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Immunotherapy for Lung Cancer Brings Treatment Breakthroughs

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Published on December 22, 2020

Immunotherapy Offers New Treatment Options for Lung Cancer Patients

Immunotherapies have radically improved treatment for non-small cell lung cancer (NSCLC) patients. In fact, the PD-L1/PD-1 blockade is a bona fide breakthrough. What does the changing treatment landscape and this fast-moving course of research for lung cancer patients? 

Find out during this Answers Now segment, as Dr. David Carbone, MD, PhD, Medical Oncologist at The Ohio State University who specializes in creating cutting-edge treatments for lung cancer patients, discusses the existing PD-L1/PD-1 treatment options and the ones that are currently in development. He is joined by hosts Lisa Goldman and Michele Nadeem-Baker. 


Transcript | Immunotherapy for Lung Cancer Brings Treatment Breakthroughs

Michele Nadeem-Baker: Hi, I'm Michelle Nadeem-Baker, and welcome to Patient Power. I'm a blood cancer patient, but today it is all about lung cancer as we talk about immunotherapy breakthroughs. Please welcome with me today's guests. I have Lisa Goldman. She is a lung cancer patient, survivor and advocate, and she is the Co-founder and President of ROS1ders. Thank you, Lisa, for joining us today. And Dr. David Carbone, the Director of the James Thoracic Center, hi doctor, at the James Cancer Hospital and Solove Research Institute at the Ohio State University.

Dr. Carbone: Glad to be here.

Michele Nadeem-Baker: Lisa, would you like to tell us a little bit about your journey as a lung cancer patient, please?

Lisa Goldman: I was diagnosed with stage four lung cancer back in early 2014, so I'm coming up on seven years, and I've been really fortunate. I started out on chemotherapy and did that for about eight months and then switched over to a targeted therapy for my biomarker called ROS1. So, I'm ROS1 positive, which made me a good candidate for a medication called crizotinib or Xalkori. And I have been taking that drug since late 2014. So I've been on that drug for over six years now and I've been really lucky.

Before we dive into immunotherapy, which is really the focus of today's conversation, I was wondering if you might give just a really quick overview of the traditional treatment approaches that historically have been available to lung cancer patients.

What Treatment Approaches Have Historically Been Used for Lung Cancer?

Dr. Carbone: I've been treating lung cancer for 30 years now, and historically it was chemotherapy, as I said, or nothing. And in fact, 30 years ago, it wasn't even clear that chemotherapy was of any use. And so we actually did chemotherapy versus nothing trial in advanced lung cancer, and we showed that the median survival went from four months to six months. And that was a major advance. But even then, most patients didn't even get chemotherapy. But we've improved the chemotherapies since then, so now they're much less toxic.

We have drugs that prevent side effects from chemotherapies. But the basic cornerstones of treatment today would be the targeted therapies, chemotherapies, and immunotherapies.

Lisa Goldman: Moving into immunotherapy, can you tell us a little bit about what exactly is immunotherapy? There seems to be a lot of questions just on the general definition.

What Should Patients Know About Immunotherapy for Lung Cancer?

Dr. Carbone: People use the word immune system and often it's misunderstood. I realize that. But every day our bodies are exposed to bacteria and viruses. Hopefully not COVID. But most of these infectious agents just get recognized and eliminated by our immune system. And it's active every day. It's highly specific. It recognizes things that aren't supposed to be there, and it eliminates them. 

And cancers are not supposed to be there, and many lung cancers have many differences from normal cells that should theoretically make them recognizable by the immune system and eliminated. But in fact, cancers have also gotten smart and they've learned how to avoid the immune system. They express proteins that turn off the immune cells and PD-L1 is one of those proteins that cancers can express. When an immune cell comes in ready to kill a cancer cell, if it has PD-L1, it turns off that cell.

So, most of the approaches of immunotherapy today are actually approaches that turn the immune system back on. If the PD-L1 is like a Star Trek force field around the cancer that protects it from the immune system, then the anti-PD-L1 blocks that and it removes the force field and lets the immune system recognize the cancer. The immune system is very complicated, so there are many different ways that cancers can hide from the immune system. But the one that has really shown efficacy in lung cancer is attacking the PD-1, PD-L1 pathway.

Lisa Goldman: These are the drugs we see a lot of advertisements for that you're referring to?

Dr. Carbone: Yes, nivolumab (Opdivo), pembrolizumab (Keytruda). I'm usually told not to use brand names, but the ones that are on TV are usually PD-1 pathway inhibitors.

Lisa Goldman: Okay. Can you talk a little bit about who would be a good candidate? What type of lung cancer patient might benefit from these drugs, these immunotherapies?

Who Is a Good Candidate for Lung Cancer Immunotherapy?

Dr. Carbone: Most lung cancer patients have a chance of benefiting from immunotherapies, but the driver mutant lung cancers, such as yours or EGFR or ALK, RET, those tend not to respond to immunotherapies as well. But if you've exhausted other therapies, then those often are used. But the primary patients where immunotherapy is used as a first approach to treatment would be a patient with a non-driver mutant tumor. So you look for these driver mutations.

If you find a driver, you match a drug, such as the one you're on. And if you don't find a driver, then you use immunotherapy. And then now there are multiple options for immunotherapy in that setting, which we can go into if you'd like.

Lisa Goldman: Well, before we get there, so I just wanted to clarify, a patient should first test for biomarkers before starting immunotherapy. Is that what I heard you say?

Information on Lung Cancer Biomarkers

Dr. Carbone: Oh, absolutely. I think it's a major mistake to not do exactly that and not to wait for the result, because many patients are understandably terrified when they get the diagnosis of lung cancer. And I'm sure you went through that with your diagnosis. You want treatment to start not tomorrow, but today. But the fact is that there's a lot of benefits to making sure that the treatment you're getting is the best one for your tumor and not just the expedient one, one that's on the shelf that we can give you right away.

It may not be the best one for your tumor, and you were lucky you started on chemotherapy and transitioned to the targeted therapy. But most studies show that if you start on the targeted therapies, first, you do better than if you start on chemotherapies first. And who would want to struggle with chemotherapy if they can take a pill that makes their cancer shrink in a durable way, such as yours has?

In fact, if you start on immunotherapy and then find a mutation and then switch, sometimes there's a problem there because the immunotherapies can cause what's called pneumonitis, which is inflammation of the lung, and so can some of the targeted therapies. And so you may find that you have more toxicity that way.

So even though you're panicked, you're distressed by the diagnosis, I think it's really the responsibility of the doctor to calm you down and say that it's better to do the right thing than then convenient thing, do the appropriate tests and match the treatment to the tumor as best as possible, and not just start something because you're in distress.

Lisa Goldman: So if a patient gets a biomarker test and doesn't turn up anything, is there another test that they do to determine if they're a good candidate for immunotherapy, or do they just investigate?

Dr. Carbone: Well, we really benefited from biomarker testing in the targeted therapy space where virtually everyone with an ALK fusion responds to alectinib (Alecensa) and virtually everyone with ROS responds to crizotinib. Right now, the best biomarker we have for immunotherapy is PD-L1. It's the expression of that protein on the tumor cell. That's just as much a biomarker as EGFR, ALK, or ROS. It's a biomarker that everybody should have tested, and the treatment is different depending upon the biomarker status.

In my own practice, if a patient's tumor has a really high PD-L1, then I use immunotherapy alone without chemotherapy, and that can save the patient significant toxicity and has very good efficacy. So that's another biomarker, but it's not as good a biomarker as EGFR or ALK or the other gene mutations. Because even with the positive biomarker test, only less than half of patients still have a major response. So we're looking for better biomarkers and better ways to match immunotherapies to patients.

Lisa Goldman: Is that test for PD-1 or PD-L1 included in, for example, NGS testing that also tests for the targeted therapies, or it's a separate test that you have to take sequentially?

Dr. Carbone: Some of the commercial platforms test for both. I won't name names, but you can order both, but they're completely different types of tests. Most patients aren't molecular biologists or have a PhD in genetics to understand the details of the tests, but the NGS you mentioned is next generation sequencing. That's a DNA test and that's best at detecting mutations like for EGFR. Some of the gene abnormalities are gene fusions where two genes are linked to each other when they shouldn't be. That can be tested for by other technologies, one of which is called FISH.

But that also can be detected by NGS. PD-L1 is a protein marker, not a DNA marker. And that's tested for by a test called immunohistochemistry, but patients don't need to know all that stuff. I'm hopeful that their doctors do and order the right panel of tests.

Lisa Goldman: Yes, I agree. We don't need to know the details. I just wanted to clarify so that patients know if they've had NGS, they might still need to get additional testing to see if they're candidates or good candidates for immunotherapy or not.

Dr. Carbone: Knowledge is power, right?

Lisa Goldman: Just need to know what to ask your doctor for and when to ask it. Do you have any advice on that? When should a patient have a conversation with their doctor about immunotherapy?

When Should Patients Ask Their Doctor About Immunotherapy as a Treatment Option?

Dr. Carbone: Well, I mean, you can say you should do it on your first visit, but that's awful hard to do because often you're there and you don't know A from B or an adeno from a squamous or a KRAS from an EGFR. Patients really need to get up to speed quickly and learn a totally new vocabulary and get the trust of a totally new person that will be guiding their therapy. I think ideally you would ask the doctor that you're seeing, "I have cancer, but I've read on this website, or my daughter tells me that I should have those tests done."

And now there are some really good websites out there. The major foundations and organizations have very good patient-oriented information. If a patient can educate themselves on the basic terminology of lung cancer before that first visit, that's when you should ask. You should say, "I want complete biomarker testing and the immunotherapy marker as well," and have it done at the very first visit.

In fact, in our clinics, I've taught our pulmonary doctors and our surgeons, when you do a biopsy for lung cancer, you send these tests before the patient even gets scheduled to see me so that the results are there on my first visit with the patient. And I think ideally those should be reflexive and available right away.

Lisa Goldman: If a patient has been in the system for a while, they've already started some treatments, but they never had that immunotherapy test, should they ask for it? For example, should I go ahead and get tested now, even though I'm not in need of it immunotherapy at the moment? Or when should patients like me ask?

Dr. Carbone: Well, markers can change with time. Often the driver mutation stays the same, but then, for example, with ALK mutations, you can get new mutations in the ALK gene that make it resistant to certain drugs and allows... If you know about them, it allows your doctor to intelligently pick another drug that might be sensitive to. Sometimes biomarker testing needs to be done over and over again. PD-L1 in specific can change with time.   

Often, it's the case that we repeat the testing at the time when we're considering immunotherapy on a current lesion. But there's a lot of generalities. Every case is a little bit different, and I probably would not go out of your way right now to test for PD-L1.

Lisa Goldman: Right. So it sounds like at the beginning of your treatment or anytime you're evaluating when to make a treatment decision would be a good time to consider that.

Dr. Carbone: Well, anytime you need to change therapies is a good time to really relook at the landscape of what's available, and there's a lot of clinical trials going on now. And if the drugs that you're on stop working, I mean, look for clinical trials, look for brand new drugs. We've had more FDA approvals in the last three years than in the previous 30 in lung cancer. And doctors are confused by all of the new drug names that are being approved.

So, I think it's really important that every time the treatment stops working, that you look around again, ask if there are additional biomarkers that need to be tested, and ask if there are clinical trials available. And just to make a personal point, doctors will often say that Ms. Smith failed chemotherapy. I really think that that's absolutely not true. It's the chemotherapy that fails the patient. So, I always try to say that when the treatment stops working, rather than the patient fails a treatment, for example.

Lisa Goldman: Yeah, I agree.

Michele Nadeem-Baker: I have a quick question for you, doctor.

Dr. Carbone: Sure.

Michele Nadeem-Baker: Out of your lung cancer patients in general, what percent are on immunotherapies right now?

Dr. Carbone: A very high percentage. Right now about 10 or 15% of patients in the majority of the United States have driver mutations. The 85% that don't have driver mutations, I would say the vast majority of them are on some form of immunotherapy now, which is a major transformation from 10 years ago when it was just being studied in some of the first trials. So virtually every lung cancer patient has a chance of being on immunotherapy.

And even with a driver mutation, like I mentioned before, if you exhaust all your options with driver targeted therapies, then chemotherapy and immunotherapy are still potential options to try.

Lisa Goldman: Doctor, is there any data that shows a comparison between the effectiveness of immunotherapy in contrast to traditional chemo or targeted therapies?

Is There a Difference in Efficacy between Immunotherapy, Traditional Chemotherapy and Targeted Therapies?  

Dr. Carbone: Yes, of course. I mean, that's how the immunotherapies were approved. Generally, the ones that are in use today were compared to chemotherapy alone and shown to be often vastly superior. And not just in time to progression of the disease, but in real terms of survival. I mean, years ago we did a trial with the best chemotherapies available, it's the ECOG trial, comparing four different chemo regimens. And the median survival in that study was eight to 10 months.

And there were just a handful of people out of a thousand that were still alive three years later. Now with the immunotherapies, we're seeing people alive five years later. A large fraction of patients alive five years later who received immunotherapy, and actually we've now been able to stop treatment on some of these patients. And I have many patients who've had two years of immunotherapy and we stopped them, and now they're years later with no evidence of recurrence. This is totally unheard of historically in lung cancer.

Michele Nadeem-Baker: If someone goes to a community doctor and a community hospital, should they be getting to someone who is a specialist? Would the community hospitals necessarily have the latest in immunotherapies for them or be knowledgeable about them?

If a Lung Cancer Patient Goes to a Community Hospital, Should They Also Seek an Opinion from a Specialist?

Dr. Carbone: Well, things change rapidly, and there are some really good community hospitals and community doctors who keep up with the latest advances and do the right thing. Hats off to them. They often see every type of cancer, prostate cancer, breast cancer, colon cancer, leukemia, blood diseases, and they have to know the state-of-the-art in all of those different situations. And cancer has gotten so complicated.

I often tell patients, they may be recommending the right treatment, but it doesn't hurt to get a second opinion at a major center where there are doctors that specialize in lung cancer. At my hospital, we have nine medical oncologists who do nothing but lung cancer. And we are in touch with the latest therapies and studies. And even before they're published or FDA approved, we're often using things in patients that will be FDA approved in the next year.    

And we have access to clinical trials of the next generation agents. Today's clinical trials are tomorrow's standard of care. I think an informed patient who has the time to scope out what's available in terms of trials and get a second opinion will be better off. And often I tell patients, what your doctor is recommending is exactly what I would give you here. It's better to get it down the street than to get it three hours drive away.

Lisa Goldman: I always tell patients, it's nice to have a team. I have a local doctor, but I also have a relationship with a specialist that's a little further away that I consult for very precise questions about my diagnosis. We have a question from the audience about combining immunotherapy with other treatments for lung cancer. Do you have any thoughts about combining immunotherapy?

Can Immunotherapy Be Combined with Other Lung Cancer Treatments?

Dr. Carbone: Well, immunotherapy, since it's been so successful, the way we as medical oncologist do things is we often say, "Well, it works by itself. We'll try it combined with other things." Immunotherapy can be combined with chemotherapy. That's now fairly standard and that's used often for tumors that are lower expression of PD-L1. It seems to be better for the low expressing tumors. But also there's a recently approved regimen that combines two different types of immunotherapy without chemotherapy.

And there are clinical trials now combining immunotherapy with many different experimental drugs. The answer is yes, there's a lot of immunotherapy combinations being studied.

Lisa Goldman: What about combining it with targeted therapy? That was one question we got.

Dr. Carbone: It's being asked, but some of the early trials combining with targeted therapy showed really no benefit. And in fact, at least one of them had a large number of deaths from toxicity. I think it's not standard of care right now to combine targeted therapies with immunotherapies.

Lisa Goldman: I've also seen that in the ROS1. We had one or two patients kind of go off the beaten path and try it and had really high toxicity levels, so I’d proceed with caution there. Since immunotherapy affects your whole immune system and all your cells, I assume that it has side effects in the same way that chemotherapy that affects all the cells has more side effects than for perhaps targeted therapy, which doesn't necessarily affect everything. Can you talk a little bit about the side effects for immunotherapy?

What Are the Side Effects of Immunotherapy?

Dr. Carbone: All therapies for cancer are really potent and people can have side effects from targeted therapies. They can have side effects from chemotherapies. But specifically for immunotherapies, actually the side effects are usually not very significant. I tell people that the most common side effect from immunotherapies is usually a mild skin rash. Maybe 20% of people have that. The next most common side effect would be thyroid abnormalities, about 10 or 12% of people.

And that's really mostly a blood test abnormality that's easily taken care of by taking thyroid medicine. But beyond that, there are some serious side effects. And some people have very severe inflammation of their bowels, like a colitis it's called, which causes diarrhea and pneumonitis and inflammation of their lungs, and both of those last two things can be fatal in fact, but they occur in less than 1% of people. 

One out of a hundred people have the serious side effects. And then there are very rare side effects of other endocrine disorders and lots of other things. But most of them are reversible if you catch them and treat them appropriately. Overall, the side effect profile of immunotherapy is quite good, and I've been impressed. Many of my patients are on it and can hardly tell they're taking anything.

Lisa Goldman: That's amazing.

Dr. Carbone: It really is.

Michele Nadeem-Baker: Do you think that it's safe to say in the next, I don't know, 20 years, 10 years, that we will see a cure for any of the lung cancers?

Is a Lung Cancer Cure on the Horizon?

Dr. Carbone: I used to tell my patients on their first visit when they're very distressed and they're asking, "What does this mean? How long am I going to live?" I hardly ever tell them a number unless they really push me and say, "What's the median survival?" But I say some people live a longer time and some people live a shorter time. But then I used to tell my patients, "You have an incurable disease, but a treatable disease. Nobody lives forever. My job is to give you the longest, the best quality of life I can."

But now I don't tell people that it's incurable, because like I said, I have multiple patients that have had a course of immunotherapy, have had beautiful responses, and their scans are totally clean for years now off of immunotherapy. So I actually think that there is a subset of patients, especially those treated with immunotherapies, that could be cured by that treatment and die of something else.

That's what I think is so exciting these days. Advanced lung cancer that used to have an average survival of four months, now we can see patients in our clinic years and years out off of all treatments and doing great. It's just very gratifying.

Please remember the opinions expressed on Patient Power are not necessarily the views of our sponsors, contributors, partners or Patient Power. Our discussions are not a substitute for seeking medical advice or care from your own doctor. That’s how you’ll get care that’s most appropriate for you.

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