I’ll ask Jack and Gilberto to weigh in on 1 of the more interesting abstracts. This year was the phase 3 trial looking at—I think I’m pronouncing it right—aumolertinib. When I looked at the data, I thought I was looking at the FLORA trial. It’s almost superimposable on the date. Does anyone want to take a crack at reviewing the study design, or can I ask Jack to do this and give your thoughts about that?

 Sure. The AENEAS trial is aumolertinib vs gefitinib [Iressa] in a Chinese patient population with 

 mutation–positive previously untreated disease. It’s a 1:1 randomized study of 429 patients to either a treatment of aumolertinib at the dosage of 110 mg daily vs a treatment of gefitinib at 250 mg daily. This is a youngish population, so almost all patients are 60 years old and just under two-thirds of the patients in both arms were women. More than two-thirds are never-smokers, and almost all the population hasn’t had any carcinomas.

The highlight is that there was a difference in progression-free survival [PFS] that echoed what we saw with the FLORA trial and blew our minds in fall 2017. That was when we saw the data without overall survival. What we see is a median PFS of 19.3 months with aumolertinib vs 9.9 months with gefitinib, and a hazard ratio of 0.46, which is extremely significant. The response rate wasn’t very different, which is what we also saw with FLORA, and about every patient subgroup—brain metastases, age, mutation, performance status—all highly favored aumolertinib.

The safety of aumolertinib looks very good and really doesn’t have any signals of toxicity issues. If anything, it may have lower diarrhea rates than we would expect to see from some other drugs. In fact, there was about a 16% rate of any grade diarrhea with aumolertinib vs more than twice that—about 36% with gefitinib, but gefitinib is generally not that toxic. If we were talking about afatinib [Gilotrif] or erlotinib [Tarceva], the differences would be quite pronounced.

Overall, I wouldn’t want to overstate it. It’s a cross-trial comparison when we make inferences about osimertinib [Tagrisso] vs aumolertinib, but the results look astonishingly similar. It’s another agent that has a phenomenal difference in progression-free survival against a worthy competitor that we had previously thought was a great choice until 2017. It’s not against chemotherapy, it’s against another EGFR inhibitor, and we don’t have CNS [central nervous system] activity, so that has become, as I already alluded to, an aspect of something we want so that we have a choice. When you have osimertinib with CNS activity better than some alternatives, we don’t want to give that up.

We also like the tolerability of osimertinib in general—it’s not perfect, but it’s pretty darn good. Aumolertinib looks to be in that ballpark. I don’t know if we can split hairs about which medication is better, but you don’t seem to be giving up anything, in terms of tolerability, with aumolertinib. We don’t have overall survival, though I’d be optimistic that it’s going to echo what we’ve seen with osimertinib, but we don’t know that. There are some data still to be obtained, but compared with what we saw in 2017 on FLORA, this looks remarkably like that. If you had obtained that data, you could replicate it with a drug that costs less than half of what osimertinib does. To me, that’s overcoming 1 of the biggest barriers. The only thing that would make us hesitant about osimertinib is its high cost.

Gilberto, you alluded to some of your Asian colleagues, not necessarily seeing the data in Asian populations as similar to Caucasian populations. Is there any concern, from your perspective, that there’s a population issue with this Chinese experience? Or are 

 That’s a great point. Before we knew the 

 mutation story and learned about alt translocations and other rare yet significant driver mutations, we had the big question, “Is the trial, done in Japan, something we can extrapolate and use to infer what’s going to happen in California or Florida?” With 

 mutations, with the known specific subtype and the ability to stratify for all the factors that interfere, we don’t know about 

, and we don’t know a few other things that bear some importance in prognosis and predictability of treatment. But in general, we would think that these things can definitely be extrapolated.

I wouldn’t be worried that this is a trial that was done specifically in Asia. It wouldn’t be different from if this was a trial in gastric cancer, as Afsaneh Barzi can talk about later. But for patients with 

 mutations, we would believe that these data are most likely true, and we should be able to extrapolate them to the United States, the West, Europe, and Latin America.

Videos

Experts in cancer care review the phase 3 AENEAS trial with aumolertinib and the cost-effectiveness.

Review of AENEAS Trial and Similar Agents

Gilberto, give us a quick overview of EGFR inhibitors and their role in the first-line treatment of 

-mutant disease. What are the NCCN [National Comprehensive Cancer Network] Guidelines? What do you typically do in the first-line setting with these patients?

 We’ve been using, as you know, gefitinib [Iressa] and erlotinib [Tarceva]—first-generation TKIs [tyrosine kinase inhibitors]—for about 20 years, and we’re now at a new generation where we tend to use osimertinib [Tagrisso] as our first-line agent in the United States, based on phase 3 trial data showing that you get better PFS [progression-free survival] and better overall survival, even if just by a few months, as well as lesser toxicity. We wouldn’t discuss the cost of osimertinib if it wouldn’t have to be so expensive—we’re talking about a factor of 10 when you put it in—but now we have generic erlotinib in places like Canada and lots of countries in Latin America and Asia. It truly is a big difference in price, so even though it’s an amazingly effective drug, we discuss cost because it’s not a cost-effective therapy when you do usual health technology assessment. But without a doubt, it’s the No. 1 go-to option that we have in the United States.

There are different options as well. We also have the approval of the combination of erlotinib [Tarceva] with ramucirumab [Cyramza], the EGFR and VEGF pathway. In addition, in GI [gastrointestinal], we often don’t do those 2 pathways together because you don’t get better results, you might get more toxicity and possibly worse outcomes. But in the lung cancer arena, for EGFR mutants, it has been chosen. In some places in Asia, it has become the preferred choice for first-line treatment because you get a median progression-free survival that’s similar to the PFS with osimertinib. But you might have certain benefits—I don’t quite believe in them, but some of my colleagues in Asia do—such as not seeing an overall survival benefit for osimertinib vs gefitinib-erlotinib for patients who are of Asian descent or have L858R. Those benefits exist in PFS. Those are pretty much the data we have for ramucirumab plus erlotinib, so I don’t see a preference for that combination, in my opinion. I don’t see many patients in which I can’t use osimertinib. Maybe somebody who was on osimertinib and then developed CHF [congestive heart failure] would be someone you might consider, but it’s a very iffy kind of indication. I would love to hear your opinion, Jack and Mark.

 Beyond that, of course, if cost is an issue and you can’t have osimertinib covered by insurance, you can still use first-line EGFR TKIs—that would be better than chemotherapy alone.

Jack, does cost come into your thinking in this space?

 It hasn’t historically because we’ve always had a high price for EGFR inhibitors, which have gone up overtime. But osimertinib set a new benchmark for cost and also for efficacy. You’re going to go with the best treatment you can in this setting. The cost vs the efficacy, or vice versa, hasn’t been so out of proportion that it’s challenged our thinking. We haven’t had a good alternative. Erlotinib is way less expensive, enough to justify its modest inferiority. In general, in the United States at least and in much of the world, when you have osimertinib available. Not because it’s a great value but because it’s good at what it does, and we haven’t had something that’s been a competitor for it.

Gilberto or Jack, when you think about 2 of the competing first-line options that have the highest PFS, if we use that as our primary end point, that’s osimertinib vs erlotinib plus ramucirumab. Does anyone have a sense of what’s more expensive or what’s cheaper when you factor in everything with regard to financial toxicity?

 They also have to factor that in for the ramucirumab. You’re going to have to come into the practice, and you have costs associated with the infusion center, etc.

 That’s still cheaper, but not cheap enough that I’d consider it as 1 of the main options. I continue using osimertinib.

 We haven’t seen overall survival data for ramucirumab as well, so those are definitely put into consideration. If anything, you might prefer to use chemotherapy plus erlotinib or gefitinib because we have some suggestions that you might have better overall survival there, at least in Asia.

We have ongoing trials with FLORA that will address that issue too, so there are more data to come.

Mark Socinski, MD, Gilberto Lopes, MD, and Jack West, MD, provide an overview of the role of EGFR-targeted TKIs in NSCLC and the costs.

EGFR-Targeted TKIs in NSCLC and Cost

I would love to have the FDA factor in costs, financial impact, and some semblance of value to whether drugs should be sanctioned, should be approved. For instance, if there is a drug that is a lateral move in efficacy and tolerability, but significantly less expensive, that’s an incremental benefit. I think that should be factored in. You could run a trial, if it came in the same, but looking at the cost, that should be valued as much as significantly improving some hematologic or nonhematologic toxicity. I think that if a drug is very expensive and provides little or no demonstrated benefit over things that we already have, I don’t know if we need 5 ALK inhibitors or 8 immune checkpoint inhibitors that are all comparable and many of them showing the same efficacy against an old, obsolete comparator. I think it would be reasonable and appropriate for the FDA to look at, “OK, is this coming at a price that is going to change anything? Or is it just going to come in 2% or less different?” I think many companies will rise no further than the bare minimum that is asked of them, and because of that, the FDA absolves itself of any role in price and is hands off; they don’t have anything to do with that. Because of that, we are in this mess as a country, of getting so little for the incredible amount that is spent on health care in general, and cancer in specific, relative to every other health care system.

Yes, we need someone to be the first disruptor, as you said. We have a number of PD-1, PD-L1 inhibitors coming onto the market, and to my knowledge, to date there hasn’t been a disruptive cost strategy employed. I can’t believe it wouldn’t be welcomed by the payers. Very quickly, how often does the cost of the drug we’re dealing with, appealing to a payer, and all these sort of things, how often does it come up in each of your practices? Is this something that happens every week? Do you have people that deal with it, or do you deal with it? What’s it like?

: I would say we deal with it all the time. It’s baked in so much that we don’t think about it. If drugs weren’t as expensive as they are, we wouldn’t have to do peer-to-peer discussions for standard-of-care therapies. A challenging and frustrating aspect of what we do is we have to move heaven and earth to get treatments that we would say the evidence strongly supports—let alone things that are a bit more of an extrapolation. But having to pay a king’s ransom for many of these medications makes everything we do so much less efficient because we have to spend our time waiting for justification to do something that we shouldn’t be wasting our time doing.

Gilberto, did you have a comment about that? I didn’t mean to cut you off, or have Jack cut you off before.

: Jack made excellent points. I was going to comment on your last comment and say that in this country [United States], we haven’t seen drugs come in at different price points, it isn’t something we’re used to seeing. But when I was practicing in Singapore, for instance, gefitinib had just been taken off the market in the United States because the patients not selected for EGFR trials didn’t show a benefit, but we thought it had a benefit in patients who were EGFR-mutated, so gefitinib stayed on the market in Asia. Gefitinib came at a discount compared to erlotinib, so it quickly became the drug used by 80% of patients and oncologists because of the price competition. So, it’s not like you can’t have competition based on price in health care, and in oncology in particular, but it’s just that in this country, everybody’s afraid of decreasing the price today, so when they have the next drug, another company will come in and decrease their prices as well. Of course, there isn’t competition if we only have 1 drug per indication, but we now have a number of different options in the PD-1, PD-L1 arena, where I would welcome to see some price competition.

Jack West, MD, and Gilberto Lopes, MD, share their thoughts on the impact of payers when dealing with the cost of treatments.

Impact of Payers on the Costs of Drugs

Afsaneh, let me ask you, if you could wave your magic wand and make all of these therapies generally affordable for everybody, and also keep up the pace of drug development, getting to that holy grail of truly personalized medicine for the patient, what do you think is the most significant barrier to getting there?

: I think the ability of Medicare to negotiate prices of therapies with the providers is an important step in that direction. When we look at the countries that have more national health—the United Kingdom, Canada, and other countries in Europe or other parts of the world—they have much lower prices for the drugs. Health care is generally more affordable, and it covers a lower percentage of their GDP [gross domestic product]. I would say that the patients aren’t completely protected from financial toxicity, but perhaps they experience less financial toxicity. I think as oncologists we should be careful, because we are framing the benefit for our patients. I want all of us as oncologists to be careful how we frame the benefit. If a patient wouldn’t have been a candidate to go on trial X, which established the benefit of drug Y, because of their other issues, are they going to achieve the same magnitude of benefit seen in that trial?

: The answer is perhaps no. So, as we frame the degree of benefit for our patients, we should keep that in mind, and not exaggerate the benefit they can achieve, which would in essence drive them to go in a direction that increases their financial exposure to the cost of the drug. No. 1, I’m glad government is stepping in to help with that. No. 2, I want my oncology colleagues to be fair, in terms of explaining how much benefit can be achieved from a drug in different individuals, with their background comorbidities and other issues.

Jack and Gilberto, are there barriers you would point out?

: I agree with Afsaneh. That’s a great point. If I had 1 shot, that’s what I would ask for in the United States, to allow CMS [Centers for Medicare & Medicaid Services] and Medicare to have some sort of mechanism of ability to negotiate prices. As we know today, because of the legislation that was passed for Medicare Part D in the Bush administration, we weren’t allowed to discuss it. More recently, with Obamacare, there’s blame for both sides. Wedecided we wouldn’t have health…assessment as a way of deciding coverage, at least in the federal realm in this country as well. We have been shackled in the sense of being able to discuss, debate, and negotiating prices, at least for some federal programs. Having said that, I don’t want us to have the situation you have in other places, where you have a monopsony power, where there’s 1 big buyer and that big buyer decides the price. I think our way of pricing drugs isn’t optimal, and it’s not efficient. We have to be able to balance bringing in new drugs, doing the trials and bringing that research that will lead to innovative ways of treating cancer to light. But we cannot make it so unaffordable that we have a crisis in the system as a whole, so we need to come up with a better system than what we have today.

For example, as Afsaneh said, and I agree, we need to be more honest about the benefits that our drugs bring. Some of the most honest discussions I’ve ever had was when I was practicing in Singapore. We would have patients asking, “Doctor, this bevacizumab that you’re adding on adds $5000 to the bill versus $2000 for the chemotherapy. Does it really have 2 and half times the benefit that those other drugs bring?” Of course, we know that it doesn’t. I think those are some of the honest discussions that we don’t have today, and that we should. When we get the drugs that are potentially curative, those are the drugs that we need to have better mechanisms for access. This is one of the things that, I think, we’re going to start seeing more and more globally, as we start to realize how much benefit certain patients can get with immunotherapy.

Gilberto Lopes, MD, and Afsaneh Barzi, MD, PhD, discuss personalized treatment plans based on innovative therapies and affordability.

Personalized Therapies Based on Innovation and Affordability

What I struggle with a lot is that most financial toxicity is simply incurred by getting the diagnosis—being diagnosed with cancer, having to do radiation treatment, having to be admitted to the hospital. Jack mentioned grade 2 or 3 nausea, and vomiting. Do we consider the financial toxicity of antiemetic medication and all these sorts of things that we inflict on our patients? It’s easy for us to give a recommendation, or give a prescription, but there are things that are very stressful for patients. I’ve had many patients, over the years, talk about how their daughters run out of vacation time from work and they don’t have a ride to the infusion center to get treatment because she can’t take any more vacation days or she doesn’t have gas money. We all hear these stories. Gilberto, let me ask you, how much does this play into your day-to-day treatment decision-making factors?

: It depends on the setting I am practicing in that day. I practice both at the Sylvester Comprehensive Cancer Center, which is a university-based academic cancer center, and I also attend our fellows clinic at our county hospital, Jackson Memorial Hospital in Miami, Florida. It’s a slightly different world. Most of the time, at the cancer center, we have no issues accessing immunotherapies or targeted agents as long as the drug is approved and included in NCCN [National Comprehensive Cancer Network] or any standard guidelines. We usually don’t have any issues getting those approved. There are a couple of insurance companies that are a little less permissive in terms of allowing all NCCN-approved or NCCN-sanctioned, if you will, therapies to be included, but that’s usually not the routine. For most of my patients in the cancer center, we usually don’t have issues, except for co-pays and oral drugs. We can discuss that a little later. In the county hospital, it’s a little harder. We have a formulary, and it’s one of the few situations in the United States where an institution looks into cost effectiveness as a way of deciding what goes into our formulary. For instance, for patients who are PD-L1–negative in non–small cell lung cancer, I’m not allowed to use immunotherapy with chemotherapy. This isn’t because there isn’t a benefit in survival, but because the decision-making entity within that health care system decided it’s not something cost effective that they will pay for.

Jack and Afsaneh, you’re both from the City of Hope in Duarte, California. Is there hope?

: I would say, it’s interesting, in terms of factoring into our decision-making, I think of it like EGFR inhibitors and efficacy in the brain. When we didn’t have anything that worked in the brain, we didn’t agonize about it much because we couldn’t control it. It was like whining about the weather. It’s like, “What is it going to do for you?” But when you have choices, you can vote with your feet and say, “Wow, I can now choose an ALK inhibitor, or an EGFR inhibitor, and prioritize something that not only works extracranially, but works intracranially.” I think, if we have a choice of drugs that can be effective, tolerated, and aren’t extraordinarily aggressively priced, that’s wonderful. But historically, sadly, we haven’t seen that newer agents entering a market have led to a drop in cost.

: That’s been really unfortunate, and I think it would be disruptive to change that.

: But if we did, I think we would act accordingly.

: I would say there are 2 different financial toxicities we are talking about. Gilberto, when you were talking, there’s an objective financial toxicity, which is from the perspective of a payer, or from a societal perspective, thinking about Medicare. There is also a subjective financial toxicity, or what a patient experiences. That isn’t something that can be easily measured in any cost effectiveness analysis. Even if you look at a large cost effectiveness model, such as what NICE [the National Institute for Clinical Excellence] does, there is still the patient portion of the care, transportation, or a care provider, or something like that. That’s not fully pictured into that cost effectiveness model. So, we have a massive objective financial toxicity. The portion of health care in the GDP [gross domestic product] continues to rise. I look at the graph and I’m like, “Oh my gosh, where are we going? What are we taking off the plate, education?” There is also subjective financial toxicity, and that varies by individual. Even those who have good insurance that would pay for anything and everything covered by the guidelines that we want to do, those patients still experience financial toxicity because of the loss of wages. It’s not uncommon for us to see our patients lose their job and ability to work, and with out-of-pocket costs, that is outrageous. With this oral prescription drug, that is something that worries me, because the IV [intravenous] drug model for out-of-pocket cost is a little different than it is for the oral drug. That is the direction oncology is going and is something we should pay attention to.

Let me ask you this, maybe it’s because of where I’ve practiced historically, but I’ve never been in this situation and I’d be very interested in the 3 of you telling me if you have been in this situation. I’ve never been in the situation where the drug that I thought was in the best interest of the patient we couldn’t eventually get for the patient by some mechanism. I’m wondering if you’ve ever had, what must be a terrible experience for an oncologist, where what you believed to be the most effective therapy for the patient in front of you, you couldn’t get it for that patient. Has anyone had that experience?

: Gilberto, not similar to your situation, but I was with USC [University of Southern California] for many years, and we had a private cancer center. Across the street, we had the Los Angeles County Hospital, which is one of the largest hospitals, and we were providing specialist care. We had a GI [gastrointestinal] clinic, we had a lung clinic, and we had a GU [genitourinary] clinic, and all of those. There were prescriptions we couldn’t provide to these patients. These patients weren’t capable of reaching out to foundations that provide coverage for many of our patients who practice in large cancer centers. So, I have seen that, and that’s really unfortunate.

: Unfortunately, the subjects of that group are those who are the most in need of any support we can provide them.

Yes. We could spend a lot of time talking about health disparities, as we saw a little of that at ASCO [American Society of Clinical Oncology annual meeting] this year. It’s an important topic.

Experts in various specialties of oncology management share their insights on the role of financial toxicity on making treatment decisions for patients.

Role of Financial Toxicity on Treatment Decisions

 titled, “Balancing Innovation and Drug Pricing in Global Cancer Care.” I’m Dr Mark Socinski. Joining me today in this discussion are my colleagues, Dr Gilberto Lopes, from the University of Miami Health System in Miami, Florida; Dr Afsaneh Barzi, from the City of Hope in Duarte, California; and Dr Jack West, from the City of Hope. Today we are going to discuss a number of topics pertaining to how we can best balance the use of innovative cancer therapies with disruptive drug pricing, to make therapies more available to patients worldwide. We’ll also be looking specifically at EGFR-targeted therapies, as well as PD-1– or PD-L1–directed treatments to identify best practices for optimizing drug development and cost effectiveness to advance global health care. Let’s get started on our first topic. I decided I would pick on my good friend Jack West to set the stage. This isn’t a topic that we are necessarily experts in—and if I’m insulting any of my colleagues by saying that, please correct me—but it’s something we all deal with, as physicians who see patients on an ongoing basis. Jack, what do you think about this term financial toxicity, what does it mean to you, and why should we be discussing it?

: Financial toxicity, I think, is a term that has only come up in the last few years, but it’s a topic that should be considered “where have you been all my life” because as the cost of our drugs, specifically for cancer, have escalated over the past several years, or decade or two, that potentially has a negative impact on people’s quality of life because of the cost of the treatment itself. We are used to thinking of toxicity in terms of nausea, vomiting, or diarrhea, etc, but truthfully, when you have drugs that cost potentially thousands of dollars per month, that may be forcing patients to make tough choices about what treatment they have to do without, and that in itself impairs quality of life. I would say what’s also relevant is that financial toxicity is borne not just by the patient and their family, but by broader society. So some of these issues are not limited to our conversation in the exam room, but have an impact in terms of raising the cost of health insurance premiums for people who can ill afford them and are struggling to pay for basic necessities, such as heat and food, medicines, and things like that. When costs increase 5% or 10% every year for health insurance for a family, that’s a real impact. We need to choose wisely in terms of treatments that provide value, not just in terms of the patient in front of us, but for the many people we can’t see. Especially if we’re raising the cost of treatment for other people or choose not to fund other things, whether that’s prenatal care for people or roads and schools, but something has to give, and the cost of therapies needs to become part of the equation.

: I think the term financial toxicity was coined in 2009, and the reason “toxicity” was put into the name was to draw the attention of oncologists. We all know that we call adverse effects toxicity, so in order to make the name align with how we name and use this to bring attention to it, and to make it part of our routine, that name was created. I agree with Jack that it is an important concept that we have to think about. Unfortunately, we don’t have any control over it. None of us, as oncologists, set drug prices, nor prices for other practices we do. Beyond that, it’s not the patient, the consumer of our services; they’re not in control of that. Price is dictated by an insurance industry that has its own direction in terms of choosing, selecting, or reimbursing the cost. Is it important? Yes, very important and relevant to diversity, and to health equity around the world and in the United States. I think the term toxicity is used to draw attention to oncologists—this is a common term for us.

: I agree. I think that was the genesis of calling it financial toxicity. We’ve been doing health technology assessments and looking at the costs and specific clinical benefits of interventions for decades. Jack has done some of it, and I have also done a number of different analyses, in terms of cost effectiveness, budget, etc, for research. But the term financial toxicity brings it to the realm of our patient-physician relationship, and that brings forth the issue that some of our patients cannot afford a number of our newer therapies that have changed the way we treat cancer and have changed the lives of our patients. We have to remember that treatment cost can have an impact on finances, and that health care issues are the most common cause of bankruptcy for individuals in this country [the US]. While I agree that we don’t have direct control, we as oncologists have a huge role. We can see examples, for instance, when our colleagues at Memorial Sloan Kettering Cancer Center decided they weren’t going to use aflibercept, that pretty much killed the drug in the United States. I’m not a GI [gastrointestinal] oncologist any longer, but that’s one example where having the bully pulpit made all the difference. We have that power, and we are the ones who should be informing society so we can have honest discussions and debates about this issue.

Jack West, MD, Gilberto Lopes, MD, and Afsaneh Barzi, MD, PhD, provide a definition for financial toxicity.

Jack West, MD, City of Hope

Articles

Review of AENEAS Trial and Similar Agents

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Impact of Payers on the Costs of Drugs

Personalized Therapies Based on Innovation and Affordability

Role of Financial Toxicity on Treatment Decisions

Definition of Financial Toxicity