As the most common cancer worldwide, lung cancer impacts approximately 2.1 million people each year. Hope for millions is on the horizon as 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. Immunotherapy for lung cancer, alone or in combination with conventional treatments, can significantly improve outcomes for lung cancer patients. Join medical oncologist Dr. Patrick Forde, M.D., of Johns Hopkins Medicine, to hear about several recently approved immunotherapy options and ask your questions about how immunotherapy is advancing the treatment of lung cancer. We’ll discuss PD-L1 expression, treatment response, length of treatment, clinical trials, and more.
Tamron Hall: Welcome back to our next session for day two of the 2021 Cancer Research Institute Virtual Immunotherapy Patient Summit. It’s time to talk about lung cancer, the second most diagnosed cancer worldwide, with more than two point two million new cases each year. Joining us to talk about advances in immunotherapy for lung cancer is medical oncologist Dr. Patrick Forde from Johns Hopkins Medicine. Also with us is Oswald Petersen, a non-small cell lung cancer survivor treated with immunotherapy who will share your questions with Dr. Ford. Be sure to put them in the Q&A box. Thank you, Dr. Ford and Oswald for sharing your expertise and insights with us today.
Dr. Patrick Forde: Hi, everyone. I’m delighted to be here today and thank you to CRI for organizing this amazing event. As mentioned, I’m a medical oncologist at Johns Hopkins in Baltimore, USA, and today I’m going to talk a little about some of the developments in immunotherapy for lung cancer, and then hopefully we’ll be able to address some questions and have some conversation.
So I would first of all, I will talk about some of the history in terms of lung cancer. Going back to the early 80’s, chemotherapy up until the early 2010s was a cornerstone of treatment, essentially any new patient cell or any medical oncologist, so we had one option really chemotherapy. We did have some developments between 2000 and 2010 and in terms of targeted therapies for a minority of patients, but really, we did not have other options. These were all very similar combinations and a very modest benefit for most patients.
Thankfully, over the last seven or eight years with work from patients, from investigators and from support organizations such as the Cancer Research Institute, we’ve seen great new developments, particularly in terms of the use of PD one therapies and these are antibodies which block CO inhibitory molecules around the tumor cells, which block our own immune system from recognizing the tumor and eliminating it back in 2014 and 2015. We saw this at the first evidence of these agents being approved, for example, from melanoma, and then in 2015, we saw the first approvals in lung cancer, and these were for patients who had received chemotherapy first and either had not responded or had progressed after treatment, and in these studies, it was shown that drugs such as pembrolizumab or Keytruda and nivolumab were effective for four such patients, particularly for those patients whose tumor cells expressed high levels of this protein PD-L1.
More recently, in 2016, there was a large Phase three trial which looked at moving these medicines forward for patients with newly- diagnosed lung cancer, and this combined chemotherapy, which was standard, with an anti-PD-1 medicine pembrolizumab, and this showed that there was an approximate two-fold increase in survival for patients when they had pembrolizumab added up front to chemotherapy, rather than reserving it as single agent later. Since that time, really PD one inhibitors, or PD PD-L1 inhibitors, which is the ligands of PD-1, have become a cornerstone of therapy for most patients with advanced or metastatic lung cancer. In 2018, we saw the first signals that these medicines could work for patients with earlier stage disease, particularly for those patients with stage three lung cancer, which was treated with definitive radiation. We have not seen any advances for this stage of disease for about 20 years, and then we saw durvalumab a significantly increased survival for these patients as well, which is an anti-PD-1 antibody.
It’s not just in non-small cell lung cancer, we have seen this, the efficacy of combination immune checkpoint blockade, and that’s a combination of nivolumab with ipilimumab, which is another checkpoint blocker for patients both with non-small cell lung cancer, but also for patients with mesothelioma and another serious cancer, which affects the lining of the lung. We’ve also seen approvals in small cell lung cancer with the addition of atezolizumab to chemotherapy or durvalumab chemotherapy, improving survival for patients with small cell lung cancer in the last couple of years, we’ve seen these medicines advance into the very early stages of lung cancer, and these are for patients who have surgery for lung cancer with the intention of cure. Previously, we really didn’t have an option of giving a perioperative chemotherapy, however, the benefit was relatively modest, at about five percent in long term survival, and this year, we’ve seen phase three trials both giving immunotherapy prior to surgery and also for four patients after they’ve had their tumor removed. These have shown a lot of promise and have been probably some of the major developments in lung cancer this past year. There are also lots of new types of immunotherapy being developed, including combinations of the PD-1 inhibitors with other immune checkpoint blockers and also with targeted drugs targeted at specific mutations in the tumor or what we call antibody drug conjugates, which essentially are complexes of antibodies plus chemotherapy, and many investigators are looking at combining those with traditional PD-1 inhibitors.
I think we’re going to really see in the next few years that immunotherapy has become a foundation of treatment for non-small cell lung cancer, small cell lung cancer and mesothelioma, we’re seeing many hundreds and even thousands of clinical trials ongoing looking at novel therapies for patients focused on immunotherapy, including things such as cellular therapies with CAR-T and other tumor-infiltrating lymphocyte therapies. These are entirely new ways which we may be able to build on the success we’ve seen with PD-1 inhibitors, so I think I’ll leave it there, and if we have, we have about 20 minutes for discussion and conversation about this topic, and I’m happy to try and address any questions anyone may have.
Oswald Peterson: Thank you very much, Dr. Forde, for that very informative for that very informative session. I would like to first start by saying my name is Oswald Peterson, I am an ImmunoAdvocate for Cancer Research Institute and we thank you for being here today, as well as being here, Dr. Forde, we thank you as well. I’d also like to let you know if you would like to submit a question, please feel free to leave your question in the question and answer chat to the right of your screen. So we’re going to dive right into the questions right now. Dr. Forde, our first question is “Does immunotherapy only work for specific lung cancer types or for all?”
Dr. Patrick Forde: I think as we’ve seen and the immunotherapy has the potential to work for all patients with lung cancer, however, the likelihood is it works probably differs by certain characteristics of the tumor in particular. So that protein marker PD-L1, which I mentioned earlier, high levels of PD-L1 expression on the tumor cells, does predict a higher likelihood of the tumor responding to PD-1 blockers, such as pembrolizumab. However, on the other hand, your tumor may not be a PD-L1 expression, and it could still respond. However, the likelihood of it responding is lower. There are other certain characteristics. For example, certain patients with non-small cell lung cancer, their tumors have what they call driver oncogene are single mutations in the tumor driving it grow, and here are things like ALK or “Alk”. Those tumors are more likely to respond to targeted therapies rather than our current immunotherapies. So a lot goes into when we see a patient with newly diagnosed lung cancer. There’s a lot of different things we look at, but some of the main ones would be the presence of the PD-L1 protein on the surface of the cells and the presence, of or absence of, some of those mutations, which are more or less likely to predict response to immunotherapy.
Oswald Peterson: So can you explain to us exactly what is a PD-L1 score?
Dr. Patrick Forde: Yeah, so the PD-L1 score is a relatively simple test. So many labs across the country and across the world are capable of performing it. It’s what we call an immunohistochemical assay or an IHG assay, and essentially what happens is when you have a biopsy taken of your tumor, the pathologist in the lab takes a slice of that tumor and puts it outside and is fixed and you stay with a marker called PD-L1, and it’s essentially a stain put on this on the surface of this slice of the tumor, and depending on how many of the tumor cells take up that stain when it’s the surface of the tumor, that gives you a score from zero. So if none of the tumor cells take up the marker to one hundred, where every tumor cell is expressing the PD-L1 marker and it’s kind of a continuous variable, so within that score of zero to one hundred at the higher the score, the more likely at the tumor to respond to the therapy. There are some nuances, and that’s mainly around the question of if you’re a tumor has a driver mutation like thank you or that ALK duration, I said sometimes you can have high PD-L1 and not respond to immunotherapy, but in general, that is a pretty good predictor of response for tumor has, say, 50% or above. That can help guide us in terms of recommending immunotherapy versus chemotherapy.
Oswald Peterson: Excellent, so our next question then asks “What if a patient or person does not have a predictive biomarker like PD-L1? Are there any immunotherapies that can still be used?” But first, can you please explain what is a predictive biomarker?
Dr. Patrick Forde: There’s two kind of different biomarkers, and one is something that’s prognostic. So for every patient with a particular cancer, if they have a particular marker on their tumor, it’ll so you give an idea of how their tumor will do irrespective of therapy. A predictive biomarker is one that if you find that in the tumor, it tells you this is the treatment I should use. And so one important thing to keep in mind about PD-L1, is that while it’s a relatively good predictive biomarker for PD-L1 blockers for immunotherapy, it’s not a perfect one, and there are a significant number of patients with PD-L1 negative cancers who still respond to immunotherapy and. What we found is that for those patients whose tumors are tier one negative, usually a combination of chemotherapy with immunotherapy is preferable, and that actually has quite a lot of efficacy and improved survival by anything from 30 to 50%, giving chemo therapy to patients with PD-L1 cancers versus chemo alone. So that’s important to keep in mind when, if you’re a patient and you hear my tumor is PD-L1 negative, my thinking is he has no role. That’s not true. It has.
Oswald Peterson: Thank you very much. Our next question asks “What are the new promising clinical trials for lung cancer? Would you be able to explain to us or tell us any new trials that you know of?”
Dr. Patrick Forde: I think there’s a few areas are very interesting at the moment. What we’re seeing in patients with newly diagnosed lung cancer is that we’re starting to see studies of PD-1 blockers, which are the approved drugs, plus other checkpoint inhibitors, and one of those is a checkpoint called TIGIT T-I-G-I-T. So that’s it’s a very similar concept to PD-1, it’s just a different inhibitory checkpoint, and there are several trials looking at combining, for example, pembrolizumab or ATCC Mab, which is another approved PD-1 pathway like a blocker with TIGIT blockers, and they’re available kind of across the U.S. and really across the world at various settings. What a lot of people are also trying to look at is can you combine this new class of medicines called ADC’s, or antibody drug conjugates? Can they be combined with PD-1 blockers, and they’re in clinical trials as well, and some of those medicines, these ADCs, have shown a lot of promise in other cancers. For example, in breast cancer, back in September, we saw a lot of information on this a medicine called in HER2, the HER2 blocker, and that drug has shown a lot of efficacy in breast cancer is now being looked at in lung cancer patients, both on its own and in combination therapy. The other broad bulk of clinical trials, I would keep an eye on this therapy trials, and these are a different class of immunotherapy to the PD-1 blockers in that it’s, it’s not really a drug you can get as an infusion. The cellular therapies are looking at either harvesting immune cells from tumor and boosting outside your body, giving them back to you to boost the immune response, or in some cases, modifying them outside your body in a process called chimeric antigen receptor, or CAR-T, and those are also being looked at for lung cancer, a whole lot of other malignancies and they’re in an earlier stage and development than a lot of the other things like the ADC’s I mentioned, but they’re looking promising, and they’ve really shown they’re most promising in things like leukemia. We’re finally starting to see clinical trials for lung cancer, and I think that’s another area to an eye on.
Oswald Peterson: That is excellent. Like with me, I know in my case, when the immunotherapy was introduced to me, I was already in the hospital. It was in clinical trials and it was the option, the only option for my cancer. If I’m a patient going through cancer, as our next question is asking, “How can I find a clinical trial? How would they be able to look for the clinical trials and where would be the best resource for them to look for these clinical trials within their area or even somewhere outside of the area?”
I had stated that in my case, I was in the hospital when immunotherapy was introduced to me, so I was fortunate to be at a location to where they had the clinical trials going on outside of my situation, where can someone go to find clinical trials for lung cancer, either in their area, or how can they look outside their area to find those specific clinical trials?
Dr. Patrick Forde: Exactly, actually, I think that’s a great question Oswald. So in the U.S., there are a lot of cooperative groups, so of oncologists across the U.S. and many of these are led by academic centers at large university hospitals, but if you don’t live near one of those large university hospitals, or often community cancer centers who run these trials as well, in most parts of the U.S., there are community cancer centers available who run clinical trials for lung cancer. It’s just sometimes, say you’re in a small town and you have five oncology offices or three offices that may be trying to work out which one of those are mostly technical networks. There’s also the option of having a consult with oncologists, a lung cancer doctor at a major center, and then bringing that information home to your own oncologist. That’s something I would often recommend if you live a good distance for the academic center, it may be worth contacting them, and maybe speaking with them, at least get a plan in place, you know?
Oswald Peterson: I remember I was fortunate enough going through my immunotherapy that I had very little side effects. Many people who go through cancers feel that side effects let you know, the cancer’s working. Our next question asks, “Does side effects mean that the immunotherapy is working?”
Dr. Patrick Forde: Again, it’s not a linear relationship, but there is some data to suggest that patients who have more side effects from immunotherapy may be a little bit more likely to have a tumor response to the treatment, but what I would say is I have a lot of patients who have had no side effects from immunotherapy, and I’ve had a significant tumor response. So it’s a much less strong association than, say, the PD-L1 marker I was talking about. So if I were a patient, I wouldn’t be too worried if I didn’t have side effects. In fact, I’d probably be happy. I think at the rate of side effects with immunotherapy in general is lower than with the chemo, for example. I really don’t factor it into when I’m seeing patients as having their therapy. I don’t really factor too much in the side effects in terms of how easy they are to do well or do or not do well, you know?
Oswald Peterson: Exactly my experience was really, I don’t want to say “great”, but I had little to no side effects. I was able to start going back to the gym. I went back to work shortly after. So in my experience, I had very little side effects, which really made immunotherapy the best treatment for me. We’re going to move on to a live question that we have from Lenny. Lenny is on Keytruda, and Lenny says that he was diagnosed in 2019 with stage four non-small cell cancer. He is on immunotherapy combination as maintenance. His last scan showed no evidence of disease. How long can or should Lenny stay on Keytruda? Thank you for your question, Lenny.
Dr. Patrick Forde: Yeah, that’s a great question, Lenny, and it’s one we struggle with, you know, I think, but it’s a good struggle in some ways to have, you know, because it’s showing the treatment is working. So the clinical trials of these drugs, they generally continued them on to two years of therapy, and my personal approach is generally to continue, for example, Keytruda, for two years, but when you got out to that 18-month period or even in the second year of therapy, I have a relatively low threshold for stopping the treatment if there is a toxicity or for a treatment break, you know. The other thing to keep in mind is that Keytruda is now available to be given once every six weeks, whereas previously it had to be given every three weeks, and that is an option as well for patients, which may allow them to live a more normal life and not be tied to the oncology office, but after two years, if there isn’t any evidence of active tumor on the scan I generally favor from many patients holding it at that point, if they’re comfortable with that decision as well, you know, and there is the option in the future to retirees if the cancer were to grow back.
Oswald Peterson: Excellent. So we’re going to jump down to another live question, and this live question comes from Pat, Pat says. “My mom is eighty-two years old and has stage three non-small cell cancer. And is not eligible for standard treatment. She wants immunotherapy, but they say Medicare won’t pay for it until stage four.” Pat would like to know; would a clinical trial allow her to receive this treatment.
Dr. Patrick Forde: Well, I think that’s a difficult one, you know, so everything is kind of different subtleties there, but stage three lung cancer, where you’re not suitable for radical treatments that can often fit into the same bucket as stage four lung cancer, you know. So that’s something I would probably discuss further with her oncologist, and the other possibility is whether she’s physically fit for treatment in general and the broader discussion. I wouldn’t, in a patient who, for whatever reason, is not suitable for surgery or is not suitable for what we normally do for stage three, which is definitive radiation, so radiation for six weeks, in that situation, many people would fit that patient into the same bucket as stage four cancer, and in that case, often discussing with the patient’s insurance are indeed submitting that information for Medicare approval can often lead to a change in that decision, you know, so that’s something I would explore further with the oncologists, and if necessary, if feasible, to seek a second opinion from lung cancer specialists, those to you.
Oswald Peterson: Exactly, I do recall that me, when I when I arrived in the hospital, I was at stage four already. My cancer was very, very advanced, so they were able to give it to me because I was at that level, but I do also remember there was a little back and forth with some of the insurance companies because it was so new. We’re going to jump into our next live question, which comes from Sheldon. Sheldon wants to know, “How does precision medicine inform the application of immunotherapy to various patients?”
Dr. Patrick Forde: Yeah, so I think it’s becoming more and more important, you know, there’s this thing we call a next generation sequencing or mutation testing, and we do a lot of non-squamous or for lung adenocarcinoma, which is the most common type of non-small cell lung cancer. It has become a standard to do this next generation sequencing test, and that’s essentially looking for mutations in the tumor cells, which are not present in your own normal cells, and that can help guide especially this form of treatment, pill treatments, for specific mutations If you’re present in the tumor and that has a particular interplay, then with how we use immunotherapy because, for example, if we find one of those mutations present a tumor and these are things like EGFR, the ALK gene I mentioned, ROS-1, so there’s a whole host of them now that can sometimes mean that the first, best treatment is a targeted therapy, but it doesn’t rule out the use of immunotherapy later. Also some of those mutations can, some hint that perhaps immunotherapy wouldn’t be the best first choice. So it’s a complex area and it’s rapidly developing, but I think it’s a very exciting area because it helps us be a little bit more precise, as the name suggests in terms of our recommendations.
Oswald Peterson: Excellent. We have time for one, maybe two more questions, but I think that this next question is very important. Our next live question asks, “Are there any major cancer centers that will consult remotely for immunotherapy?” In the case of this person, their mom is older and finds it very difficult to travel. So if you’re finding it hard to travel, are there any major cancer centers that will consult that will consult remotely?
Dr. Patrick Forde: Yeah, so it’s a difficult one at the moment in that we were actually doing a lot of telemedicine during the COVID pandemic, but those rules unfortunately have changed back in the last couple of months. Many of the states have changed their licensure rules, making it more difficult to do telemedicine. However, I would say that many of the major centers, including Johns Hopkins, Memorial Sloan- Kettering, I know the University of Colorado out West, do have a remote program, and it’s publicized on many of their websites. So what I would suggest is, for example, for Colorado, if you put in “lung cancer in Colorado” and “remote” into Google, it will likely come up. One of the other questions is about the insurance coverage of that, and that’s something also to clarify with those programs when you contact them, whether it’s a personal cost you or it cost your insurance company. But I would encourage if it’s if it’s possible, and I think as a community, we need to do advocate for more telemedicine if we can do it, you know.
Oswald Peterson: Exactly. Now this question, I believe, is very relevant because we don’t know how things react, the patient is asking, “Are patients who are very young versus very old, treated differently for lung cancer?” and I would like to add. Does immunotherapy work better in older or younger, or is it or is age even a consideration when considering immunotherapy?
Dr. Patrick Forde: Yeah, it’s a little bit like the toxicity and that there have been a small few studies suggesting perhaps that the older patients that don’t derive quite as much benefit. It’s a very loose relationship and, again, I would not rule out immunotherapy for any patient based on age. What do we look at really when we see new patients coming into the clinic is what we call performance data, and that’s really how active that patient can be day to day? Are they sleeping more than 50% of the day, for example, are they able to look after themselves? That performance that is more so than age predicts how much side effects they’ll have from the treatment and how beneficial that treatment will be. So age is definitely not a barrier, and we have 90-year-olds who are who are very active and we have 30-year-olds who unfortunately are not so active, so it’s more of what we call this performance status rather than age. But I think it’s a good question and it’s relevant, and I think again, seeking an opinion from the oncologist and having a comprehensive assessment is important.
Oswald Peterson: That is excellent advice. Dr. Forde, I would like to thank you on behalf of Cancer Research Institute for taking the time to be with us today, just to let you guys know if you submitted a question and it was not answered or would like to continue submitting questions, you can do that and the questions will be answered by a panel of qualified doctors and medical professionals. Once again, Dr. Forde, we thank you very much for taking time to be with us today once again. We’d also like to thank all of you for joining us here at Cancer Research Institute Summit. On behalf of Cancer Research Institute and all of us involved, we thank you all for being here and wish you all the best. I’m Oswald Peterson. Thank you very much and have a great day.