Afsaneh Barzi, MD, PhD, medical oncologist, director, AccessHope, associate professor, Department of Medical Oncology and Therapeutics Research, City of Hope, discusses the need for more sensitive minimal residual disease (MRD) testing in colorectal cancer (CRC).

Although MRD testing has become more common in CRC, there is room for improvement in terms of enhancing the validity of the predictions obtained from available assays, Barzi says. Data from the TRACC trial (NCT04050345) presented at the 2021 ASCO Annual Meeting showed that 9% of patients with stage II/III CRC who were MRD negative following surgeryrelapsed, Barzi says. Seventeen percent of patients with stage III disease who were MRD negative relapsed, Barzi adds.

These results emphasize that the risk of relapse in patients who are MRD negative is not zero, according to Barzi. Additionally, the data underscore the need for more sensitive MRD testing to better identify patients who are at a higher risk of relapse who could benefit from adjuvant treatment, Barzi concludes.

Videos

Afsaneh Barzi, MD, PhD, discusses the need for more sensitive minimal residual disease testing in colorectal cancer.


Dr. Barzi on the Need for More Sensitive MRD Testing in CRC

Afsaneh Barzi, MD, PhD, medical oncologist, director, Employer Strategy (AccessHope), associate professor, Department of Medical Oncology and Therapeutics Research, City of Hope, discusses the combination of VEGF inhibitors and immunotherapy in microsatellite stable (MSS) metastatic colorectal cancer (mCRC).

Finding appropriate treatment combinations is important for patients with MSS mCRC since immunotherapy has not proved beneficial or effective, Barzi says. These combinations could make tumors sensitive to immunotherapy, Barzi adds. The utilization of a VEGF inhibitor plus immunotherapy represents 1 intriguing combination, Barzi explains.

Specifically, regorafenib (Stivarga) is a multi-kinase inhibitor that targets the VEGFR2 receptor making it an intriguing option to combine with immunotherapy, Barzi continues. Due to regorafenib’s single-agent activity in mCRC, adding it to pembrolizumab (Keytruda) could create an intriguing combinationwith a mechanism to overcome resistance to pembrolizumab alone, Barzi concludes.

Afsaneh Barzi, MD, PhD, discusses the combination of VEGF inhibitors and immunotherapy in microsatellite stable metastatic colorectal cancer.


Dr. Barzi on Utilizing VEGF Inhibitors Plus Immunotherapy in MSS mCRC

We’re getting close to the end of our discussion. I want to thank all of you. This has been a great discussion and very informative. We’ve covered a lot of things, which we’ve expressed our opinions on. Before we close for the evening and conclude the discussion, I wanted to get some final thoughts from each of you in terms of the topics we’ve covered. I’ll start with Gilberto. Give us some of your final thoughts in closing the program.

: We still have a lot of work to do in lung cancer. We have certainly done a lot better in the past few years than we did in the couple of decades before, but of course, there’s a lot of work to do. If we look at targeted agents, most patients eventually will progress. If we look at immunotherapy, most patients don’t benefit from it. So of course, we have to continue bringing new drugs to the market, and we need to find out what this sweet spot, the perfect balance, is between bringing innovative drugs to the market and charging for them. And I don’t know that we have that answer today. We need to continue looking for that.

:I think, as oncologists, we are all trained to take charge of helping our patients and protecting them as much as we can. I think the financial toxicity is real and is here. It isn’t going to go away unless we step in, and I don’t want to say solve the problem, but be part of the solution of this real problem for all of our patients, regardless of the disease and regardless of the treatment.

: I think that we have some agency here. I used to do more GU [genitourinary] oncology, as well as thoracic, and we saw sipuleucel-T, or Provenge, basically die on the vine. I don’t think that was because the data were so poor, but because the world wasn’t ready for a drug that cost $93,000. Now, today that would be extremely restrained, but the world wasn’t ready for it at that time. Because of that, it just didn’t get uptake. We have more modern agents, like ramucirumab has a survival benefit, but people weren’t that impressed by it. It gets intermittent use as well. Necitumumab was FDA approved, but I don’t think anyone ever used it because it didn’t seem to provide meaningful benefit relative to the cost of the drug, and arguably, the toxicity. So we do have some control where FDA approval isn’t the same as a mandate to use something clinically. I think that’s especially true when you have fungible choices, like multiple ALK inhibitors or PD-L1 inhibitors, etc. We also see that when we have the enviable problem of effective treatments, we can start to pull back. Just like we had a debate about, “Well, how long is too long for immunotherapy, and can we do as well with less treatment?” I think we can start to ask that about the financial toxicity. We should ideally not have to choose between effective drugs and unfathomably ridiculous pricing. While I appreciate that we want to incentivize companies to innovate, we are too far on the end of unchecked price restraints, and have very little incentive to control costs. There’s plenty of room for companies to still make a healthy profit, for us to respect and protect that, while not giving away all controls to the point of bankruptcy and forcing us to make choices we shouldn’t have to make, considering how much money we dedicate to health care.

Thank you all. One final thought that I would render, and we didn’t have a chance to talk about this, is that if we’ve learned anything over the past couple of decades, we’ve learned that in oncology, one size doesn’t fit all. All of us would be happily willing to use a drug—I’m not saying without cost concerns—if we knew the drug was going to be highly effective. And if we knew the drug was going to have no effect, we wouldn’t use it. That brings up the issue of biomarkers, and if we can truly personalize medicine and say, “This therapy is going to work, or this therapy is not going to work,” to a greater degree than we do today. We are certainly better than we were 20 years ago, but we’re not where we would like to be with regard to using ineffective therapy in patients, which isn’t attractive to any of us. If we would have a greater ability to identify the patients who are truly going to benefit, that would go a long way to helping us with the cost effectiveness of all these things. That’s my parting comment.

I want to thank all 3 of you. It’s been a great discussion. I also want to thank our viewing audience. We hope you found this 

 discussion to be useful and informative. Thank you.

Experts in cancer management share their final thoughts on effective treatment and individualized care vs financial toxicity.

Final Thoughts on Effective Therapy and Financial Toxicity

: Let me bring up a slightly different perspective. In lung cancer, I can’t remember the last time—I think it was probably bevacizumab—that a cooperative group led to drug approval. We’ve transitioned from our government, and I think this happened, in my opinion, when Bristol Myers Squibb acquired paclitaxel in the 1980s. Drug development went from the NCI [National Cancer Institute] to the pharmaceutical industry, so if I were on the industry side, I would say, “Do you know how many dollars we spend on negative trials that never become FDA approved?” I don’t know what that figure is, but I’m sure it’s eye-popping in terms of the dollars that are spent on clinical trials for the development of drugs that never reach FDA approval, and therefore are never able to be reimbursed. So, how do you balance? We ask industry to be innovative and to bring us all these new drugs. For industry, many of the large companies are as good as any academic medical center we can think of; they have a cadre of PhD-type people who figure this out, much like our great universities and cancer centers do. How much do we balance this innovation and say, “Well, OK. We want you to be innovative, but we want cheap drugs at the same time.”

: We don’t want cheap drugs, we want drugs that are fairly priced. The way we have the system today, drugs aren’t fairly priced. What’s the ideal price of a movie theater ticket? We know what that is because there’s an open market. There’s not only 1 company making movies, there are a number of different companies making movies. You have competition in the market and the market sets that price. We have a right to patent, which is the way we used to incentivize those pharmaceutical companies to bring those drugs to the market, but we cannot abuse that patent process. We have to be cognizant that we need to bring competition to the market, and the place to bring competition is where we have several drugs for the same indication. Historically, companies have protected their turf by not bringing the prices of those drugs down. We will need new entrants that have more to win. We will need new companies not in the medium to be able to break that stalemate.

: I want to add one comment. There’s something in health economics that’s called “price elasticity.” Price elasticity for the pharmaceutical industry does not exist. What does that mean? It means that the competition doesn’t set the price for the pharmaceutical industry. The reason for that is the way the pharmaceutical industry is set up. They aren’t set up to sell to an individual, which would then drive the market to set the price. They are set up with big contracts that the individual, who is the end user, is not able to influence. So if you look back at the hypertension market, which is a big market, the lack of price elasticity is actually well described in the antihypertensive market. In oncology, we’re getting there, but price elasticity doesn’t exist. The only thing that can change that, I think, with the competition between the United States and the European market, is the introduction of Chinese companies bringing forward products with cost differences that can be drastic. Giving an example, going from $10,000 to $5,000, would redirect the contracts, and is the only thing that can potentially introduce price elasticity to a market that isn’t open to this competition to set the price of drugs.

: Let me ask you 2 questions. Do you believe that will impact innovation? And do you believe that it will have an impact on how quickly we get those drugs to market?

: If you look at the global market as innovation—the entire globe and how we innovate—it won’t change the innovation because there will be other companies in other countries with lower running costs that would still bring new products to the market. If you look at the United States, potentially, I think one thing that needs to be looked at is the cost of running the trials. When I wrote my first investigator-initiated trial in 2011, the cost per patient for the trial was in the $5000 to $8000 range, and that was with biomarkers. Now, we are talking about a cost of $30,000 to $40,000 per patient.

: I started at $1500. Mark probably started at less than that.

: That’s the problem, and we’re generating data that we aren’t using. The FDA is asking for PRO [patient-reported outcome] and quality of life that we aren’t using. We have to step back and ask, “How much of the data that we are generating are we actually using?” Maybe we should take the waste off the plate in the design of our trials. That may result in keeping the innovative market in place without impacting the cost and financial toxicity.

: And the speed to market, yes. We’re generating this massive amount of data but we never go back to use it.

I think that’s getting back to your point about flooding the market with other choices. It was part of the strategy with the FDA, to allow submission of external United States data in considerations for the drug, particularly in the PD-1, PD-L1space, where we have all these antibodies. That seems to be the most effective strategy, assuming that someone takes that first step and changes the price of the drug. If everyone has the same price because no one wants to take the step forward, then I don’t think we can get anywhere in this setting.

: I agree with Afsaneh. I think it’s going to take disruptors from outside of the United States and Western Europe, and it could be China, it could be India, or it could be Brazil. However, it looks like it’s going to be China.

: The other issue is that when they come forward, what pricing would they put on their product? Are they going to select pricing that looks at the United States market, and therefore it’s not going to make a big change? Or are they going to come in with prices that are truly different?

: Time will tell, and if they do, are we going to take them?

: I don’t know. Remember, we are not the decision-makers. That’s the complexity of health care, there are so many layers that it makes it hard for any of these things to happen.

How do we think about this in terms of moving beyond cancer? We have a bunch of diseases, such as rheumatologic diseases. There are so many TV [television] commercial for psoriasis. It’s incredible how many there are, I can’t keep track of them. I should keep a list of TV commercials that I see of all these other diseases, but I think the same issue is ongoing in other areas.

A panel of experts debate the cost of innovation vs disruptive pricing of therapy.

Innovation of Therapies vs Disruptive Pricing

 Let me make a statement, and get a consensus opinion, about the significance of PD-L1 testing in this disease. I assume we all agree that it’s the standard of care. Everyone gets it.

 If they stopped doing PD-L1 tomorrow, I don’t know if I would miss it that much.

That’s where I was going with this. I’ve evolved in my practice. Even if you’re greater than 50%, I want you to be greater than 90%, so what’s the true cutoff point? Many patients who fall into the indication for the 3 drugs here have lots of symptoms, and when you look at the scans and if they have a big tumor burden, they really need a response. I’m not doing single-agent immunotherapy. I’d do chemo-immunotherapy of some flavor—depending upon other factors, obviously—but I’ve said that PD-L1 is useful only for finding those 90% to 100% expressers that have relatively low-volume disease and minimal symptoms, where you might give immunotherapy too. That’s how my practice has evolved. Otherwise, everyone is getting chemotherapy–I/O [immuno-oncology] of some flavor. Does anyone disagree with that or want to challenge me on that?

 Actually, I’d do it a little differently. I certainly agree with the principle that you’re never going to be wrong giving chemotherapy-immunotherapy if you don’t have a driver mutation, but we discussed that we don’t want to overtreat these people either. Pemetrexed-carboplatin-pemetrexed is a great regimen, but there’s a reason it’s not in the water supply. This is a medication that you’d want patients to get if they needed it, and not before then if they’re destined to do well on immunotherapy alone. I don’t want them to be on an ongoing vestigial pemetrexed acid and pembrolizumab [Keytruda], for 4 years potentially, when only 1 is doing the heavy lifting, and you don’t know because you automatically, reflexively gave 1. I wouldn’t hesitate if someone was losing weight on repeated visits every 2 weeks, or had escalating pain, or their scan showed that their tumor significantly grew from their initial ER [emergency department] visit that led to the start of their work-up. But if someone has pleural studding as their advanced disease and isn’t very symptomatic, I don’t think 75%, 80% of patients with high PD-L1 necessarily need to get chemotherapy pembrolizumab. I don’t know exactly what it is—it may be south of 50%—but even if it’s not a wrong choice, I’d say that you’re consigning people to a lot of gratuitous chemotherapy that may just be alligator repellent.

 We have to be cognizant of the consequences of saying, “Don’t do PD-L1 testing.” Are people going to stop doing other testing? Are they going to equate that we don’t need testing? That’s not the idea. We should be careful about the talk about testing. If you say, “PD-L1 testing probably doesn’t change the treatment with regard to the immunotherapy space,” then I don’t want people to think, “Maybe we can skip testing if we don’t need it right away.” That’s 1 thing that you have to be careful about.

A panel of experts in cancer treatment review the need for PD-1/PD-L1 testing for immunotherapy. 

Significance of PD-L1/PD-1 Testing in NSCLC

 I’ll ask Gilberto to give us a brief overview of I/O [immuno-oncology] options in this setting and explain the impact that it’s had on the standard of care. It’s changed everything in the first-line setting.

 Absolutely. When we look back 10 years, when we had median survivals of less than 10 months without chemotherapy, and 10 to 12 months with chemotherapy, without a doubt that we have much better situation today. That started with the target agents EGFR, ALK, and so on. But for the majority of patients we still don’t have target agents. Chemotherapy plus immunotherapy has become the standard of care for patients that don’t have a PD-L1 equal to or greater than 50%. In that specific subpopulation, we now have the option of using immunotherapy alone, and we’ve already alluded to the 3 approved drugs: imatinib [Gleevec], atezolizumab [Tecentriq], and pembrolizumab [Keytruda]. As you mentioned, Mark, I’d be very comfortable using any of those. I tend to use pembrolizumab more than anything else in that situation, because we’ve been using it from the beginning and it was the first agent to be approved in that specific subpopulation. We also have questions in terms of using pembrolizumab in the earlier settings, but I’m not going to discuss that too much. We now have IMpower110 trial data suggesting that there’s a benefit, at least in disease-free survival, in patients who are PD-L1 1% or more and especially 50% or more. I’d be very comfortable using atezolizumab for patients in the advanced setting, who express PD-L1 at 50% or greater. I’m waiting for the approval to start pushing for patients with 1% or greater. I don’t think I’ll use it for patients that don’t express any PD-L1.

 It’s important for our audience to know, and it’s something that all of us probably see on a weekly basis in our practices, but we never saw these patients who would have these deep responses that would last for years. I’m sure all of us can tell stories, and some people that I thought didn’t have a very good prognosis and were quite sick with I/O therapy—either alone or with chemotherapy—get through 2 years. Every time I see them in the third year to get a scan every 3 months, I’m keeping my fingers crossed, but things are holding up and people are doing well. We didn’t see that before.

 What’s remarkable is a few things: No. 1, we have a bunch of targets and therapies for nonsmokers with an adenocarcinoma, but we had 10, 15 years without very much to suggest for people who didn’t fit that demographic. Some patients have a driver mutation with a smoking history, and even somewhat squamous, but not most. Too many of our breakthroughs are great news for the same sliver of patients, but this is something that’s applicable to a big, broad swath of patients. If you’re practicing in Kentucky, you see a ton of patients who can benefit from these therapies, whereas you don’t see that many Asian nonsmokers, as we do in California or up and down the West Coast. That’s great, and it’s common, in addition to the 28% to 30% of patients with high PD-L1, and immunotherapy combined with chemotherapy benefits other patients too. You’re talking about a big population of patients who have the potential to redefine what we thought was possible for metastatic cancer and get in a realm similar to what we’ve seen with targeted therapies that blew our minds 10 to 15 years ago.

I love targeted therapies—don’t get me wrong, they’re highly effective—but I don’t view them necessarily as curative. But I’m beginning to think that we might be curing some of these patients who we were all trained to believe weren’t curable. It’s very different. Dr Barzi, I want to invite you back into the conversation and get your perspective on the general concept of immuno-oncology in GI [gastrointestinal] tumors. Where do you use it? What are your thoughts? Has it been as impactful as you hear the lung cancer crowd endorse its impactfulness? What are your thoughts?

 Unfortunately, it hasn’t been as impactful in GI as it’s been in lung cancer—with the exception of HCC [hepatocellular carcinoma] or liver cancers—and it probably has changed its standard of care. In other parts of GI, not so much, but in MSI [microsatellite instability]–high site-agnostic cancer—remember, the approval for pembrolizumab for MSI-high is site agnostic—that’s the meaning of tumor biology. It’s the tumor biology that drives the outcome, regardless of where the site is. I always say that’s as close to a cure as we get. For these are patients who I’ve treated, when I get to 2 years, I stop their treatment. You still see things on their imaging, but they do fine and I don’t think we’ve seen, in oncology, at least in my area, the term of cure without surgery. Now we’re seeing that. That’s remarkable, and we shouldn’t forget about it. When you look at the immuno-oncology in other fields, immuno-oncology has a footstep in every cancer—solid or liquid—that we look at. Many trials have established their efficacy, many with guidelines. Even in small diseases—rare diseases by guideline case studies, case cohorts, or smaller studies—there isn’t an area of oncology that you look at and can’t see a footstep of some form of immuno-oncology.

Experts in cancer care management review PD-1/PD-L1 immunotherapy for patients with NSCLC and GI cancers.

Impact of Immunotherapy on Standard of Care for NSCLC and GI Cancers

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.

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.

Afsaneh Barzi, MD, PhD, City of Hope

Articles