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Immunotherapy Side Effects
Jennifer Litton, M.D.
March 3, 2021

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Dr. Jennifer Litton is a board-certified medical oncologist and professor of breast medical oncology at the University of Texas MD Anderson Cancer Center in Houston, TX, where she is vice president of clinical research. She also is a member of the Breast Immuno-Oncology Task Force of the National Cancer Institute.

Dr. Litton joins us for this episode to talk about the side effects that may be caused by the two immunotherapy medicines approved for breast cancer: Keytruda (chemical name: pembrolizumab) and Tecentriq (chemical name: atezolizumab).

Listen to the podcast to hear Dr. Litton explain:

  • how these two immunotherapy medicines work
  • the side effects that are unique to the immunotherapy medicines
  • how doctors monitor immunotherapy side effects
  • tips how people can monitor themselves for side effects

Running time: 20:44

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Jamie DePolo: Hello, thanks for listening. Dr. Jennifer Litton is a board-certified medical oncologist and professor of breast medical oncology at the University of Texas MD Anderson Cancer Center in Houston, where she also is vice president of clinical research. Dr. Litton also is a member of the Breast Immuno-Oncology Task Force of the National Cancer Institute. She joins us today to talk about the side effects that may be caused by the two immunotherapy medicines approved for breast cancer: Keytruda, also called pembrolizumab, and Tecentriq, also called atezolizumab.

Dr. Litton, welcome to the podcast. It’s so nice to talk to you again.

Jennifer Litton, MD: Oh, thank you so much, Jamie, for inviting me. I’m so glad to be here.

Jamie DePolo: Thank you. So, just in case everyone that’s listening isn’t familiar, could you give us a short overview of how the two immunotherapy medicines for breast cancer work?

Jennifer Litton, MD: Sure. So, immunotherapy is not new to cancer treatments, but it’s definitely newer as far as what’s available for breast cancer.

There’s really been two, so far pivotal, phase 3 randomized clinical trials in metastatic triple-negative breast cancer. The first one was the IMpassion130 study, and this looked at patients with metastatic or inoperable locally advanced triple-negative breast cancer. And they were randomized to either atezolizumab and nab-paclitaxel [brand name: Abraxane] versus a placebo and nab-paclitaxel. And in the primary progression-free survival analysis, it did show improvement, but specifically in the subgroup that had a biomarker, which is PD-L1, staining on the tumor infiltrating immune cells. So the FDA did approve atezolizumab in that setting.

And there’s been several further follow-ups in both the primary time that they presented as well as at a further meeting in ASCO in 2019 showing a survival benefit of potentially up to 7 months for people who receive this therapy. There really does appear to have significant improvement when given in the first line with chemotherapy as well as the tumor stains positive for this PD-L1 staining.

Now subsequently, there’s been another trial, and it’s called the KEYNOTE-355 trial. And this was also a phase 3 randomized trial of a similar size, and randomized pembrolizumab and chemotherapy to placebo and chemotherapy. And in this trial, there were multiple different chemotherapy arms that could be chosen — it could be paclitaxel [brand name: Taxol], nab-paclitaxel, or gemcitabine and carboplatin — with the primary endpoint also being progression-free survival.

Now, they also saw an improvement, especially with that PD-L1 staining showing that difference. And based on that, the FDA has also recently approved this for metastatic triple-negative breast cancer.

So, we now have two therapies that are FDA-approved for patients with metastatic triple-negative breast cancer and the tumor has been biopsied and stained for that PD-L1 protein, [they] are both options now for our patients.

Jamie DePolo: Thank you. And so, I want to focus a little bit in on, could you tell us what does it mean for a cancer to be PD-L1 positive, first, like what does that mean? I think that’s a little bit less familiar than, say, the hormone-receptor status to some folks. And then also, why has much of the research, it seems to me anyway — not a scientist — but looking at immunotherapy, and it’s focused on metastatic triple-negative disease? So, why is it that particular subtype?

Jennifer Litton, MD: So, it has been tested in pretty much every subtype of breast cancer. It’s been tested in ER-positive, HER2-positive, as well as triple-negative. Now, there’s a couple of things about triple-negative that makes it very different from ER-positive breast cancer and why it’s moved forward faster than phase 3 studies with the therapies we’ve had.

So, first of all, in a lot of the earlier studies looking at ER-positive breast cancer, we really didn’t see that same signal of improvement or response. HER2, I’d like to say something slightly controversial, that I feel that trastuzumab has been an immunotherapy long before immunotherapy was popular, and I think that is a form of using that as an immunotherapy. But combining it with these new drugs, such as atezolizumab and pembrolizumab, these checkpoint inhibitors, there are several phase 3 trials looking at this right now and several through the cooperative groups.

The triple-negative breast cancer moved forward in this because of some very specific features to triple negative. Now, I know that we’ve talked before, Jamie, and you know triple-negative breast cancer is not one disease, it's a group of diseases that are all grouped together by what they’re not. But they tend to be faster growing, they tend to be actively dividing more, they have increased mutational burden, and they look more unlike the other breast tissues. So, the body’s already starting to see it, in many cases, as, “This is not part of our body, we’re going to start sending immune cells and start to infiltrate into those tumor cells.” And the way that these particular immunotherapy drugs work —

Tumors can get very smart. They can put up shields to hide from the immune cells that the body is sending in to kill the tumor cells, and these drugs actually can take those shields off. So, if there’s immune cells sitting in the tumor cells, in the tumor bed itself, it makes it more effective to go in and start destroying the tumor cells. And this is something that we don’t tend to see in the luminal, or the ER-positive, breast cancers. PD-L1 is one of those markers of those shields that we’re talking about, where the interactions of the T cells to the tumor cells and the immune cells. So, having expression of those receptors as you’re trying to block them and make the immune cells more available to destroy the tumor cells is really the strategy of these drugs.

Jamie DePolo: Okay. So, I’m going to put that in my words, and you can tell me if I’m understanding correctly. The PD-L1 is kind of like the shield that the tumor is using to block the action of the immune system on the tumor. And these PD-L1 checkpoint inhibitors, which is Keytruda and Tecentriq, they kind of block that so the tumor doesn’t have the shield anymore so the immune system can act more strongly on the tumor. Am I understanding right?

Jennifer Litton, MD: It is. And I think I would just horrify my friend Jim Allison calling it a shield like that. [Editor’s note: Jim Allison, Ph.D., chair of immunology and executive director of the immunotherapy platform at MD Anderson Cancer Center, pioneered the development of immunotherapy drugs to treat cancer.] But when I kind of think of it that way — so, there’s a lot of different protein interactions between tumor cells and the immune cells, so interrupting these interactions can really make the immune cells more likely to see the tumor cells and kill them.

Jamie DePolo: Okay. And I definitely want to underscore it’s not actually a shield, it’s a protein reaction. But it’s kind of helpful for me to visualize it that way.

Jennifer Litton, MD: I do. You know, I have a teenage son, so when I’m trying to describe it to patients I always kind of bring up Harry Potter and the cloak of invisibility, and that seems to be very helpful.

Jamie DePolo: Yeah. It’s like the tumor has this invisibility cloak, and these drugs take it off so the immune system can find it. I like that.

Jennifer Litton, MD: Exactly. So, tumors that have immune cells already sitting in there are going to be more effective, versus a lot of ER-positive tumors where you can take a slice of the tumor and there’s no immune cells. So if you ripped off that cloak, not much is going to happen because there’s not cells there. Now, I am not saying that there isn’t a role for immunotherapy in these other subtypes, and we’re really looking into it. But you’re going to see these studies looking at ways of depositing or causing reactions that bring those immune cells into the tumors like we tend to see at a higher proportion of triple-negative, into some of the other tumor types.

Jamie DePolo: Oh, okay, that’s good to know. So, now we’ve kind of got all the basic stuff we’ve talked about. Let’s get into the main point of the podcast, which is really the side effects of these immunotherapy medicines. Because I think a lot of people are familiar with chemo or radiation side effects because the treatments have, for breast cancer anyway, they’ve been around a little bit longer. And some of the Keytruda and Tecentriq side effects are the same, you know, fatigue, nausea, diarrhea, low white blood cell counts.

But the immunotherapy medicines also have what I think of as a suite of very unique side effects like lung, liver, colon problems, problems with other glands that make hormones like the thyroid and the adrenal glands. So, could you talk about those side effects that are kind of specific to immunotherapies that way?

Jennifer Litton, MD: So, I’d like to say that you did a very good job presenting a lot of those side effects. But I think you’re absolutely right, I do think it’s a different toxicity profile than our standard drugs and how we monitor them. And patients may experience — especially if they’ve had chemotherapy before and little things that we might say, “Okay, well, watch that or take a Tylenol,” we’re not going to do when you’re on immunotherapy. So, there’s a lot of things.

I pretty much say anything that can get inflamed could potentially get inflamed. Some of the more common things that we see could be rash or itching or colitis or hepatitis; pneumonitis, so inflammation of the lungs; arthritis, rarely, but can be severe. It could be myocarditis, so actually of the cardiac muscle cells. Encephalopathy, neuropathies, eye toxicities, and I’ve also seen several patients with nephritis, or actual kidney issues, that start off that look like a urinary tract infection but is in fact an immune reaction to the drugs.

Now, a lot of those we can turn around and we treat. But the other side effects that you mentioned, specifically the endocrine ones when we think about the thyroid either going way up or way down, or you can actually develop a type 1 diabetes, or adrenal gland or the endocrine, the pineal gland in your brain. If these get affected, one of the things that’s really different from some of the other toxicities and other chemotherapies is that if you develop these, they’re usually lifelong. So, we can continue on the therapy, but will be treating type 1 diabetes or hypothyroidism and starting those medications.

So, that is a really important factor and something that we really need to make sure we’re clear about when we’re prescribing these immunotherapies. I do think they’re very exciting. I think we’ve just scratched the surface of this first class and the next group of immunotherapy drugs I think are also very exciting, but the toxicities are different.

When we’re prescribing these, and if your doctor is suggesting them to you, they’re likely going to be looking for things that we don’t normally check or you’ve had the experience of having checked prior to other cancer therapies. And they really go with the side effects we just talked about. So, first of all really making sure that you have discussed with your physician if you have a history of autoimmune disease, it requires treatment, it’s significant. In a lot of the trials if there was any autoimmune disease, you were excluded.

I will say that as we’re getting more and more experienced across cancer there is more data about mild autoimmune disease still being able to have the benefit of these drugs with active surveillance; panels for checking for infection like hepatitis and HIV; and checking for baseline endocrine, thyroid, diabetes, adrenal gland. Things that we don’t normally do for breast cancer treatment may be part of the work-up depending on your situation when considering one of these immune therapies.

Jamie DePolo: Okay, that’s good to know. Now, do these conditions, I guess these autoimmune disorders, do they need to be monitored anymore closely? Like I’m thinking if you’re on chemo, maybe you get checked for stuff once a month or something like that. Like, is monitoring the autoimmune more frequent?

Jennifer Litton, MD: So, first of all, we had to make sure our whole breast center was aware that one of the first questions when someone calls is, “What therapy are you on?” And it goes down a different tree kind of decision if it’s immunotherapy. I tend to see patients as they did in the trial, seeing them prior to each cycle of therapy. But for people who have been through chemotherapy before, and you have a headache here or there and we just kind of watch for a little bit of shortness of breath or fatigue, we might, on chemo, just say, “Well, that’s part of the chemotherapy.” But on immunotherapy it is more likely that your clinical team is going to kind of jump on that a little bit sooner. And you may think that they’re being overprotective, and that’s okay, let them be overprotective.

So, headaches, I really want to look for that gland inside the brain. If there’s shortness of breath, getting imaging, if there’s any sign of inflammation, getting the lung doctors involved. If there’s severe fatigue, we don’t want to just say, “Oh, well, you’re on therapy.” We want to make sure all of the endocrine things are okay, the thyroid, the adrenal gland, and all of that. And intervening early is important here.

So in the beginning of this, we’re trying to sort things out. We may watch the grade of it, so how severe it is either on the lab or your symptom, and if it hits a certain severity, even while we’re working up, we may just start steroids while we’re still doing the work-up. Others we can watch while we’re doing the work-up, and there’s been really, I think, great national guidelines out there really helping physicians and patients on the symptoms and what are the different levels of treatment needed. And I think that they are only going to improve as we get more and more dissemination of the information from these trials.

Jamie DePolo: Okay, thank you. And finally, you have a patient that’s on immunotherapy, do you give them any tips or things to watch for? I guess, how can people themselves play an active role in this monitoring for side effects?

Jennifer Litton, MD: Absolutely. I think that we are really specifically letting them know that they’re not bothering us — a lot of times patients are, “Well, I really have a headache and I don’t want to bother.” On immunotherapy I’d say those rules are out. Please, if you start having new headaches, you start having new shortness of breath, you start having severe fatigue, it is always better to overreport that rather than underreport it. Because I have seen some of these symptoms really escalate even in a 2-, 3-, 4-day period of time. So, I would rather you err on the side of over — even if it’s, “Okay, we’re going to watch you for the next day, but I need to hear from you tomorrow.” But I would err on the side of overreporting on this.

There’s a lot of really exciting clinical trials right now with new patient-reported outcomes, apps that can go to your phone. I think specifically I’m excited about some of these trials for immunotherapy where if we can check in remotely at periods of time potentially at a future state, and find the beginning of these symptoms or we can intervene with minimal intervention, I think that immunotherapy is right for this sort of new style of managing and reporting side effects from patients.

And I would encourage anyone on this — obviously I feel deeply about clinical trials, we could talk about that at another time, at any time. But you know, if you have an opportunity for some of these trials with patient-reported outcomes, I think these could be really game-changing not just for patients on trials, but long after the therapy becomes available.

Jamie DePolo: Okay. So, if I’m understanding right, somebody would have an app on their phone and they’re on immunotherapy and they got a headache, they would just put that in the app and that would get transmitted to their care team. And then they could say, “Oh, this person has a headache, let’s get in contact with them and find out what’s going on.”

Jennifer Litton, MD: Right. We’re not there yet, that’s a future state, but I think that there’s a lot of exciting new research and apps being developed to do things just like that, and I’m excited about some of that research.

Jamie DePolo: Okay. Now, it sounds like, too, I know you said for anyone if they’re on immunotherapy, you’re not bothering your physician by contacting with a side effect. It does sound like, too, that you want the patients to report anything and everything as soon as it happens rather than say, “Oh, I have a headache. I’m going to wait until tomorrow and see if it goes away.” Is that right? Because by tomorrow it may be 5 or 10 times worse.

Jennifer Litton, MD: I hate to say, “Every time you have a twinge you’re going to call your team.” There has to be some discretion there if you usually have headaches every day, you know? But when you start to have something that’s new or more severe or more frequent, the earlier you report that on immunotherapy I think it’s important. At least so they can start tracking you for that symptom.

Jamie DePolo: Okay. Okay, that sounds great. Dr. Litton, thank you so much. I really appreciate your insights on all of this.

Jennifer Litton, MD: Oh, it’s my pleasure. Thank you so much.

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