06:25] 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?

[00:06:31] 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.

[00:07:17] 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,

[00:07:45] 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.

[00:09:15] John Marshall, MD: Right.

[00:09:15] Mark J. Ratain, MD: She left for industry. And basically, in the paper,

[00:09:20] John Marshall, MD: She's quite a social media person too, by the way.

[00:09:23] 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.

[00:10:23] 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?

[00:11:56] 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.

[00:14:07] 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?

[00:14:48] 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.

[00:15:06] 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.

[00:16:08] Mark J. Ratain, MD: Thanks, John.

[00:16:10] 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.

[00:16:57] 

Learn more by watching:
MedBuzz: Monopoly Concerns with Oncology Acquisitions: Should We Be Worried? 

Oncology Unscripted: Are You Overdosing Your Patients?

This transcript has been lightly edited for clarity.