The lung cancer death rate in the United States has dropped dramatically over the last few years with the introduction of new treatments, including immunotherapy, that offer hope for millions. At the 2020 CRI Virtual Immunotherapy Patient Summit, we hosted a special breakout session on lung cancer and immunotherapy to educate and empower patients, caregivers, and advocates. Leena Gandhi, M.D., Ph.D., director of the Clinical Center for Therapeutic Innovation at Dana-Farber Cancer Institute, led the breakout session and answered questions from the audience.
Dr. Gandhi opened the session by discussing several recently approved immunotherapy options and how immunotherapy is advancing the treatment of lung cancer. She noted that within the last seven years, “immunotherapy has become a cornerstone of therapy to treat multiple types of thoracic cancer. We hope that our new therapies will build upon these successes and extend the benefits of immunotherapy to more types of patients and more individuals.”
Dr. Gandhi focused on the promise of a type of immunotherapy known as checkpoint inhibitors, in particular those that block the PD-1/PD-L1 pathway, which acts as a “brake” to prevent our immune system from attacking healthy tissue. Tumor cells use this pathway to trick and hide from the immune system. Checkpoint immunotherapies block this interaction, thus enabling the immune system to remain active and attack the cancer.
The level of PD-L1 expression has become an important biomarker for predicting the success of checkpoint immunotherapy response. Dr. Gandhi pointed to recent research that indicates checkpoint inhibitors are important to consider as first-line treatment, especially for late-stage lung cancer.
Finally, Dr. Gandhi reflected on the importance of ensuring patients and caregivers are educated and aware of all treatment options available to them at the time of diagnosis, including those in clinical trials. She explained that immunotherapy may “have the best chance to make an impact at the time of diagnosis.”
Immunotherapy and Lung Cancer Breakout Session Transcript
Tamron Hall: If you're just joining us, it's my pleasure to welcome you to the first ever Cancer Research Institute Virtual Immunotherapy Patient Summit. Here to tell us more about lung cancer immunotherapy is Dr. Leena Gandhi. Dr. Gandhi joins us from Dana-Farber Cancer Institute in Boston, where she is the Director of the Center for Cancer Therapeutic Innovation. Brian Brewer from the Cancer Research Institute will be sharing your questions with Dr. Gandhi, so please be sure to put them in the Q&A box. Dr. Gandhi, thank you for sharing your expertise with us today.
Dr. Leena Gandhi: Thank you very much, Tamron, and it's nice to be with you all. I'm going to spend just a few minutes reflecting on how immunotherapy has changed our treatment landscape in lung cancer before we get to questions. I think for many of you who are patients who have had loved ones with lung cancer, you may know that for a long period of time, probably from the 1980s or even earlier until 2014, chemotherapy was the mainstay of treatment for lung cancer. And chemotherapy certainly constitutes different drugs, but many of the trials at that period of time in the 80s and 90s were of different combinations of chemotherapies, all of which had pretty similar efficacy, and all of which were not very good. They offered small amount of benefit with a lot of toxicity.
In the 2008-2009 era is when we first started putting lung cancer patients on immunotherapy trials. And we'll fast forward maybe to 2014, where we saw that in the course of those studies on the next slide, you can see that that led to actually multiple approvals of PD-1 agents to treat lung cancer. What we found in those phase one trials is that PD-1 therapies benefit patients with both non-small cell lung cancer and small cell lung cancer. And we also from testing patient's tumors, found that PD-L1, or the ligand that binds PD-1 on immune cells could be expressed at high levels in tumor cells, and this happens not uncommonly in lung cancer. And it could be a good predictive marker of who was most likely to benefit.
And in 2015, PD-1 or PD-L1 therapies were first approved for the treatment of non-small cell lung cancer after chemotherapy. But it was very, very soon after that there was a flurry of activity in many other settings, because when we saw that immunotherapy could benefit some patients with lung cancer, we always want to try to treat patients with the best possible therapies as soon as possible, which meant that we were studying, well, if PD-L1 is a good predictor of benefit, could it actually replace chemotherapy in the first-line setting?
And that's exactly what a study, Keynote 24, which was started in 2014 I think, studied for patients who had high PD-L1 expression over 50%. When you compare to head to head how that performed against chemotherapy, it was actually much better. And that led to its approval as a first-line treatment instead of chemotherapy for patients who had high PD-L1 expression.
And I think that that kind of advance was very important, but PD-L1 expression is high in less than a third of patients. So a lot of activity in clinical trials in the last 10 years has been focused on, how can we enhance the benefit of PD-1 therapies? Can we improve upon that with combinations? And because chemotherapy can potentially stimulate immune responses by killing cancer cells and releasing antigens for the immune system to recognize, chemotherapy was a natural combination to study.
And in 2017, the first accelerated approval happened after pembrolizumab was shown to improve progression-free survival with chemotherapy, and we conducted a larger phase three trial that demonstrated that that combination improves overall survival for all patients, even those with who have no PD-L1 expression, which really changed the standard of care for all patients to receive immunotherapy upfront and treatment.
Around that time there were also phase three studies going on of treating patients with immunotherapy using durvalumab after chemotherapy and radiation for locally advanced cancers. And that was also shown to improve survival. So chemotherapy in addition to immunotherapy was becoming a standard of care for more and more patients.
In the last couple of years, we've seen those impacts even more broadly in areas of small cell lung cancer, where immunotherapy was first approved as third line agents, but has now been also combined with chemotherapy in the first line, and shown to improve overall survival. And we've seen that same kind of improvement with immunotherapy in mesothelioma as well, where a combination of two immunotherapies, ipilimumab and nivolumab, actually have been shown just very recently to be superior to chemotherapy in helping patients live longer. That kind of combination of ipilimumab and nivolumab has also been recently approved for the treatment of first-line metastatic lung cancers, non-small cell lung cancer. So there are multiple options now for immunotherapy for many different kinds of patients.
And I would say there are hundreds, if not thousands of ongoing studies that could have impacts in the field of building on those immunotherapies in the future. And that includes testing new therapies in advanced lung cancer, as well as testing PD-1 inhibitors in other kinds of settings, such as before surgery to see if we can improve the rates of cure.
So overall, I think when I just really illustrate this timeline to say that from the times in the last really only seven years, we've seen that immunotherapy has become a cornerstone of therapy of treatment for multiple different kinds of thoracic cancers. And our new therapies will really build upon the successes we hope, and extend the benefits of immunotherapy to more types of patients and more individuals. And I'm very hopeful about the future of us doing even better than where we are now.
Brian Brewer: Well, thanks so much, Dr. Gandhi, you led right into my very first question about the standard of care and how rapidly it's been transformed. And I thought one thing that was very interesting was, you started off by asking, or many, many clinicians were asking, would immunotherapy work better and eventually replace chemotherapy? And now we're finding that the combinations seem to work better, and work better and more patients. So that's great to hear. Are there other types of therapies that are being tested in combination? Not chemotherapy, but you mentioned surgery, other treatments.
Dr. Leena Gandhi: Yes, there are all kinds of trials looking at all kinds of different combinations. And I would say those are combinations of other kinds of therapies. And those could include radiation, which can under certain circumstances affect an immune inflammatory state, including surgical approaches. Other kinds of approaches like cryoablation, many kinds of localized approaches are being combined with immunotherapy, as well as targeted therapy. And I would say that early trials with targeted therapy were a little worrisome, because there was an increase in immunotherapy related side effects that we're seeing.
But I think what we're trying to do is tease apart how we can best combine these types of therapies safely. And I am confident that we'll see some improvement there as well. We're still at the early stages of understanding how targeted therapies can influence the immune system as well, and what is the best way to potentially combine them with immunotherapy. There are also, as you may have talked about in other sessions, many, many trials combining different kinds of immune stimulants with anti PD-1 inhibitors, and there's all kinds of novel approaches being taken, as well as multitalented molecules that are trying to do two things at once, or three things at once within the same drug. So we look forward to those kinds of studies as well.
Brian Brewer: Are there any clinical trials in specific that really excite you, or look very promising or maybe farther along?
Dr. Leena Gandhi: Yeah, I would say there are many exciting things happening. For the most part, those are still quite early, meaning they are still in phase one studies. Although I would say that I would encourage patients, if there are patients here for whom clinical trials make sense from discussions with your own doctor, to consider participating in those trials. Because the only way we'll know how much potential those have is actually in partnership with patients who agree to participate in those kinds of trials.
There are some, there are a couple of areas that are further along. There are phase three studies going on now in non-small cell lung cancer and small cell lung cancer combining anti-TIGIT antibodies with PD-1 antibodies. TIGIT is a protein that can repress T-cell activation, and can be potentially a mechanism of resistance to PD-1 therapy. So the hope is that if we combine that approach, it may add to the benefit of PD-1 therapies. That's still yet to be seen, but it is in late stage trials.
The other trials that I'm very excited about are early stage trials of testing immune therapy combinations before surgery, because I think one of the things that's been very challenging for the field of lung cancer is even when we diagnose lung cancer early, there is a high risk for recurrence and metastasis, which would then make a cancer incurable. If we can improve the chances of cure upfront, then I think we've really achieved what we really want to achieve, which is getting rid of cancer permanently.
And I think we've seen very exciting early studies suggest that in more patients, we can see responses with immunotherapy than we might in the metastatic setting, suggesting that maybe tumors might be even more susceptible to immune stimulation in the early stages. And we know that surgery can be an effective immune stimulator too. So I'm very excited about there are a few phase three trials ongoing looking at immunotherapy combinations, either with chemotherapy or with CTLA-4 inhibitors before surgery, to see if we can improve the chances of cure.
Brian Brewer: You mentioned PD-1 blocking antibodies and PD-L1 expression levels. And that was covered in some of yesterday's discussions on the basics of immunotherapy. So if are you seeing that PD-L1 levels are potentially higher at earlier stages of disease? Is that something you're looking at, or...
Dr. Leena Gandhi: Yeah, that is definitely being looked at, but actually that's not exactly what we're seeing. It's quite interesting that the PD-L1 as a biomarker of response has been somewhat controversial for a long time, because unlike some kinds of mutations in lung cancer, which are genetic changes and fixed changes that are clearly markers of response to targeted therapy, PD-L1 is a protein, which means it can be dynamic. Its expression level can change with exposure to chemotherapy or radiation or surgery, or what have you. So in the advanced setting, it does seem to have predictive value, particularly at high levels. In the early stage setting, it's actually not so clear. And it might be that as cancers become more advanced, you develop more exhausted T-cells and then start to stimulate expression of this PD-L1 to further evade the immune system and allow cancers to metastasize. So it may not be the most important thing in early stages.
We have seen in small studies so far that the number of potential recognition factors in the immune system, or neoantigens in a tumor may be a more important predictor in the early stage setting than PD-L1 expression. But I think that's still actually not really fleshed out. And we hope that some of these larger scale studies will tell us what's the right selection factor for sure.
Brian Brewer: Well, that's a great segue into another question we've received from one of our viewers who doesn't have high PD-L1 expression. And you already touched on at the beginning that in combination with chemotherapy, some of these treatments or patients, more patients respond. But are there other immunotherapies for patients with low PD-L1? You just mentioned neoantigens, which can lead to... Go ahead.
Dr. Leena Gandhi: Yes, so one surrogate measure we have for neoantigens is something called the tumor mutational burden, or TMB. And that's really what we think can be reflective. If there's a high tumor mutational burden, there may be a lot of high abnormal signals to the immune system. And we have seen that immunotherapies of various kinds can be more effective in patients who have high TMB. And this includes PD-1 inhibitors alone, like pembrolizumab, which was recently improved actually for all tumors, all tumor types that have high TMBs. But it's also true that in lung cancer, we have seen an association of the combination of nivolumab and ipilimumab, efficacy with high TMB. I will say that in the early stages of those kinds of studies, that was felt to be potentially a good predictive biomarker. In later stage studies, what we see is that high TMB can be also what we call a prognostic marker, meaning it can predict for better overall outcomes for patients who have that in general.
So although nivolumab and ipilimumab is approved in first-line lung cancer, you don't need to be selected only on the basis of high TMB. In fact, it seems to be beneficial in a broad range of patients even with a high PD-L1 expression and low PD-L1 expression. So that is another option for patients, in addition to pembrolizumab, in addition to pembrolizumab with chemotherapy and atezolizumab with chemotherapy, or atezolizumab alone. So there are multiple different options, which we think is a good thing.
Brian Brewer: Absolutely. The more options the better for all patients. Before we leave this discussion on biomarkers and TMB and PD-L1, just a question is, do patients have to ask for these screens, or are they now incorporated into the standard of care also?
Dr. Leena Gandhi: Yeah, well, I would say the one thing about lung cancer and immunotherapy is that lung cancer physicians were very primed, I think for many years, to look for biomarkers to help us our treatments for lung cancer patients. And that came from studies of small numbers of patients who have specific mutations that predict response to targeted therapy. But because of that, we've been doing genomic testing or looking at genetic alterations in lung cancer for a long time on a standard basis. And because of that, I think it's been quite easy and very rapid to incorporate both PD-L1 testing, which is a protein test, as well as tumor mutational burden, TMB testing, which is a genomic test, into our standard of care approach for treating all lung cancer patients. So hopefully your doctor should have that information upfront and should be testing for that automatically. You shouldn't have to ask.
Brian Brewer: Wonderful. So another question from one of our viewers is that they have been treated with an immunotherapy, their latest scans have shown no evidence of disease. And now they're just wondering how long do they need to stay on an immunotherapy?
Dr. Leena Gandhi: Yeah, that is a great question. And a very important question that hasn't been studied so well, because unfortunately it hasn't been the case for most patients. When you really have no cancer seen on a scan, that's something we call a complete response, which is fantastic. It doesn't happen that often. But there certainly are small retrospective studies suggesting that if that happens, those responses can be maintained longterm. And that's been seen not only in lung cancer, but other cancers. And so there are many doctors who would stop therapy at that point and continue to monitor closely. In the early days, I would say many immunotherapy studies just continued treatment indefinitely. Some started to put a stopping point on that therapy if you have seen a response. And for pembrolizumab studies in particular, two years was actually implemented as a stopping point in trials for all patients who had a partial or complete response. And that's where we've seen the good outcomes with pembrolizumab.
There is data to suggest that if you restart therapy after you've been off of it, if the cancer starts to grow again, that you can get a response again. It isn't a hundred percent clear overall how long people really need to receive this therapy, particularly if you get a very good response. I think there's a lot of individual decisions that happen at this point between a patient's comfort level, their doctor's comfort level, and maybe side effects that you've been experiencing. But it's an active area of research to try to better understand, well, how long do we really need to use these treatments? And we'd certainly not like to give people more treatments than are necessary.
Brian Brewer: Well, thanks for that. You mentioned something, partial response, which doesn't sound completely awesome to someone listening in, but it didn't sound so bad when you just said it. Can you just speak a little bit more about what a partial response is?
Dr. Leena Gandhi: Yes. It may not sound completely awesome, but it is actually completely awesome, because what it means is that the tumor is shrinking in response to the therapy. And I would say in the world of cancer, as many of you know, we think any response is awesome, because it means that the tumor is no longer growing, which is really what counts. There's a third term called stable disease, which we also think is pretty good, because again, it means that the cancer isn't growing. If we actively see the cancer shrinking, what we're looking at on a scan, even if we still see something there in a setting of a partial response, that could be dead tissue, that could be cells that just aren't ever going to grow. We really don't know. But seeing any shrinkage really tells us that we're doing something very positive with the treatment. So I would say any kind of response is a great response.
Brian Brewer: All right. Thumbs up to that. A new question that has come in is, actually a few times today in the other sessions as well is, how long does immunotherapy stay in the body, and how long is it active?
Dr. Leena Gandhi: Yeah, it's a very good question. It relates to the other question about how long do you have to continue the treatment? Because what we've seen specifically with PD-1 inhibitors is they can actually last quite a long time in the body, particularly if you've been getting them for a little while, their half-life becomes much, much longer. So when you stop an immunotherapy, it could be present in your body for up to six months or possibly even longer after you stop the treatment. Whether that's really contributing to why we see sustained responses, we don't know. Certainly some responses last much longer than that, they last years.
But it also is a factor that we have to think about when we think about other treatments. If you came off of an immunotherapy because the cancer was growing, it can be a factor when you think about clinical trials that you might consider, or even other types of treatments. And we don't know for sure whether it contributes to an observation that's still yet to be fleshed out, but that we can sometimes see better responses to therapies after treatment with immunotherapy, other therapies than if people had never received immunotherapy.
Brian Brewer: Very interesting. And also just to reiterate something you said just before that, which was another question we'd received. So you're predicting what our audiences is very curious about, and I imagine that's from all your expertise and experience working with patients directly. But the question was about side effects. And I think we should talk a little bit more about that, because the side effects of chemotherapy may be different from immunotherapy, and how we handle that. So would you just speak a little on that?
Dr. Leena Gandhi: Sure. I think that one of the parts of... One of the reasons people were excited about immunotherapies early on is that we felt that overall they have less toxicities than chemotherapy. That's not to say they're without any toxicities, but with chemotherapy, I would say the majority of people get some side effects, and sometimes severe. With immunotherapy, I would say the majority of people actually don't get side effects. Now there can be a minority though that do get side effects, which can sometimes be serious. And they're mostly related to inflammation. And particularly for lung cancer patients, a particular type of inflammation that we worry most about is inflammation within the lungs, because that can affect some of the same kinds of symptoms that you might even have from cancer, or from other underlying lung disease that preceded the cancer.
So I wouldn't say immunotherapy side-effects are nothing to worry about, but the good thing is, is they happen in a minority of patients, and that because of increased recognition and understanding of those kinds of inflammatory side effects, I would say both doctors and all kinds of caregivers, pharmacists, nurses, and the patients themselves, I think are alerted to be very vigilant to look out for these. And what we've learned from early trials, where sometimes people got very sick and irreversibly sick, is that the earlier we can recognize these and get on top of them by treating with anti-inflammatory drugs, the more we can keep these under control and from getting serious. And we have also seen that treating patients with anti-inflammatory drugs, like steroids doesn't necessarily harm the overall outcome of the immunotherapy.
So I think we continue to learn more and more about the side effects, but I think the good things are that they're overall less frequent than those with chemotherapy. And with a lot of vigilance, we can keep them from getting serious. That's not to say that for everybody, immunotherapy is a piece of cake, and definitely immunotherapy side effects can affect your ability to receive these drugs. But I think the important thing to remember is that the goal of all therapy is to keep you as well as possible for as long as possible, which means that if immunotherapy does have a lot of side effects for you, it may not be the best thing for you. Every person is different and needs a personalized solution, I would say.
Brian Brewer: Do we know anything yet about the long-term impact of side effects from immunotherapy?
Dr. Leena Gandhi: Well, we know that in some cases, immunotherapy side effects are not reversible, meaning that you can develop inflammatory problems or even auto-immune problems that are not reversible. Again, I would say that the sooner we get on top of those, the less likely that is to happen. There is also some small amounts of data that suggests that people who get some of these toxicities might be the ones who might have a chance to respond to those therapies. This has been most clearly observed in melanoma, where one of the auto-immune problems that can occur, vitiligo or skin deep pigmentation can be associated with long-term response. And we've certainly seen that in some lung cancer patients, that initial inflammation, sometimes that leads to, you have to stop the therapy because a patient will get sick. And then we see that a patient may not need therapy for a long time, but that initial inflammation may have contributed to the inflammatory and anti-tumor response from your immune system.
I wouldn't say that we're looking for people to have side effects, though, so I want to be cautious about that. And I think we still don't know really fully who's at most risk for those kinds of side effects, and what those really mean for the impact of the immunotherapy, but they're areas of active investigation. And a lot of people are studying to try to better understand that so that we can, again, for every individual, tailor our treatment the best that we can.
Brian Brewer: Very good, very good. And here's a timely question. Can a person receiving immunotherapy, a lung cancer patient, take a flu vaccine?
Dr. Leena Gandhi: Yes. Patients can and should take a flu vaccine, who has lung cancer is receiving immunotherapy. What we do know that there can be risks for getting live vaccines with immunotherapy, because the immunotherapy is an immune stimulant, and sometimes live vaccines have a higher risk of inflammation, and that can be exacerbated. But almost all flu vaccines are not live vaccines, and those are safe to take with immunotherapy. And because those can be a risk to your health too, and your lungs, we absolutely think you should get them.
Brian Brewer: Good to know. And very briefly, of course we're in the middle of a pandemic, COVID-19, those who develop severe symptoms, it can often manifest with issues around lung inflammation. Any special considerations for lung cancer patients these days?
Dr. Leena Gandhi: Yeah. I would say that we worry that risk factors for getting more severe complications of COVID-19 do include patients with lung cancer, honestly. We have seen that for patients with all types of cancers, they can be more at risk for complications with COVID-19. But because some lung cancer patients can have compromised lung function, that can also put you at increased risk, because we worry that COVID-19 most severely affects your lungs actually, and your breathing. So I would say that lung cancer patients should absolutely be taking as much precautions as they can around this. And I think what we have seen from living with this pandemic for some time is that taking precautions like wearing masks and not being around people who you know have COVID-19, or in areas of crowds, washing your hands frequently, all those sorts of basic safety rules go a long way actually to protecting each and every one of us. So I would certainly encourage every cancer patient and lung cancer patient should be doing all those things.
Brian Brewer: Thank you. Thank you for answering that question. Another question from one of our viewers who had tumors in the lungs, but that was not the primary origin of the... It wasn't actually a lung cancer, I guess. Would a lung cancer immunotherapy work for that patient?
Dr. Leena Gandhi: Well, so when we think about how we define cancers, we think about where they started, because that's sort of the tissue or organ that it started helps define the characteristics of the lung cancer. Many different types of cancer can metastasize or travel to the lungs, but they will retain the features of that original cancer. So I think that the best way to treat a cancer that has metastasized to the lung is based on where it originated from. And certainly your doctor would know best about how that should work for your individual situation. But there's also nothing specific about lung cancer in terms of immunotherapy, as I think you've talked about during this conference. PD-1 or PD-L1 inhibitors are used in a variety of different cancer types. So it may be that that could be a good treatment for your type of cancer, depending on where it started, and how it's best characterized.
Brian Brewer: You mentioned, we're almost out of time, so I'll just remind our viewers to please continue to leave your questions in the Q and A, if we don't get to them all today, we'll be sure to follow up with as many as possible in future. Anything else you'd like to add, Dr. Gandhi, top of mind for someone right now who's just newly diagnosed with lung cancer, what would you recommend to that individual?
Dr. Leena Gandhi: Well, I would say, I think particularly if you're newly diagnosed, that can be a very scary time, and lots and lots of questions may arise. There are so many things that you'll see on the internet, and there's many different subtypes of lung cancer with different kinds of mutations, which may lend themselves better to different therapies. And I would say from a doctor's perspective, what we really try to think about when somebody is newly diagnosed is how can we understand as much as possible about this individual's cancer, so that we can have the best treatment plan for you? And that means doing comprehensive genotyping or genetic testing to see what are the changes in the lung cancer, and what are the therapies we should be thinking about upfront.
It is not always immunotherapy for every patient. For some types of patients, more commonly those who have never smoked, they are more likely to have very specific changes that lend themselves well to very targeted therapies. And that may be the right first option for you. For other patients who don't carry those, immunotherapy may be a good first option. For patients who have underlying auto-immune disease or other things that might make immunotherapy more risky, maybe chemotherapy or other kinds of options are better. So I would say what is really important is to figure out with your doctor, what do we know about my cancer? What are the things that you know, and what will they tell you about what's the best treatment for me? We do think that we have the best chance to make an impact at that time of diagnosis. So it's an important time to ask as many questions as you can, so that hopefully you get the best plan possible to help your cancer.
Brian Brewer: Thank you. I'm glad you touched on autoimmune disease also, because that was another question I was about to follow up with. But that's all the time that we have. Dr. Gandhi, thank you so much. Very, very informative. And I'm so delighted to see the progress and the excitement that you have, and knowing that behind that smile are a lot of healthy cancer patients or ex cancer patients. So thank you very much again.
Dr. Leena Gandhi: Thank you very much. It was my pleasure.
Tamron Hall: Thank you, Dr. Gandhi, for answering our lung cancer immunotherapy questions. If we didn't get to your question today, don't worry. Dr. Gandhi will follow up with more answers on the Cancer Research Institute blog. In the meantime, I encourage you to continue exploring the CRI Resource Guide. And if you haven't already, schedule your free confidential clinical trial navigator consultation. Now we'll take a short break before we talk about melanoma and immunotherapy. We'll be right back