DR LOVE: How do you explain in general to patients what tumor mutations are, what an EGFR mutation is?
DR SEQUIST: I explain to people that some but not all cancers, and lung cancer in particular, have a driver mutation. And I describe it like a light that’s been stuck in the “On” position, a signaling light. And our healthy cells go about their business, and they use these lights to signal. Sometimes the lights are on. Sometimes they’re off. And what can happen in cancer is that one of the lights can get stuck in the “On” position and just be telling the cell to grow all the time.
So the idea with genetic testing is to see which light might be driving the growth, because lung cancers could have one light or another, and the treatment is specific for the light switch. So you have to match the light that’s stuck in the “On” position with the treatment.
DR LOVE: And I guess a lot of people when they hear the idea of a genetic change think about hereditary change. But this is not a hereditary abnormality.
DR SEQUIST: Yes. And that’s really important, because people, their first thought is for their children or their grandchildren when you say you want to do genetic testing. And so that’s usually the second thing out of my mouth after I say “genetic testing,” is, “This is not the type of thing that can be passed down from generation to generation. Your children or grandchildren aren’t at risk for the things we’re testing for. These genes aren’t in every cell throughout your body. They’re only in the cancer cells. They are characteristic of the cancer cell, which is why we’re going to test your biopsy.”
DR LOVE: And we know that when you look under the microscope for non-small cell lung cancer, which is the majority of lung cancer in general, people think about it as either a squamous cell cancer or nonsquamous, something else. And this lady had a nonsquamous, an adenocarcinoma. What’s the correlation between what you see under the microscope with these mutations?
DR SEQUIST: Most of the mutations in lung cancer that we find are in adenocarcinoma, but they can rarely be found in squamous. I think that the relationship is that squamous tumors are more likely to happen in smokers. And these mutations are much more likely to happen in nonsmokers. So these things tend to run with the adenocarcinomas. But occasionally they can be found in squamous. And it’s really most important to look at the mutation type when you’re thinking of targeted therapies and not worry as much about the histology.
DR LOVE: So in the metastatic situation as opposed to adjuvant or locally advanced situation, we’re talking about palliation rather than being able to cure. What are the types of mutations that are seen? And what are the therapies that are utilized?
DR SEQUIST: So in lung cancer, there are more and more mutations being uncovered. It seems like every year, there’s 1 or 2 more. I think for someone who’s newly diagnosed, what you really want to be sure not to miss are the ones that have FDA-approved treatments in the first line available. Some of the more rare mutations are patients who could benefit from a clinical trial, and maybe there’s not an approved drug.
But the 3 big ones you don’t want to miss in lung adenocarcinoma are EGFR, ALK and ROS1. Those all have FDA-approved treatments that could be used right away in the front-line setting. And so those are the ones you’ve got to be sure to test for.
DR LOVE: And, of course, normally when you think about treatment of metastatic non-small cell, we think about chemotherapy, maybe bevacizumab. But, amazingly, there’s actually been a bunch of studies that actually randomly compared chemotherapy to targeted therapy for these mutations. And I guess the targeted therapies, the oral agents, the patients did better.
DR SEQUIST: Right. So when the cancers have one of these lights that’s stuck in the “On” position and they have a driver mutation dictating their behavior, they are supersensitive to these targeted treatments. And they tend to be more effective than chemo.
DR LOVE: And, I guess, in general, better tolerated?
DR SEQUIST: I think that depends on the patient. Certainly in the randomized trial — they’re not tolerated more poorly than chemo, but I do think as providers we can get into trouble promising patients that the oral drugs are going to be better tolerated, because some of these oral drugs do have significant side effects. And then what I’ve seen as an unintended negative consequence when it is time for the patient to switch to chemo, they’re very, very hesitant, because they think it’s going to be this horrible thing. And honestly with our chemo, especially with pemetrexed and some of the newer drugs, it’s pretty well tolerated.
DR SEQUIST: This is a lovely 69-year-old never smoker who is a college professor and started having some headache and neurologic symptoms. Came into the emergency room and unfortunately was found to have a solitary brain mass. Staging was done in the hospital and it looked like it might be from a lung cancer source, because she had a lung mass.
But with the swelling and the symptoms from the solitary brain met she went to surgery, so the diagnosis was made on the surgical resection of the brain. And she ended up having a lung cancer with an EGFR mutation, L858R.
DR LOVE: And what was the tissue type?
DR SEQUIST: It was adenocarcinoma.
DR LOVE: And was she a smoker?
DR SEQUIST: No. She was a never smoker.
DR LOVE: And when did you first encounter her?
DR SEQUIST: So I met her after that, after the surgery had been done and she knew about the diagnosis. And she was in the process of getting some radiation to the area of the surgery. And we were going to talk about systemic treatment.
DR LOVE: What was her state of mind at that point? And, incidentally, we tend to explore more about the personal aspects of this on the nursing program. What was her state of mind at that point? And what was her circle of loved ones? Did she have a spouse?
DR SEQUIST: Yes. Obviously she was shocked to find out that she had cancer, as most people are when we meet them. I think she was having a particularly hard time because it had been less than a year that her husband had passed away from cancer. I believe he had esophageal cancer. So she was really still mourning that and trying to regain her footing. So this was really quite a shock. But she did have a supportive community of friends around her.
DR LOVE: And when you saw her and evaluated her, what were some of the thoughts that you had? Did she have the disease anywhere else besides the brain and the lung?
DR SEQUIST: No. No. So we were mostly thinking about what kind of systemic therapy — her symptoms had been neurologic. And they were relieved after the treatment. She wasn’t really having respiratory symptoms. So the main thing was treatment.
DR LOVE: I guess EGFR is the most common type of tumor mutation that you see. What difference does it make in terms of what type of mutation you have? And what are the options in terms of specifically what targeted therapy to use?
DR SEQUIST: So that’s something we’re still learning about. EGFR mutations, there’s a whole family of different subtypes. And some of them are more common. Some are more rare. Most of them have a very good response to these targeted treatments.
In the clinical trials that have been done, the EGFR-positive patients have usually all been grouped together. Only in the last couple of years have we started to realize that for different subtypes, there may be preferences. There may not be, but for the different medications we shouldn’t just lump them together. We have to stratify and consider them separately. So there’s still a fair bit of discussion. I think most of the data show that all 3 of the approved drugs, gefitinib, erlotinib and afatinib, are very good for all of the EGFR mutations. There may be some subtle differences.
DR LOVE: So what did this lady end up being treated with?
DR SEQUIST: So this lady ended up being treated with afatinib, which is maybe the newest of the 3 drugs. And there is some data, though not consistent, that it might be a little bit better. There’s certainly good practical experience that it may be a little bit more toxic, too. So it’s kind of got the good and the bad side of it.
But I’ve had a fair amount of experience giving afatinib. And I do like giving it. It definitely requires more care for the rash and the diarrhea and the nail changes that you can get from EGFR drugs. So you have to be vigilant and proactive.
DR LOVE: How did she do on the afatinib?
DR SEQUIST: She did great. The beginning was rocky, I think, just with the diagnosis and her husband having recently passed away. But after a few months, she kind of got back up on her feet and went back to working full time and really did quite well.
DR LOVE: And I guess one of the things that’s interesting, I guess, about this targeted therapy is that most patients, I guess, respond.
DR SEQUIST: Yes. The response rates tend to run in the 60% to 70% range, but even people who don’t meet official response, usually they have a minor amount of shrinkage or stable disease. The number of patients who frankly progress through these treatments is very, very low.
DR LOVE: So at that point, the tumor was just in her lung, but it shrunk down on imaging?
DR SEQUIST: It had a really nice shrinkage. And of course her brain tumor had been removed. So she had very minimal disease for some time.
DR LOVE: So I guess one of the problems with these agents is that even though most people respond, most people then at some point progress. They have disease progression. How long does it usually take before they start getting worse again?
DR SEQUIST: So with the first-line EGFR drug, the average is about a year until you start to see some tumor growth. So it depends on your frame of reference. For most patients, that’s not a great amount of time. For a lot of oncologists, compared to chemo it’s pretty good. But this lady happened to get about 2 and a half years, actually, out of hers. And she just recently started to have some growth.
DR SEQUIST: So what happens is the cancer actually sheds DNA. We talked a little earlier about how the mutation isn’t throughout the body. It’s only in the tumor. That’s still true. But the tumor is near blood vessels, and so debris from the cancer falls into the blood vessels. And then it can get filtered through the kidney and go into the urine just like everything else in the blood.
So there are many companies and different academic centers out there developing tests that can look in the blood, and potentially in the urine, and look for tiny fragments of DNA that come from the tumor and actually find these mutations.
DR LOVE: And, of course, obviously it’s a lot easier to get blood drawn or give a urine specimen than actually have a biopsy, particularly in a patient where you’d have to biopsy the lung.
DR SEQUIST: That’s right.
DR LOVE: What I’ve kind of heard is a general paradigm about these blood or serum tests and urine is, if it’s positive you can believe it, but if it’s negative not necessarily.
DR SEQUIST: Right. So they’re very sensitive. And if you do see the mutation in the blood, it’s pretty believable, but not all cancers are shedding debris into the blood. So if your blood test is negative, it may mean that the DNA did not have the mutation, or it may mean there just was no DNA.
DR LOVE: What I’m hearing more from people in practice is they get the serum. If it’s negative, then they start thinking about tissue.
DR SEQUIST: And I think that’s a good way to approach it.
And now we do have an FDA-approved serum test. So when these folks were getting their biopsies, I don’t think it was approved yet. But now there’s an FDA-approved serum test, which is great.
DR LOVE: And it’s interesting. We only have seen some data on urine analysis of assays fairly recently. But I don’t hear too many people talking about it. And yet to me, it looks like if it’s positive, it gives you the same message.
DR SEQUIST: Yes. The urine tests aren’t as advanced as the plasma test at this point. Right now through commercial vendors you can get a next-generation sequencing panel from the plasma, which I really like, so not only to look at EGFR or maybe the one thing that you’re most suspicious of, but it can look at a bunch of other genes, too. And sometimes you’ll find something that can be helpful. The urine tests are just one-offs at this time, but you never know.
DR LOVE: What do we know about osimertinib both in terms of efficacy, as well as side effects and tolerability?
DR SEQUIST: Yes. So I think the osimertinib is one of the third-generation EGFR drugs, they’re called. And there’s some others in this class as well that aren’t yet FDA approved, but some of them might get there. What’s really cool about this whole class of third-generation drugs is not only does it hit the most common resistance mutation, the T790M, but it also does not hit the wild-type EGFR, the main bugaboo that gave us the side effects from the initial drugs.
So the EGFR wild type is found in the skin and the gastrointestinal tracts. And that’s why EGFR inhibitors are usually associated with rash and diarrhea. These third-generation drugs do not hit wild type, so they have very, very low rates of rash and diarrhea, very well tolerated.
DR LOVE: The other thing that I wasn’t really aware of until recently — and again, you’ve done a lot of this work — is it seems to be particularly effective in the CNS.
DR SEQUIST: Yes. That’s nice.
DR LOVE: Not just the brain, but even meningeal disease. Can you talk about what we know about that?
DR SEQUIST: Yes. So even though a lot of these oral inhibitors can get into the brain, which we had mentioned, a lot of times you still see failures.
In fact, the first patient of mine that we talked about, she had this failure in the brain as her first site. And that’s very common, unfortunately.
Osimertinib seems to be, at least in the realm of EGFR inhibitors, the best at getting in the brain. And there was a study looking at patients with leptomeningeal disease and brain mets specifically. I’ve had this with many insurance companies. You can sometimes get the drug approved even if patients don’t have T790M or you don’t know their status, if they’re progressing in the brain on another EGFR drug, because of the trials that have been done.
DR LOVE: In order to get into targeted therapy, why don’t we hear about your 49-year-old lady.
DR SPIGEL: Yes. This is a very sweet 49-year-old woman, perfectly healthy otherwise, no medical conditions ever, who presented with actually pain in her right upper quadrant. And an evaluation led to initial abdominal imaging, which found lesions in the liver. Ultimately, we found lesions that looked to be a primary lesion in the lung. Brain was clear, but symptomatic, very symptomatic in the right upper quadrant.
A core biopsy was performed of the liver, and a nonsquamous non-small cell lung cancer was discovered. But more relevant was an L858R EGFR mutation was discovered. And so we proceeded with erlotinib for her. And it’s funny, Neil. I was with one of our colleagues you know well at another meeting where she sent me a message. The patient sent me a message saying, “Dr Spigel, you won’t believe it. I took the first pill 45 minutes ago and my pain is gone.”
And I shared that with some of my lung cancer colleagues before we did our session, and they said, “Oh. That’s the placebo effect.” And I said, “Okay.” But I got back to Nashville, and we followed up. And she was completely better. Months of pain that was progressive was gone. And she really asked me if we could look early. And so I did a scan at about 3 and a half weeks, and she had a CR.
DR LOVE: Wow!
DR SPIGEL: Complete disappearance of cancer. And so it went like that. She was so happy, so thrilled that everything was going so well and life was good again. And I was shocked when, about 4 months into it, she reached out to me between clinic appointments and said, “David, I think it’s back.” And I said, “No way it could be back. We just did scans a month ago, actually, and there’s no evidence of cancer.” She said, “I just feel the pain coming back.”
So we did scans early, 1 month after her previous scan showed no cancer, and her liver was filled with tumor on this other scan. I couldn’t believe it. And she’s hurting. This is the kind of pain where we needed to do something yesterday. And so we sent off a blood-based testing for T790M. And we can talk a bit about that, if you want. But it came back very quickly with the presence of a T790M mutation.
And so I switched her immediately to osimertinib, which was approved just not long before this all happened. And the same thing happened, Neil. She said within minutes, her pain was better and she knows this is working. And we didn’t agree to do scans in 3 weeks, but she hung in there for me to do them in 8 weeks. And sure enough, she was correct. Her cancer was gone. No evidence of cancer anywhere.
We went like this for about, I think, 5 or 6 months, not a very long period, and the same story happened. She started complaining again of right upper quadrant pain. And of course I believe her any time she tells me something, because she’s right every time. And she was also not acting right. Her husband had told me that she seemed a little loopy at times, not exactly as alert as before. So not only did this time on imaging we found growth in the cancer in her liver return, we found multiple lesions throughout both hemispheres of the brain, so quite disappointing.
We can get back into the therapy in a moment, but she ended up receiving whole brain radiation and is currently on chemotherapy with carboplatin and pemetrexed, doing great.
I know we’re only about 3 or 4 months into it right now, but she also got the quick response, relief of pain, when we started that.
So a fascinating story, because we’ve seen a drug work well, designed to work that way, but not work as long as we expect it, the development of resistance. We’ve addressed that with a targeted drug, worked like it’s supposed to, but then not as long as it should, and now on to chemotherapy. And so it’s very disheartening that these great targets, these great drugs we develop, in this case didn’t do enough for her.
I included additional molecular testing we did. And she had several other alterations that we regard as very resistant mutations. And you wonder if that’s playing some role in why she doesn’t hold these responses. But kind of an exciting history and the way we helped her, but then disappointing that it wasn’t prolonged.
DR LOVE: So I want to pick out a few of the points along the way with this lady from a teaching point of view. First, going back to when she first presented, you said that she had an L858R tumor mutation. First of all, again, how do you conceptualize what’s going on? Is this an inherited type thing? Do people ever ask questions about it? And what are the different types of EGFR mutations that you see?
DR SPIGEL: Yes. That’s a real good question, because you get caught up in talking about alteration mutations as a provider. And you forget that that’s a confusing term. So not a heritable alteration. This is something that is acquired. We don’t know why. That’s the subject of a Nobel Prize, is understanding why these EGFR mutations are acquired in patients who tend to be young nonsmokers. There can be many alterations in this receptor complex, but the 2 most widely described are what are called deletion 19 in exon 21 or L858R mutations. Those are the most prevalent mutations you’ll see.
And we know that those are what’s called sensitizing mutations, which means that if you give a pill — in this case, erlotinib — it can bind that signal. I tell folks, “Think of a light switch. And when the switch is turned on, a circuit is completed. And that sends a signal to the cancer to grow. And what drugs like erlotinib do is they bind the switch, the light switch, and prevent the tripping of that circuit, disrupting that signal.” And as long as it stays in that pocket, what’s called ATP binding pocket, you prevent signaling.
Now remember, there’s millions of receptors throughout the body, wherever the cancer is. And so maintaining that occupancy or blocking of that signal is the key to these drugs working. And so we can test for this. There are simple tests that can be done, often at your own institution or sending out to an outside laboratory. It should take about 5 days these days to get those kinds of results back. EGFR testing at our center, a community hospital, takes us about 5 business days to get that result back.
If you find that mutation, that means immediate use of a pill, an EGFR tyrosine kinase inhibitor. And these days we have 2 of them, afatinib and erlotinib. Erlotinib just happens to be what I prefer in a situation like this. And it can work well in most people.
DR LOVE: Can you talk a little bit about the difference between afatinib and gefitinib and how you go about deciding between the two?
DR SPIGEL: Yes. You mentioned the third drug, gefitinib. Gefitinib is a drug that’s used all over the world, but not in the US anymore, although it’s approved in the US.
It’s just I don’t think it gets used that much. I shouldn’t say that, that I know it’s not used, it’s just erlotinib’s been here a while. Gefitinib kind of was here, left and came back.
Afatinib’s maybe the newest drug. And afatinib’s story is a bit complicated. It was late to the scene. It’s approved to be used at a dose of 40 mg a day. And that’s the problem, is that at that dose, you’ll see high rates of GI toxicity in the form of diarrhea and mucositis. And folks that use a lot of afatinib will tell you that they don’t start at 40. They start at 30 and rarely work up. Or they stay at 30 and it works fine. I think because its approval was at 40 that it’s hindered its use broadly in the US, at least. It’s a very good drug. And there’s a suggestion it may be a better drug in patients with this deletion 19 mutation, but we don’t know that. There’s not head-to-head studies versus erlotinib. So both drugs are fine.
It’s interesting right now that communities and hospitals following pathways are now having to make decisions between whether they give one or the other drug. My guess is most people use erlotinib in the US. Afatinib does get used, and it’s a very good drug. I don’t think there’s any data that would say one is better than the other.
DR LOVE: So this lady kind of also followed a very similar clinical course in that she responded to the first-line TKI, in this case erlotinib. But then after a period of time, in her case, it wasn’t that long. But sometimes it may be 9 months or a year. You see disease progression. How do you think through what’s going on at that point? And where does rebiopsy fit in at that point?
DR SPIGEL: Yes, my whole thinking on this has changed. Basically, because we have the ability to give an outstanding second drug, osimertinib, in patients with this acquired T790M resistance mutation and because we have to show evidence of that mutation to actually get that medication dispensed, the first thought is, do we need to make a change? And then how do I prove a T790M mutation?
The part about “Do we need to make a change” depends on how much cancer is growing. Is it a little bit? Are they doing fine symptomatically? I think there are these slow progressers where you don’t really have to make a change per se. Or maybe it’s a solitary new brain met you just treat with radiation therapy and keep them on erlotinib. I think that strategy can work well for a lot of people for many, many months.
But for most people who progress, they’re going to either have symptoms or clear evidence of growth. And making a change is really going to be what most people want to do. And so proving the T790M mutation, so here we are. Basically, we now have 3 ways to do it. And I hear of a fourth way being developed.
So we could either rebiopsy — and there’s ways to do that. You can bronch. You can do CT guidance. And that’s what we’ve done forever. There are blood-based tests. And without naming vendors, there’s many vendors right now that offer this testing. The idea is simple. You draw 2 vials of blood. In 10 to 14 days, you get your results back. And then there’s urine-based testing, something I just have not been a believer in, because the other 2 ways work fine for me.
Let me give you 2 quick examples of why the way I practice has changed. So I care for an elderly woman who’s been on erlotinib. Erlotinib has stopped working, and she doesn’t like it. We’ve lowered the dose, and it’s toxic. So we drew blood testing on her to look for a T790M. She’s about 87. We drew it, and it didn’t come back, wasn’t present. I waited about 2 months and drew it again, because we strung her along with low-dose erlotinib on alternate-day schedules. And her cancer wasn’t growing that fast. But it came back negative again.
So then I talked her into a navigational bronchoscopy biopsy. I’m fortunate to work with a colleague who just has convinced me that can be quickly and safely done. And indeed, that’s what happened. So Neil, we did this biopsy in an 87-year-old woman. It came back positive for T790M. She’s on osimertinib. I saw her last week. She’s a month into it, doing great. So that taught me that you can’t just stop with blood-based testing. You have to go after tissue.
So then I manage another woman who has progressed in her brain on erlotinib. And she’s desperate for something new. She can’t do a clinical trial, because of the brain issue right now. And she knows about osimertinib. She wants it. So we did 2 things. We drew a blood-based test on her — came back negative. Then we had biopsied the brain lesion. We actually excised it, because it was symptomatic. And we tested that, Neil, and there was no T790M in it.
And so she said, “Is there any other way to get me osimertinib?” And I said, “No, but there is this urine test. We could try to check.”
So I drew urine on her, and it came back with T790M in it. And so we’re going to start her on osimertinib based on that test. And so now I’m wondering, “Do I have to draw urine on everybody?” Maybe that’s the only test I draw. I know one of our colleagues, Heather Wakelee, she tells me that she does the 3 tests on a lot of her patients. I’m a believer in that strategy.
You don’t want to get cost involved here. And somebody looks at this and says, “Oh, that’s rare, David. It’s expensive. You can’t do that in everybody.” I don't know. I’m a believer in it right now.
One of my colleagues has complained a little bit about the urine test and the quantity of urine. Collecting it in clinic that day is not easy. But in this case, it was as simple as it could be. And I’ve heard there’s a saliva-based approach being developed.
DR LOVE: Saliva. Oh. So that’s the fourth way. Interesting.
One more question about osimertinib. One of the things that we’ve heard is that the tolerability is much better than with afatinib and gefitinib in terms of the classic EGFR-type reactions, like skin and bowel. Is that what you find in your own practice?
DR SPIGEL: Yes. I mean, a lot of people on osimertinib now. It’s been on the market for over a year. Yes, I would agree with that wholeheartedly. You know very well, though, patients with these sensitizing mutations, with any of the 3 approved EGFR first-line drugs, you can get to that tolerable dose for patients. But you’re right. With osimertinib at 80 mg, you often don’t have to dose reduce. You just keep them on that dose.
DR LOVE: The other thing I’m curious about is, I’ve heard stories — and, actually, I think there are data in the literature — about the issue of osimertinib and brain and CNS mets. And my understanding is that you see responses in the brain and, actually, even with carcinomatous meningitis with osimertinib. Is that your experience?
DR SPIGEL: Yes. Yes. I’m not ready to jump on that bandwagon yet. I’ve not been convinced of it. And I still think it’s the greatest challenge we face in oncology, if not lung cancer, is dealing with the prevention of carcinomatous disease or CNS disease. It’s just there’s nothing more frustrating than doing well systemically and then having problems in the brain. It’s the big failure that we’re all dealing with, that we haven’t solved that problem. I hope osimertinib can do better. I hope the ALK inhibitors can help solve a lot of that too, in that space. But we haven’t come close to solving that.
MS REED: This is a 44-year-old white male, nonsmoker. His mother actually passed away from lung cancer when she was in her forties. She was a heavy smoker. But he lost his mother when he was very young and, therefore, had a long aversion to smoking. He is an accountant, so he was planning his wedding, going about his ordinary life. And he developed a dry, hacky cough. He lives in the Southeast near Nashville, where we have atrocious allergies. They’re pretty notorious. It was spring, so he thought it was allergy season, just ignored it. It was tax season for him, wedding planning time.
So he got married in May, went on his honeymoon for 2 weeks and when he got back, his now wife finally convinced him to go for evaluation, as wives do.
And he went and had a chest x-ray, which unfortunately showed a large left hilar mass. Further workup showed other areas concerning for metastatic disease. He underwent a biopsy, which was non-small cell lung cancer. And then several days later, we found out that he did have an ALK rearrangement.
So he was initially started first line on crizotinib. He tolerated it well. Like a lot of patients on crizotinib, he initially had the visual disturbances, this phenomenon where they see kind of light changes going from light to dark in rooms and vice versa. It can be alarming to the patients. Fortunately, it’s not harmful. This patient described it as psychedelic. So those did resolve with time, and he did well and tolerated crizotinib well and had a nice response.
But about 9 months in, he unfortunately did develop a seizure. And so at that time, he ended up in the emergency room. And a workup revealed brain metastases. And he had enough brain metastases to where he needed whole brain radiation. Obviously at that point, too, he had true disease progression, so it was time to move on to another line of therapy.
So he underwent whole brain radiation, and then he was started second line on alectinib.
And right when he started alectinib he did very well, but he actually started responding really soon. He had a great response. He had had some other systemic, mild systemic progression as well, not too much systemic progression. It was more in the brain. But, of course, the brain mets were treated with the whole brain, but he had continued shrinkage even when he started alectinib. So we feel that the alectinib definitely has helped him continue to have benefit in the brain. It tends to have more brain benefit than a lot of other targeted therapies, especially crizotinib.
DR LOVE: What’s his current situation?
MS REED: Yes. His current situation, he had minimal disease at this point, and he had large brain mets. He had some 3-cm tumors. And at this point, they’re pinpoint. And he’s been on alectinib going on 3 years, so he has gotten excellent brain protection from it and really just some pinpoint lesions that have been very stable.
Now, he does still have some deficits just from having the whole brain radiation. He still manages to work full time, but a somewhat modified schedule as an accountant. But overall, he’s done very, very well. And he’s tolerated the alectinib very well. He’s had some mild fatigue, but no major issues with constipation, swelling and some of the other side effects.
DR LOVE: So he’s basically had metastatic cancer of the lung now for 4 years and is walking around with fairly minimal disease, feeling pretty good.
MS REED: He is. It’s really, truly remarkable. I wish we could see this in all the patients.
DR LOVE: And what’s happened in terms of his personal life? You mentioned that he’s working, but what’s going on — I’m not sure. I guess he already was engaged at the time that he found out about this diagnosis. What’s been going on between him and his wife during this time?
MS REED: They’ve definitely had to change their life plans, given the situation, even though his cancer has been more manageable than most metastatic cancers. I think when they were planning their wedding, planning a life together, they planned on children. And they’ve had to rethink that. And that’s one other thing that, when you have these young patients that you sometimes have with these mutated lung cancers that tend to occur in young nonsmokers, they do have to change their life plans.
We obviously do a good job educating the young female patients about contraception, but sometimes people forget to educate the male patients, but the same applies for them as well. So then they’ve had to rethink their long life plans. They instead have animals that they focus on and are really just focusing on enjoying their time together has been their priority.
But I think it was really hard for him emotionally when he got the diagnosis, because he had already lived through losing a parent to lung cancer. And he saw the same thing waiting for him. Of course he didn’t have children, but all of his life plans were completely uprooted at that point.
DR LOVE: So I want to go through a few of the teaching points of this case and also hear a little bit about how you explained things to him, because I’m always curious about how people try to get across some of these concepts to patients. Now, he’s an accountant, so maybe he can understand things a little bit better, maybe, say, than the average person. But I’m curious how you explained to him what kind of lung cancer he had. He has ALK-rearranged lung cancer. How did you explain that to him?
MS REED: Right. So for him, he does have a higher degree of understanding, higher educational level than many patients. But it can still be very complex to explain that. I explained to him that the type of lung cancer he has isn’t the typical lung cancer that a smoker gets. Especially the laymen, they all still correlate lung cancer with smoking and assume it just happens to smokers. And this particular gentleman had lost his mother, a heavy smoker, to lung cancer.
So we explained to him that the type of lung cancer he has usually is not in smokers. It’s a very small population. It oftentimes affects younger people but that he has a genetic rearrangement that’s driving his cancer, and so we now have targeted therapies available to block that and prevent his cancer from being able to divide and survive.
DR LOVE: When you sit down with a patient to start the crizotinib, what are some of the things that you go over with patients?
MS REED: Right. Definitely the visual disturbances with the crizotinib. That’s one of the top ones. We also talk to them about the importance of keeping their follow-up appointments, because of the potential for liver toxicity. This particular gentleman did not experience any liver toxicity, but some patients certainly do. It’s one of the things you worry about with crizotinib. And so talking to them about keeping their appointments, showing up for their appointments and explaining why they need to have lab work checked, why they need to show up for these appointments is very, very important.
Some patients can also get some GI toxicity from crizotinib. So we certainly talk to them about that. And then again, these ALK-rearranged lung cancers can occur in young patients that are still of childbearing age. And oftentimes, people forget to discuss that with patients. We’re used to, in the cancer world, taking care of older patients oftentimes. And we have these lung patients that are younger. It’s easy to just skip over that, but it is a very important educational point for these young patients.
DR LOVE: What point are you talking about? Actually, are you talking about the issue of conceiving a child while on this drug?
MS REED: Exactly. Yes.
DR LOVE: Really? I never thought about that. Do we know anything about whether that’s safe or not?
MS REED: It’s not recommended. It’s not been studied. I don’t think anyone would want to study that. But it is not recommended for both males and females.
DR LOVE: Really? That's interesting. Hmm. What about quality of life? And I don’t know how many people you’ve actually treated with crizotinib. I mean, these are not that common. But do most patients feel well on crizotinib?
MS REED: Patients feel great on crizotinib. And these patients with newly diagnosed lung cancer, they come in to see you, they think they’re going to get chemotherapy. They think they’re going to be knocked on their feet, lose their hair, unable to work, nauseated, vomiting, kind of that whole picture of what a cancer patient has historically looked like.
And so these targeted therapies, it really kind of changes the face of their treatment. Most of these patients feel really good and are able to continue with their normal activities, work and do whatever they want to do for the most part.
I think one of the key things, though, is keeping an eye on their brain when they’re on crizotinib and really asking them about any developing neurological issues and remembering to order some routine imaging every now and then. It’s hard to get insurance, sometimes, to pay for imaging of the brain if a patient’s asymptomatic. But oftentimes you can manage to get one squeezed in there every 6 months or so with no insurance issues.
DR LOVE: What are some of the neurologic symptoms you specifically might talk to a patient about?
MS REED: Right. Well, this patient, obviously, when he developed brain mets, his was pretty dramatic, what you don’t want are the seizures. But asking them if they’ve had any headaches, and then, of course, when they’ve had the visual disturbances, which they can get from crizotinib, those typically happen early on and then resolve. So if you’ve had a patient on crizotinib a while and they start to develop other visual disturbances, new visual disturbances, make sure there’s been some imaging of the brain.
Also some focal weaknesses, maybe some weakness on one side of the body, one extremity, that type of thing, those are some telltale signs, even some paresthesias or some numbness on the face, kind of around the mouth area. That’s kind of another sign that would make a red flag go off and think, “Uh-oh. We need to scan their head.”
DR LOVE: We’ve been hearing about these visual things with crizotinib ever since it first came out. What do patients actually tell you? I’ve heard something about when they go from dark to light or something. What do they actually say? And what did he say?
MS REED: Yes. This is the patient that used the term “psychedelic.”
DR LOVE: Yes, I’ve heard that.
MS REED: And so he said that when he would go from one extreme where it was dark to another extreme where it was light, it would almost be like yellow flashing lights that he would see, and then it would resolve. And he was anticipating it. We had educated him up front about it, so it wasn’t quite as alarming. But if you forget to tell your patient, it can be really scary for them.
DR LOVE: And so does this just happen when you go from dark to light, or is it with them all day long? What happens?
MS REED: It’s mostly, from what my patients have told me, with changes in light. But some do experience it more than others, sure.
DR LOVE: Wow! So what about alectinib? So you’re saying it doesn’t cause the visual disturbances. Do you see anything with alectinib?
MS REED: Alectinib, people feel good. He felt great on alectinib. And most of my patients on alectinib have felt great. A lot of them have fatigue. And it’s hard to know with any of these cancer drugs. Is it disease? This particular gentleman had whole brain radiation.
He’s got a lot other factors playing into it, but fatigue, some constipation, some swelling as well.
Another thing to make sure to educate patients about that are going on alectinib is the photosensitivity, especially in the summer months. Oftentimes, we do forget to educate them about that. And then again, checking their liver function tests, making sure they’re coming in for these toxicity checks and lab work as appropriate.
But he’s felt really well and done very well and still been able to work a modified schedule and travel and enjoy life while on alectinib.
DR LOVE: Have you seen patients respond in the brain to targeted therapy with, for example, alectinib or crizotinib?
MS REED: Not to crizotinib. Crizotinib just doesn’t penetrate the brain as well as some of these newer-generation ALK inhibitors. But we’ve definitely had some patients on alectinib, and even a newer-generation ALK inhibitor, lorlatinib, with great responses in the brain without treatment, specifically radioactive therapy to those brain mets.
MS KELLY: So I think when patients are first diagnosed with metastatic lung cancer with an ALK mutation, we typically put them on crizotinib. Alectinib is great for patients with CNS disease. It has better CNS penetration. But I still think the norm is to start our folks on crizotinib.
And when I do the teaching session with these folks, it’s a lot like my EGFR patients where I talk about that it’s a specific mutation to their cancer, which turns their cancer on and not something that they inherited from their family or will pass on to their children.
And the side effects for the ALK inhibitors are some changes in energy, some changes in appetite, sometimes some visual changes with crizotinib, so floating or trailing lights, difficulty with transitioning from a dark space to a light or vice versa. There’s a rare risk of pneumonitis. Sometimes they can have elevation in their liver function tests. Crizotinib can cause esophagitis or nausea/vomiting, diarrhea, sometimes some lower extremity edema, even some upper extremity edema.
I do have 1 patient who actually developed significant esophagitis related to her crizotinib. So I think you always have to be mindful of reminding patients that they have to take their crizotinib with a full glass of water and sit upright for at least an hour after dosing. I have to admit that I didn’t always remember that teaching point until I had this patient develop really a significant esophagitis, so lots of painful belching, pain with swallowing, heartburn, nausea. She was referred to the GI group and was found to have a bad esophagitis and was put on high-dose omeprazole for about 12 weeks until it eventually improved.
She went on to then get alectinib. And alectinib was much better tolerated. She didn’t have the GI side effects. Folks on alectinib don’t typically have diarrhea, don’t typically have the visual disturbances, don’t typically have issues with edema. Sometimes we still see elevation of their liver function tests, elevation in CK and so some muscle aches and pains, requiring sometimes a dose reduction. And the benefit to the alectinib is it has better CNS penetration.
We don’t use ceritinib all that much. I think ceritinib unfortunately has more GI side effects. We’ve certainly seen patients with more nausea and diarrhea on the ceritinib. And then we have the benefit, like I said, of having a lot of clinical trials at our disposal.
And so we have a fair number of patients on lorlatinib as well, which I think is the next ALK inhibitor, also really well tolerated, not as many GI side effects, obviously, as crizotinib. Some issues with edema we’ve seen with lorlatinib. We’ve certainly seen issues with increased appetite on that therapy and significant weight gain in some of our patients. And lorlatinib can also cause some mood changes.
DR LOVE: Checkpoint inhibitors, obviously the most exciting story not just in lung cancer but I think in oncology in general. First of all, I’m kind of curious what your vision is and how you explain to patients what a checkpoint inhibitor is.
DR SPIGEL: The conversation has changed to really the 101 class on immunotherapy to, “Oh, I’ve heard about that, David. Not only have I seen commercials, but I know President Carter’s situation. I know exactly what you’re talking about.” So it’s interesting how much has changed in just a short period.
But usually what I tell folks is kind of the simple story of can we give you a therapy that stimulates your body’s own immune system to fight cancer for us? And whether we’re successful at that depends on a lot of things. That may have to do with just your innate ability to mount an immune response. It might be because of the drugs we use or the combinations we use. But these therapies, now 3 in lung cancer, are all approved because they’ve shown improved outcomes. And, pointedly, they’ve allowed patients to live longer compared with patients who’ve received more standard therapy, namely, docetaxel.
So usually when you talk with patients, they kind of want it as their only therapy, because they’ve heard about it and they view it as this, I guess, newer and perhaps safer way to treat cancer. And it’s anything but chemotherapy. And I think that’s its appeal.
The one thing that’s changed for me in the last few years has been my discussion of safety. I mean, I guess I was guilty of probably not getting too deep into the safety conversation, because our experience was so good with most people. One percent of folks were experiencing really serious issues. But now, with longer use and follow-up of patients and different agents, the profiles we’re seeing deserve a really broader discussion with patients about if it’s a different safety concern.
These are still unusually rare. But when you get them, they could be quite serious, even life threatening. And we talk about it. And then the question is, “How would we deal with that, David, if that developed?” We’d use steroids or even more serious drugs that can soften your immune response, if that were to happen.
So very much endorse immunotherapy, the checkpoint inhibitors, the combinations that we’re studying. But we certainly do a much better job, or I do, of balancing out the toxicity risks that we see.
DR SEQUIST: So I think a really important thing for new diagnoses of lung cancer, squamous or adeno these days is to get PD-L1 testing, because now we can use immune therapy in the front line.
DR LOVE: Can you explain what PD-L1 testing is and how it relates to checkpoint inhibitors?
DR SEQUIST: So PD-L1 is a stain — it’s an immunohistochemistry study. So it’s not looking for a genetic change like EGFR, but it’s looking at does the tumor pick up this stain or not? And it gives you a percentage from zero to 100. And if the percentage is above 50%, we can use immune therapy in the front line.
I mean, the PD-L1 testing is a little different than the genetic testing. If you come back with an EGFR mutation, you have a very, very high chance of responding to an EGFR inhibitor. The PD-L1 doesn’t — it does correlate. The higher your PD-L1 is, the more likely you are to respond. But even low numbers, it doesn’t absolutely rule it out. It’s more of a best guess. It gives you a lead. But there’s been a lot of controversy and discussion about understanding PD-L1. There’s different stains that you can use. Different companies had been using different stains. So I think we’re still learning about it.
DR LOVE: So, of course, checkpoint inhibitor, if the patient has an elevated PD-L1 level is a great option, a lot less toxic than chemotherapy.
But for the patients who aren’t going to get a checkpoint inhibitor, how do you sort through the various chemotherapeutic options that you use in metastatic squamous?
DR SEQUIST: I think pemetrexed is the only lung cancer drug that really isn’t approved in squamous. It doesn’t seem to be as efficacious. You have lots of other good choices between paclitaxel and nab paclitaxel. You’ve got gemcitabine, and of course you can use docetaxel.
And even ramucirumab, one of the VEGF inhibitors, is allowed in squamous cell, although I haven’t been using it much in squamous cell. But there’s lots of choices. I tend to use a platinum with either gemcitabine or a taxane up front. And then whichever one I didn’t use, I use that later, after immune therapy, as well.
DR LOVE: You mentioned ramucirumab. Can you explain what that agent is and in what situations, if any, you use it?
DR SEQUIST: Yes. So it’s kind of a cousin of bevacizumab. It’s a VEGFR inhibitor. And it’s approved in combination with docetaxel in the second line. It’s approved for both squamous and adeno patients. It improved outcomes compared to docetaxel alone. And the thing is that it didn’t improve outcomes a whole heck of a lot, just slightly, and it did increase toxicity a good amount. So I think that it’s something to consider in very robust patients. But now that immune therapy has come out, we have really good second-line options with immune therapies. So I think ramucirumab is a little lost in the transition to immune therapy.
DR LOVE: Another agent that you hear discussed in squamous cell is the anti-EGFR antibody necitumumab.
DR SEQUIST: That’s right.
DR LOVE: What is that? And again, in what situations, if any, do you utilize it?
DR SEQUIST: So that’s an EGFR monoclonal antibody. It’s a cousin of cetuximab. And it is approved in the front-line setting as a triplet regimen with chemotherapy. And again, this is one of those trials where technically it was positive. Statistically, the p-value was less than 0.05. But realistically and practically, it doesn’t improve things too much. It looked like it added a little bit to the chemotherapy.
DR SPIGEL: She’s a woman I met about 3 years ago who presented with advanced squamous non-small cell lung cancer. So she was pretty sick with dyspnea and a cough. She’s a heavy smoker and so somebody you would just say has bad bronchitis all the time. But she was sick from her cancer.
And her imaging, Neil, has been very complicated for us, because she’s got a large cavitation in her right upper lobe that either has cancer or infection in it at any one time or both. And so that’s always played some challenge in interpreting her response to therapy.
So here’s what happened in her care: We went through the normal evaluation with imaging, staging, looked at her brain. That was clear. And her disease is primarily in both lungs. She does not have skeletal involvement and actually does not have any other visceral involvement, just bilateral lesions and symptomatic. We do profile patients even with squamous cancers at our center, but there wasn’t anything immediately targetable in her profile. And so we offered her, actually, a trial.
Normally outside of a trial, I would probably treat a patient like that with platinum and a drug like gemcitabine or paclitaxel or nab paclitaxel. But we had a study at that time, I know you think we all only put patients on studies, but we had a trial at that time that was pretty good. It was carboplatin and paclitaxel. And you got randomized to a PI3 kinase oral inhibitor. She went on that study and did well for many, many months.
And then about that time, immunotherapy trials were just really hitting their stride. And so she progressed on that study and we had an opportunity to enroll her on a nonrandomized study that was, at the time, atezolizumab, or MPDL3280A. It’s the PD-L1 inhibitor alone. So that was the therapy. You didn’t get randomized — you didn’t get it with chemotherapy. You just got atezolizumab, and it’s as a single agent.
So here’s the interesting part of her story: She went onto it, and she did well. We watched her for many months and were happy to report her progress to the company, the trial sponsor. And then we started noticing growth and changes in that cavitary area. And we had conversations with the study team. And the study was very generous in allowing us to keep her on longer. But we reached a threshold where, by criteria, she progressed. And I had to take her off the drug.
So that’s what happened. And she went on. She had these changes on her scan that forced her to come off the study. But she was asymptomatic. I ended up having her go onto another study — it’s a side story, but it’s docetaxel with a drug called a WEE1 kinase inhibitor, pretty interesting drug looking at cell cycle inhibition. But she didn’t like this combination at all. She had a lot of GI toxicity and came off that very shortly, not for progression but for GI toxicity. She never really had any change in her tumor even with that therapy. The side effects forced her to come off.
So here we were deep into her therapy, still asymptomatic, and these scans that had this large cavitary area. And she says to me, “David, why can’t I just go on nivolumab? It’s on the market, approved. Is there a problem with me getting that?” And I said, “No.” And she said, “You probably should have left me on that other drug,” and I said, “I should have, but I couldn’t. But we can do nivolumab.”
And that’s what we’ve done. And we’re now almost a year and a half on nivolumab. As I said, I just saw her this past week. She’s doing great. Her scans don’t look any worse — we have times where some nodules go away. In fact, this last week we had scans. And some nodules went away. But as it turns out, there’s a little rim just inferior to the main cavitary area that’s larger. And she and I talked about this. And I said, “I don't know if that’s slow progression, but you’re doing well. Let’s watch you further.”
And when I reflect on this, I say, “I think she’s basically been on immunotherapy now for 3-plus years, doing well.” I don’t even count the docetaxel piece she got in between. And that’s what the experience tends to be for other patients on a variety of these checkpoint inhibitors is this steady period of no real changes on the scan, no symptoms, feeling well. And except for having to come in to see you, I think it’s as good a quality of life as you could hope for most people.
DR LOVE: I guess, as you said, the intriguing thing about these so-called checkpoint inhibitors is that sometimes you see these prolonged periods of benefit. Is it more likely to see that if the tumor actually shrinks, or you’re just as likely to have that happen, like with her, where it kind of really doesn’t change?
DR SPIGEL: I think the data suggests that the responders have the longest disease control. But there’s more people who don’t achieve a response. The response rate in the refractory setting is about 20%. There are more people that won’t get a response. And they also seem to have prolonged disease control, a little bit more variable.
This is the group that most interests me and where I spend a lot of time I don’t want to say educating, but talking to my colleagues about being careful about the decisions you make. You certainly don't want to keep somebody on a therapy that’s not helping them, expensive therapy that does have side effects. But if you think they’re doing well and there’s a chance they’re benefiting, I’d rather err on the side of keeping them going rather than spill to docetaxel or ramucirumab or something else.
So I think that’s the struggle. The worst thing you could do, though, is keep somebody on a failing therapy just to do it because it’s easy and you don’t want to make a change for whatever reason. That’s the mistake. And I’ve probably gone down that path a few times. I’m trying to learn better about not doing that. But I do think we’ve got to learn a lot more about how to manage people that don’t get these dramatic responses but are seeming to have good disease control.
DR LOVE: Just a couple of other points about this case, first of all in terms of her initial therapy for metastatic disease — again, this is squamous cell cancer as opposed to nonsquamous — she got carboplatin with paclitaxel. You mentioned the other 2 common doublets using nab paclitaxel or gemcitabine. From your point of view, what are the advantages or disadvantages of each, and why, for example, in this case — she was on a trial. But what do you normally do outside a trial? Which one of these 3 do you use?
DR SPIGEL: Yes. I’ll tell you. I’ve thought a lot about this and considered the economics of it and toxicity profiles.
My preference these days is nab paclitaxel, and I’ll tell you why. It’s a weekly schedule, and that’s not good. It’s the neuropathy. Gemcitabine is a fine regimen. I’ve used it for a long time. I find that you can only push that so far before you start getting more thrombocytopenia and the nuisance of fevers, even, in patients.
Paclitaxel’s a great drug. We tend to give that in an every 3-week dosing. Alopecia is sooner with that. But neuropathy is the problem. So neuropathy with paclitaxel compared with nab paclitaxel will be greater and less reversible. And so I proceed with nab paclitaxel. And you throw in the fact that the response rate appears to be higher with that combination than with paclitaxel — I know it’s more expensive. And I think if you could throw cost out, it’s clearly the winner to me. But I get the cost issues, and I deal with pathways and the issues we face in the community setting. And so I think paclitaxel and gemcitabine are very reasonable regimens, just not my first choices.
DR LOVE: So another issue about nab paclitaxel is that you don’t need to use corticosteroids.
DR SPIGEL: That’s right.
DR LOVE: And there’s a shorter infusion time. From a practical point of view, how important is that from your point of view?
DR SPIGEL: Yes. That’s a real good question. The shorter infusion time doesn’t really bother me. I think community oncologists kind of get knocked — they need that to be true. But that’s not true. I mean, I think it doesn’t really help you treat more patients or less patients. I think for the patient, him or herself, yes, being in a chair in a clinic, less time is more important than sitting in a chair a much longer period.
The steroids are really a big issue. I think patients love the steroids in the beginning. They like the feeling they get. And you can give that to them any time you want. But when you start getting deeper into therapy, to have to keep doing that, you start to realize that the steroids have more negative consequences than positive. And so a steroidless regimen, I think, is preferable, if you can get away with it.
DR LOVE: What are some of the options down the line both for squamous cell as well as nonsquamous after you get past a checkpoint inhibitor? And two that I’m curious about that are fairly new, one is the use of ramucirumab with chemotherapy and the other is necitumumab, the anti-EGFR antibody. Can you talk about what we know about those agents and any other new approaches, again, after checkpoint inhibitors?
DR SPIGEL: Yes. It’s a great question, and the field is really changing right now. Since the fall, we’ve realized that there’ll be about a third — 30% of our patients, 25% to 30%, are going to be getting immunotherapy up front. And I think for those patients, doublet chemotherapy will continue to be standard for them, whether it’s squamous or nonsquamous.
I think for the more difficult situation, as the one you’re pointing out is, they’ve received platinum doublet chemotherapy. They’ve received a checkpoint inhibitor. Now you’re looking for something else. What is that going to be? Is it going to be docetaxel? Doctors hate doing that.
Is it going to be ramucirumab? I think that’s the logical kind of next step. That regimen was already approved before drugs like pembrolizumab and nivolumab became more standard.
But I’ll tell you, as much as that makes sense, I don’t think there’s a lot of doctors doing it. I’ve used that regimen once in this situation. And I’m not sure why that is. Maybe because you’re third line and it’s not as appealing to give a patient a combination regimen like that. That regimen is approved for squamous and nonsquamous. And remember, it was approved after first-line chemotherapy, not necessarily after immunotherapy.
There is necitumumab. Neci’s had some challenges. Its approval, of course, is in squamous lung cancer. It’s approved with cisplatin. It’s a cisplatin-based regimen, gemcitabine and cisplatin. And I don’t think that’s very popular. I don’t think a lot of doctors are using that first line. And I don’t think there are doctors who are using neci by itself. It wasn’t approved to be used that way. I use necitumumab. We’ve used it in studies. It’s a drug that is, I guess, similar to cetuximab but perhaps less dermatologic issues.
The DVT risk is still there. There’s a cardiac issue with arrhythmias that we watch for. I just don’t know how much necitumumab-based therapies are actually being used. I don’t think it’s wrong to consider it for somebody who’s never been exposed to it, but technically the label is not really in that setting, certainly not as a single agent.
I don’t think erlotinib is a choice people are pursuing anymore since its label’s been changed. Afatinib is interesting. It’s a drug I think some people consider for squamous lung cancer in this refractory setting. My own option is that’s probably not the most active option for a patient. But, admittedly, there’s not a lot of great options in terms of active regimens in this line anyway. What I end up doing is choose single-agent chemotherapy on some friendly schedule, whether that’s gemcitabine or weekly docetaxel. But that tends to be, I think, where most doctors go outside of a trial.
DR LOVE: Can you talk specifically about the way these agents typically cause toxicity? And what are some of the common side effects and problems you see?
DR SPIGEL: Yes. For most people, I think it’s fair to say you don’t really see much in terms of severe toxicity, certainly.
But when you think about your immune system kind of going haywire or getting activated, in theory, any organ system can be impacted by that. So when we think about kind of more benign or easier things like the thyroid gland or the skin, it might be a rash you complain of. It might be something we see. You didn’t notice. It might be something in your lab, like a thyroid test is abnormal and you don’t really complain of anything. Those are kind of easier, milder side effects to address.
The ones that we get a bit more concerned about are inflammations of major organs, so things like your liver, your lungs, your pancreas. We’ve seen issues, obviously, in the central nervous system. And so we get deeper into the conversations about the risks of those things and the implications of that, an inflamed liver, an inflamed pancreas, an inflamed lung.
Inflamed lungs and serious colitis can lead to hospitalization — rarely, death or major surgery and death. And so we don’t want to take those things too lightly.
The main thing is, the risks are quite rare. They tend to build up slowly. And so if you’re seeing patients on a regular basis, you tend to be able to mitigate those things, first step being, almost always, just stop the therapy and then later using things like steroids in high doses. I guess the one thing I’d say about steroid use, or 2 things, is the use of prophylaxis for a PCP. We’re not used to that. But that’s something you really need to think early about starting: Sulfamethoxazole, double strength, once daily.
And then stopping steroids too early, this idea of a 4-day run of prednisone or a 6-day run, that’s not going to be sufficient. You’re often talking weeks of steroids. And sometimes your clinic is becoming kind of like a warfarin clinic. You’re having patients just come in to recheck their LFTs so you can make a decision on whether to lower the steroid dose or not. That’s not fun for a patient, but it’s the way you have to manage patients to make sure they don’t get into serious issues.
We’ve seen the serious side effects, even the more morbid issues that lead to fatality. And even though they’re rare, you’ve got to be aware that those things can happen.
DR LOVE: Just to clarify, when you’re talking about PCP prophylaxis, you mean while they’re on the steroids?
DR SPIGEL: Yes, sir, while you’re on steroids. I think we never consider that, because our steroids are low dose and brief. But these can sometimes be 3 months of steroids or longer. And my infectious disease colleagues, they say if you’re on anything more than about 20 mg more than 3 to 4 weeks of prednisone, you need to consider PCP prophylaxis.
DR LOVE: You do occasionally see people who have these great responses. And the question is, do you just keep the treatment going indefinitely or do you stop it? In some cases, people stop because of toxicity. How do you determine how long to treat?
DR SPIGEL: Yes. It’s easy to kind of follow the studies, right? So your patients are on these trials. We just follow the rules. Stay on a year, stay on 2 years. But now that these drugs are on the market and you’re treating more patients off study, it’s a hard question. We deal with it pretty often. Most patients tend to lean toward staying on therapy. And I am one of those doctors too who doesn’t like to rock the boat when things are going well.
But I’m also the first one, even without toxicity, to agree — taking a break. If I see that there’s any hint that they just don’t want to keep doing this, this is not the life that they want to lead, we’ll stop immediately. So it’s a minority of patients I manage where they’ve made a decision to stop, knowing the cancer’s in good control. But I think it’s a reasonable choice. And we certainly would go back on the same therapy if cancer came back again.
DR LOVE: I am specifically interested in your experience with pneumonitis. I mean, these patients, a lot of them have chronic lung disease. They have tumor in the lung. And I’m kind of curious what happens when they get pneumonitis and how you figure out whether it’s related to the drug or related to their COPD or cancer.
MS REED: Pneumonitis is complicated. And I would say it’s one of the most complicated immune side effects to manage, especially in this lung population.
And so what happens is, the patients will usually complain of worsening shortness of breath, cough. You always need to bring them in for evaluation. A nurse that takes that phone call should not ignore that and say, “You have lung cancer,” or say, “Let me get you an antibiotic. Let me find someone to write you an antibiotic.”
These patients need to come in for evaluation. And those symptoms do need to buy them a full workup for pneumonitis. The percentage of patients that are going to develop pneumonitis, especially from a single-agent checkpoint inhibitor, is very low.
These patients are more likely to have pneumonia, COPD exacerbation, disease progression, a pulmonary embolus. All of those scenarios are much more likely than pneumonitis, but you have to keep this on your list of differentials and work them up appropriately.
So one key, key component to the workup is getting a good O2 sat. And I see this done, oftentimes, where O2 sats are not checked routinely on patients in certain clinics. And what happens is, we have a lot of smokers here with COPD. Their baseline O2 sat may be 88/90. So when your patient comes in on a checkpoint inhibitor complaining of dyspnea, cough, you bring them in. You get an O2 sat. If you don’t have something to compare it to, you’re not going to know if it changed. So that is one thing that I’m constantly harping on, “Make sure we get O2 sats on these patients, especially the lung patients.”
But with those symptoms, that needs to buy them some imaging, ideally a noncontrasted CT. But in the age of insurance and time and precertifications and peer-to-peer reviews and everything else that can go into that and getting a CT scheduled, at least a chest x-ray. And differentiating drug-induced pneumonitis from these other issues is very difficult.
What you’ll see oftentimes, though, is that if they do have pneumonitis, it oftentimes can be found more in the upper fields. It can be found anywhere in the lungs, whereas a true pneumonia oftentimes will be in the lower fields of the lung. Also look at their white count. Is your patient febrile? Do they have a high white count? Are they colorful sputum? If they have that whole constellation of symptoms, then it’s probably more of a pneumonia.
But with the pneumonitis, oftentimes, their white count’s normal. They’re afebrile. And what you’ll see when you get imaging is infiltrates, oftentimes bilateral, if it’s severe enough. They’ll develop hypoxia. And at that point, that’s when treatment needs to be held and they need to start on high-dose steroids right away.
And with pneumonitis, you do not want to underdose the steroids. That’s probably one of the biggest mistakes that people make in treating pneumonitis, is they will give them a methylprednisolone dose pack, which is not going to work. You’ve got to go with 1 to 2 mg/kg of prednisone, or the equivalent, per day. And if it’s pneumonitis, go high. You can always taper down on the steroids, but go high and do a very slow taper, because if you get them off the steroids too quickly, what’s going to happen is the pneumonitis can rear its ugly head again, or you could even induce an adrenal insufficiency.
DR LOVE: What typically happens when you give the corticosteroids? Do the patients quickly get better?
MS REED: Not as much with pneumonitis. So with other immune side effects, like the colitis and some of the hepatitis, you’ll quickly see recovery in those issues as soon as you introduce the steroids, for the most part. But I find that the pneumonitis lingers longer. You have to have them typically on a slower steroid taper. And, of course, what that means is, you’re going to get more side effects from the corticosteroids.
You’re going to see the patients get thrush. So I tell nurses, “If they’re complaining of taste changes, ask them to stick out their tongue,” because they’re going to get thrush. They’re going to get hyperglycemia. They’re going to have insomnia. All those great side effects from steroids you’re going to start seeing, especially in these pneumonitis patients, because they’re going to be on high-dose taper for a longer period of time.
Also at our practice, we do order imaging again before we even consider restarting per PI guidelines. If they’ve got a Grade 3 pneumonitis, which means they’re dependent on oxygen, per PI guidelines with these drugs, they’re supposed to stop it. But if they’ve got a pneumonitis and they are, it is appropriate to consider restarting them once it’s resolved. We do order imaging before we do that to make sure it’s better. And oftentimes you’ll see improvement in their symptoms ahead of improvement in the actual imaging.
DR LOVE: Another issue that comes up is — I don't know how often you see this, but knowing that the toxicity relates to stimulation of the immune system, the question is, what happens if you have a patient who already has an autoimmune condition? For example, Crohn’s disease, multiple sclerosis. What do we know about what happens if you give somebody like that a checkpoint inhibitor? And what do you actually do in your practice? I don't know if you’ve even faced that situation.
DR SPIGEL: Yes, we do face it. It depends on the issue, right? So irritable bowel or inflammatory bowel disease can be quite different than somebody with mild RA or lupus in the distant past.
So a few things I’ll tell you about this, not to bore you. Number 1 is, the studies all forbade us for enrolling those patients on studies. So we didn’t have any experience from the trials.
More recently at ASCO, we’ve seen data, we saw retrospective data with different checkpoint inhibitors suggesting that the patients with autoimmune conditions were able to safely receive those drugs and did see a heightened toxicity profile related to their autoimmune conditions. But it appeared to be safe. It didn’t appear to be that there are flares leading to death. I think you just have to do it on a case-by-case basis.
I manage a woman with lung cancer who’s actually on erlotinib, as it turns out. But she’s got awful Crohn’s. I mean, awful Crohn’s. We’re constantly dealing with — that was before I met her, while we’ve been treating her on erlotinib for years now. And when I think about her, let’s pretend she didn’t have an EGFR lung cancer and I really wanted to give her a checkpoint inhibitor. I mean, I’d be nervous about it. That makes her miserable. And I probably would look for other ways to treat her before I gave her a checkpoint inhibitor.
I had a guy once, though, who had awful squamous lung cancer, very wealthy guy who wanted to buy nivolumab before it was even on the market. And I told him, “We have a trial.” He said, “I have a history of RA.” I couldn’t get him on the study. We couldn’t give him a checkpoint inhibitor. Went on down the road, other standard therapies and ended up dying. I mean, you wonder, a guy like him, would I have taken the chance and just given him an immune inhibitor? Because RA didn’t really bother him. Lung cancer did. I probably would have taken that chance. It wouldn’t be an absolute contraindication in my view.
DR LOVE: So another really important question — and it really became an issue in the last year — has been the question of where, exactly, do you integrate these checkpoint inhibitors into the treatment of metastatic disease? We know most people aren’t actually going to respond. But those who do maybe can have a long response. And now we’ve seen some data actually using it up front as first-line therapy of metastatic disease. Prior to that, it was used more the way this patient got, as second-line therapy. Where are we today in terms of trying to figure out when to give these drugs? And what about actually testing the tumor for PD-L1 levels to try to help make that decision?
DR SPIGEL: Yes. I mean, everything’s changed in just a short amount of time.
In the last few months, we finally saw data that showed that chemotherapy, in this case platinum doublets versus pembrolizumab, that chemotherapy’s inferior in terms of overall survival.
So pembrolizumab in the first-line setting — and I think in everyone’s view — is the standard of care now, but only in patients with PD-L1-positive tumors; 50% expression by immunohistochemistry or higher.
We think that’s 25% to 30%. It’s funny, that story keeps shifting. It was a higher percentage at one point. Some even suggest it’s 15%. I think the latest data, it looks like it’s 25% to 30% of our patients will meet these criteria. In my view, I think all of those patients should be offered pembrolizumab or a clinical trial. I mean, those patients are candidates for up-front immunotherapy. We have a randomized head-to-head study that shows they do better. They outperform patients that just would get a good doublet chemotherapy. And it’s not like chemotherapy is bad. It’s just this is better.
For the other 70% to 75% of patients who don’t meet that PD-L1 expression, I think we’re in this territory where, outside of a clinical trial, it’s chemotherapy still. What’s interesting are the events where a very small study from a few months ago has led to a strategy of rapid approval of a combination of carboplatin and pemetrexed with pembrolizumab in all comers in terms of PD-L1 expression, that’s a regimen that looks positive in an early data set of about 120 patients.
And so we may have a new standard in the next year, where patients who are PD-L1-positive get pembrolizumab by itself, squamous or nonsquamous. Patients who have nonsquamous tumors who are PD-L1 anything can get chemotherapy, in this case carboplatin and pemetrexed, with pembrolizumab.
DR LOVE: So I’m really interested in your 69-year-old man, heavy smoking history, retired optician — that’s interesting — National Park Security Officer, even more interesting, multiple comorbidities. Wow!
In any event, so he presents with an adenocarcinoma. It looks like he got chemotherapy and then ended up on a checkpoint inhibitor. And I guess this was in May of 2016, so not quite a year ago. And he went, actually, on a trial and received nivolumab, the anti-PD-1 antibody. So can you talk a little bit about what his condition was when he started the nivolumab and kind of what happened?
MS REED: Sure. So this is actually one of my favorite cases. So this patient had large, bulky disease when we got him on nivolumab. He had multiple tumors in the thoracic area. And some of these tumors were 6 centimeters, very large disease. At this point, we were looking for a fourth-line therapy. So we started him on nivolumab when it was still in clinical trial, fourth line.
So what you worry about with nivolumab is that it can take time to work. These immune checkpoint inhibitors don’t necessarily go in and melt the tumors in several days like a chemotherapy is capable of doing. The whole process of upregulating the immune system does take a little bit longer. But at this point, we didn’t have many more options for this gentleman. And testing for PD-L1 was not required for this trial, as it’s not for nivolumab second line or later.
And so we enrolled him in the clinical trial. And he was symptomatic with his disease. At that point he was working a little bit, but he was already retired. He worked more in the national parks as a security officer just for something to do more than anything. So he had cut back on work, because he was definitely symptomatic.
So he started nivolumab in May of 2014.
DR LOVE: And it’s interesting, if I’m thinking about this — so this was, like, about a year before it was approved.
MS REED: Yes, sir. Exactly.
DR LOVE: So you mentioned the fact you have so many trials available to your patient. He’s a pretty good example where somebody can benefit, because he got a drug that was not approved in 2014.
MS REED: Absolutely. And he was someone with multiple comorbidities, too. So a lot of people would have looked at him as maybe a borderline clinical trial candidate and so on and so forth, with his significant cardiac history and diabetes and all of the other medical issues that he had.
But he started nivolumab in May 2014. And he had his initial scans — on this particular trial, I believe it was 8 to 9 weeks into therapy, which is a little bit early for an immune therapy to really be looking for a response. But he was an early responder. He had a significant reduction in his tumor burden even on that first set of scans. And he did beautifully, very few side effects. And, of course, the side effects that can happen from nivolumab oftentimes are delayed side effects. But he was a very early responder. We don’t anticipate seeing this degree of response in every single patient that we put on immunotherapy.
About 1 year into treatment with nivolumab, he attained a complete remission.
DR LOVE: I guess we have to point I think only 20% of people even respond to start with. So he is an unusual patient. But again, it’s understandable why you want to talk about somebody like this. How did he feel as he was getting treated? How did he feel when he started treatment, and how did the treatment affect the way he felt?
MS REED: Right. So when he started treatment, his disease was symptomatic. Like I said, he had a very large disease burden in his chest, very large tumors up to 6 centimeters in size. He was symptomatic. He had pretty severe dyspnea. He wasn’t on oxygen, but a bad cough. He wasn’t able to work full time and do the degree of walking that was required for his work at a national park. And so he had really kind of cut back on life for the most part. And he was frustrated, because with his cardiac history, he was gaining weight because he couldn’t be as active and he was trying to keep an eye on that.
But once he started therapy, his symptoms were improving as well. And we were suspecting that he was responding early on, because he was saying that he felt so much better. His breathing was better. His cough had significantly improved. And he did, early on, or a few months into therapy, develop that phenomenon where he can get hyperthyroid initially and then they later on become hypothyroid. But he was asymptomatic the entire time. And so we just kept on treating him and didn’t have to interrupt therapy at all.
DR LOVE: So you just picked this up in his blood work?
MS REED: Yes. So of course this was a trial, so it was checked regularly. But even in clinical practice now with nivolumab, we need to watch the thyroid closely. We check it at baseline. You don’t have to check it before every single treatment, but every few months while they’re on therapy. And what you see is, they can develop this autoimmune thyroiditis where initially the thyroid becomes enflamed. It’s spilling out T3/T4. And so they get this hyperthyroidism, where the TSH gets very low, because the pituitary gland says, “We don’t need any more right now.”
Most of the time, these patients are very asymptomatic. It’s something you pick up on blood work when they’re hyperthyroid. And we just keep on treating and, lo and behold, if you just wait it out, a few months later you’ll see that TSH shoot up and their free T4 levels will decline. And at that point, you can start titrating levothyroxine. And again, unless the patient is symptomatic, which they rarely are, if you’re checking the blood work, as you should, you can go on and treat them. And this is something that you, like I said, don’t need to interrupt therapy for. You don’t need to give steroids for this immune side effect if they’re asymptomatic.
DR LOVE: So he goes into complete remission, which is really amazing. What’s his current situation?
MS REED: Yes. So we treated him after he attained a complete remission. We treated him for another year. And, interestingly enough, as I’ve mentioned already, this patient has a significant cardiac history. And he was following up routinely with his cardiologist and was found to have a slight blockage in a vessel. And his cardiologist calls us, wondering, “Should I even do anything? This guy’s got metastatic lung cancer, Stage IV. I don’t think I’m going to do anything about it. I think his lung cancer is going to get him before this will.”
And we were telling him, “No! Do the procedure.” I mean, we’re reluctant to ever use the “cure” word still. But, I mean, he’s had a very durable response. And we don’t know how long it’s going to last. And this patient actually wanted to stop treatment after 2 years. He had had stable disease for a year. He was up to 6 miles a day walking at his job as a security officer in the national park. He felt great. And he was traveling to come get this drug. At that point, we told him, “It’s FDA approved. You can get it locally.” But he just said, “I’d rather watch and see what happens. I can restart it if I need to.”
DR LOVE: Wow!
MS REED: I think now he has utmost faith in us. And so he’s done really well, and we’ve continued to follow him with routine imaging at 3-month intervals. And he has maintained a complete remission.
DR LOVE: Wow! So how long has he been off therapy?
MS REED: Off therapy? He’s been off therapy about 6 to 9 months at this point.
DR LOVE: And he had the cardiac procedure?
MS REED: He did. He did undergo the cardiac procedure.
DR LOVE: Wow!
MS REED: And recovered beautifully, went through cardiac rehab and has done quite well.
DR LOVE: So I’m starting to understand why he’s your favorite patient. But, I mean, what’s it like for you? What was it like for you to watch this, to be part of it? I mean, obviously it doesn’t happen every day, but what an amazing experience.
MS REED: It really was. I mean, I think I cry just as much as the patients do, because so many times in the job and the role that I have, I’m giving bad news. And so when I actually get to go in there and tell someone this wonderful news and then get to tell them over and over, it’s just as life changing for me, and especially with lung cancer, where it’s had such a dismal history for so many of the patients. To see someone like this with huge bulky disease attain a complete remission — and, as of now, a very durable remission — and be able to continue about his life and enjoy his retirement.
DR LOVE: How do you see him as a human being, having gone through this experience?
MS REED: Yes. He definitely has. He’s focused on health more, for sure. It’s really important for him to make sure he’s doing his exercise, following up with us, eating healthy. He’s trying to manage his weight, really manage all of his comorbidities. He’s also taken up new hobbies. He’s decided he wants to paint. He actually painted me a painting as a thank-you. It was of the mountains in East Tennessee.
DR SEQUIST: So this is a guy who I had known for a while, because actually I cared for his wife. She had lung cancer about 5 or 6 years before he did.
DR LOVE: Wow!
DR SEQUIST: And we treated her for Stage III adenocarcinoma, and she was a survivor.
So he was down visiting his daughter for the holidays a couple of years ago and just started having this cough, went to an emergency room and was found to have a big mass in his lung, so cut his Christmas vacation short.
DR LOVE: He’s a smoker?
DR SEQUIST: He was a former smoker, pretty decent number of pack years, but had quit recently, in the last 20 years or so was not a smoker. But came back up to Boston, and we biopsied the mass. And it was a squamous cell lung cancer.
DR LOVE: And what was the extent of the disease at that point?
DR SEQUIST: So he did not have any metastatic spread, but he had a pretty big tumor that did not look like it was going to be amenable to surgical resection.
DR LOVE: So he was basically locally advanced, I guess, like his wife, right?
DR SEQUIST: Yes.
DR LOVE: And because I was struck by the fact that you said she survived, globally what fraction of people with locally advanced non-small cell lung cancer are cured?
DR SEQUIST: For definitive chemoradiation alone, if there’s no surgery involved, which was the case for both his wife and him, ironically, the 5-year survivals are low. Looking at the studies, anywhere between 7% and 20%.
DR LOVE: And typically what people receive as treatment is both chemotherapy and radiation therapy. Is that what his wife got?
DR SEQUIST: Yes. His wife did get that. She got concurrent carboplatin and paclitaxel with her radiation.
DR LOVE: And how do you find that people in general tolerate chemoradiation? How did his wife tolerate it? And I guess that’s what he got too, correct?
DR SEQUIST: Yes. He actually got EP5050, so slightly different regimen. She was a bit more frail than he. And when I see Stage III patients, unresectable, I usually consider their strength, because it is a tough regimen to go for 6 or 7 weeks of daily radiation, getting chemo along the way, often have some esophagitis. And so the nutritional status can go down.
And his wife had lost quite a bit of weight already and actually had a brachial plexus, paralysis of her arm. So she was just really weak. And that’s why we chose carbo/paclitaxel for her. For him, he was more robust at the time that we were doing this treatment, and so we chose a little bit more aggressive regimen with the EP5050.
DR LOVE: And what is EP5050?
DR SEQUIST: So it’s cisplatin and etoposide. And the 5050 just refers to the dose — doses of 50 mg/m2.
DR LOVE: Now, he had a squamous cell cancer. And we were talking before about the difference there. But in the nonsquamous, you were talking before about pemetrexed. You mentioned a couple of the regimens, but pemetrexed has also been used with locally advanced disease with cisplatin. What do we know about that, and is that a regimen you ever utilize?
DR SEQUIST: Yes. So his wife was diagnosed before that was an available regimen. But nowadays if I were to see an adenocarcinoma patient who is getting radiation, I would give them cis/pem. We just recently had a Phase III trial comparing EP5050 with the cis/pem, and they give equivalent outcomes but better side effects with the cis/pem.
DR LOVE: So kind of like the same story in metastatic and, for that matter, adjuvant.
DR SEQUIST: Yes.
DR LOVE: People use pemetrexed not so much because it’s more effective but better tolerated.
So he gets the chemoradiation. How did he do? Did he have esophagitis?
DR SEQUIST: He had a little, but he actually did very well, really was a trooper through the treatment and had a very nice tumor shrinkage. So he did very well. He had no sign of recurrent disease for about 10 months, but then even though he had had really a dramatic shrinkage, it kind of came back. And this is the classic textbook problem with squamous cell is that it can be very locally resilient. And a lot of patients die without really widely metastatic disease but just a local tumor that keeps coming back.
DR LOVE: Is that a typical time for recurrence?
DR SEQUIST: It’s actually probably a little early for a definitive chemoradiation. Even though the recurrence rates are high, they tend to happen 18 to 24 months later. So his was a little early. When his cancer came back, it was right after the first immune therapy was approved in lung cancer. So he ended up going on nivolumab, which is a checkpoint inhibitor. It was approved at that time for squamous cell patients. So he had squamous cell, and we put him on it.
DR LOVE: I guess the one thing about that is that the approval is in patients — at least at that point and kind of now, at least for that agent — was in people who had chemo.
DR SEQUIST: Yes.
DR LOVE: And he had chemo, but it wasn’t for metastatic disease.
DR SEQUIST: Right. So we didn’t follow the letter of the law. But his prior chemo had been within a year. And so what I was really worried about was that his cancer wasn’t really going to respond to another round of platinum-based chemo.
DR LOVE: So he was able to be treated with nivolumab. What happened when he got treated?
DR SEQUIST: So he tolerated it pretty well, at least initially. And his tumor started to shrink. And so we were all very happy and celebrating for several months. After a while, he did start developing some of the autoimmune side effects from the immune therapy.
DR LOVE: So what specific problems did he encounter?
DR SEQUIST: So first he had a bizarre — almost presented like a carpal tunnel syndrome. His hands were kind of weak and tingly. And he got outfitted with some braces that you use for carpal tunnel. And that seemed to help, but he really couldn’t do that much with his hands. It wasn’t that it was so painful, but it really impacted his daily life, because he was pretty functional. And then all of a sudden, he had a hard time grasping things with his hands and manipulating. So it was pretty handicapping.
DR LOVE: And did he see a neurologist?
DR SEQUIST: He saw a rheumatologist. We put him on some steroids, because we had a suspicion that it was from the immune therapy. And that seemed to help somewhat.
DR LOVE: What do you think was going on? Was this like autoimmune peripheral neuropathy, or what?
DR SEQUIST: We weren’t sure. And we’re seeing a lot of that with the immune therapy. He ended up seeing a rheumatologist. And he saw someone who saw carpal tunnel surgeries who did some local injections for him. And it got better but not completely better.
Then, the next thing that hit him in the middle of all the wrist problems was colitis. And the colitis was also pretty bad for him, lost about 20 pounds from disease and just not eating.
DR LOVE: What was the nature of the colitis? Was it bloody?
DR SEQUIST: It was not bloody. And a lot of times with immune therapy, it’s not like an infectious colitis. It doesn’t tend to be bloody. It can just be copious, voluminous and people can get really dehydrated.
DR LOVE: So when he presented that way, did you work him up, or you just started him on the steroids?
DR SEQUIST: We did. We sent off stool studies to make sure we weren’t missing something infectious. But we just started him on steroids at the same time.
DR LOVE: Now, he was still on the nivolumab at that point?
DR SEQUIST: He had stopped it for a period of time with the wrists. And then we had restarted it. And not that long after we had restarted it, maybe a month or 6 weeks, he started getting the diarrhea. Then we stopped it again.
DR LOVE: And what happened once you stopped it and put him on corticosteroids?
DR SEQUIST: It took a long time to recover. So he had pretty bad diarrhea, but not bad enough — sometimes with the autoimmune, they actually start giving people more — autoimmune treatments that are developed for Crohn’s disease and things. So he didn’t get to the point where he needed the infliximab treatment. But still, he was on steroids for quite some time.
Probably about 3 months, I think.
DR LOVE: Are there concerns, particularly in cases like this, for the patients on corticosteroids for a while? We know that corticosteroids can be immune suppressants.
DR SEQUIST: Yes. There’s concern about that. I don’t think we know for sure. There certainly are anecdotal stories of patients from the original nivolumab trials who had to stop for autoimmune problem and then never resumed. And their cancer never came back. But I think in practice, even if you stay on the nivolumab, you’re still unlikely to be one of those 2- or 3-year survivors that we hear about from the trials.
DR LOVE: So what was going on? You had to stop the treatment. Was the tumor still staying in remission?
DR SEQUIST: So by the time we got his diarrhea under control after a few months of steroids, he had one set of scans where things looked quiet. And so we just said, “Let’s leave well enough alone, just check again in a couple of months. No treatment yet, because we don’t want the diarrhea to start back up.”
But then when we checked again a couple of months later, it had regrown.
DR LOVE: What a difficult situation. You have a lethal disease. You have a therapy that was working. What a difficult situation. What did you do?
DR SEQUIST: So because of how bad — I mean, he had actually been admitted a couple of times during the diarrhea episodes. And we all decided that it wasn’t worth the side effects for him of going back on an immune therapy. So we moved on to a different chemotherapy.
He ended up getting some weekly nab paclitaxel.
And then, unfortunately, that didn’t work. So then we were going to switch to, I believe, gemcitabine. He just recently passed away. So his tumor kept coming back locally and eventually had an obstruction problem.
DR LOVE: So what about the choice of the chemotherapy?
DR SEQUIST: Yes. So I favor pemetrexed almost all the time in adenocarcinoma patients. It doesn’t make you lose your hair, very well tolerated. And based on the Scagliotti data, we know that it has special activity in adenocarcinoma, although to be fair, that didn’t compare to taxanes. So I think over the years a lot of oncologists have migrated to using pemetrexed in adeno.
Cis versus carbo is also a style thing. In the US, most people will give a patient with metastatic cancer carboplatin, although in Europe, honestly, they give cisplatin much more. And personally I have started using cisplatin more myself. I think what US oncologists have been hesitant about, one is the chair time. It takes a lot longer to treat someone with cisplatin, because they have to have fluid before and after. But second, the nausea in the old days was much worse. But we have stronger nausea medicines that we can give with the cisplatin, and it’s much better.
DR LOVE: So I hear that lots of patients — not just lung cancer, it seems like every cancer — are walking into the office saying, “I saw this ad for the checkpoint inhibitor on TV.” our knowledge base is changing so quickly. But what about the patient with a targetable mutation, T790M-negative? Now you’re going to give something else, checkpoint inhibitor versus chemo/bevacizumab.
DR SEQUIST: Yes. So they don’t put this information in all those commercials on TV. But the checkpoint inhibitors are very unlikely to work in patients, lung cancer patients, with a targetable mutation like EGFR or ALK. We’re not quite sure all the reasons behind it. We think that tumors, in order to respond to immune therapy, need lots of different antigens. And these oncogene-addicted cancers are really much more homogeneous, and they don’t have a lot of different antigens. It’s certainly something to try for an EGFR patient, but not before chemo for sure. Usually after 1 or 2 types of chemo you could try that.
MS KELLY: So a 57-year-old gentleman, a finance professor, very active, who started to develop bilateral shoulder pain. And that prompted a visit to his PCP and plain films, which unfortunately showed a left upper-lobe mass as well as some suspicious lesions in his scapula. And he was eventually found to have metastatic squamous cell lung cancer. That workup was all done at an outside institution.
Then, he came to us specifically interested in clinical trial options. And we had a trial for him, a randomized trial of carboplatin plus nab paclitaxel. And then he could be randomized to either observation or nab paclitaxel maintenance therapy.
DR LOVE: So can you talk a little bit about how you all think through patients who have squamous cell cancer and metastatic compared to nonsquamous cancer, such as adenocarcinoma? What’s the typical path that they take both ways?
MS KELLY: Yes. So for your adenocarcinoma patients, for those folks we tend to pick pemetrexed as their first line of therapy, a platinum doublet including pemetrexed. And they may receive bevacizumab as well.
DR LOVE: And that’s with carboplatin?
MS KELLY: With carboplatin, typically is what we use, right, for metastatic patients, just because it’s better tolerated than the cisplatin. So when we’re trying to optimize quality of life, we pick carboplatin as our platinum backbone. So typically an adenocarcinoma patient, they’re the patients who may have activating mutations. We see those less in squamous cell patients. So for the adenocarcinomas, they typically get carboplatin/pemetrexed plus or minus bevacizumab. And for our squamous patients up front, that would be more carboplatin/paclitaxel or nab paclitaxel.
DR LOVE: What’s the reason for the difference in choice of chemotherapy partner with the platinums, a taxane with squamous in your situation, and yet pemetrexed with adeno or nonsquamous?
MS KELLY: Yes. So studies show that the pemetrexed was beneficial in patients with the adenocarcinoma subtype and specifically not helpful in patients with squamous.
DR LOVE: And when you have a patient who’s about to get started on carboplatin/pemetrexed — and you mentioned bevacizumab — incidentally, how would you decide whether or not to use bevacizumab?
MS KELLY: So bevacizumab, we make choices based on whether or not they’ve had a history of a heart attack or a stroke, if they’re on anticoagulation, if they have brain mets, if those brain metastases have been previously treated or any hemorrhagic, if they come to us with hemoptysis at the time of diagnosis. All of those are contraindications for using the bevacizumab.
DR LOVE: And do most people end up getting bevacizumab with the carbo/pem or —
MS KELLY: I would say the majority do not. Many folks who come to us have a history, a recent history, of a DVT or a PE. And, unfortunately, a good proportion of our patients at the time of diagnosis have brain mets as well.
DR LOVE: What was this man’s general physical condition and symptomatology at the point at which he started the treatment with the carboplatin with nab paclitaxel?
MS KELLY: By the time he came to us, he had actually underwent up front some palliative radiation to his bony metastases. So he came to us on long-acting opioids. He was still working full time as a finance professor. He has 2 young children. He was still involved with their Boy Scouts, but he was fatigued. He was losing some weight. His mood was pretty low, knowing that he was going to be on the chronic opioids.
DR LOVE: And what happened when he got started on treatment?
MS KELLY: He actually did quite well. So his energy improved. His stamina improved. He actually picked up a couple of extra classes. In terms of side effects from chemotherapy, like I said, his energy improved and his weight improved. His appetite actually improved as we got his cancer under control. He really didn’t have any significant nausea or bowel changes. He didn’t develop any neuropathy. He did run into some problems with his blood counts.
So with the carboplatin/nab paclitaxel, the carboplatin is given every 3 weeks. The nab paclitaxel is given weekly. So frequently he would come in — he would receive his day 1 therapy of the carboplatin plus the nab paclitaxel. He would come in the following week for his day 8 of nab paclitaxel. And then his day 15 nab paclitaxel was frequently held for low neutrophils or platelets.
DR LOVE: So he gets the carbo/nab and then nab maintenance. And how long was he on that total therapy?
MS KELLY: Correct. So he received the doublet therapy for 4 cycles and had a smashing response, greater than 40% reduction in his tumor burden. And then after 4 cycles of the carboplatin/nab paclitaxel, he started his maintenance nab paclitaxel. His initial restaging after 2 scans showed stable disease. And then after an additional 2 cycles of therapy, he started to progress.
Over this time, because of the recurrent issues with neutropenia, some of his treatments had been delayed or held. I mean, we had to reduce his dose twice. But after his fourth cycle of maintenance therapy, he started to progress with a new left hip met that was symptomatic, some new subcutaneous metastases on his back and on his chest and minimal progression in his adenopathy.
DR LOVE: And in terms of the patients who end up getting on, let’s say, carbo/pem and bevacizumab, what are some of the key patient education points you make when they start that therapy?
MS KELLY: Sure. So again, for any general chemotherapy we talk about how unfortunately it’s not targeted directly at your cancer. It hits any cells that are rapidly dividing or still growing. So we hope that’s more of the bad cells, your cancer cells, which are, by definition, abnormally growing cells. But we know that the chemotherapy is going to affect your good cells. That’s where we get our side effects.
Main side effects are fatigue, changes in your appetite, changes in your blood counts, so neutropenia, which increases your risk, obviously, of infection, and the importance of calling us if you were to get a fever or kind of focal symptoms of infection, like a junky cough or lots of diarrhea or irritative voiding symptoms, problems with the lining of your gut. So dry mouth or changes in your taste, mouth sores, nausea/vomiting, changes in bowels, diarrhea or constipation, though I think in general we see more constipation when folks are more tired, not moving around much, when patients have a low appetite, aren’t drinking as much. And some of our antiemetics are constipating as well.
With the carboplatin, we do talk about the risk of hair loss or hair thinning. We do talk about risk of peripheral neuropathy, though we see it more frequently with cisplatin. We talk about problems with kidney function tests of electrolytes if your kidneys aren’t so happy, so the importance of staying well hydrated and eating small, frequent meals. We talk about the risk of an allergic reaction or hypersensitivity reaction, which is typically occurring in the infusion unit, so letting their nurse know if they were to have chest pressure or shortness of breath, wheezing, flushing, itching, hives, that sort of thing.
With the pemetrexed, we talk about the need to start folic acid and to start vitamin B12 injections every 9 weeks. We talk about the risk over time of some fluid retention in the ankles, or we talk about the risk of a rash and the necessity of taking some steroids around the time of chemotherapy to minimize that.
Specifically to the patients getting bevacizumab, we talk about the risk of increased bleeding and the risk of poor wound healing. We ask them to give us a call, obviously, if they’re having nosebleeds, blood in the urine, blood in the stool, dark stool, sudden onset of severe abdominal pain, because it’s been associated in a rare number of patients, but a very significant problem of perforated bowel. And we’ve actually had folks who have been hospitalized for that.
So those are, I would say, are our main teaching points for the carboplatin/pemetrexed plus or minus bevacizumab.
DR LOVE: And then on the other hand, when you have patients with squamous cell and even adeno who are going to be getting taxanes, you mentioned nab paclitaxel, paclitaxel, also docetaxel. What are some of the key patient issues there?
MS KELLY: So similar in terms of the changes in energy, appetite, changes in blood counts with the taxanes. We focus a little bit more on the neuropathy, so the numbness/tingling in the hands or feet, a little more on the fluid retention. The taxanes can also cause excessive tearing, which can be bothersome to patients. We don’t have to focus on the steroids taken around chemotherapy for the rash or certain vitamins, but certainly I would say more significant fatigue, changes in appetite, mucositis can be a little bit more significant. And I think with some of the taxanes, we end up seeing more diarrhea than constipation. So I may focus a little bit more on the loperamide instructions.
DR LOVE: And I’m kind of curious in general what your experience is with nab paclitaxel and whether you think it’s any different than paclitaxel. I guess a couple of things that are different is the infusion is shorter and you don’t need corticosteroid premedications.
MS KELLY: Correct. I would say in general we give more paclitaxel as opposed to nab paclitaxel. And it’s probably location alone. We’re a large academic medical center in the heart of the city. It’s difficult for patients to come in weekly to see us.
So I think frequently we give the paclitaxel or the docetaxel so that the therapy is still every 3 weeks. But the nab paclitaxel we certainly use for folks who have problems with their blood sugar, so poorly controlled diabetics, because of the benefit of not having to give the steroids.
DR LOVE: And other than that, anything else that you can tell in terms of the difference? Do you think there’s any difference in the neuropathy that you see?
MS KELLY: I think with my patients personally, the neuropathy has been better with nab paclitaxel. I think that they run into more issues with their blood counts. But I think that the neuropathy has been better. And I think overall the therapy has probably been better tolerated in terms of fatigue or GI toxicity when you’re breaking up the dose, instead of giving them the whopping dose every 3 weeks.
DR LOVE: And I’m curious what your experience is with patients who have incurable cancers with minor children.
MS KELLY: So often at the time of diagnosis, that’s one of their greatest concerns, how they’re going to explain their disease to their children, how they’re going to explain “how this happened to me and what the next months or year or longer might look like in terms of me going to the doctor, receiving treatment, what side effects I might experience and how that might change our home life and our normal routine, if I’m not feeling well,” how they explain mortality to their children and planning for the future, how they make the most of the days where they feel well and how they can kind of build their legacy to leave behind for their children.
So talking about parenting at this time is really difficult. And again, we have the benefit of a wonderful palliative care group who often gets involved with our young patients to help with coping and, kind of, legacy building. And we also have a team of psychologists and therapists in a group called the Parenting at a Challenging Time, or PACT, group. And we can often refer them. And they have lots of resources in teaching our patients how to communicate with their children, how to alleviate some of the fears.
And we often have patients bring their young children into the clinic. They’re seeing us once a week or a couple of times a month. And so their children will come in for the visits and get used to the team, sometimes go up to the infusion unit with them. And I think that that takes away some of the anxiety.
DR LOVE: Any personal reflections on this issue?
MS KELLY: I met with a patient and I had to give her bad news last week. She’s an older woman. She’s about 70 years old. She has children my age. And she has small grandchildren. And it’s terrible to give people — good people, bad news, right? Or it’s terrible to give bad people bad news. It gives you a lot of perspective.
And her husband has a very difficult time coping. He’s a pharmacist, so he understands some disease processes and medical terminology but not a lot of the decision-making in our practice. And he has lots of questions about why we can’t do this, that or the other thing. And as I’m delivering this bad news, he kept interrupting me and holding my hand. And I became a mother this year, so I have an 8-month-old, and he just kept telling me to go home and hug my child, to go home and hug my husband and to never take a day for granted.
And my team calls it “pulling a Kelly,” because I often cry before my patients. So I think I have a good perspective about the bigger things in life and what’s important because of what I do. But sometimes I certainly cry with my patients and certainly around patients’ fears about leaving their children behind.
The most important part of my job, I think, is identifying with the patients. I think I had told you before when we were at the ONS conference that my father had lung cancer when I was younger.
DR LOVE: That’s why I brought it up. I remembered that. Yes.
MS KELLY: Yes. Yes. And he was a police officer. He was a big, strong guy. And he was a former smoker, but he had quit about 20 years before his diagnosis. And I think he had a lot of guilt about developing lung cancer and leaving us behind and “did he do this to himself.” And he passed away within 2 years. He was originally diagnosed with what we thought was curable disease. And he metastasized very quickly after his initial therapy. And he passed away within 2 years.
And I always said that I wanted to work in oncology, but I could never do lung cancer because it was a little too close to home. And then I fell into this job with my group, and I couldn’t be happier. I think it gives me a great perspective.