COMMENTARY

Immunotherapy Hype and Oncologists' Fear of Failure Drive 'Hail Mary' Treatments

John Marshall, MD; Tanios Bekaii-Saab, MD; Leonard Saltz, MD

Disclosures

June 14, 2018

Editorial Collaboration

Medscape &

John Marshall, MD: Hello. I am John Marshall, chief of hematology oncology at the Lombardi Comprehensive Cancer Center and director of the Otto J. Ruesch Center for the Cure of Gastrointestinal Cancers at Georgetown University in Washington, DC. Welcome to Medscape Oncology Insights. I have two insightful people sitting next to me. Tanios Bekaii-Saab is a professor of medicine at Mayo Clinic College of Medicine and Science in Phoenix, Arizona. Next to him is Leonard Saltz, the executive director for value and sustainability at Memorial Sloan Kettering Cancer Center in New York City.

Len, we stole you from the poster session [here at the American Society of Clinical Oncology annual meeting] to come and talk a bit about a pretty spicy subject that is [one aspect of] how to manage end-of-life care. Patients have run out of options and yet, we hear all this hype about new medicines—on TV, in bus ads, and stories about how this will fix people. [The hype] is around immune therapy in particular. I believe that is where it is probably the most sensitive. Tony, what data do we have on using immune therapy in the wrong patient?

Tanios Bekaii-Saab, MD: Data about using immune therapy in the wrong patients does not exist, aside from two facts. One, we know that in most patients, immune therapy has no effect. Two, there are significant risks to immune therapy that have to be accounted for,[1,2] including the possibility of death, and a miserable death, with agents that have absolutely no value. We know that there are a lot of cancers that see absolutely no value from these immune therapy agents.

Marshall: Len, we all get backed into this corner. How do you get into this dilemma of a patient asking for or your wanting to give a treatment like this?

Patients...are coming to expect a miracle that too often we can't deliver.

Leonard Saltz, MD: It's very difficult and it's getting more difficult because, just as you say, the progress that has been made, which is legitimate, is being hyped to a degree that may be beyond legitimate. Patients are coming in primed by the Internet, primed by the advertising that's coming at them—be it from the companies, be it from our own centers—to expect a miracle that too often we can't deliver. There are great anecdotes of times when we do succeed in coming up with something very useful for an individual patient. But we have to work both to help our patients and their families, and often ourselves, to understand what our limitations are. It is important to remember that, as an oncologist, no matter how bad a situation is, we have a remarkable ability to make it worse if we're not careful.

Marshall: We could shorten our patients' survival.

Saltz: We can shorten their survival. We can take away the quality of life for the time they have. We can keep them from having those crucial interactions with the people who matter in their lives that they need to have. And we can also set them and their families up for tremendous disappointment if their hopes are too high for us to manage.

Marshall: At each of our centers we have the advantage of having access to clinical trials. So we have an excuse, right? We can always say, we have run out of standards but we do have this trial if you're eligible.

Saltz: Those last few words are so critical: If you're eligible.

Marshall: But that makes it easier on us, right? So we can talk about it. I am thinking about the community oncologist who doesn't have access to the trial. And the patient's sitting there looking fine and saying, why can't I try these medicines?

Because of market dynamic, patients will always find a place willing to give them the therapy they want.

Bekaii-Saab: Absolutely. We have an advantage, but most of the institutions that run these trials are in proximity to a lot of these community practices, and certainly our centers would be willing to see these patients to come have these discussions with us. Overall, even in academic centers—and we have had these discussions multiple times with patients—when you say "phase 1," [safety and efficacy], what they want is to try the immune therapy agent before they even think about phase 1, because they heard about an immune therapy agent that worked wonders. You see those fluffy ads on TV with people hugging each other and loving the world, and you understand. It creates that false image that frankly says, "This treatment is making a big difference in every cancer," and when we deprive our patients of that immune agent or immune therapy, we essentially are depriving them of life and quality of life. But unfortunately, because of the market dynamics in the United States, patients will always find a place that will be willing to give them the therapy they want.

Marshall: Absolutely. Even in the patient with microsatellite instability (MSI) colorectal cancer, I think about this. In our world, it's the microsatellite stable (MSS) colon and maybe pancreatic cancers, where there really isn't any evidence or data. But even in the patients with MSI colon cancer, it's not like everyone is being cured with these immunotherapies. Only half may be benefiting and getting a little better. But it's still not a home run in that group.

Saltz: If all of our other options were as good as immunotherapy for MSI patients, I think we would feel better about where we are. But there are limitations to what we can do. It is also important to remember that the MSI population is only 2% to 4% of the metastatic population. For the other 96% or more, we don't have an immunotherapy that works. Clinical trials are trying to change that, but the therapies that are starting to show nibbles of activity in the clinical trials are far from nontoxic. And so the idea that we'll have something as straightforward as the kind of PD1 inhibitors that are working in the MSI tumors for the average patient with a gastrointestinal cancer, we are not there yet. We wish we were, but we're not.

Marshall: I have never seen a time when it was so easy to get drugs off-label. You just send an [emotional] email to whichever company and, all of a sudden, they've given you approval, even without a biomarker. I believe that is also part of this co-conspiracy of giving what I would call false hope to patients and keeping that lightbulb of hope alive to try something. Have you all ever seen a precedent like this?

Saltz: It is certainly a change in strategy. Companies are being very liberal, at least several of them, with their products for off-label indications. They may be hoping to change practice in that perspective. If I thought it was the right thing for patients, it's something I would do on a regular basis. There have been circumstances where I thought we had enough data to say this makes sense in this patient population. For example, before it was in NCCN guidelines to use PD1 inhibitors [for anal cancer], but we had seen compelling data that there was activity. I was delighted that I was able to get the drug for my patients through the companies.

Marshall: But you have some evidence [of benefit in that case].

Saltz: Right. But then we went to the other extreme. Look at the atezolizumab-plus-cobimetinib data; very preliminary data got an awful lot of people very excited. And now, we're hearing that the top line of that phase 3 trial is negative. We haven't seen the details yet, but it just shows us that we have to be careful, especially remembering that this MEK inhibitor is not a nontoxic agent.

Marshall: To go further, not only did Genentech, the owner of those two drugs, go directly to phase 3, but everyone else followed based on four patients who responded initially.

Saltz: I don't fault them for going to phase 3. I fault anyone who says we can't wait for that phase 3 result.

Marshall: Yeah, or to go try to get it [outside a trial]; there was some of that.

Bekaii-Saab: But again, that reflects the dynamics of the competitive market: When you have a lot of agents trying to get into that line, sometimes you skip some [steps]. The phase 1B trial itself was not complete before they jumped to phase 3, and those numbers continued to trickle down and became less and less interesting. That also caused a lot of other companies to try to follow along. Lots of them. But that brings us back to the discussion. We have patients who got second opinions. Believe it or not, some patients do ask for second opinions beyond Mayo Clinic. And they came back with recommendations for MSS colorectal cancer for a MEK inhibitor plus a PD1. Essentially, the physicians who were discussing [this option] wrote that in their notes, saying that this [approach] is transforming the disease from a cold to a hot tumor, and this is a new hope.

The FDA...is approving drugs and regimens on the backs of relatively small phase 2 data.

Marshall: I believe the same problem holds for the FDA and regulators, that now they are approving drugs and regimens on the backs of relatively small phase 2 data. On the back of a phase 2 randomized study, the NCCN just said it is okay to give a BRAF inhibitor with cetuximab. That's a culture, right? And then the doctors become used to [the idea of] being ahead of the curve. They want to make that recommendation because who knows—the drug may be approved tomorrow, right?

Saltz: Remember, we're all looking for that next Gleevec (imatinib), which was approved on the basis of a phase 2 nonrandomized study of 43 patients. And nobody objected because if you look at those data, they are striking. We are looking for that kind of striking data but we are accepting more minimalist data. And that's where I think there is a trap.

The New York Times published an article a couple of months ago that discussed this concept, using the term "desperation oncology."[3] I didn't care for the article because it promoted that [desperation] as a sort of good thing, an understandable thing that we should be endorsing. I respectfully disagree. I would suggest that the antithesis of desperation oncology is what I call evidence-based medicine. Evidence-based medicine is what we have always said we owe to our patients, and we owe it to ourselves to demand that for our patients. When we start getting desperate, we start losing sight of our obligation to use the knowledge we have gained as doctors to guide our patients and to protect them from things that are far, far more likely to do harm than to do good.

Marshall: That is a perfect segue. Now we have the new "right to try" law. I think I know how you all feel, and maybe even corporate Pharma was unhappy about this law being passed. It really enables this sort of desperation oncology, and whether a drug is in a trial or not, in theory, it loosens the regulations around providing that drug. But it doesn't really change our world very much, in my opinion.

Bekaii-Saab: It is unlikely to change our world. It's unlikely to change much, frankly, at this point in time. The way I understand its complexity, in simple terms, is that you have to have run out of all options to get to this stage. And then there's the complexity of how you get the drug; who will pay for it; how will we get it to the patient. We have to go through an institutional review board. There are a lot of processes that have to be put into place. And then you have to convince me, [the oncologist], to give it. Frankly, it doesn't make sense. That is why we have clinical trials. That is why we ask these questions in a very standardized fashion. That is why we have the path of development for these agents. This is not a productive way to do it. But in all honesty, I do not believe it will change a bit what we do in clinic—perhaps a tiny bit, but it will not be noticeable.

Saltz: There is often a misunderstanding between trying something that has virtually no data versus situations where the regulatory mechanisms have remedied a problem and compelling data are in the public domain, and we know this is an active agent. The administrative process of approval was taking [too long] and there were patients who understandably should not have to wait for that. That is quite different from using a completely unproven phase 1 agent.

Marshall: Yeah, this [scenario] is, "My cousin Joe sent me an email. He read something in the local paper and he says you should get this drug because it'll fix me." And then the patient and the family bring that to you and you're spending all of your time defending why you're not [doing that].

Bekaii-Saab: That issue is typically taken care of by expanded-access programs. There are ways to do it.

I wish I believed that this was good for patients. I don't.

Saltz: And those have addressed many of the problems that are often cited by those who feel that "right to try" legislation is going to be a good thing for patients. We are all in the business of trying to come up with good things for patients. That is our priority. I wish I believed that this was good for patients. I don't.

Bekaii-Saab: What about "do no harm?" In many ways, the "right to try" approach can actually cause harm. This is the premise of what we do—do no harm. And I think, in all [good conscience], we could refuse instilling some of the trickle-down effects of this legislation, if it ever actually affects what we do, by the "do no harm" principle. We know that most of these drugs will prove to be quite toxic in the early phases of development. They have to be given in a very controlled way. [The dilemma is most acute] when the patient is sicker—when the performance status is very poor, when they have one foot in the grave and we are giving them a drug that could prove to be toxic or lethal.

Marshall We agree that the "Hail Mary" pass is not the right thing to do. If you have solid evidence, there are mechanisms [that can make a treatment available to the patient]. But if you don't have good solid evidence, or at least some evidence to support what you're doing, the right thing is to not give the treatment. This is the discussion we all dread the most. We have worked for 2 or 3 years with our patients, trying to keep them alive, trying to inspire them and keep that lightbulb of hope alive. And we get to a point where we are really done. Would you be willing to share a little bit about how you handle that?

Saltz: First, I believe that it is important to emphasize that we're never done with the patient. We may be done with fighting the cancer, but we are always taking care of the patient.

Marshall: That is not really true. I'll charge that your center does not let you take care of that patient anymore. Those patients go to hospice or palliative care to get care. The patients are on your radar. You are getting emails from them still—that sort of thing. But you hand them off, and it's an admission of failure. It feels like failure for us as oncologists, and I believe that is what makes it so difficult. You don't want to say that you don't have anything else for them.

Saltz: Right, but we do need to be honest with our patients from the beginning about what we can and cannot offer. In the very early phases of consultation with patients, as often as possible in the first visit, I try to get across the idea that we can help you. Your disease is treatable. I cannot realistically offer you a shot at cure. I don't have the technology that can render you cancer free. But I have things that I truly believe can be substantially helpful. And I am going to be honest with you all the way through. I am going to give you bad news when I have it because when I have good news, I want you to be able to take it to the bank and not worry about reading between the lines.

Marshall: Of course, that discussion happens at different points during your relationship.

Saltz: So much will depend on the individual patient and what he or she is able to absorb at the time. Part of our skill set when we interact with our patients is taking the temperature of the room and figuring out what the patient, family, and caregivers are able to absorb, at what time, and trying to move them in a direction that balances optimism and realism all the way through.

Bekaii-Saab: I agree completely. It is all about expectations. The most successful end-of-life discussions are the ones that begin the day you meet the patient, with that expectation in mind. These patients understand that you are trying to do everything possible to move this line from "there" to "here." But they know and they expect that there will be a time where we are going to have that discussion. Not now, but we are going to talk about it when the time comes. We are going to push it as far as possible, but when the time comes I will have that discussion and it's to your benefit, and [then] we go through the reasons why without a lot of details. That is something you nurture along the way. Every time we switch therapies, [the patient] always has the option of no treatment, regardless. Like all human beings, patients want to be in charge of their own destiny [as much as is possible]. They would like to know where they are going. They like to know their options. Often, physicians don't take the time to go through this. We say, "We're going from FOLFOX to FOLFIRI. This is good for you." No discussion.

Marshall: You two certainly lived up to your billing. [This discussion was] insightful, indeed. And I thank Medscape for letting us share our thoughts.

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