Oncology Unscripted With John Marshall

[00:00:05] John Marshall, MD

Hello, everybody. John Marshall from Oncology Unscripted. Do you know where I was this past weekend? I was in San Francisco. It's actually pretty nice weather there in San Francisco. I go pretty much every year. In fact, I have gone to every GI ASCO. 

Skipping This Test in Frontline Metastatic Colon Cancer? That’s Malpractice.

[00:00:24] It's really usually my first business trip of the year. Usually, the weather out in San Francisco is kind of rainy and gloomy in the fifties, but it was pretty sunny compared to here out east where it was cold and snowy. So it was kind of good to get away, but that's not really why I go. It's also not a meeting you go to learn a lot of new science. That's usually ASCO and ESMO and other places. Occasionally there's some data, and I'll talk about some of that in just a minute. The reason most of us go to GI ASCO, and I with my perfect attendance at GI ASCO, is to see the people. The GI cancer community is very, very close. Some of us argue that that may be why we haven't made more success, but we are a very, very close community. And this gives us an opportunity to get together, share meals, share ideas, compare notes, and become better at what we do through our camaraderie and our collaboration. 

But I do want to make sure and give you the highlights of what happened at GI ASCO. Now the first, and this has really been true for many, many years there is I've been very discouraged, as you know, in the progress that we're making in GI cancers. For example, colon cancer, I have been giving essentially the same adjuvant therapy for colon cancer for 20 years. There is no other cancer where we have failed to make some advances in adjuvant therapy over the last two decades. Essentially, until a paper that was presented in San Francisco, I had been giving the same frontline treatment for metastatic colon cancer until now. Yes, we had MSI, but that's kind of its own different disease. But now what we have is a 9 percent wedge of colon cancer that has BRAF V600E mutations. I remember, because I'm this old, when it used to be bad to be HER2-positive for breast cancer. Now, you want to be HER2-positive for breast cancer because we know how to control that pathway, right? It's a good thing when you're HER2-positive. 

BRAF, for a long, long time, was just bad news. We had nothing we could do for it, and it was just a bad prognostic marker. So why would you care about knowing? Now you have to know because now we have frontline therapy, proven combination BRAF, EGFR therapy with chemo, big increase in response rate, big increase in Overall survival, new FDA approval that you have to know about for BRAF patients. So no longer can you wait till later to do your RAS and BRAF testing in colon. You have to, or it is malpractice if you don't- yes, sir, yes, ma'am. You need to do it frontline so you can incorporate your frontline treatment of your patients because now that BRAF has some drugs to target to it, we can, in fact, improve the outcome for those patients. So, for me, that was the biggest data set that was out there. 

Let me share two other high-level observations. And that is one that we were part of, but others have also shown a similar data set, is that does specialized care is only seeing GI and not knowing anything about breast cancer and lung cancer, et cetera. Does that make me a better doctor? Does it make our team have a better product than if you're a general practitioner who's having to see all of the new treatments and understand all of the nuances all at once? And there's a couple of different beliefs in this. One is that as long as you're practicing the guidelines, as long as you're following the rule book, you in fact do just as well as those who are writing the guidelines and writing the rule book. But some new data we presented and others also presented there suggested that if you are a specialist, things like proper molecular profiling, time to treatment, those kinds of things, can overcome even social determinants of health, which, by the way, with our new administration, there are no imbalances in social determinants of health. That's all gone. it's just wiped away. But those of us who know they still exist; specialization might allow you to prioritize that. So then the question becomes, how do we connect our specialists, those who live one disease day in and day out, to our community docs who are doing most of the work of treating most of our patients in this country and doing a fabulous job. How do we help them? How do we help them to do even better out there with making sure our patients get the best care? And that's our next step of going forward. And that was a theme that came out of the ASCO GI meeting. 

But the last piece I want to really emphasize, and this is again back to that frustration of lack of success. Is that there are a lot of new drugs coming for GI cancers. One is that there are some very successful RAS targeted agents that are on the way, with very good response rates in pancreas cancer, colon cancer, and other diseases. The problem this has created is that patients know about them, doctors know about them, but there aren't enough slots for all the patients that are out there. So, I was actually engaged in a bunch of discussions with folks about how do we as a cancer community get access to these agents before their eventual FDA approval that doesn't hurt their eventual FDA approval. Essentially that phase four kinds of study, but before so it doesn't spend all the money of the company doesn't hurt their ultimate package. And this is a really important issue. If you thought about it, it would be true with immunotherapy before. But now with the RAS targeting agents, there's more of it there. But it's not just that there are a lot of people nibbling at the edges of different signaling pathways, improved immunotherapy outcomes, in microsatellite stable GI cancer. So, this is going to get better and it's going to get better fast if we can keep the machine going.

NCI Silenced, Grants Frozen—What This Means for Cancer Care

[00:06:43] And what we really talked about at GI ASCO was the new administration. On Wednesday, the meeting started on Thursday, a good friend of ours, was on a review committee. He's on a normal NCI grant review committee. And during the Zoom, 20 minutes into this review, they'd all done their work. They were presenting their grades, if you will. somebody interrupted the meeting from the grants group and said, this meeting's over. There are no more grant reviews going to happen because of the freeze that a certain president put in place. So, they stopped. Think about if you're a researcher or what not, that grant renewal, that grant application is your career, it's your salary, it's everything, right? And you've spent your whole life to try and achieve that, and now you are uncertain whether it's going to happen at all. so, this was just devastating.

Then I ran into somebody at the airport, a very good friend in the airport, she was saying that their institution interpreted the freeze as there would be no more indirect. So, you know, you get a grant for 100 grand, you get some extra percentage to keep the lights on and the heat on and running water so that you can actually do the science. And that's always the way it's been. But there was some suggestion based on their interpretation that the indirects were going to go away, right? All of that. 

Then we got to the meeting, landed, had the airport discussion. We're all anxious. We get to the meeting, and I ran into one of my NCI friends, and the only reason he was there was that he left on Wednesday, because if he had left on Thursday, he would have been shut down, not able to travel, So there was no NCI representation at GI ASCO, and they do a lot of great science there, right? And they were shut down and said, You can't come at all. And in fact, you can't communicate with anybody. You can't share information. You can't put out your bulletins or the information that is your job basically to do. And that person had to go back. They couldn't even stay at the meeting because they only were there for the day. And then they had to go back because of the freeze. Right? 

So, this has created this wave of uncertainty, fear of panic among many of us out there. So, is there going to be ongoing research funding for us in the cancer world? At a time when we've never known more! At the time we were about to cure this set of diseases, we run into this administration that doesn't believe that science is real or that progress is something that we can have. But it does cost money, but they don't want to spend it on us. 

Then think about the DEI piece of all of this. Every NCI designated comprehensive cancer center is required currently to have a DEI section in it and everybody's like I talked to actually a few cancer center directors in the last week. They're all saying that's gone. They're just going to take that out and we'll just don't worry. We'll keep doing it. We'll fold it into other things. Yeah, right. You know, there are people who are hired at cancer centers in order to meet that grant requirement in order to play out what we need in terms of DEI support for folks out there. 

If you offer institution, any sort of gender affirming care. Right. What touch words those are gender affirming care. Then we're going to cut you off. We're not going to give you any support, which would go to education, medical school, research, other things, right? Progress and science. So, if you do that, you're no longer eligible for this. And so, you talk about dictating and governing. And it's not just gender affirming grants, it's all grants that go to your institution, right? And we all know that the government helps support. 

Now, where's that money come from, from the government? Guess what? It comes from us. I just got my tax form for last year. Just paid the government a whole lot of money to spend. I'm thinking it is on our behalf, right? Not on certain people's behalf, on all of our behalf. So indeed, we have to make sure that everyone knows how disruptive it will be. 

Now, another piece is that communications have been cut off. So you believe what you see on your feed, right? You do from certain sources. You don't from others. Sometimes you're not sure. Well, if communications out of the NCI and the government are cut off, then you have the right not only to invade the Capitol. It's a new right that you have, apparently, but you have the right to die of bird flu. That's a new right you have. And of course, you have the right to die from cancer because we're not going to communicate any new data about cancer and the cures for it. So, let's face it, this was disruptive.

The last story I want to tell you Is this came from my daughter. My daughter is in school becoming a social worker and a minister, and she spends after school time with preteens and kids helping to mentor, helping to guide. And of course, when this all came out, around immigration, these children at school were given a pamphlet on what happens if ICE comes to your door. You all have kids out there. What if your kids came home with a pamphlet that says what are you going to do if ICE comes and knocks at your door? I just want us all to think about that a little bit, what we have done in just one week.

Now, it is the next Wednesday after GI ASCO. This will air a little later. So, who knows what will have happened by the time this airs. But just today I saw on the Washington Post, also owned by a billionaire who was on the podium during the inauguration, so you got to wonder in the Washington Post, it's been rescinded. For all the confusion it has caused. it's confusing because they didn't know what they were doing. They just think all of this is the right thing to do. 

So they're just blowing up stuff and then figuring it out later. we're uncertain here. We are trying to keep our heads down. We are trying to take care of the patients. I'm on service right now. So I'm trying to make sure we manage keeping our eye on the ball of taking care of people who need us in the medical translational research community. but it is very hard not to be distracted by what our world is becoming, what's happening to it, how it's being nibbled around the edges and how it's being exploded only to say, Oh, no. We were kidding. We didn't really mean it, but we could mean it in the future. 

I don't know what to tell you. But I encourage all of you who out there are listening is to throw some comments in shoot me a note, put it in the chat, if you will, but let's get this conversation going and get it noisy so that those people not too far from here on the other end of Pennsylvania Avenue for me, hear it loud and clear and understand that their whims have major impact on our future. What is it to be a great nation? It is to take the success that you have and share it with others. That is really what we have lost. I think with this election is this concept of sharing it with others. It is what we do in the healthcare world. We take the gifts that we have we share them with others. I really hope that you have a chance to share your gifts with others. John Marshall for Oncology Unscripted. Until next time.   [00:14:39]

Why Dr. Marshall Needs a Hug—And Maybe You Do Too 

[00:14:39] You know, our world is getting turned upside down every day. There's a new pronouncement of what's going to be. I sort of am afraid to read the Washington Post every morning for every page. There is something else that I'm like, how could that be? And then you turn the page and like, how could that be? I have been thinking a lot, of course, as we all have about our lives and how they may be changing dramatically. Earlier this week, knowing that our team here at our cancer center is spending a lot of time, we're in Washington, thinking about the changes. We're thinking about the impact on research if they cap the indirects. We're thinking about how are we going to continue with NIH fellows who come here. For their training, if they shut down the NIH, etc. So, there are a lot of sort of scientific research questions. But then over the weekend, what really started to strike me is what's happening to our patients during all of this. You know, they come here for security, for care, for answers in what may be one of the most difficult times of their lives as they face cancers or hematologic problems, they're coming here for us to provide that. And that is what we and our whole team are called to do is embrace that patient in front of us and care for them and try to deliver the best message. But we know that on both sides of that exam room, there's a lot more anxiety underneath all of this, right? We as providers, the back of our heads are like, what's tomorrow going to hold? How am I going to hold up myself when all of this is going on? But at the same time, you have to be outwardly for that person in front of you and focused on the medical issues for the person in front of us.

Let's face it. Our jobs are hard already. Right? To get up and do what we do every day, year after year. But now you put this added burden on us, it makes it even that much harder. Think about who's on the other side of that room. What are they going through as they're confronting life threatening illnesses and side effects of treatment and all the different things that go with that. And they too are dealing with all of this unsettledness that's out there in the world. And so, I'm not sure I have any answers, but I did ask my team um, and I told them, uh, Officially that if they saw me and looked at me and said that guy needs a hug that I would welcome that hug, and vice versa. We need to take care of each other because our job is to also take care of those in front of us. So, what I've encouraged our team here. What I encourage your team there to do is huddle up. Make sure that you are talking and caring with each other so that we can do what is our most important job and that is caring for the person across from us, who knows what next week holds, who knows how unsettled our world will be, but stay tuned because we're going to review it right here.

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The Economics of Cancer Care: Who Pays for Progress? 

John Marshall, MD: What do you guys think? What do you think I'm looking like today here in Washington D.C. In January 2025? Well, What I'm trying to look like is the new administration, which is moving in just down the street from me there. 

There is an unfortunate casket, a hundred-year-old man inside, draped in the American flag. What I think of as a sort of heroic politician. And in a couple of weeks, we're going to have a parade here for next wave of politicians. So, we're all getting ready here in Washington, D.C. For the 2025 ahead. I hope you are out there as well. 

Welcome back to Oncology Unscripted. My name is John Marshall shooting to you live from Georgetown University here in Washington, D.C. 

And as you know, those of you who are following this, we have been trying to drill down on a government thing called the Inflation Reduction Act, and we've had a couple of episodes on that already and interviewed some important smart people in the space, and we've got another important smart person coming to you in this episode, as well. But I want to talk a little bit more about the specifics of how we got here and the problem at large.

So, let's just look at the cost of the product that we in oncology are putting out day in and day out. So, 95% of new cancer drugs in the US cost $100,000 per year, on average, more than that. And the median annual cost was almost $200,000 just for cancer drugs for one individual. And most of that's being driven by, of course, this new cooler stuff, the gene therapies and viral therapies leading the way. But very interestingly, based on an interesting paper, it didn't cost more if your therapy worked better or had some novel mechanism of action. That didn't matter. So, magnitude of benefit was not connected to cost. It's just going up and up and up. 

And, oh, by the way, if you ever watch television or have a phone or have an email, you know that all of these new medicines are being advertised no matter how esoteric the disease is, or the problem is. We have national campaigns, often in the middle of Jeopardy, which makes me think that Jeopardy viewers are having the most illnesses. I know I'm a big Jeopardy viewer. My wife was a Jeopardy champion a long time ago, so I never win at Jeopardy, but I do like watching. But these ads are running all the time. What do you think an ad on national television costs? And every time I see one of those, I'm thinking, well, how many new prescriptions do they have to fill an order to pay for that ad? Based on what I just told you, maybe only one, you know, if you get one new patient at those kinds of prices, maybe it pays for the ad itself. Now, you also know that there is a new group coming to town, and one of the members of this new group, we think, is going to be this guy named RFK Jr., who is compelled to make our nation healthier. So, the first thing he's going to do is get rid of all vaccines that that'll do the trick. But I don't know if you know this one of his big pet peeves is that he would like to get rid of ads. So quit spending all of that money. And by the way, they spend close to 30 billion in 2024 on ads. So, take that 30 billion and quit spending it in direct-to-consumer marketing.

This is what RFK Jr. wants. But he also wants equal pricing. You know we've talked about this before. You're already aware of it. We here in the United States pay more for all of our drugs than anyone else in the world. And sometimes that delta can be a huge difference. And the argument has been, well, we can afford it. And that reinvestment that delta that we're providing the world is going into reinvestment for new drug development. And that's really what the IRA, the Inflation Reduction Act is all about is to try and close that gap. And so, if you thought that might go away under the new administration, it's I think maybe the opposite. They may double down on it if RFK Jr. has his way by taking away ads and leveling the playing field for new payment. And of course, this has got everybody on their heels a bit because they don't know what budgets will look like if they don't have this margin from post marketing, if you will. So, it really put a big wrench in cancer drug development as we've talked about before.

[00:05:12]

MedBuzz: Is Divorce the New Trend in Oncology Partnerships?

Let’s look a little bit of how this is beginning to trickle down into our world of cancer research and cancer care. And I have a couple of sort of high-level things. You probably heard about both of them. One of them is a very, very famous scientist and clinician, Brian Druker, who is essentially He invented Gleevec, got it to come out to treat all the diseases that has been treated, been the head at Oregon for many, many years, a dynamic leader, fundraiser and everything else. Just a couple of weeks ago, on a dime, he resigned. 69 years of age, got plenty of life left in him, I hope. And he basically said, look, we're not aligned with healthcare systems and research. We don't know how the two are going to play together. I work at a big health care system here in the Baltimore, Washington area, and we're trying to maintain an NCI designated comprehensive cancer center inside of a big health care system that values productivity and margin and all of those things. And so, we've been lucky enough at our health care system to maintain that margin, right? But a lot of healthcare systems did not maintain. And so even though there's a big nest of philanthropy that the team there has, the job all of a sudden became too much for Brian. And he said, no, I'm not going to do it anymore. And he's going to go back to his lab and do something different, more focused. It was really rocking our world that news. 

I know you've heard about this, is there's trouble up there in Boston. If you remember, lots of the healthcare systems, Dana Farber, Mass General, and the Brigham were all working together. Well, they decided about a year ago to have a divorce. And so, they're splitting up as general and Dana Farber, but it's interesting because then all going to go partner with different folks. So, they're getting a divorce and then kind of remarrying, in new structure. And, and you know what, this was really a split over is that one of the institutions wanted their own cancer building in the hospital. Not like we have here at Georgetown, for example, where it's all over the place. They wanted their own freestanding building. A hard thing to do in the middle of a busy city. So, they got a divorce over what they thought should be the most appropriate cancer care out there. 

[00:07:38]

I want to just sort of close this discussion about us. talked about the health care system and the troubles it's having. We talked about the Inflation Reduction Act and the impact on pharma, legislation that may come forward about ads and all of that. So, we talked about that, but what about us, the health care consumer? And you know, it really starts with us here in the United States with this concept of insurance. Now, probably everybody listening out there has car insurance, you have house insurance. That model is you put in five bucks a month and if your house burns down, everybody chips in and builds you a new house. And that works because most people's houses don't burn down that often. You don't have too many car wrecks. So, the insurance model, shared risk, works in that setting. 

When health insurance first came along, it was, the only thing that was covered was sort of catastrophic health. You needed an operation. You were in a car wreck. You had something that required being in the hospital. Didn't happen all that often. We all chipped in. And you can pay your five bucks a month and that would cover it. it has evolved to managing hypertension, hypercholesterolemia, erectile dysfunction, and all the other things, you know, obesity, weight loss drugs, etc. All the other things that have become maintenance. We don't have mow-your-grass insurance, right? Where we all agree to chip in, unless you live in a big complex, you all agree to chip in to mow your grass. Then it's everybody's grass, right? So, in healthcare, we're all chipping in to pay for everybody's maintenance. So not catastrophic stuff, maintenance. But then with this health insurance model, we've been removed from the actual costs of what it is to get healthcare. It sometimes feels free. My Medicare-taking father at 90 years of age talks about, well, that won't cost me anything, but wait a second. Yes, it does. pay taxes, my salary here for my healthcare policy, I'm paying. Georgetown who pays the insurance company, right? And they're paying and they would have been paying me. So, what if I instead said, forget it. You're not getting health insurance through work. We'll just increase your salary by whatever you're paying. What we're paying now, you're on your own. To deal with health care costs. Let's go back to cancer drugs. It's $100,000 a year for a cancer drug, and that's a cheap one. If I gave you $10,000 back into your salary and said, okay, instead of health insurance, here's the cash, spend it as you would, you've got to imagine there'd be some competitive pricing. So, this whole price structure we live in in the United States As you know, is a false economy. And it's coming out of our individual pockets to create a bigger pocket, which increases the national debt, by the way, fund our health care and our health care system. So, while I'm very nervous about the upcoming administration, I do think of our health care system as a balloon is continuing to be blown up. And that one day, one day it's going to pop. And so can we be smart enough before it pops to let the air out slowly? All need to talk about this. We need to bring these issues forward. We need to develop a real economy for health care. And we need to think again about the Inflation Reduction Act, the cost of medicines and cancer care and other places as well. Our insurance model and think about how could we reshape that so that it continue to exist to provide excellent health care, but at the same time reduce that cost. And don't let that balloon pop.

[00:11:48]

The IRA’s Ripple Effect: A Candid Conversation with John Newby 

Now, I promised you an interview. And the interview today is with John Newby. Now you will see that Mr. Newby is an expert in this world of drug development and costs here for the state of Virginia and this region. And so, I think you're going to find this quite interesting. So, tune in and continue to listen to our interview. 

I am honored to be joined by John Newby. He is the CEO of the Virginia Biotech Association, and he is joining us today to talk a little bit about a new challenging subject of the Inflation Reduction Act and its impact on cancer care.

So, John, thank you so much for joining us.

John Newby: Thanks, Dr. Marshall. Happy to be here.

John Marshall, MD: Tell us a little bit about your role and, and what's your crossover with all of this and how the IRA may be important to you. 

John Newby: Sure. So, the Virginia Biotechnology Association is a trade group here in Virginia. Our members are life science and biotech companies of all stripes all over the Commonwealth. We have over 300 members and we've been around for 32 years now. We're headquartered out of Richmond, Virginia. We're located on the campus of VCU of the Biotech Park, Virginia Commonwealth University of the Biotech Park.

and our main goal in life is to support our startup companies, survive the gauntlet of this thing called biotechnology entrepreneurship, mainly trying to help them, with obtaining funding from investors for what they're trying to do into putting solutions in the hands of patients and also speaking on behalf of the entire industry from a government relations and policy perspective, federal government, state government to make sure we're protecting our companies anyway we can.

John Marshall, MD: Know, I want to jump right in on that. So, first, thank you for what you're doing. I was just at a meeting this past weekend where a series of biotech companies were presenting to us as colon cancer experts, their ideas. And I used to joke about, there's three guys in a garage, and who are the ones who invented whatever the drug is, or the new approach is, and that's where really innovation is.

Yes, there is some in big biopharma and the like, but a lot of it comes from individuals or small groups that get together, form a biotech company, generate their preliminary data, and that part's relatively affordable, I guess, or there's ways you can get that kind of funding. I used to think that there was just the bucket load of venture capital and others that was around that people were like, let's bet on that one or that one. But that's really been tight lately, as I understand it. And so, to get from that really good idea in this case was around colon cancer too, you know, clinic is a big investment, and that's really difficult nowadays, isn't it?

John Newby: the big investment in time and effort. the larger companies you reference nowadays, typically, like to keep an ear to the ground what's happening in basic science and then translational science and then ultimately, getting that science in the hands of hands of patients, but really on the front end, the risk really is born by the inventors, in some cases, the universities. Before the larger companies come in and acquire those companies, kind of how the ecosystem works. So, it's really on the shoulders of those great folks doing presentations to you to get out there and find the capital, you know, whether it be non-dilutive at the front end with NIH grants or other things all the way through venture capital and ultimately acquisition before a patient can get that therapy in her hands.

John Marshall, MD: And that just takes too long, right? I mean, you know, there in my world, there are people dying down there in my clinic. And how do we get this accelerated so that it's not five to 10 years, but more like one to two years to bring these therapies to market? And I, this, this model of how we found this is, you know, yes some fail, and yes, bets are lost, but it seemed to me this was a very rich pot of, of opportunity that we are unnecessarily delaying.

John Newby: Yeah, we need to do all we can to support this activity at the levels we're talking about. Too many great ideas are left on the shelf, and not funded because the investment environment is challenging always for life science and biotech. We had a good go of it for obvious reasons during the pandemic period, but it's kind of returned to the very difficult periods. But here's, here's the golden rule, good companies will always get funded. Good, good teams always get funded. Good science, mix all that together, get funded. So, we need to support that.

John Marshall, MD: I agree with that. Now, one of the main themes we've been talking about is the Inflation Reduction Act, and our audience has been hearing, you know, how did we get here and, and the current, efforts that are being made to negotiate for drug prices and this kind of stuff. And was in some meetings where those who are doing the investing in new therapies are hesitant right now because of the Inflation Reduction Act and the uncertainty that that's bringing to their bottom line, I guess.

Maybe reflect a bit on that and the impact it's having on the businesses you represent.

John Newby: Well, the bottom line is just talking generically about Any investor, you or I, even on a personal level,  we don't want to put our money somewhere where our chance of, achieving our gains. Are basically eliminated. Here, you know, withartificial prices being negotiated air quotes, is, is exactly that circumstance. You have, you have a company that invests millions, if not billions of dollars more often. in their drug pipeline. And if you have a drug that is now subject to this negotiation at some point in the future, whether it be nine years for a small molecule or, at 13-year point for biologics, The government's going to put a price down and, and lock it there, irrespective of how much money it took to get there. And also more importantly, John, you know, there's irrespective of the technologies and cures and treatments that can be gained from that same drug after that 13- or 11-year point that are now no longer going to be obtained as far as a return on investment. So, this is just a, not a good idea broadly speaking, but if you're looking at investors and the incentives. You're basically cutting that incentive off at the, at the hip.

John Marshall, MD: Yeah, I do, you know, I, we've talked a little bit about. US versus ex US, because I do think a lot of drug development depends on the US investment, and the current structure of how things are going. I also have been a drug developer all my career, you know, I do know that. We don't win every one we go after, so there are many medicines that we do put significant investment in that in the end fail.

So, those are losses. So, on the one side, I was hoping that we could get more efficient, like not turn off drug development altogether, but be better at picking the winners. If you will and optimizing that. But I also thought this was an opportunity for regulators to look at, you know, this relationship of drug approvals, patent half-life, intellectual property, and all of this to think about ways of. incentivizing the investment that we are making so that if you do when you get changes in your, you know, your IP or your duration of your, your patent life or something like that. Do you think that sort of evolution could happen as a result of this?

John Newby: I think the way you describe what will be a commonsense way forward is exactly why it's not going to be done anytime soon. You can't reduce all that you said to a bumper sticker. You can't reduce all that you have just said to, we're going to cut drug prices.

John Marshall, MD: Right.

John Newby: So that's the problem. That's really an issue here. it is a very complicated system that the U.S. has to get drugs into the hands of patients, but it's the best in the world. And I think the world recognizes that. And indeed, the world benefits from what we do here in the U.S. Yes, I do think that all those things that you just mentioned should be done eventually to look at things holistically and get to a better place. but that's not really how it's being approached from a political, political will, if you will. So, we have to deal with each attempt from policy makers to help and try to ameliorate the hurt that they're actually doing in this new system.

John Marshall, MD: But, you know, the other side is, as an oncologist particularly, I do a lot of trial-and-error medicine, right? We try a drug or try a therapy, see if it works. It's not inexpensive. It has side effects. You know, I need to be more efficient too. And I think about the payer side of this. Right. So, there's the private payers and then there's the federal payers that are actually funding health care. That money's coming out of yours and my, you know, our pockets, whether whoever we work for our health insurance or taxes. And. That's to a side of this that I've always struggled with the inefficiency of what we do on the other side. So, and again, this is some sort of idealistic world. I've just painted. Of that there would be more recognition of the inefficiency on this side improved development on the other side to a place where we're actually, you know, spending less money for better outcomes.

John Newby: That's the desire. Let me, let me, also throw something else in there. Not only is it the fact, and you know, firsthand this john, that it takes a lot of money and effort to develop drugs. The chances of success are lower than low in many cases. add on to that the threat of the reduced investment in this space, which is what the IRA potentially could do. So, there was a recent survey that was conducted by PhRMA, by the large Pharmaceutical Research Manufacturers Association that we're all familiar with. 78 percent of the companies that they surveyed said they expect to cancel early-stage pipeline projects that no longer makes sense given the short timelines that are being established in the IRA for setting prices for small molecules, large molecules.

So not only at the outset, is it already hard enough to get a drug. successfully through the pipeline. Now I have now I have companies saying, okay, now we're going to take away project money to begin with, because it just doesn't make financial sense, given these artificial deadlines and price, restrictions are going to be put on the drugs.

So, we're getting it from all ends, both from the scientific end, which is already difficult enough. Now the funding ends and we need to change that funding piece and deal with the uncertainties of the science because it is science. but let's not hurt ourselves with cutting ourselves off from the funders with, with such a regime that we're talking about.

John Marshall, MD: And I think it is important for our audience. I know they know this, but you know, cancer, we've sliced and diced it into subgroups that molecular profiling makes smaller and smaller markets for drugs when we get them there. And so, when we talk about trimming the sales, in terms of reinvestment and development, those small markets are the ones that are going to be lost just at a time when in fact, we understand better how to treat the different subgroups. So, I'm anxious about that along with you. Let me ask you one, one last question. 

So, what's going to happen next year?

John Newby: If I knew that I, I wouldn't be talking to you right now. we don't know. But you know, I wanted to make one more point, particularly when it comes to this audience and oncology experts and the IRA. So, the IRA does something else as well when it comes to orphan drugs. Most, many orphan drugs are obviously small molecule, targeting cancer, rare diseases, you know, those, those diseases affecting 200,000 or, or, or less, Americans. Currently it really, the IRA does, really hurts incentives for orphan drugs that are primarily for cancer. It only exempts from these price setting, this price setting regime, those orphan drugs that only treat one disease condition. Now that should absolutely make everyone's head spin in this community, right? Because we all know many orphan drugs that are approved in year seven, ultimately go on to be approved for 3, 4, 5, 6 more indications in seven years, eight years, 10 years in the out years. Currently the IRA cuts off that possibility because it says only orphan drugs that are indicated for one disease can be accepted from the price setting regime. Virginia bio and many other organizations, big bio pharma are advocating to change that provision. pretty soon. but that's just yet another example specifically how this impacts this community here, given the orphan drugs are really those small molecules that are at issue in your community. 

So, we all need to kind of come together and encourage our policymakers to look at big picture. This is an education process. It's like anything else in our space. Many of the folks on Capitol Hill don't have direct experience in what you do every day. So, it takes time for education, and we have gotten on Capitol Hill and my counterparts across the states and our national organizations have. But it's a process. Who knows what this new administration is going to do? And how, how well they're going to receive, our positions based in science and fact. But all we can do is continue and with your support, get the word out and, and, and encourage our policymakers to do the right thing.

John Marshall, MD: God, let's leave it right there. I think that's a, we, it's a charge and a call to action for us all in the year ahead. This is John Newby. He's the CEO of the Virginia Biotech Association, who's taken some time this morning to share his thoughts on the IRA. 

John, thank you so much for joining us.

John Newby: Thank you for having me. 

John Marshall, MD: I promised you that a good interview. That was a great interview. We appreciate all of the insights he brings forward as we look forward to the year ahead and all of our both scientific but also financial challenges that we have ahead of us in health care. Nowhere is that brighter shining is the issue more critical than around cancer care, where our therapies are getting more and more effective, but they are also going up and up in cost, and we're going to have to figure out how we're going to manage those two opposing factors for more people to get access to these lifesaving therapies, new innovations, new cures for patients with cancer out there. Join me next time for oncology unscripted, where we'll continue to dissect the world of oncology and healthcare in general. And what you're going to see will surprise you join us 

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MedBuzz: The PBM Pushback

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John Marshall, MD: Ho, Ho, Ho, everybody out there. This is John Marshall for Oncology Unscripted, and we're going to talk a lot about pancreatic cancer today. We're also going to talk about some other things as well, but I thought I would sort of start off with a little holiday story. 

See that stocking? I've had this stocking for a long, long time. I actually keep it right over there in my drawer, and it's a reminder of what we do for a living. So, a patient almost 30 years ago gave me this. It was actually a breast cancer patient I was covering for one of my colleagues who was out on maternity leave, and during that three-month window, I was the one who gave her the scan that showed the recurrence of her breast cancer. And so, I was the messenger if you will, of the bad news. And she pretended like nothing was really a big deal, and it was fine. My colleague came back and managed things from that point on. But then that Christmas season, that year, I got a very beautifully wrapped box. I thought, oh, how nice that this patient I was covering for those three months, many years ago had given me this gift and I opened it up and inside was this stocking. I thought, well, that's pretty nice. I don't really understand it. And then I felt and inside the stocking is a lump of coal. And this was a patient who had taken a lot of trouble to wrap me up a pretty gift with a stocking in it, mainly to make sure I knew that I was the Scrooge for her holiday season. 

And so, as we enter this holiday season with our patients, with our colleagues and our teams around us, remember. It is a special time of year for all of us. It's an important time of year, but it's also a time of year when bad news carries a little bit harder weight with our patients. So, avoid getting one of these from your next patient if you get one of those bad scans, which sadly is common among our pancreas cancer patients.

But before we go there. talk a little bit about one of our past topics, a little bit of gossip that's out there, and that's the pharmacy benefit manager. If you remember, we talked about this a few episodes ago where this group CVS Caremark, and there are many of them now, nearly three big ones, are controlling the pricing of our medicines in such a way that they're ramping up pricing, controlling the distribution, and really kind of undermining a lot of the free enterprise, if you will, out there. And so I'm sure it wasn't our video and commentary that caused this, but there's been some backlash from the PBMs who now are like filing lawsuits against the Federal Trade Commission, claiming that basically they're fiddling with all of this is unconstitutional. And they've had full page ads running in the Washington Post. We always know when there's something going on here in Washington because they'll take out a full-page ad saying we're right. You're wrong. You should support us. I guess it’s sort of subliminal messaging for our Congress people as they go to work in the morning. Nonetheless, there's now this pushback from PBMs to say, stay out of my business. It's not the government's business. 

And so now I'm thinking about what's coming in the year ahead. You don't want regulation. Okay, you voted for him. He's not going to have any regulation, at least as far as I can tell. But this is one of those examples of what's going to happen if we don't push back, it's going to affect all of us going to affect the cost of health care. And we won't be the ones who are benefiting from this. These third-party managers, such as the PBMs, will be the ones that are benefiting. So, it's going to be to see what happens in the year ahead. Just how much changes in regulation, particularly for us in health care, will have an impact on outcomes, cost, access, all those important things that we are trying to get for our patients. So, I don't know. Stay tuned. More stories to come on the PBMs.

What’s Making the Impossible Possible in Pancreatic Cancer?

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Our main topic today is really all-around pancreatic cancer. We just got out of November. And as you know, November is Pancreatic Cancer Awareness Month. Now, did you know that there are about 60, 000 new cases of pancreatic cancer every year? Not that many survivors, right? Because most patients present with metastatic disease,  and is there such a thing as early pancreatic cancer? And so, the teams that have been trying to advocate for new science in pancreatic cancer have made headway. First, you need a month. So, they got November 2nd. You need a ribbon. Do you know what color the ribbon is? Yep. Yep. You're right. It is a purple ribbon. So you got to have a ribbon. You have got to have a month. Got to have a few five K's. You have got to have some money. to distribute out there for research and you've got to create a home for patients to go to,  so that they can learn more about their disease.

And so Pancreatic Cancer Awareness Month has really been something that I would say has been positive for our patients and our medical team in this space. 

I want focus on a paper actually that came out last month in the JCO, and this paper by Ludmir et al, was kind of breaking a rule, but it worked.

Now, you remember that in colon cancer, not pancreas, colon cancer, you can resect metastatic disease. In fact, you should for some patients because sometimes there's only one or two weeds in the yard. And if you remove the metastatic disease, you cure that patient. But generally. We don't do that for other cancers routinely, but this group published their data looking at pancreatic cancer patients with five or fewer lesions, metastatic lesions, randomizing them between just continuing chemotherapy versus this metastectomy or localized treatment, and wouldn't you know it, it seemed to work. So, the next time you're in your GI multidisciplinary tumor board, and somebody, some surgeon usually says, what if we just took those mets out of the liver? And that you would use to say, nah, it's pancreas cancer. There's no data. Now, there is data. So, I strongly encourage you to look up that paper, maybe present it at your next multidisciplinary tumor board so that you too can be cutting edge, if you will, on trying to do a better job with pancreatic cancer.

Now, the other piece that happened in November is we have our annual Ruesch Center Symposium here at Georgetown. We invited people from all over the country to come and start off with a think tank. What do we know? What don't we know? Actually, we know a lot more than we used to know. We then celebrate this with a series of presentations and a CME symposium. And I wanted to sort of really drill down on pancreas cancer for a little bit, because we've made progress, believe it or not. 

So, it really starts with an understanding of there is such a thing as early phase pancreatic cancer premalignant lesions within the pancreas. There's increasing ability to detect these things. Now, how do we prevent them from becoming a cancer? That's another challenge. How do we identify them as a screening tool? There's new data that supports being able to do some of these new screens,  both with blood testing, as well as with imaging, et cetera. So, there is hope that soon we will be able to incorporate routine screening in patients to try and find early-stage pancreatic cancer, even premalignant. 

The second, and this is a big deal, is we have been saying that RAS is untargetable. 90 percent of pancreatic cancers have a RAS mutation. And we basically said, we're sorry, your driving mutation is untargetable until now. It started with G12C and now there are, gosh, some people say more than 20 new drugs that are targeting RAS, increasingly more successful. Some are very specific to a certain mutation. Others are pan RAS inhibitors, but there are a lot of clinical trials, a lot of new therapies, and a lot of investment that's going into this space of targeting RAS in pancreatic cancer. And our hope is that Maybe even by this time next year, we have some positive randomized data that would lead to FDA approvals.

My guess is between now and then, we will also be seeing some phase 2 data that suggests significant positive responses. All of a sudden, we're seeing waterfall plots with pancreatic cancer, not with just one patient, 10 percent, having a response, but now approaching 50 percent of patients having response. And I am really excited about RAS inhibition in pancreatic cancer now.

The last piece of this is that you think of pancreatic cancer as sort of an immune silent disease. disease that there's no treatment for therapy, no role for immune therapy in these patients. But newer studies looking at novel combinations of immune therapies are starting to show some improvement in waterfall plots as well. 

So, when we got everybody together here at our symposium and our think tank, what really came out of it is that It's now on us to figure out how to put together these immunotherapy approaches and these RAS targeted agents along with our existing systemic agents to move the bar in pancreatic cancer. 

Is it about time? Yes, it is. Do we have the right drugs? We at least have a good wave of drugs That will move us forward in this space. So, if you're out there taking care of patients like me with pancreatic cancer, now's the time to be looking out for trials and other options as these agents come through the mix. Hopefully, this time next year we have improved survival and a path forward about how to make that even better. So, I'm optimistic around pancreatic cancer. 

To really get into this area of pancreatic cancer, we've invited not only a good friend, but someone who I think maybe single handedly has had more impact on the outcomes, the investment, the support for pancreatic cancer. There's no one out there on the planet, in my opinion, except this person, Julie Fleshman, who started, founded, grown, this organization the Pancreatic Cancer Action Network. 

Shaping the Future of Pancreatic Cancer: Interview with Julie Fleshman

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Welcome everybody back to Oncology Unscripted. No script at all on this one. And the person who's joining me right now, really, doesn't need a script because she wrote it. She was the one who really defined, in my opinion, what advocacy is all about. Taking maybe one of the most difficult, if not the most difficult, cancer, inspired by a personal story to change the outcome for people with pancreatic cancer. And I'm proud to say she's my friend, but she's also one of my mentors, as she has shown the way for so many as to how to really move the bar in advocacy.

And this is Julie Fleshman, who is coming to us live and we're so grateful, Julie, for your joining us. So, first, welcome to Oncology Unscripted. 

Julie Fleshman: Thank you so much for having me. It's always a pleasure to talk to you and be with you.

John Marshall, MD: You are so awesome. And you know, I think that, but let me start from the beginning, because a lot of people were coming up on a change in our world. And we know that advocacy is a critical component to our success in making advances in healthcare. It's not just handed to us. We have to push the forces around us to make it happen. Maybe give us your quick version of, you know, what inspired you and the value of advocacy in the world of pancreatic cancer. 

Julie Fleshman: I have a personal story. 25 years ago, now, my dad was diagnosed with pancreatic cancer. 52 years old. Died four months after diagnosis. And I was devastated, and I didn't understand why there was nothing offered for him. Why were there no options? And about that. At the same time PanCAN was founded and I was lucky and privileged to be hired as the first employee almost 25 years ago.

And I've really just watched, you know, the field, the pancreatic cancer field back then, there was nothing. There was no federal funding. There was no philanthropy. There was nobody studying the disease. There were no resources for patients and families. And you know, I really believe PanCAN has been a catalyst for changing that. And today there is a robust pancreatic cancer research community. And I think a lot of exciting things on the horizon for patients. And so, you know, I believe advocacy being the voice of the patient, not backing down when everyone tells you this isn't the way that we get things done, but it makes the most logical sense for overcoming a hard disease and you keep at it, and you keep chipping at it.  and I believe advocacy is what gets us to where we're going and accelerates the rate of progress. And in this case, I think has really helped to build a field that just didn't exist before.

John Marshall, MD: You did all that stuff. Let's talk about the important stuff. Why did you pick purple for the ribbon?

Julie Fleshman: So actually, our founder who lost her mom to pancreatic cancer, her mom's favorite color was purple. That is the story.

John Marshall, MD: I love that.

Julie Fleshman: So yes, so you know, and it was one of the colors not taken, right? You need to have something different than the other cancers, but it is a great color.

John Marshall, MD: But all kidding aside, yeah, I actually have several purple ties now because of the of the purple ribbon. But, but all kidding aside, I mean, you and your team have built an incredible infrastructure, not just a Hill presence and advocacy there. Not only a clinical research infrastructure that we'll talk about in a minute, but also operators standing by patients can call in and get advice about what they should do with your team members. And in fact, I think that feeds back to the practicing clinician, because there's a lot that we don't know that's going on out there, particularly the general oncologist in the world of pancreatic cancer. I'm assuming each one of those was a decision and you needed to have the bandwidth to do it. Like how, how much struggle was that to get all of those resources together?

Julie Fleshman: Yeah, I mean, you looked at and said, Okay, where are the gaps, and 25 years ago, there were a lot of gaps. One of the first and most obvious areas was, you know, when someone is diagnosed with this disease, there's no place to go for information or resources. So, building that patient services program in the early days, you know, was so critically, I believe, important for helping patients be informed so that they can make the right decisions about their care and go in and be an advocate with their, you know, doctor. Just as you said, many physicians don't see hardly any pancreatic cancer patients. And so, to have someone come in and ask you questions about clinical trials, about testing, about these different things, hopefully it will also help educate the health care professionals.

John Marshall, MD: Yeah. And you've given these folks a home, a club, if you will, where they can share thoughts. And I think with our, you know, the bad cancers, there isn't that sort of survivorship that you see in some other cancers. So, you've, you've provided that place where people can interact and teach each other, which to me is just critical.

Julie Fleshman: Everybody needs a cheerleader, right? Whether you're a researcher, a doctor focusing on this tough disease, patients and family, someone who's lost someone. And I think that's what PanCAN does. We rally the troops. We make people feel good about the work that they're doing and that there is hope and that we're going to get there. We just all have to work together to do it.

John Marshall, MD: Yeah, I couldn't agree more. Now, the year ahead, we're all pretty sure that the NIH budget is not going to get bigger. We're panicked that it's going to be significantly smaller. And so, I think about a group like yours that has successfully advocated in DOD budget,  negotiations to get pancreas cancer research funded there, there's certainly a high priority around pancreatic cancer in the NIH budget.

What are some of your worries as you look to the year ahead and new administration changes?

Julie Fleshman: Yeah, I was actually just on Capitol Hill last week with Madison Marsh, Miss America 2024, who lost her mom to pancreatic cancer. And so, she's been using her platform to talk about the disease. So, she and I were up on the Hill together and talking about increasing the DOD line item for pancreatic cancer research, and just trying to understand the current environment. And definitely what we heard is most likely it will be flat funding. There probably will not be any increases. And I think there is just a lot of concern about what's going to happen to these agencies and what could this look like. So, PanCAN along with the other cancer advocacy organizations are going to have to stay on top of it. I think the good news is that usually health related problems do better during change like this. And so, let's hope that's the case, but this will be a time where the voice of the patient, the voice of advocates is going to be extremely important.

John Marshall, MD: Let me kind of drill down on something you and your team were clearly setting those standards when you develop the concept around Precision Promise. This was an understanding that molecular abnormalities occur. There are different ones in different patients. We have targeted therapies. Could we drive progress in pancreatic cancer through that? And you, a lot of work, a lot of investment, a lot of science went into this, but it didn't turn out the way you want to maybe reflect a little bit about that and that experience for others, because, you know, for me personally, I think it's exactly the right way to go. And lessons we could share for others trying to do this and other diseases.

Julie Fleshman: Yeah. So, Precision Promise was an adaptive clinical trial platform. And so, you know, basically the goal behind it was that you could develop a drug with fewer patients, less cost, less time,  a way to accelerate new treatments for patients. All of that's true. And I think we learned a lot about that sort of process, and does this platform concept work? And I think the answer is yes. However, financially, in order to make it financially work,  you have to have constantly have new drugs coming into the pipeline on the platform. And that was the part that turned out to be the challenge. Part of that was, you know you were convincing a pharmaceutical company or a biotech company to develop their drug, that PanCAN was going to develop their drug, they were going to lose control. So that proved to be an obstacle. The pharma and biotech companies, you know, changed their priorities and their strategies. And so maybe at one point they were developing this drug in pancreatic cancer and six months later they were deprioritizing the asset. And so all of those things became challenging.

We also had, you know, the last couple of years it's better today, but the last couple of years, I mean the funding for biotech, you know, really dried up.  I still think many of them are challenged and so there wasn't even funding to do something even like this that would be less expensive. So, with all of those things, it became a financial risk for PanCAN was the bottom line.

The trial will go on. another organization that is going to launch a new,  you know, basically Precision Promise version 2.0 and learn from all the things that PanCAN learned over the last, you know four years. And, you know, some people have said it was before its time, you know, now with there's so much excitement around drug development and targeting KRAS and all of these things that maybe, you know, if we were launching it today, it would be a different story. We launched it in 2020 in the middle of COVID. It was, you know, couldn't have been a worse time to be launching a big, you know, basically phase three clinical trial for an organization like us that had never operated one before. So, you know, we didn't have everything working with us,  we did this, but we certainly learned a lot.

And I think, you know, the investigators that were a part of the network and the sites that were running Precision Promise, really, that part ended up being pretty amazing. That network, and the camaraderie and the sharing and the learnings. And you know, I think that those things will continue far beyond. 

John Marshall, MD: Yeah, no, I totally agree with you. You know, we just held here at Georgetown at the Reusch Center, a think tank around pancreatic cancer. And we invited a bunch of very smart people, some of the smartest people in our country around this disease who've made a lot of progress. And the whole point of the think tank was to say, why haven't we cracked this nut? Why have we had a few new medicines? They've helped. Yeah. But we really haven't cracked the nut the way we want to. And it was interesting. One of the participants got up and said, “But wait, we have done it, or we have about to do it and all we really need to do is give it time and ongoing investment. But we're about to reap these rewards in pancreatic cancer, whether it's targeting or new understanding of immune therapies, understanding,  how to control  cancers and the like.  I went into that meeting discouraged thinking there wasn't going to be much in our summary document, or what we were going to be able to share. But I left that meeting maybe as excited as I've ever been, and I'm an old GI oncologist, about the future of where we're going in pancreatic cancer. Reflect a bit where you all are on that and that stance. And the one concern I had, again, is how do we make sure that that investments there, to your previous point? How do we make sure that patients have access to these trials and new medicines around the country? So that all can move this faster. 

Julie Fleshman: I've heard multiple physicians and researchers say that they feel we're at a tipping point, and I've never heard, you know, that kind of talk before. I mean for 25 years, I've been told KRAS, RAS super important, but it's undruggable. And suddenly, it's druggable. And so that's pretty amazing and exciting. You know, there are multiple, multiple companies with targets for KRAS for pancreatic cancer. The first phase three trial just launched last month, and then lots of phase two, phase one trials that are in development. So, I mean, this is exciting. This is really important.

John Marshall, MD: Yeah, I was going to say that I saw a bunch of waterfall plots. Everybody knows what those are. Where I'm used to seeing one patient and being excited about that. This was half the patients were below the line. We were seeing lots of responders in those patients.

Julie Fleshman: Absolutely. Most likely it won't be the silver bullet. I think we've learned that in this disease. So, the next step is what do we need to combine it with? What is that going to look like so there's durability and, and we get, you know, even we extend patients’ lives even longer. I think that'll be the sort of immediate next step that we need to begin working on. But I was really heartened at the AACR pancreatic cancer meeting in September. That already it feels like the field is thinking about that, and they're working together across institutions. They're getting together in groups and trying to solve the problem based on different expertise. And so, I do feel like we have a very special community that knows this is hard. That this isn't just going to be the answer, and we're going to have to continue to work together. And PanCAN wants to play that role. 

John Marshall, MD: I would go one step further, Julie. I don't think we would be where we are today with that progress without your work and PanCAN's work that's driven this and made sure that in the top of everybody's mind is how We're all tired of taking care of pancreas cancer patients with not much to do. And we are all looking forward to the future in large part, thanks to you. So, I very much thank you for taking the time for talking with us today and wish you well as now we watch that survival curve improve.

Julie Fleshman: Thank you so much. I always appreciate your passion and enthusiasm, and all you do for patients. So, thank you.

John Marshall, MD: I really can't thank Julie enough for joining us in our series Oncology Unscripted. As you can see from our discussion, she’s just all there is out there. She has been such an advocate and positive for so many of us in the space of GI cancers and pancreas cancer in specific. So, a great shout out to her and thank everyone out there for joining us today as we've sort of started to dig in deeper in the world of pancreatic cancer, our hope for the future, as we've developed new agents and new support for our patients that are out there. Join us next time on Oncology Unscripted.

Thanks everybody. John Marshall.

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Is the Inflation Reduction Act a Threat or Opportunity for Oncology?  

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[00:00:05] John Marshall, MD: Hey everybody, John Marshall live from Washington DC where all the action is happening. A lot of moving vans are likely to be coming here soon as the new party comes in to take over maybe everything. We're going to have to see how that goes. We're all living in this crazy state of uncertainty about just how much. Are they saying is going to happen? But we'll see. That's our future. 

[00:00:34] But what I really want to talk about on this episode of Oncology Unscripted is the beginnings of a discussion around health policy in oncology and the reason I'm bringing this up is I just recently came across my radar, something called the Inflation Reduction Act. Well, sure, I knew about the Inflation Reduction Act, but I didn't know how that was going to affect cancer. And then I started to think about, yeah, I do. They're going to negotiate drug pricing on cancer. And there's been this big turmoil about we can't do that. It'll break the system. We need the fixed drug pricing, et cetera, and I want to talk about that because it's starting to be put into place, and it might actually get wiped off the map in a couple of months, but maybe it won't. And I wanted to talk about it because it will affect what I do for a living, and that's to try and develop new drugs for cancer.

[00:01:29] But in order to do that, let's start by at the beginning of when the whole thing needed to be created in the first place. And that is go back to 2003 Bush II, Bush II to put into place a health modernization Medicare Modernization Act, which at the time was praised. Now, remember where we were people with Medicare didn't really have drug benefits. You went and paid cash at the pharmacy. But drugs were getting more and more expensive. And so, seniors weren't able to afford the drugs. And so, we needed to figure out how US health care was going to cover those drugs. And this was the deal that was cut now out of that deal. So, seniors got access to drugs. But for the tradeoff that always happens here in Washington, D.C. Now, the first one was that there was an agreement that we would not import new drugs from other countries. So, in other words, you couldn't manufacture it in Canada and then ship it across the border at Canadian prices. We weren't going to allow that. So, the borders were closed to import so that we could save the price structure here in the United States. And with that rule came another corollary is that we could not negotiate drug pricing with the manufacturer. Whatever they said was going to cost, that's what CMS would pay. And as a result, that was when we could no longer judge value as a nation. So, if you can't connect magnitude of benefit, which is what the FDA judges, did it work or not, to the cost, that's what CMS has to do, you can't judge value. Right? There's no way. Okay, it'll cost $100,000. Okay, but what do I get for that? Well, it could only be 6 weeks. And that would be enough for it to get FDA approval. And Medicare would have to pay. the third component was something called 340B pricing, and that is institutions like mine and many of the institutions around the United States pay a reduced amount for the product, get paid by insurance companies, the delta, and with that extra money that we get as a healthcare institution, we're supposed to provide All those other things that cancer care delivers. A nutritionist, a social worker, nursing support, et cetera, that don't have any billing infrastructure for it.

[00:04:08] And so that non negotiated price, the rising cost of cancer drugs, and this 340 B pricing is our current economy. And with that, all of our industries more or less dependent on that pricing structure. So, the inflation reduction act is a threat to that, right? Because if we're going to start picking and choosing drugs that can be negotiated on price, then how does that affect the revenue stream?

[00:04:37] And how does that affect the reimbursement into research? And so, our whole series on the next few episodes is going to be focused on the Inflation Reduction Act and what it does now, and what it could do in the future. And why we're worried about it. We hope to get some good folks who are in the middle of this discussion to talk to us about it. It's a fairly sensitive subject. So, we are hoping for that. So, stay tuned to future episodes. 

Cancer Care in America: Equal Access or Uneven Outcomes?

[00:05:05] But as part of this episode, I wanted to talk about yes, U.S. health care, but I wanted to talk about. Does everyone get the same U.S. healthcare? Now, the reason this has become important to me is that we just did a study here in Washington, D.C. between two of our main hospitals that I work in. They service very different patient bases and neighborhoods. They're both busy cancer hospitals. They both provide specialized cancer care. That's important. But one, quote unquote, has a lot of issues with social determinants of health. Barriers to access to cancer care, because as we've talked about, cancer care is complicated to receive, it's complicated to give, and if both parties are doing okay, then it's okay, but if one is challenged, then it's not okay, right?

[00:05:54] So what we did is a big study of a thousand patients with colon cancer, and actually extracted from their charts, 400 from one hospital, 600 from another, and believe it or not, We were expecting to see a difference in outcomes that the social determinants of health were in fact going to affect the outcomes for those patients. But not only did we see no difference, we saw that. In fact, our record here in our health care system was better than published national averages. Molecular profiling, time to treatment, survival, all the key points we want. And after an initial sense of pride, I'm like, well, wait a second. That is not what we were expecting, right? We were expecting there to be a difference because of the populations that we were serving was different. 

[00:06:42] And so we then developed a new theory, which we are testing now, that can a general oncologist, nobody out there get offended, keep up. With everything that needs to be kept up with in every disease, and I think if you ask most general oncologists, they would say they do a very good job, which I would agree with, but maybe not as good as it could be. On the other hand, what if you live in a remote part of the world in our country? How far do you have to go to even find a cancer doctor or a place where you can get an infusion? So, we have this issue of general oncologists and remote access, right?

Bridging the Distance: Can Rural America Get Equal Access to Cancer Care?

[00:07:23] And so there have been a couple of, you know, announcements lately about new projects. There was 1 that looks like it was funded by ASCO and it's in rural Montana where they're going to use a hub and spoke model where there's going to be infusion sites around in the. and then they'll be in a remote country, but then there'll be centralized care. It's exactly how Canada does it now, all the doctors live along the southern border of Canada, right? Because that's the only place where there's not snow all the time. And they've talked to, using telemedicine, patients who live up further away. And then there are local nurses and general doctors who administer the cancer care. So that hub and spoke model we know works in the Canadian health care system. 

[00:08:08] , There was recently Iowa, as you might imagine, great centralized cancer care, but how do they care for folks out and around? So, the University of Iowa bonded with Mission Cancer and Blood, 280 million dollars changed hands, but to basically deliver cancer care in a remote areas. Now this is great. This is what we need for our people and for everyone around our country is good access to cancer care.

[00:08:37] But what our little study may be hinting at is maybe this also needs to be done by cancer specialists. Should we begin to divide even general practice knowledge into its subcategories because it's gotten so complicated? The analogy I like to use is if I had a bunch of okay. And the answer is no, I can be an expert in one or two, but I can't know all the nuances of all the different board games. So we're going to have to figure out not only provide cancer care for everybody, but Through these kinds of networks, hub and spoke model, but how do we make sure that we're actually delivering the highest level of cancer care that we can so that our patients can get the best outcomes and the best and the right therapies on time, et cetera.

Is the U.S. Health System Designed to Fail Its Patients?

[00:09:30] So the last point I want to make about all of this health care policy. It really comes from a recent survey paper that looked at the different health care systems and outcomes around the world. And we always think, because we're the United States of America, that we have the best of everything. Well, we do have the best hamburgers that I'm going to give us. Maybe the best fried chicken, too. I would say that's probably true. Best bourbon? Yeah, I think we have that. But in terms of the best care and healthcare, when you look at the top, like richest countries, we don't. We're in fact, of the top ten, guess what number we are? We're the worst in terms of access to care. Bad health outcomes. Bad worse. So, 9th administrative efficiency. I didn't need to tell you that. Equity, we're 9th in that where we are. The best is what they call care process. So if you're in the system, we got all the bells and whistles, but we leave lots and lots of people behind. 

[00:10:40] And so, as we think about going forward, we have the inflation reduction act, which is trying to make cancer care more accessible and more affordable for our patients. We've got administrative and economic pushback on that. We have a new administration that, who knows what they're going to blow up going forward. But we know for sure. One of their priorities is not equal access to everybody around our country.

[00:11:04] So as we spend the next couple of months reflecting on where we've been and where we're going, fingers crossed, that reason will prevail, that we will prioritize the patients in general. That access does matter that we want to level the playing field to health care as much as we can for all of our patients across our great nation. And I think with that, we will show how we can work together and how we can bridge our divides as we walk forward over the next 4 years. John Marshall for Oncology Unscripted. 

Pandemics, Presidents, and Perseverance: A Candid Conversation with Dr Anthony Fauci

You know, I've interviewed a lot of people in my career, but I don't think I've ever had quite the joy of interviewing someone who, honestly, I think almost everybody in this country, there's some who don't feel this way, but, almost everybody, in this country who think is a real modern day hero, and this is Dr Anthony Fauci, and he has agreed to join us and talk about a few subjects that sort of near and dear to maybe both of our hearts and share them with us all. And on a second note, I want to welcome him as he's flying the Georgetown University flag behind him. I've been here on the faculty for 31 years and I'm not sure I've, I don't want to insult any of my other colleagues, but I'm not sure I've ever had quite so, such an esteemed colleague from my own university, join me. So, Dr Fauci, first, thank you very, very much for joining us today. And let me give my own personal Hoya Saxa welcome to Georgetown University.

[00:12:35] Anthony Fauci, MD: Thank you so much, John. Pleasure to be with you.

[00:12:38] John Marshall, MD: Well, you're awfully nice. Part of what has sparked my interest in talking with you just beyond all that you've been through and all that you've led us through over the years, is really some subjects that came forward in your book. It was really an impactful book. If you haven't gotten it yet, gang out there, it's called On Call. It’s a terrific book available on audio as well for those of you who like to walk and listen at the same time. It's really an extensive review of your own life and the impact that you've had in your own reflections on very, very dramatic moments in medical history. And I wonder if you just start by kind of sharing the sort of inspiration to write it and sort of the emotion and what it took to stop and get all of that down.

[00:13:25] Anthony Fauci, MD: Yeah, well, thanks, John. I decided to write the book because when I came to what I was projecting to be the end of a 54 year career at the NIH, Almost 40 years of which was as the director of the NIAID, which positioned me to essentially be in the eye of the hurricane in the evolution of, as you mentioned, the most impactful pandemics in modern history HIV in the early 80s and through the next 40 years, and then followed by COVID-19.

[00:13:57] That started, at least in the United States, we had the impact of it in the early months of 2020. When I decided I was going to step down, I thought it would be important, given I had the unique experience of this, journey through these two major pandemics, but also in between advising seven presidents of the United States from Ronald Reagan through the Bushes, through Clinton, through Obama, through Trump, and then finally the seventh. when I spent two years as the Chief Medical Advisor to Joe Biden. I thought that that was such a unique experience. My thoughts were two-fold. One, I thought from a historical standpoint, I thought it might be useful for people to see what that was like to go through the early years of the pandemic with HIV and then throughout COVID, but also hopefully to serve as an inspiration for younger individuals who might have an inkling they might want to go into science or medicine or public health. And my description of the early years I believe were important because right now with HIV, we have a single pill with three antiretrovirals that can put a person into complete remission by bringing the level of virus to below detectable and keep it there, essentially indefinitely.

[00:15:27] But I hearken back in the book, in the memoir, to those early years from 1981 through the mid-80s, the late 80s. And the early 90s, when we did not have adequate therapy, and I found myself as a physician who, prior to HIV/AIDS, was rather successful in developing remission inducing therapeutic protocols for auto inflammatory disease, where most of my patients who thought they were going to die actually went into remission, then entering the arena of caring for and studying persons with HIV. I describe it in the memoir as the dark years of my medical career and the stress and the strain. Of seeing virtually all your patients, mostly young, otherwise previously healthy gay men who are dying terrible deaths, no matter what you did. And it was like putting bandages on hemorrhages. You know, I described in the book, I still to this day have flashbacks of what I call a version of post-traumatic stress. Because. When you were taking care of these people early on in the early 80s, you could not get emotionally involved in it because you had too much work to do, and your job was to take care of the patients. So, you suppressed it. It only was years later when you reflect on what you've been through that you understand that you didn't have time to burn out because you had too many people to that you had to take care of. But it was an extraordinary experience, which was an important part of the book to describe those early years of HIV.

[00:17:17] John Marshall, MD: Yeah, well, and taking care of yourself was had to be last on the list because everybody else needed you and there were no, you know, it was sleep, eat and take care of people. I remember in 1988 when I became an intern here at Georgetown walking the halls and those floors still exist. There’s new tile, but the floor still exists. And, you know, I remember the faces of the young men that you describe in there and being the guy who had to go in the gown and get the blood because we didn't have phlebotomists back then and being afraid actually to have a needle in my hand and have an HIV patient that I needed to get blood on or to put a line in or something like that, but at the same time they were alone and you wanted to be there with them because the way the rules were in hospitals as they frequently couldn't have visitors and certainly that was traumatic for me and I, like you say, I probably tucked that away. Then I decided to take on the easy task of trying to cure GI cancers. Not done nearly as well as you've done with viruses

[00:18:16] My experience was then my wife gets breast cancer. And I thought she was going to die. And now all of a sudden I knew what it felt like to be a caregiver or to be a patient. when in fact, I had probably tucked that away for many, many years. and when it, then I tried to, back to we're busy and we got to cure people, deliver that care for every cancer patient that was here. I realized there was no way that you can deliver that level of cancer care, the cancer care that we received as patient and caregiver. I couldn't turn around and give that to everybody who walked in the door. And that was in essence my source of burnout because I was feeling the impact. I was feeling the shortcomings, and actually had to get away for a while. And, and part of our book reflects on that. I think the young people today, and I would love to hear your sort of comparison because I experienced both, you experienced both pandemics, but a lot of our gang around here, you know, they cut their teeth on a pandemic. The interns and residents were on call, and you know, burning their clothes at their door on the way home in that same sort of way we felt with HIV.

[00:19:22] Do you have a sense of how they might be different or how they were different for you, the two experiences?

[00:19:28] Anthony Fauci, MD: Well, yeah, they were different for me, John, for the following reasons, that through the early years of HIV, even after I became Director of the Institute, I was very actively involved in the individual care of individuals, which led to that very stressful, emotional experience that I mentioned to you a moment ago. When it came to COVID, for me personally, it was a different experience because I was in a position of public health influence where I was, you know, as part of the coronavirus task force in the White House, making decisions that were difficult because we had an evolving outbreak that was not just selectively impacting a subpopulation, it was global that everyone was at risk. So, we had a true global health and domestic health catastrophe with COVID, and we had to, to the best of our capability, make decisions about what public health recommendations would be that would involve everyone, not just a small subset of people. 

[00:20:45] At the same time I had the responsibility, together with the pharmaceutical companies, to develop the vaccine. And I could say that was one of the things that we're very proud of, is that my group at NIAID, the Vaccine Research Center that I established 20 plus years ago, was the group and the organization that developed the vaccine the highly immunogenic immunogen that partnered with the mRNA platform to create a vaccine in 11 months, which as you well know, that is a fraction of the normal time it takes to develop a safe and effective vaccine, which usually averages, 7 to 10 years. So, a combination of major investments on the part of the government, the scientific input from my group, and the incredible work that the pharmaceutical companies did. We had a vaccine in 11 months. So that was very, very different from the multiple years it took before we could get a drug for HIV. Remember the first patient that I admitted, with HIV, was in 1981. The first drug that had any effect on HIV was 1987, and it wasn't until 1996 that the triple combination of drugs were made available, which actually dramatically diminished the viral capability and viral load.

[00:22:18] John Marshall, MD: I used to say back in the day that the only reason the HIV success happened was that gay men, essentially, became very powerful self-advocates, and demanded this when there was probably a public sentiment that you were up against even then to do this. 

[00:22:34] With the pandemic, even though you did have global support. You did also have to climb a hill over some who thought this was all some sort of conspiracy. We all know that, but so we are grateful for that. But it does require that sort of will to do it. But to your point, if the will's there and the science is ready for it, it can be done. And so to reflect on that, you coaching me as an oncologist, do you think that if the will were there and we spent the money that we are spending every year on cancer care and cancer medicine, if we spent it more wisely, could we in fact have better outcomes than we do now? What's your thought on that?

[00:23:15] Anthony Fauci, MD: I think so. I mean, if you look at the focus concentrated effort that was put into drug development for HIV, it is one of the greatest success stories of modern medicine. I mean, where all of your patients are dying from an infection that you just could not treat at all to years later when you have a single pill that can essentially drop the level of virus to below detectable and keep it there, not only saving the life of the person, but making it impossible for that person to transmit the virus to someone else.

[00:23:51] John Marshall, MD: at the time, we had like 90 percent accrual rate on clinical, everybody was on a trial, right? It was uncool. Not to be on a trial.

[00:23:59] Anthony Fauci, MD: Yeah, that's exactly what it was. I mean, and you know, you mentioned a moment ago, John, the importance of the AIDS activists in getting community involvement in everything from the design of clinical trials to make it more user friendly to them, to challenging the rigidity of the regulatory process to get drugs approved. Because the FDA process prior to AIDS was very well accepted. It provided safety for the American public, and it got drugs out. But it was ill suited to the emergent nature of HIV, where when someone had clinical disease, it was 12 to 15 months before they died, and interventions before they got through the FDA process would take six years, seven years. It just didn't work for them. So, they pushed back, and the scientific community and the regulatory community didn't listen to them. So, they became very provocative, theatrical, iconoclastic, disruptive. And then I finally listened to them. And when I did, it became clear that they were making perfect sense. And if I were in their shoes, I would have been doing exactly what they were doing. So, it's a very interesting part of our history, the very positive role of the activist community. In getting HIV drugs out sooner and getting them out in a more efficient manner.

[00:25:35] John Marshall, MD: And I've always wondered why the cancer community hasn't been able to sort of create that same unified, not just a pink tent or a brown tent in my case, but a unified rainbow tent to go up and say, we need to change how we do this increase, you know, we're at 8, 9 percent at best on clinical trial accrual now accepting bad diseases and not really pushing. And yet, spending whole lots of money on health, you know, on both screening and on therapy. And it's always been a disconnect.

[00:26:04] But, let me shift gears a little bit because one of my favorite interviews I've ever heard of yours was on a Saturday morning driving around for Wait, Wait, Don't Tell Me. It was just the best thing ever. It's a great show, best show ever. And as you know, on that, they bring famous people like you on and they say, well, we're not going to ask you about viruses. In that case, they asked you about computer viruses. If my memory is correct. Well, I'm going to do the same thing and ask your advice to all of us. You know, what are the secrets to avoiding burnout? What are the secrets? What do you do? What are some of the things you would advise those of us behind you, if you will, to do a better job of taking care of ourselves? You know, we have a common friend who, you know, you played three on three basketball with. I know you're a basketball junkie, but what is sort of your, your advice to us on that

[00:26:53] Anthony Fauci, MD: Yeah, I think it has, you have to have an outside, source of, of support. I was very fortunate in my wife, at the time, was a nurse, who was specialized in the clinical care of persons with HIV. She currently is the chair of the Department of Bioethics at NIH, and she actually is a Hoya all the way down. She went to undergraduate nursing school. She got her PhD at the Kennedy Institute of Ethics with Ed Pellegrino.

[00:27:31] She was very, very helpful in grounding me when I would come home after losing two or three people, mostly, as I mentioned, young, otherwise previously healthy, gay men to just get me to realize to focus on the potential good that you can do and not the disappointments. Because if you focus on the fact that you didn't succeed, even though you tried, you can really get very discouraged. So, what you got to do is focus on the positive nature of the effort that you put in, hoping that someday that effort is going to result in something that's much, much, much more favorable. And that's exactly what happened because years later, what went from everyone dying to essentially people leading normal lives on medication. So, support structures are incredibly important. Yeah.

[00:28:36] John Marshall, MD: so disappointed that you didn't list bourbon as one of the options, but apparently that should be lower on my list. And famously, it is 1 of my vehicles, but never, never before 6, but let's make this be clear. But anyway, so. I hear you loud and clear. And I think it's great advice for all of us. Not the bourbon, by the way, you out there listening. That's not good advice. Let's close, you know, you've as you mentioned, and you reflected in your book this incredible duration of advice, you know, the folks that you have provided insights to in our leadership of our country. And one of the areas of focus on our series right now. Is what's called the inflation reduction act, lots of us are not really aware of it, but why it's coming to a head in oncology is in fact, they're starting to talk about negotiating drug price. And so, I'm actually taking our audience back to the beginning when Bush II signed into law. The revised Medicare support bill you know, no importing of drugs and no negotiation of drug price because more and more oral agents were needed, and Medicare didn't cover oral agents. So, we needed a vehicle to do that to now Biden's institution of the Inflation Reduction Act. To now a new administration that might wipe that away. And I realize you, you don't know everything and can't see the future, but I'm just wondering what you're thinking is about what we should look forward to what ahead to in terms of health care policy and changes

[00:30:08] Anthony Fauci, MD: Well, John, that is the big unknown question right now that's causing a lot of anxiety in the medical community. For my colleagues at the NIH, for my colleagues at the CDC, at the FDA, is that, will there be a dissolution of things that were very helpful to us, and will there be new things that are put into the hopper that might impede what our ultimate common goals are. And the answer is we don't know. And that's the reason why we're in a state of somewhat heightened anxiety because of not really knowing what exactly is going to happen. So my only advice would be to, you know, think positively that the better angels will prevail and that we'll have things that are sensitive, you know, to the needs of our patients and to the things that we're responsible for doing.

[00:31:06] John Marshall, MD: But bourbon wasn't on the list for that one either. But I understand completely. Why not? We're all talking to those angels right now to make sure that what we can do and what the progress we have can continue in the years to come. 

[00:31:20] I've kept you long enough. I could keep you all day. Dr Anthony Fauci, who is really a world's leader in healthcare and global health. think of the number of people out th`1 ere in the world that he has saved. He wouldn't take credit for that personally, but we should give it to him. So, Dr Fauci, thank you very much for joining us.

[00:31:37] Thank you, John. It's a pleasure being with you. Appreciate it.

[00:31:40] Amazing to talk to Dr Anthony Fauci on his own personal experience, the impact that he's had as an individual on so many around us, but also his own reflection on his own health and his own well-being and some advice to us all. So, I hope you enjoyed our talk with Dr Anthony Fauci and will join us again on Oncology Unscripted.

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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.

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